Table of contents :

• dietary supplements
• rehydration therapy / fluid resuscitation : the restoration of water or of fluid content to a body or to a substance which has become dehydrated
• oral rehydration therapy (ORT) / oral rehydration salts (ORS) : oral administration of a solution of electrolytes and carbohydrates in the treatment of dehydration

	WHO	ESPGHAN	Dicrodrol 60®	Reidrax®	GES 60®	Sodioral®
osmolarity	330	200-250	221	225	270	215
glucose	110	74-111	90	75	111	88
Na	90	60	60	60	60	60
K	20	20	20	20	20	20
Cl	80	> 25	37	60	50	30
HCO3-citrate	30	20	14.3	10	30	17
kCal/L	80	55-80	66	54	80	64

• parenteral physiologic solutions
• multiple electrolytes injection
• multiple electrolytes injection type 1 : sodium, potassium, magnesium, chloride (may also contain acetate, acetate and gluconate, or acetate, gluconate, and phosphate)
• multiple electrolytes injection type 2 : sodium, potassium, magnesium, chloride (may also contain either acetate and citrate or acetate and lactate)
• multiple electrolytes and dextrose injection type 1 : dextrose, sodium, potassium, magnesium, calcium, chloride (may also contain acetate, acetate and gluconate, acetate and phosphate, phosphate and lactate, or phosphate and sulfate)
• multiple electrolytes and dextrose injection type 2 : dextrose, sodium, potassium, magnesium, chloride (may also contain acetate, acetate and citrate, acetate and lactate, or gluconate and sulfate)
• multiple electrolytes and dextrose injection type 3 : dextrose, sodium, potassium, chloride (may also contain ammonium, acetate and phosphate, or phosphate and lactate)
• multiple electrolytes and dextrose injection type 4 : dextrose, sodium, magnesium, calcium, chloride, gluconate, sulfate
• multiple electrolytes and invert sugar injection type 1 : equal amounts of dextrose and sucrose*, sodium, potassium, magnesium, chloride, phosphate, lactate
• multiple electrolytes and invert sugar injection type 2  : equal amounts of dextrose and sucrose*, sodium, potassium, magnesium, calcium, chloride, lactate
• multiple electrolytes and invert sugar injection type 3 : equal amonts of dextrose and sucrose*, sodium, potassium, chloride, ammonium
* = or an equivalent solution produced by hydrolysis of sucrose.
• amphoteric electrolyte / ampholyte : a compound containing at least one group that can act as a base and at least one that can act as an acid
• colloidal electrolyte : an electrolyte in which one or more of the ionic components is of macromolecular dimensions.

	Na+ (mEq/L)	K+ (mEq/L)	Cl- (mEq/L)	Ca2+ (mEq/L)	lactate (mEq/L) (used instead of Cl- to maintain electroneutrality : it is converted to HCO3- by hepatic metabolism)	glucose (g/L)
normal (0.9%) saline (NS) :  0.45 g / 50 mL 0.9 g / 100 mL 4.5 g / 500 mL	154	0	154	0	0	0
dextrose 5% in water (D5W)	0	0	0	0	0	50
D5W 2 NS	77	0	77	0	0	50
2.3 D5W 1.3 NS	50	0	50	0	0	33
lactated Ringer's	130	4	109	3	28	0

Maintenance water requirements :
• first 10 kg of weight : 4 mL/kg/h = 100 mL/kg/day
• second 10 kg of weight : 2 mL/kg/h = 50 mL/kg/day
• each kilogram above 20 kg : 1 mL/kg/h = 20 mL/kg/day
Volume of distribution : a dilution method for determining the volume of fluids, e.g., plasma, in a body fluid compartment. A solute (e.g., inulin) is injected into the compartment and, after it is equally distributed, a sample is taken. Then the quantity of solute removed (as by metabolism, excretion, etc.) is subtracted from the quantity administered, and the result is divided by the concentration per milliliter in the sample.
Expected plasma volume increase = (infused volume ^. normal plasma volume) / distribution volume
Infused volume = (expected plasma volume increase ^. distribution volume) / normal plasma volume
Perioperatory fluid management :
• preexisting deficiencies
• approximate quantity of intraoperatory blood loss
• evaporation (duration of operation)
• third space losses
• maintenance requirements
• every type of current loss
20 drops from defluxors = 1 ml (varying according to arm movements)
• hemotherapy / hematherapy / hematotherapy : treatment of disease by the administration of blood or blood products, such as blood plasma
• blood or plasma substitute : a fluid which may be used instead of whole blood or plasma for replacement of circulating fluid in the body
• fresh frozen plasma (FFP) : plasma separated from whole blood and frozen within 8 hours; it contains all coagulation factors including the labile factor V and factor VIII.
• normal human plasma : sterile plasma obtained by pooling approximately equal amounts of the liquid portion of citrated whole blood from > 8 adult humans, used as a blood volume replenisher.
• antihemophilic human plasma : normal human plasma that has been processed promptly to preserve the antihemophilic properties of the original blood; used for temporary correction of bleeding tendency in hemophilias.
• pooled plasma : a mixture of plasma from several donors.
• salt plasma : blood plasma to which a neutral salt has been added to prevent clotting, such as ...
• oxalate plasma : blood plasma to which ammonium oxalate has been added, formerly used to prevent clotting.
• citrated plasma : blood plasma treated with sodium citrate, which prevents clotting.
• true plasma : blood plasma drawn directly from the blood without any change in its gas content.
• plasma volume expander / artificial plasma extender : a substance that can be transfused to maintain fluid volume of the blood in an emergency, supplemental to the use of whole blood and plasma
• special intravenous gelatin solution : a 5 or 6% sterile, pyrogen-free solution of gelatin in isotonic sodium chloride solution
• colloid : a substance comprising very small, insoluble particles, usually 1 to 1000 nm in diameter, that are uniformly dispersed or suspended in a finely divided state throughout a continuous dispersion medium, not settling readily; either phase can be solid, liquid, or gas. The particles are often called the dispersed phase and the dispersion medium the continuous phase. Colloid can refer specifically to the particles or to the system of particles plus dispersion medium.
• antimony trisulfide colloid : antimony sulfide (Sb₂S₃), a pharmaceutic aid.
• association colloid : a colloid in which the dispersed particles are each made up of many molecules.
• dispersion colloid : sometimes specifically an unstable colloid system.
• reversible or stable colloid : a colloid that can be dispersed after having been precipitated or a gel that can be converted into a sol.
• irreversible colloid : a colloid that once precipitated cannot be dispersed
• emulsion, lyotropic or lyophilic colloid : a stable colloid system in which the dispersed phase is relatively liquid, usually comprising highly complex organic substances, such as starch or glue, which readily absorb solvent, swell, and distribute uniformly through the medium.
• hydrophobic colloid :  a lyophobic colloid in which the solvent is water.
• lyophobic or suspension colloid : an unstable colloid system in which the dispersed phase particles tend to repel liquids, are easily precipitated, and cannot be dispersed with additional solvent.
• hydrophilic colloid : a lyophilic colloid in which the solvent is water.
• protective colloid : a hydrophilic colloid polymer that is able to prevent the precipitation of another colloid by acting as a stabilizer, suspending or thickening agent, or emulsifier.
Marketed products :
• first-generation colloids :
• second-generation colloids :
• human serum albumin (HSA) 20% (Albuminar^®, Albumina Retard^® : yellowish phials) : a preparation of serum albumin fractionated from human whole blood, serum, plasma, or placentas; used as a plasma volume expander for emergency treatment of shock or hemorrhage and to increase the binding capacity for bilirubin in the treatment of hyperbilirubinemia and erythroblastosis fetalis; it has also been used to correct hypoalbuminemia of nephrotic syndrome or cirrhosis. Administered intravenously.
Side effects : neurodevelopmental delays were seen in 5-year-old children treated with human albumin : aluminum, which is introduced into human albumin during processing, may be responsible for the delays since it is a known neurotoxin.
• third-generation colloids : less anaphylaxis and coagulopathy, reduction in the capillary leak (=> less pulmonary oedema and better partial pressure of oxygen in the arterial blood), licensed in Europe for a daily dosage up to 50 mL/kg per day and can be repetitively dosed according to the patient's needs
• starch : 1. any of a group of polysaccharides of the general formula (C₆H₁₀O₅)_n, composed of a long-chain polymer of glucose in the form of amylose and amylopectin; it is the chief storage form of energy reserve (carbohydrates) in plants.  2. a preparation consisting of the granules separated from the mature grain of corn or wheat, or from potato tubers, occurring as irregular, angular, white masses or fine powder; used as a dusting powder and as a filler, binder, and disintegrant in pharmaceutical preparations.
• starch glycerite : a preparation of starch, benzoic acid, purified water, and glycerin; used as an emollient in pharmaceutical preparations intended for external use.
• pregelatinized starch : starch processed to rupture all or part of the granules in the presence of water, and subsequently dried; it occurs as a moderately coarse to fine, white to off-white powder and is used as a tablet excipient in pharmaceutical preparations.
• soluble starch : starch partially hydrolyzed with hydrochloric acid so that it is water soluble; usually amylodextrin.
• 6% hydroxyethyl starch (HES) is the most appropriate artificial colloid (100% volume effect lasting approximately 4 hours with some persisting effect up to 6 hours)
• HES 600 (6% Hetastarch-Baxter^®)
• HES 550 (Hextend^®)
• HES 200 (Elohast^®)
New-generation HES is valuable in trauma patients with head injuries and do not passess the altered BBB. Certain characteristic complications of HES, notably renal impairment, hemorrhage and pruritus, have been well documented with all types of HES solutions. The use of HES solutions with lower molecular weight and substitution has been claimed to minimize these safety risks. In particular, solutions of 200 kDa molecular weight and 0.5 substitution (HES 200/0.5) and of 130 kDa molecular weight and 0.4 substitution (HES 130/0.4) have been advocated for their superior safety profile. A critical appraisal of the available evidence does not provide reassurance that these or other HES solutions are risk free. Most evidence indicates the equivalence of HES 200/0.5 and HES 130/0.4 with respect to effectiveness for volume expansion. Since HES 130/0.4 is newer, its safety profile is less well characterized; however, it appears to share the same complication risks as those of HES 200/0.5. In randomized clinical trials employing sensitive markers, both HES 200/0.5 and HES 130/0.4 have been shown to impair renal function. Both coagulopathy and clinical bleeding have been documented after administration of either HES 200/0.5 or HES 130/0.4, and the magnitude of negative effects on hemostasis has been similar for these two HES solutions. Pruritus is a common side effect of all HES solutions, including HES 200/0.5 and HES 130/0.4, and can occur in diverse clinical settings in some cases after only small HES doses. Typically presenting as pruritic crises of delayed onset, this complication is often severe, protracted and refractory to treatment. An additional risk of HES infusion is the occurrence of potentially life-threatening anaphylactoid reactions, which are 4.5 times as frequent after HES as albumin exposure. Limiting the dose and duration of HES therapy may be helpful in lessening the risk of undesired side effects; at present however, reliance on particular HES solutions does not appear sufficient to ensure safety^ref
• 6% hetastarch (Hespan^®) : a starch containing < 90% of amylopectin, and that has been etherified so that an average of 7 to 8 of the OH groups in every 10-D-glucopyranose units of starch polymer have been converted into OCH₂CH₂OH groups; used as a plasma volume expander, administered by infusion.
• 10% pentastarch : an artificial colloid derived from a waxy starch composed of > 90% amylopectin that has been etherified so that an average of 4 to 5 of the OH groups in every 10 D-glucopyranose units of the starch polymer have been converted to OCH₂CH₂OH groups; used as an adjunct in leukapheresis to increase the erythrocyte sedimentation rate.
• dextran : a high-molecular-weight polymer of D-glucose, produced by enzymes (glycosyltransferases) on the cell surface of certain lactic acid bacteria. Uniform molecular weight dextrans from Leuconostoc mesenteroides preparations are used as plasma volume expanders. Specific preparations are designated, according to their average molecular weight in thousands, as
• dextran 1 (Promit^®) usually prevents anaphylactoid reactions to larger dextrans. When it is administered immediately before dextran 40 or 70, dextran 1 acts as a hapten inhibitor that binds dextran-specific antibodies and blocks larger molecules of dextran 40 or 70 from forming immune complexes. Hapten inhibition with dextran 1 has been found to reduce the incidence of severe dextran-induced anaphylactoid reactions from 1 in 2000 to 1 in 70,000^ref. The Food and Drug Administration's Blood Products Advisory Committee recently recommended adding information about the prophylactic benefit of dextran 1 to the package insert for dextran products to increase awareness among providers^ref. Hapten inhibition reduces the incidence of allergic reaction to dextran solutions. Such reactions are rare in children
• dextran 40
• 6% dextran 70
• and so on
• polygeline : a polymer of urea and polypeptides derived from denatured gelatin; used as a plasma expander in hypovolemia
• 4% succinylated gelatin solution (Eufusin^® (source : Fresenius Kabi Italia S.p.a.); Gelofusine^®; source : Braun NPBI Oss, the Netherlands)
• 3.5% urea-linked gelatin (Emagel^® (+ NaCl + KCl + CaCl₂ + glycerol; source : Aventis Pharma S.p.a.), Gelplex^® (source : Fresenius Kabi Italia S.p.a.); Haemaccel^®; source : Hoechst, Behring-Werke, Marburg Germany) : t_1/2 = 4 hrs; 85% eliminated by renal route; 10% in stools and 2% degraded by proteases
• plasma derivatives are made from pooling up to tens of thousands of units of donated plasma
• source plasma is obtained by plasmapheresis from paid donors.
• recovered plasma is the plasma removed from whole blood donations given by volunteer (unpaid) donors.
Paid donors have higher rates of infection with transfusion-transmissible viruses, but after pooling, the pools are subjected to any of a variety of viral inactivation procedures (for example, pasteurization, nanofiltration, chromatography) that have rendered the risk of infection from these pools negligible since the late 1980s. These derivatives include intravenous immunoglobulin to treat primary immunodeficiencies and some autoimmune syndromes, albumin, and coagulation factor concentrates, used mainly in the treatment of the hemophilias. Derivatives from these huge pools, prior to the mid-1980s before effective screening and viral inactivation, were of course the source of tens of
thousands of HIV-1, HBV, and HCV infections, but viral transmission in the face of viral inactivation procedures applied under the kinds of process control required in most of the developed world is extraordinarily unusual. Process failures leading to contamination of large lots of derivatives,
while rare, remain capable of exposing large numbers of recipients. Transfusable blood components are the labile cells and coagulation factors from whole blood donations. These mainly include red blood cells, platelets, and fresh frozen plasma. They cannot undergo viral inactivation procedures, since that would destroy the therapeutic content of the component. Neither are they pooled in usual practice, so the implications of a virally infected donation extend only to the 2 or 3 recipients of the undetected infected donation. To deal with real and theoretical risks from transfusable components, blood collection facilities in the developed world employ stringent process controls, donor historical screening, reliance on volunteer donors, as well as sensitive and redundant laboratory assays. Viral inactivation techniques that target the nucleic acids of potential pathogens in transfusion components are under development and in various stages of regulatory review around the world, but are not yet in wide use due to a variety of concerns around a number of cost and risk-benefit controversies.
• buffer therapy: i.v. injection of buffer substances with the object of lowering the hydrogen ion concentration
• NaHCO₃
• Shohl solution (1 mmol sodium citrate + 1 mmol citrate/mL)
• osmotherapy : treatment by the intravenous injection of hypertonic solutions to produce dehydration
• thermal medicine in the functional gastrointestinal disorders. The functional dyspepsia, the irritable bowel syndrome, the functional constipation and the functional disorders of the biliary tract (in accordance with Roma II criteria), are the illness for which the drinking mineral waters could give a valid therapeutic support.
• antroteraphy / speleotherapy : treatment of chronic obstructive airways diseases in the conditions of salt mines microclimate in subterranean environments
• peloidotherapy / pelotherapy : the therapeutic use of earth or mud
• hydrotherapy : the application of water in any form, but usually externally, in the treatment of disease. A form of heat treatment for many musculoskeletal disorders. The hydrotherapy tanks and pools are all generally set at warm temperatures, never exceeding 150°F (65.6°C). Because the patient often performs resistance exercises while in the water, higher water temperatures become a concern as the treatment becomes more physically draining. Because of this, many hydrotherapy baths are now being set at 95–110°F (35–43.3°C). There are also units available with moveable turbine jets, which provide a light massage effect. Hydrotherapy is helpful as a warm-up prior to exercise.
• crenotherapy : any treatment incorporating mineral water, mud and vapour
• fluidotherapy : a form of heat treatment developed in the 1970s. It is a dry heat modality consisting of cellulose particles suspended in air. Units come in different sizes and some are restricted to only treating a hand or foot. The turbulence of the gas-solid mixture provides thermal contact with objects that are immersed in the medium. Temperatures of this treatment range from 110–123°F (43.3–50.5°C). Fluidotherapy allows the patient to exercise the limb during the treatment, and also massages the limb, increasing blood flow
• heliotherapy : the treatment of disease by exposing the body to the sun's rays; the therapeutic use of the sun bath
• ampelotherapy : the treatment of disease by grape
• balneotherapy : the treatment of disease by baths
• halotherapy : treatment with the artificially created controlled microclimate
• psammotherapy / ammotherapy / sand therapy : the treatment of disease by sand baths
• climatotherapy / climatotherapeutics : the treatment of disease by means of a favorable climate
• climatothalassotherapy / thalassotherapy : the treatment of disease by sea bathing, sea voyages, and sea air
• aerosolo-therapy : the therapeutic use of aerosols
• aero-iono-therapy : the therapeutic use of e
In contrast to deep heating modalities, superficial heating modalities usually do not heat deep tissues, including muscles, because the subcutaneous layer of fat beneath the skin surface acts as a thermal insulator and inhibits heat transfer. Additionally, increased cutaneous blood flow from superficial heating causes a cooling reaction as it removes the heat that is applied externally. In general, the transfer of heat (whether the purpose is heating or cooling) often is classified into 3 general types of heat transfer (ie, conduction, convection, conversion). Conductive heating is defined as heat transfer from one point to another without noticeable movement in the conducting medium. Typically, direct contact takes place between the heat source and the target tissues. Superficial heat is usually conductive heat (eg, hot water baths, hot packs, electric heating pads, warm compresses). Convective heating is produced by movement of the transferring heating medium, usually either air or fluid. Methods for providing convective superficial heat include fluidotherapy, whirlpool, moist air baths, and hot air baths. The conversion form of heating involves heat transfer by conversion of energy from one energy form (eg, light, sound) to another (heat). Superficial heat is produced by heat lamps or radiant light bakers, where heat is transferred when the conveying medium (light energy) is converted to heat energy at the skin surface. Superficial heat modalities categorized by primary heat transfer mode are summarized as follows:
• conduction - hot packs, paraffin baths
• convection - fluidotherapy, hydrotherapy, moist air
• conversion - radiant heat
Several factors determine the extent of the physiologic response to heat, including the following:
• level of tissue temperature (usually 40-45°C)
• duration of the tissue temperature increase
• rate of increase in tissue temperature
• size of the area being treated
Conductive heating is usually a simple modality that can be taught to the patient for independent home use. The disadvantages of this modality include potential burns, difficulty with application to regions exhibiting abnormalities (eg, foot), and the skin-drying effect (with the exception of paraffin or water media). Another complication that may occur is impairment of local vascular supply, due to a combination of the weight of the modality on the limb or the weight of the limb on the modality. This phenomenon also may be caused by uneven distribution of pressure on the anatomical region that the medium contacts. Hot packs or hydrocollator packs contain silicate gel in a cotton bag. These packs are placed in a hot water tank, which is thermostatically controlled at 71.1-79.4°C. The silicate gel absorbs a large quantity of water and has a high heat capacity. Hot packs are applied over layers of towels for 20-30 minutes. Most of the heat transfer from the hot pack to the patient is by conduction. Increasing the towel thickness reduces the heat flow and produces an intentional slowing in the temperature rise. Acceleration of heat transfer occurs if the hot pack leaks into the towel. The patient never should lie on the hot pack, as the body weight could squeeze hot water out of the pack into the towel and potentially cause a burn. The maximum skin temperature is obtained after 8 minutes, followed by a reduction in temperature due to increased blood flow. Repeated application of hot packs may prolong the period of temperature elevation but does not alter the temperature distribution. Other forms of hot packs include the Kenny pack (vigorous short-term stimulation/heating), rubber hot water bottle, and electric heating pad. Heat transfer is enhanced if the pad is moist or if the heated part is wrapped in moist material. The complications of electric heating pad include shock hazard if the device is not insulated properly and burns if the patient falls asleep lying on the pad. Heat output increases over time until equilibrium is achieved. Keep in mind that heat may be sufficiently analgesic to produce burns. Indications for the application of hot packs may include painful muscle spasms, abdominal muscle cramping, menstrual cramps, and superficial thrombophlebitis. Hospitalized patients receive circulated warm-fluid hot packs to minimize the potential for burns due to prolonged superficial heating application in sensory impaired patients or mentally challenged patients. Chemical packs often are available in containers which, when properly manipulated, allow previously separated ingredients to mix, thereby producing an exothermic chemical reaction that causes heat production. Paraffin bath is another form of conductive heating. Paraffin baths are particularly useful for contractures due to rheumatoid arthritis, burns, and progressive systemic sclerosis (scleroderma). Paraffin usually is applied to the hands, arms, and feet. Paraffin wax is melted and mixed with liquid paraffin. For therapeutic use, the paraffin bath is maintained at the melting point of 51.7-54.4°C in a thermostatically controlled insulated container. The 2 application methods include (1) the dip method and (2) immersion. The hand or foot is placed in the liquid paraffin bath and withdrawn when a thin layer of warm solid paraffin forms, becomes adherent, and covers the skin. The dipping procedure is repeated until a thick paraffin glove is formed. The heat can be retained by wrapping with towels for a period of 20 minutes; then, the cool solid paraffin glove is peeled away and the paraffin is recycled. The dip method is a mild heat application because only a limited amount of heat is available for transfer to the skin.
Immersion :
Alternatively, the body part is immersed in the paraffin bath for 20-30 minutes. The immersion method transfers heat not only from the solid paraffin block but also from the liquid paraffin bath itself. The heat transfer rate from the liquid paraffin bath to the skin is slowed as the solid paraffin glove provides a poor thermal conductor. This modality represents a vigorous heat application, causing a significant increase in skin tissue temperature, up to 46°C, with a marked temperature decrease in the subcutaneous tissue. Water at the same temperature applied by the same method would be intolerable because of the high specific heat and thermal conductivity.
CONVECTIVE HEATING
Fluidotherapy is a form of convective heating that uses a bed of uniform finely divided round solids, such as glass beads, into which thermostatically controlled warm air is blown to generate a semifluid warm mixture. Part of the limb or hand/foot can be immersed for superficial heating. This technique applies dry heat, and the temperature is equivalent to the hot air that is blown into the bed of beads. The usual treatment temperature range is 45.6-47.8°C. Uses of fluidotherapy may include pain relief in arthritic conditions of small joints, joint mobilization following trauma/mobility, and analgesia/sedation in young patients undergoing exercise programs with painful and contracted joints due to sickle cell anemia. Hydrotherapy can include total immersion in a large hot tub or Hubbard tank. Partial immersion is available for upper or lower extremities by whirlpool baths. As hydrotherapy also may be used in treating infected draining wounds, the equipment must be sterilized between uses. The water is agitated, and the size of the tank determines the capacity (the entire body or just the upper or lower extremities). For total body immersion in water, the temperature should not exceed 40.6°C. Partial immersion of a limb should have a maximum temperature of 46.1°C. The treatment time is limited to 20-30 minutes each session. As a precaution for total body immersion, oral temperature should be observed with water temperatures over 37.8°C to prevent a rise of body core temperature. With total body immersion, heat loss occurs primarily through the head and neck; therefore, the heat regulatory mechanism is impaired significantly. Total body immersion has a relaxing effect and may predispose the patient to hypotension due to peripheral blood pooling secondary to vasodilatation of all 4 limbs. Another convection modality is the moist air cabinet. Air saturated with water vapor at a controlled temperature is blown over the patient, causing superficial heating over a large area. The temperature distribution in this modality provides heating of skin and superficial tissue. This modality is used most commonly for back muscle spasms and polyarticular arthritic conditions. The recommended temperature maximum is 40.6°C. Contrast baths provide a method of therapeutic hyperemia for management of rheumatoid arthritis or sympathetically mediated pain (eg, rheumatoid arthritis of distal joints, hands, feet; prolonged ankle swelling after an ankle sprain/strain in refractory joint effusions). A differential of approximately 25°C exists between the hot and cold water. The hot water is at a temperature of 40.6-43.3°C. The cold water temperature is maintained at 15-20°C. The greatest hyperemia response is produced by a 10-minute hot water immersion followed by cold water for 1 minute. The cycle continues with hot water immersion for 4 minutes and cold water for 1 minute; this 4:1 cycle is repeated for a total of 30 minutes at each physical therapy appointment or for each home-based self-treatment session. Other approaches to convective heating include water-based exercise and spa therapy (balneotherapy).
CONVERSION HEATING  Radiant heat therapy is a type of conversion heating. The high-energy photons penetrate the tissues, and this energy is converted to heat. Because photons of longer wavelengths process less energy, penetration is more superficial; shorter wavelengths have a greater therapeutic benefit. The therapeutic radiant heat-producing temperature rise in tissues ranges from the spectrum of far infrared to visible yellow. Longer wavelengths of light from green to ultraviolet produce photochemical reactions that do not raise tissue temperature significantly. Most other commercially available radiant light sources produce infrared with some visible light. These lamps contain heating elements of Carborundum (silicon carbide), special quartz tubes, or metal alloys. The higher energy photons are produced by shorter wavelength radiant heat, resulting in a greater penetration of superficial tissue. The most common indications for radiant heat therapy include muscle spasms from underlying joint/skeletal conditions, rheumatic joints where direct heating of the joint is contraindicated, and treatment of superficial skin breakdown in the intertriginous areas. A treatment time of 20-30 minutes is recommended, with the maximum effect occurring at a minimum of 20 minutes. The radiant energy source is positioned at 15-24 inches (38.1-61 cm) from the treatment site. The intensity is controlled by the light source, distance, type/quality of reflector, and air movement. With heat lamps, guidance concerning treatment time is given by the patient's subjective feeling of warmth. The conventional single heat cradle with an output of 300 watts is not likely to increase body temperature; however, a double cradle could. Patients also could receive increased radiation after an hour of treatment time. Infrared radiation can be used for reflex vasodilatation where vasospasm is present. Because of the photochemical effect of lower energy ultraviolet photons, this radiant energy is used most effectively for treatment of psoriasis and other dermatologic conditions.  CONTRAINDICATIONS TO SUPERFICIAL HEAT APPLICATION
Superficial heat modalities are contraindicated in the following situations:
• Paraffin baths or fluidotherapy should not be used in open wounds that are either clean or infected.
• Hydrotherapy is contraindicated in patients immediately following surgery, as a healing wound should be kept dry.
• Special precautions should be used for therapy to be provided in a Hubbard tank for patients with either a tracheostomy or ostomy.
• radiant heat should not be used in patients with the following conditions:
• Photosensitivity
• Acute inflammation or hemorrhage
• Bleeding disorder
• Decreased sensation
Because total immersion in a Hubbard tank elevates core body temperature, patients with the following conditions that generate temperature-sensitivity should avoid this heating modality:
• Multiple sclerosis
• Adrenal suppression or failure
• systemic lupus erythematosus
• Pregnancy
THERAPEUTIC COLD (CRYOTHERAPY)
Cryotherapy has the primary effect of cooling tissue. Depending upon the application method and duration, the basic physiologic effects include the following:
• Decreased local metabolism
• Vasoconstriction
• Reactive hyperemia
• Reduced swelling/edema
• Decreased hemorrhage
• Reduced muscle efficiency
• Analgesia secondary to impaired neuromuscular transmission
Pain reduction associated with application of cold relaxes muscle spasm and minimizes upper motor neuron spasticity. The most common indications and uses for local application of therapeutic cold modalities include the following:
• To decrease swelling/edema following trauma (cooling in water at 8°C for 30 minutes decreases edema)
• To treat burns
• To inhibit spasticity (in spasticity, the muscle must be cooled; this process takes 10 minutes in thin patients and up to 60 minutes in more obese persons)
• To reduce muscle spasm
• To reduce acute inflammatory reaction
• To reduce pain
• To reduce limb metabolism (prior to amputation)
• To produce reactive hyperemia
• To facilitate muscular contraction for various forms of neurogenic weakness and for muscle re-education
• Immediate application of ice or cold packs for superficial burns and burns of less than 20% total body surface area decreases pain, edema, erythema, and blistering. For optimal results in cases of trauma, cold should be applied before significant edema and hemorrhage occur.
The most common methods of cold application include cold packs, cold immersion, ice massage, and cooling during exercise (cryokinetics). Spray and stretch is an application of cryotherapy with a vapocoolant spray, which then is followed by stretching of the involved muscles. This technique sometimes is used in the management of myofascial pain syndromes, as described by Travell and Simons. Therapeutic cold is applied for 5-20 minutes, followed by a rest period of 30 minutes. For treatment of acute sprains/strains and postoperative care, application of cold is recommended for the first 24-48 hours. For treatment of deeper tissues or for prolonged periods of cold application, physician evaluation/prescription is essential to avoid complications. The most useful local therapeutic cold applications include management of edema, muscle spasm, bleeding, and traumatic pain. The vasoconstriction effect of therapeutic cold is beneficial for reducing posttraumatic swelling and pain or for reducing hemorrhage into soft tissues. The following are conditions for which local cryotherapy is contraindicated:
• Hypertension (due to secondary vasoconstriction)
• Raynaud disease
• rheumatoid arthritis
• Local limb ischemia
• History of vascular impairment, such as frostbite or arteriosclerosis
• Cold allergy (cold urticaria)
• Paroxysmal cold hemoglobinuria
• Cryoglobulinemia or any disease that produces a marked cold pressor response
Cold packs applied to the abdomen cause increased gastrointestinal motility and gastric acid secretion; therefore, this treatment is contraindicated in those with known peptic ulcer disease. Interestingly, application of hot packs to the abdomen produces the opposite effect.
COLD VERSUS HEAT THERAPY
Both heat and cold modalities can be used effectively in various clinical conditions. Many situations lend themselves to use of these diverse modalities to take advantage of known biologic effects for managing certain ailments. The similarities of these 2 modalities include the following:
• Decreased muscle spasm secondary to musculoskeletal pathology or nerve root irritation
• Cold effectively decreases spasticity of upper motor neuron etiology; heat reduces spasticity, but the effects are short-lived and ineffective for muscle re-education.
• Both heat and cold modalities cause analgesia.
The following examples illustrate the significant differences in the physiological effects between therapeutic heat and cold treatments:
• A longer time is necessary for cooled muscle to return to normal temperature. Because application of heat increases blood flow, a heated muscle returns to normal temperature after a few minutes.
• The application of heat for relief of muscle spasm is secondary to muscle hyperemia, which decreases muscle spasm-induced ischemia/pain and interrupts this vicious cycle.
• Increased tissue metabolism occurs with temperature elevation; reduced metabolism with cold modalities.
• Heated muscle tissue can sustain a contraction for a shorter period of time; cooling to approximately 27°C increases the ability of muscle to sustain contraction.
• Blood flow increases with heat and decreases with cold.
• The tendency to bleed increases with heat and decreases with cold.
• Formation of edema is facilitated by heat and decreased by cooling.
• Immediate cooling of burns is beneficial; however, frostbite is treated by quick warming.
• Joint stiffness is decreased with heating but increased with cold.
Due to blood pooling, orthostatic hypotension is produced by application of heat to large parts or all of the body. With cold treatment, hypotension is decreased secondary to vasoconstriction^{ref1, ref2, ref3, ref4}
• trace elements
• iron (Fe)
• oral supplementation :
• ferrous sulfate / iron sulfate / FeSO₄^. 7H₂O (Feosol^®, Feospan^®, Feratab^®, Fer-gen-sol^®, Fer-in-sol^®, Fer-Iron^®, Ferodan Syrup^®, Fero-Gradumet^®, Ferospace^®, Ferralyn^®, Ferra-TD^®, Ferrograd^®, Ferrogradumet^®, Ferromin^®, Fertonic^®, ...; Feral-Z^® in combination with folic acid and zinc sulphate; Ferrograd-folic^® in combination with folic acid)
• ferrous fumarate (Feostat^®, Ferretts^®, Ferumat^®, ...)
• ferrous gluconate (Fergon^®, Ferralet^®, Fertinic^®, ...)
• iron bis(glycinate) chelate (Ferrochel^®, )
• polysaccharide-iron complex (Niferex^®, ...)
• iron citrate (Fer-Sol^®)
• liposomal iron pyrophosphate (Lipofer^®; SiderAL^® in combination with vitamin C and vitamin B₁₂)
• edetate
Side effects : constipation (50%) or diarrhea (50%)
• parenteral supplementation :
• iron dextran (Infed^®, Dexferrum^®)
• iron saccharate (Ferosac IV^®)
• ferric hydroxide polymaltose (Ferose^®)
• sodium ferric gluconate complex in sucrose (Ferrlecit^®, Ferlixit^®)
• copper (Cu)
• zinc : zinc supplementation is beneficial in the management of a number of conditions, including acute diarrhea, the common cold, acne and progressive myoclonic epilepsy. Its putative effect is the enhancement of immune function. Many over-the-counter (OTC) zinc-lozenge products are now available; in 1989, an estimated 16% of US citizens were taking zinc supplements orally.
• calcium (Ca²⁺) (Cacit^®)
• monofluorophosphate calcium salts (Tridin^®, Trinidal-F^®)
• sodium monofluorophosphate (Monotridin^®)
• calcium carbonate (Vitatridin^®, Calcitridin^®, Metocal^®)
• chromium (Cr³⁺) : supplement is absorbed better than dietary chromium. Chromium supplementation in people with chromium deficiency can improve glucose tolerance and some lipid metabolism parameters, lower cholesterol, and aid muscle development. The supplementation is indicated in persons with impaired glucose tolerance both in preclinical and manifested stadium of type 2 diabetes mellitus where increased lost of chromium in urine was documented. In these patients, chromium deficiency can participate in insulin resistance and hyperlipidaemia. Chromium is usually applied in the form of
• organic compounds
• yeast extract
• chromium picolinate (Natural Performance Chromium Picolinate^®, CVS Chromium Picolinate^®, Chromium picolinate^®, Pyruvate C Weight Loss Program^®, Fat Burners^®, Chroma Slim for men^®, Diet System 6^®, Ultra Chroma Slim^®, Ultraburn Chromium^®, Ultraformula Fat Burner^®, Chroma-trim gum^®). Cr(III) picolinate is purchased almost as often from supermarket shelves as are calcium supplements, yielding hundreds of millions of dollars yearly in sales. However, the unregulated sales of this supplement are now attracting criticism because there are indications of little efficacy in glucose homeostasis and of significant carcinogenicity (see chromium toxicity)


• glucose tolerance factor : a biologically active complex of chromium and nicotinic acid that facilitates the reaction of insulin with receptor sites on tissues (see chromium toxicity)
• chromium chloride
• iodine (I^-)

Indications :
• accidental contamination from radioactive isotopes
• thyrotoxic crisis (Wolff-Chaikoff effect)
• before thyroid surgery
• endemic goitre
• magnesium (Mg²⁺)
• selenium (Se)
• sodium fluoride / disodium difluoride : Floridine^®; Florocid^®; Villiaumite^®; NaF^®; Sodium hydrofluoride^®; Sodium monofluoride^®; Trisodium trifluoride^®; Alcoa sodium fluoride^®; Antibulit^®; Cavi-trol^®; Chemifluor^®; Credo^®; Duraphat^®; Fda 0101^®; F1-tabs^®; Flozenges^®; Fluoral^®; Fluorident^®; Fluorigard^®; Fluorineed^®; Fluorinse^®; Fluoritab^®; Fluorocid^®; Fluor-o-kote^®; Fluorol^®; Fluoros^®; Flura^®; Flura-gel^®; Flura-loz^®; Flurcare^®; Flursol^®; Fungol b^®; Gel II^®; Gelution^®; Gleem^®; Iradicav^®; Karidium^®; Karigel^®; Kari-rinse^®; Lea-cov^®; Lemoflur^®; Luride^®; Luride lozi-tabs^®; Luride-sf^®; Nafeen^®; Nafpak^®; Na frinse^®; Nufluor^®; Ossalin^®; Ossin^®; Osteofluor^®; Pediaflor^®; Pedident^®; Pennwhite^®; Pergantene^®; Phos-flur^®; Point two^®; Predent^®; Rafluor^®; Rescue squad^®; Roach salt^®; Sodium fluoride cyclic dimer^®; So-flo^®; Stay-flo^®; Studafluor^®; Super-dent^®; T-fluoride^®; Thera-flur^®; Thera-flur-n^®; Zymafluor^®; Les-cav^®; Sodium Fluoride^®
• amino acids : Corynebacterium efficiens is used for the industrial production of amino acids. Researchers are interested in this organism primarily owing to its ability to grow and produce amino acids at 40°C — 10°C higher than the closely related and commonly used industrial strain, Corynebacterium glutamicum. This feature offers potential savings in cooling costs for large-scale fermentation. Nishio et al. have compared the complete genomes of these two bacteria to reveal the three most common amino acid substitutions that they conclude to be most likely to contribute to the increased protein thermostability in C. efficiens. Detailed analysis showed that although the increase in G+C content of the genome (63% compared with 54% for C. glutamicum) correlates with a shift in codon usage, it cannot account for all the thermostabilising amino acid changes.
• FreAmine II^® : trademark for a crystalline amino acid solution for intravenous administration, containing a mixture of essential and nonessential amino acids but no peptides.
• L-ornithine
• S-adenosyl-L-methionine (Samyr^®)
• advanced nutritional supplements / nutraceuticals / functional foods : foods and food supplements marketed for presumed health benefits, such as
• vitamin supplements
• certain herbs or other botanicals
• melatonin
• chromium picolinate : used by some to control blood sugar levels or to lose weight  ; appears to be generally safe
• chaparral : also known as greasewood or creosote bush, is thought to fight intestinal parasites and treat colds, flu and diarrhea ; may cause adverse effects in some particular users
• glucosamine sulfate (Adaxil^®, Arthroaid^®, Arthryl^®, Bioflex^®, Bipron^®, Dona^®, Osteomin^®, Praxis^®, Viartril-S^®, Xicil^®) : used by some to treat joint pain and osteoarthritis (OA) (2 3-year studies indicate that it may reduce symptoms and stabilise radiographic minimal joint space width compared to placebo in postmenopausal women with knee OA); may cause adverse effects in some particular users
• hyaluronic acid (Go-On^®) : viscosupplementation for synovial fluid
• saw palmetto : a small creeping palm of the southeastern USA, Serenoa repens. The fatty-acid fraction of saw palmetto may be the active ingredient of the berry extract and that most products contain 85 to 95 percent fatty acids. The partially dried, ripe fruit of the saw palmetto, is used by over 2 million men in the USA for urination problems associated with benign prostatic hypertrophy (BPH) and hair loss; may cause adverse effects in some particular users. Sales of saw palmetto are growing, with an estimated $131 million of the product consumed by Americans in 2000. A RCT showed that 160 mg of saw palmetto taken twice daily did not improve symptoms or objective measures of benign prostatic hyperplasia^ref. Since saw palmetto is available in higher doses than 160 mg, would it not be expected that the higher-dose capsules contain more of the supposed active ingredient and thus would be more effective than the 160-mg dose? A recent systematic review of 21 randomized, controlled trials of saw palmetto found that 15 studies used a dose of 160 mg twice a day, and 5 studies used lower doses; only 1 study used a higher dose^ref
• African plum (Pygeum africanum): likely effective for the symptomatic treatment of benign prostatic hypertrophy (BPH)
• shark cartilage : thought by some to be effective against cancer
• 5-Loxin is a standardized extract of boswellic acid. The patented extraction process means it delivers 30% 3-acetyl-11-keto-b boswellic acid (AKBA), the most potent boswellic acid extract, compared with just 2-3% by other extracts. It has been available to dietary supplements formulators through PL Thomas since December 2004, was the first formal offering to come out of the ingredients supplier’s recently announced alliance with Laila Nutraceuticals^ref
In the USA, > 60% of doctors have referred patients for services that are complementary to conventional western medicine (CWM). Around 29,000 dietary supplements are available in US drugstores, and Americans spend around US$16 billion on them each year. Fears over their potential risks escalated last year after the death of baseball player Steve Bechler, who was taking the weight-loss and energy aid ephedra. While it was unclear if his death was caused by the supplement, the FDA subsequently introduced a ban on ephedra, effective from 12 April 2004. The National Academies' Institute of Medicine recommends that manufacturers should be obliged to report adverse events attributable to dietary supplements to the FDA. It has been estimated that < 0.5% of such events are currently reported
• artificial alimentation (see also diet) : the giving of food or nourishment to persons who cannot take it in the usual way, to prevent malnutrition
• gavage : forced feeding, especially through a tube passed into the stomach.  2. the therapeutic use of a very full diet; superalimentation
History :
• 1900 : i.v. glucose solutions
• 1937 : crescin hydrolysis
• 1940 : amino acids
• 1961 : lipids
• 1968 : hypertonic glucose solutions
Energy metabolism.
Calorie requirements for an average (70 kg) adult man :
• basal and minor surgery : 1450 kcal/day
• mild peritonitis : + 25%
• postoperative (uncomplicated : 1500-1700 kcal/day
• sepsis : 2,000-2,400 kcal/day
• multiple trauma (ventilator) : 2,200-2,600 kcal/day
• burns : 2,500-3,000 kcal/day
A tissue trauma in a polytraumatized patient is different from a circumscribed surgical ablation : in the first case hypotension leads to vasoconstriction and ischemic necrosis, there is no sterility and the patient experiences pain, anguish and anxiety which activate sympathetic responses. In the second case there are controlled tissue losses (e.g. vessel ligation), there is sterility and pain is controlled during and eventually even after surgery.
Routes of administrations (ROA) :
• enteral nutrition : the delivery of nutrients in liquid form directly into the stomach, duodenum or jejunum; used when the patient's condition precludes oral intake; first used for predigested proteins for dogs

Requirements : normal appetite and gastrointestinal functions
Advantages :
• maintain villous trophism
• safe, simple and anatomical delivery
Contraindications :
• absolute :
• untreatable vomiting
• intestinal occlusion
• gastrointestinal bleeding
• relative :
• diarrhea
• ascitis
• intra-abdominal infections
• nasogastric tube

Indications :
• anorexia nervosa
• depression
• esophageal or pyloric obstruction
• weight loss 20-30%
• chronic dysphagia
• starvation longer than 3-4 days after surgery
Placement :
• use the better opened narix
• lubrifying and anaesthetic agents
• seated patients with flexed head
• narix-ear measurement to calculate when the probe reaches the nasopharynx. When the probe is placed there, the patient is asked to drink and the probe is swallowed down together with water.
• check with phonendoscope the inflation of stomach during inspiration (absent if the probe has been placed in trachea)
• place the patient on the right flank and await a few hours for gastric peristalsis to move the probe across pylorus
Small silicon catheters allow lower esophageal sphincter (LES) closure and prevent GERD and rhinopharyngeal irritation. In urgencies : central venous catheters (CVC) or alimentary jejunostomy.
Solutions :
• polymeric solutions (obtained with homogenizers => require large probes)
• chemically defined solutions
• modular solutions (chemically defined formula for patient with impaired digestive function) : monomers/short chain molecules, + MCI, + essential fatty acids (EFA), lactose-free. One or more macronutrients (proteins, carbohydrates, lipids) according to their solubility, interactions and osmolarity
• daily diet, via gastrojejunal feeding tube : 1000 mL of Jevity (Abbott Laboratories Ltd., Montreal, Que.) and 375 mL of Nutren 1.5 (Nestlé Clinical Nutrition Company, Deerfield, Ill.).
Risks : malpositioning of catheter in trachea or esophagus (aspiration) => for safety reasons it is usually placed over the pyloric sphincter. Lift the body during and after administration of the nutrition. Check up gastric emptying.
Side effects :
• meteorism
• distention
• nausea
• diarrhea

Aetiology :
• excessive volume
• hyperosmolar solution
• atrophic malabsorption
Prevention :
• decreased infusion rate
• decrease osmolarity
• opium tincture

Side effect : distention and constipation in elderlies
• dumping syndrome if lower than pylorus
• metabolic side effects are rarer than with parenteral nutrition : hyperosmolarity, diarrhea, hyperglycemia (pancreas isn't activate by pyloric delivery)
• rectal alimentation : the administration of concentrated nourishment by instillation into the rectum
• parenteral alimentation : administration of nutriment intravenously
• total parenteral nutrition (TPN), alimentation or hyperalimentation : the intravenous administration of the total nutrient requirements of the patient with gastrointestinal dysfunction
History : introduced in Europe in 1960 (lipids) and in USA (hypertonic glucose solutions) in 1965
Routes of administration :
• central venous catheters (CVC) (usually inserted in the superior vena cava via internal jugular or subclavian vein) for hyperosmolar solutions

Side effects : phlebitis
• peripheral vein
Requirements :
• sterile conditions
• solutions :
• L-amino acids (4 kcal/g)
• branched
• essential (Ala, His, Pro, Arg)
• Glc 5-35% (5-10% for peripheral accesses) (3.4 kcal/g => G/A 5% => 170 kcal/L; G/A 25% => 850 kcal/L); when infused at excessive rate it may cause hyperosmolarity
• electrolytes
• vitamins
• lipid emulsion (9 kca/g : 15-40% of total calories) 10-20% + glycerol 2.5% (isotonic). Some people do not tolerate milky blood. Administer no more than 4 g/kg/day and 500 mL of 10% solution per week to administer essential fatty acids and 15-30% of calorie requirements- Higher doses could lead to acute respiratory failure
• Lipofundin^® : soy seed oil + lecithin + glycerol
• Clinimix^® :
Regimen of delivery :
• home parenteral nutrition (HPN)
Indications : total malfunctioning of gastrointestinal tract
Complications :
• mechanical (1-3%) :
• catheter tip misplacement (CXR) : tip of catheter directed outside of superior vena cava or right atrium

Treatment : redirect with a guide wire under fluoroscopy
Prevention : direct bevel of needle caudally
• pneumothorax from puncture or laceration of lung pleura (dyspnea, CXR)

Treatment : tube thoracostomy if indicated, observation
Prevention : avoid emergency procedures, Trendelenburg's position
• hemothorax (dyspnea, CXR)

Treatment : remove catheter, observation
Prevention : insert catheter using appropriate techniques
• subclavian vein thrombosis secondary to catheter (inability to cannulate)

Treatment : remove catheter, heparin therapy if clinical significant
Prevention : use silicone catheters, add heparin to solution
subclavian vein perforation
• subclavian artery perforation during needlestick (pulsatile red blood)

Treatment : remove needle, apply pressure, CXR, serial monitoring of vital signs
Prevention : review anatomy
• embolism
• air embolism due to aspiration of air into the subclavian vein and right side of the heart (coming in during breathing when the external opening of the catheter is deconnected) (dyspnea, cyanosis, hypotension, tachycardia, precordial murmur)

Treatment : Trendelenburg's position, left lateral decubitus position, aspirate air
Prevention : Trendelenburg's position, Valsalva maneuver, tape intravenous connection
• catheter embolism (sheared catheter)

Treatment : fluoroscopic retrieval transvenously
Prevention : never withdraw catheter through needle
• arrhythmias (catheter tip in right atrium)

Treatment : withdrawn catheter to superior vena cava
Prevention : estimate distance to SVC before insertion, confirm position with CXR
• cardiac tamponade
• central venous thrombosis
• infectious complications :
• Staphylococcus aureus
• Candida albicans
• line sepsis (catheter tip infected)

Treatment : remove catheter, antibiotics
• infection at skinsite (bacteria at site of catheter entry into skin)

Treatment : remove catheter, local wound care
• metabolic complications :
• acute CHF
• increased [insulin, T₄, cortisol]_plasma due to excessive glucose calories or glucose intolerance. If the at the beginning hyperglycemia and hyperosmolar nonketotic coma (due to dehydration with excessive osmotic diuresis : disorientation, lethargy, stupor, convulsions, coma, glucose 1,000 mg/dL, osmolarity 350 mOsm/kg) appear interrupt administration and inject 2 L of 20% glucose solution => if the patient experiences hypoglycemia, decrease glucose content to 5% for 12-24 hours.

Treatment : discontinue TPN immediately: infuse D5 in 0.45% S at 250 mL/hr, insulin 10-20 U/hr, bicarbonate, monitor glucose and electrolytes, potassium, pH
Prevention : monitor glucose
• hypoglycemia due to sudden cessation of TPN (headache, sweating, thirst, convulsions, disorientation, paresthesias)

Treatment : bolus D50W I.V.; monitor blood glucose
Prevention : taper TPN by 1/2 for 12 hr; then 12 hr of D5W at 100 mL/hr
• CO₂ retention (hypercarbia) due to infusion of glucose calories in excess of energy needs (ventilator dependance, high respiratory quotient)

Treatment : decrease glucose calories and replace with fa
Prevention : provide 30-40% of calories with fat
• hyperchloremic metabolic acidosis due to excessive chloride administration

Therapy : give sodium and potassium as acetate salts
• azotemia due to excessive amino acid administration with inadequate calories (dehydration, elevated BUN)

Treatment : decrease amino acids and increase nonprotein (glucose) calories
Prevention : monitor fluid balance
• hyperammonemia (lethargy, malaise, coma, seizures)

Treatment : discontinue amino acid infusions, infuse arginine
Prevention : avoid casein or fibrin hydrolysate
• essential fatty acid deficiency due to inadequate administration (xerosis, hepatomegaly, impaired hearing, bone changes)

Treatment : administer fat solution
Prevention : provide 25-200 mg/kg/day of essential fatty acids
• hypertriglyceridemia due to rapid fat infusion of decreased fat clearance

Therapy : slow rate of fat infusion
• hypophosphatemia due to inadequate administration (lethargy, anorexia, weakness)

Treatment : supplemental phosphate
Prevention : treat causative factors: alkalosis, gram-negative sepsis, vomiting, malabsorption. Provide 20 mEq/kcal
• abnormal liver enzyme (fatty infiltrate in liver)

Treatment : evaluate for other causes
Prevention : provide balanced TPN solution
• hypomagnesemia (weakness, nausea, vomiting, tremors, depression, hyporeflexia)

Treatment : infuse 10% MgSO₄
Prevention : supply 0.35-0.45 mEq/kg/day
• hypermagnesemia (drowsiness, nausea, vomiting, coma, arrhythmias)

Treatment : dialysis, infuse calcium gluconate
Prevention : monitor serum levels
• increased metabolic expenditure
• increased O₂ consume
• increased cardiac output
• bleeding due to vitamin K deficiency

Treatment : administer vitamin K
Side effects :
• cholestasis
• if the nitrogen balance remains negative despite adequate protein intake, add glucose to the daily dose
• biopharmaceuticals (proteins (except antibodies) and nucleic acids (except gene therapy)
Their immunogenicity depends on :
• structural properties
• sequence variation due to foreign origin
• non-glycosylation pattern due to production in bacterial vectors : it may lead to
• exposure of antigenic sites
• reduced solubility
• lack of tolerance if the deficiency is innate
• contaminants and impurities from initial production or downstream processing
• protein modifications
• oxidation
• deamidation
• aggregate formation (reduced by addition of human serum albumin (HSA) and/or PEGylation)
• route of administration (intramuscular and subcutaneous routes are more immunogenic than intravenous or local treatment)
• dose
• length of treatment
• immunocompetence of the patient
• unknown factors
The consequences of antibody production may be :
• none
• loss of efficacy of the biopharmaceuticals (it can possibly be overcome by increasing the dose) (eg for rhuEPO^ref)
• enhancement of efficacy of the biopharmaceuticals
• neutralization of the native endogenous factor, too. When the endogenous factor mediates a unique biological function, a clinical syndrome develops. Such has been observed in immune responses to recombinant erythropoietin and thrombopoietin, with patients exhibiting pure red blood cell aplasia and immune mediated thrombocytopaenia respectively.
Immunogenicity may be predicted by :
• degree of distribution of homology
• physicochemical characterization for biopharmaceuticals that have a high degree of homology
• animal models
• non-human primates
• transgenic animals (so immune tolerant for the human protein that they express)
• nonprotein autacoid replacement therapy
• PGE₁ : alprostadil (Prostin VR Pediatric^®)
• topical cream : Alista™, Femprox^®
• gel : Topiglan^®
• urethral suppository : medicated urethral system for erection (MUSE^®)
• intracavernosal injection (Caverject^®, Edex^®)
• PGE₂ : dinoprostone (Carverject^®, Prepidil^®)
• PGI₂ / prostacyclin (PC) : epoprostenol (Flolan^®), treprostinil (Remodulin^®), beraprost (Dorner^®, Procylin^®), and iloprost (Ilomedin^®)
• adenosine (Ado) (Adenocard^®)
• nitric oxide (NO) (INOvent^®)^ref

Clinical indications for administering inhaled nitric oxide to adults :
• acute lung injury and the ARDS
• targeting pulmonary vascular resistance
• lung transplantation
• sickle cell disease
Alternatives and adjuncts to inhaled nitric oxide :
• other inhaled vasodilators
• adjunctive therapies that increase the effectiveness of inhaled nitric oxide
• nonprotein neurotransmitters replacement therapy
• acetylcholine (Miochol-E^®)
• dopamine hydrochloride (Dobutrex^®, Intropin^®, Revivan^®)
• epinephrine / adrenalin (Epinal^®, Epifrin^®, Fastjekt^®, Fastjeckt Junior^®, Glaucon^®)
• norepinephrine / noradrenalin : levarterenol (Levophed^®)
• histamine dihydrochloride (Ceplene^®; source : Maxim Pharmaceuticals) : prevents monocytes, macrophages and neutrophils typically present in large quantities in diseased, cancerous and virally infected tissues, from releasing ROS that have been shown to induce apoptosis in NK, NKT and T cells (see immunooncology). In clinical trials for malignant melanoma (together with IL-2^{ref1, ref2, ref3, ref4, ref5}), renal cell carcinoma, and hepatitis C (together with IFN-a_2b)^ref
• melatonin : used by some to treat insomnia, depression, and jet lag syndrome ; appears to be generally safe
• protein replacement therapy (click here for transfection techniques) : nearly $10 billion worth of biopharmaceuticals are expected to come off patent during the next 5 years, and firms that produce generic drugs want to jump in to exploit the niche. The lure of less expensive medication is strong: The biogenerics market is expected to reach $16 billion by 2007. Biopharmaceutical medications are among the most expensive of drugs; some cancer treatments can cost $10,000 a month. Generics (biogenerics), on the other hand, can sell for as little as one-fifth the price of the original drug. Many generic biologic drugs are already sold in unregulated markets in China, Eastern Europe, India, Brazil, Peru, Egypt, and Mexico. Sicor Pharmaceuticals of Irvine, Calif., has made a generic version of interferon alpha-2b for more than a decade and is selling it in 17 countries. Vancouver-based Dragon Pharmaceuticals sells a version of Amgen's Epogen, a genetically engineered copy of erythropoietin (EPO), in 5 countries. Dragon is already eyeing the European Union for its generic version of EPO, with hopes of selling it there as early as 2006. The patent for synthetic human hormone EPO is set to expire there this month. Marketed as Epogen by Amgen and Procrit by Johnson & Johnson, the drug had combined US sales of more than $6 billion in 2003. But the Sandoz case demonstrates that European regulators still remain at cross-purposes as to how to interpret new rules for making and selling biogenerics. European regulators required Sandoz to conduct two sets of clinical trials on Omnitrope. Though the European Medicines Evaluation Agency (EMEA), the region's equivalent of the FDA, recommended approval of Omnitrope in June 2003, the European Commission denied approval this past March while it considers whether the Sandoz clinical trials were sufficient. The disagreement between the two agencies is considered unusual, and it demonstrates what many believe are continuing interpretive differences over rules that are just now being tested. The fact that Sandoz filed for Omnitrope approval before the European guidelines came out last December indicates that future applications may have an easier time. Moreover, Australia's approval of Omnitrope will provide Europe with some regulatory precedent.



• cytokines replacement therapy
• interferons (IFNs). The lowercase letter is assigned by the drug nomenclature agencies to differentiate one manufacturer's interferon from another's. For mixtures of naturally occurring interferons obtained from a natural source, whether the exact percentage of a mixture is known or not, the lower case letter "n" precedes the number
• IFN-a / leukocyte interferon is currently in phase III clinical trials to enhance tumour antigen presentation and cytotoxicity (systemic route)^ref. Indications : chronic myeloid leukemia (CML)
• rIFN-a_con-1
• Infergen^®; source : InterMune, Inc., SOL(0.03 mg / mL)SC
• IFN-a₂ :
• rIFN-a₂ :
• Roferon A^®; cloned in Escherichia coli; source : F.Hoffmann-La Roche/Genentech. Prefilled syringe sc in 3, 6, and 9 MIU concentrations for self-administered therapy of CML. Most frequently reported adverse reactions at > 10% (9MIU/day) : fever, asthenia or fatigue, myalgia, chills, anorexia, arthralgia/bone pain, headache, nausea/vomiting, diarrhea, depression, coughing, hair changes (including alopecia), skin rash, decreased mental status, sweating, dizziness, and sleep disturbances. Depression, together with suicidal ideation, suicide attempts, and suicides have been reported in association with alfa interferon therapy. Roferon-A should be used with caution in patients with severe preexisting cardiac disease, severe renal or hepatic disease, seizure disorders, and/or compromised CNS function
• Canferon A^®
• PEGylatedrIFN-a₂ :
• Pegasys^® (source : Roche). Indications : HBeAg⁺ and HBeAg^- chronic hepatitis B.
Indications : HBV and HCV infections, renal cell carcinoma and multiple myeloma
Neutralizing antibodies may emerge during retreatment but do not affect endogenous IFN-b or IFN-a_C^ref : they can be measured with a replicon-based bioassay^ref
• rIFN-a_2b :
• Intron A^®; cloned in Escherichia coli; source : Schering-Plough, Ireland and Biogen, LIQ(15,000,000 U / mL, 25,000,000 U / mL, 50,000,000 U / mL)SC
• PEGylated rIFN-a_2b :
• Peg-Intron^®; source : Schering-Plough, PWSO(74 mg / vial, 118.4 mg / vial, 177.6 mg / vial, 222 mg / vial)SC. Also administered via a pre-filled pen (Peg-Intron Redipen^®)
Following an i.v. dose of 30 million IU, the amount of rIFN-a_2b transferred into human milk was only slightly elevated (1551 IU/mL) when compared to control milk (1249 IU/mL). These data suggest that even following enormous doses, interferon is probably too large in molecular weight to transfer into human milk in clinically relevant amounts^ref.
Premedication : acetaminophen 650 mg PO 30 minutes prior to treatment, repeat q4h PRN
Indications : chronic myeloproliferative syndromes
• rIFN-a_n1 :
• Wellferon^®
• rIFN-a_n2
• rIFN-a_n3 :
• Alferon N^®
Regimen : 3 MIU SQ 3 times/wk
Complications : autoimmune disorders, including thyroiditis and vitiligo, have been reported to develop in 15-30% of patients who receive IFN-a therapy. Yet an association between the development of autoimmunity and responsiveness to immunotherapy has largely been restricted to melanoma and renal cell cancer
• IFN-b₁ / fibroblast interferon :
• rIFN-b_1a :
• Avonex^®; cloned in CHO cells; source : Biogen, Inc, USA. Alternate supplier for HSA as excipient, PWSO(30mcg/kit)IM
• Rebif^®; cloned in chinese hamster cells; source : Interpharm Laboratories Ltd => Serono Canada Inc., LIQ (22 mg / syr, 44 mg / syr) IL, SC, PWSO (11 mg / vial, 44 mg / vial) IL, SC
• rIFN-b_1b :
• Betaferon^® : cloned in Escherichia coli or CHO cells; source : Chiron Corp, USA
• Betaseron^®; source : Berlex Canada Inc. Alternate supplier for HSA used as excipient in manufacture of Betaseron, PWSO(0.3mg/vial)SC)
Regimen : 6 MIU SQ 3 times/wk
• IFN-g₁ :
• rIFN-g_1a (Immuneron^®) (source : Biogen and Baxter) prepared from Escherichia coli
• rIFN-g_1b :
• Actimmune^® expressed in Escherichia coli; source : Genentech, Inc. Noncovalent dimer. Low resolution crystal structure available. Monomer consists of 140 amino acids (QDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFKNFKDDQSI

QKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAIHELIQVMAELSPAAKTGKRKRS
QMLFRGRRASQ), no glycosylation or cysteines in human form. Murine form is a covalent dimer (one cysteine per monomer). Monomer 16.44 kD^ref. Standard human dose is 100 µg. High doses can cause significant side effects such as nausea, fever, and other flu-like symptoms. Effect of molecule is specific to species. Human form does not elicit toxicity in lower species at several mg/kg doses which are toxic to humans. Higher and earlier neutralizing antibody titers, increase in duration of neutralizing antibody titers, increase in MHC class II expression on APCs, increase in T_h cell levels, and an improved DTH response have all been observed when IFN-garnma was administered with an antigen. The IFN-g must be given at the same site and at the same time (within 6 hrs) as the antigen to have biological
effect^{ref1, ref2} [Heath, A. W. and Playfair, J. H. L., 1992, Cytokines as immunological adjuvants, Vaccine, 10:427-434; Heath, A., 1995, Cytokines as immunological adjuvants, in: Vaccine Design M. F. Powell and M. J Newman (Eds.) Pharmaceutical Biotechnology Series, Plenum Publishing Corp., New York; Dong, P., 1995, Cytokines as immunological adjuvants: Current status and potential applications, in: Vaccine Design M. F. Powell and M. J Newman (Eds.) Pharmaceutical Biotechnology Series, Plenum Publishing Corp., New York]
• Imukin^® ; cloned in Escherichia coli; source : Boehringer Ingelheim, Austria
Indications :
• chronic granulomatous disease (CGD)
• phase III trials for renal cell carcinoma
• adjuvant for HBsAg^ref
• phase III clinical trials to enhance tumour antigen presentation and cytotoxicity (systemic or local route)^ref
Side effects : major depression, influenza-like illness (ILI), insomnia, dysthyroidism.
• interleukins : the suffix -kin is used in naming interleukin-type substances except for interleukin 3 (IL-3) which was classified as a pleiotropic colony-stimulating factor and assigned the "plestim" stem (eg, daniplestim).  The "kin" nomenclature series was divided into subgroups with an adjuvant stem representing the numerical class of the interleukin followed by the kin   suffix.
• IL-1 (-nakin) :
• IL-1a (-onakin)
• pitonakin
• IL-1b (-benakin) :
• betaleukin
• mobenakin
• IL-1ra : anakinra (Kineret^®) 100 mg/day s.c. for rheumatoid arthritis (RA) (2-12 weeks of latency). It reduces tumour invasiveness and alleviates tumour-mediated suppression^ref
• IL-2 (-leukin) (systemic local) is currently used in phase III clinical trials to enhance NK cell and CD8⁺ T-cell immunity (systemic or local route)^{ref1, ref2, ref3, ref4} but can have both positive and negative effects on T cells depending on their stage of differentiation. IL-2 treatment during ...
• expansion phase is detrimental to the survival of rapidly dividing effector T cells
• during the death phase is highly beneficial, resulting in increased proliferation and survival of virus-specific T cells
IL-2 treatment also increases proliferation of resting memory T cells in mice that controlled LCMV infection. Virus-specific T cells in chronically infected mice also responded to IL-2 resulting in decreased viral burden.
• aldesleukin / des-Ala-1-Ser-125-hIL-2 (Proleukin^®, source : Chiron Corp, USA; Leuferon^®; source : Immunex and Roche) (nonglycosylated) used in the treatment of metastatic renal cell carcinoma and metastatic malignant melanoma. Side effects : systemic capillary leak syndrome (SCLS) (65%; due to permeability-enhancing peptide (PEP), i.e. amino acids 22-58: a point mutation at amino acid 38 completely blocks the vasopermeability effect but does not affect cytokine activity), thyroiditis and eosinophilia. Pre-treatment with tumour-targeting antibody-PEP fusion proteins is being developed as a strategy to enhance drug delivery to tumours, such that higher effective doses of chemotherapy can be targeted to tumours without additional systemic side effects.

Premedication :
• high dose, bolus (600,000 units/kg/dose) :
• acetaminophen 650 mg PO prior to each dose q8h
• NSAID (indomethacin 25 mg PO prior to each dose q8h or naproxen 500 mg PO BID during therapy)
• H2-receptor antagonist (cimetidine 300 mg PO/IV at HS or famotidine 20 mg PO/IV at HS or ranitidine 150 mg PO or 50 mg IV at HS)
• low dose, outpatient SC or continuous infusion : acetaminophen 650 mg PO prior to each dose or q4h PRN^ref
• celmoleukin (Celeuk^®, source : Takeda) for angiosarcoma CNS
• teceleukin (nonglycosylated) (Bioleukin^®; source : Biogen)
In patients with renal cancer, the expression of carbonic anhydrase IX predicts the responsiveness to immunotherapy with IL-2^ref, and the expression of B7-H1, a molecule associated with immune suppression, by a tumor can predict poor survival after nephrectomy^ref.
• IL-3 (-plestim) is currently in phase II clinical trials to enhance tumour antigen presentation (systemic route)^ref
• daniplestim
• IL-4 (-trakin) is currently in phase I clinical trials to enhance eosinophil function and T-cell activation (systemic or local route)^{ref1, ref2}
• binetrakin
• IL-5 (-penkin)
• IL-6 (-exakin) is currently in phase I clinical trials to enhance T-cell and B-cell function as inhibition of IL-6 reduces lymphoproliferation (systemic or local route)^ref
• atexakin alfa
• IL-7 (-eptakin) is produced by a subset of thymic epithelial stromal cells (TEC) and bone marrow cells and is a stimulus for proliferation, survival, and differentiation of immature thymocytes^{ref1, ref2, ref3, ref4, ref5, ref6}. IL-7 administration increased the rate of T-cell immune reconstitution in murine models of autologous bone marrow transplant as well as chemotherapy or radiation-induced myelo and immune suppression^{ref1, ref2, ref3, ref4, ref5}. Studies performed more than a decade ago demonstrated the therapeutic potential of IL-7 administered to mice with chemotherapy or radiation-induced lymphopenia^{ref1, ref2, ref3}. Sublethally irradiated mice treated with IL-7 showed accelerated lymphocyte recovery as well as increased white cell recovery in peripheral blood and spleen. IL-7 treatment of mice irradiated at higher doses resulted in preferential expansion of CD8⁺ T cells and more rapid normalization of the CD4/CD8 ratio. Morrisey et al noted an accelerated regeneration of CD4 and CD8 T cells with IL-7 administration in both spleen and lymph nodes of cyclophosphamide-induced lymphopenic mice^ref. Bolotin et al showed that relative to controls, bone marrow–transplanted mice treated with IL-7 had more rapid normalization of thymic cellularity, normal proportions of thymic cellular subsets, peripheral CD4⁺ cells, and improved antigen-specific T and B cell function^ref. Abdul-Hai et al noted that IL-7 treatment increased thymic cellularity 12-fold after syngeneic BMT^ref. More recently Mackall and colleagues^ref extended these studies to show that IL-7 administration exerts its beneficial effect on immune reconstitution via increased thymopoiesis and a direct increase in the magnitude of antigen-driven peripheral T-cell expansion. Thus, treatment with IL-7 enhances thymopoiesis following chemotherapy or myeloablative conditioning for BMT as well as antigen-driven, peripheral T-cell expansion in T-cell depleted or thymic-deficient hosts^{ref1, ref2, ref3, ref4, ref5}. A cautionary note should be applied considering the use of IL-7 therapy in the context of GVHD following allogeneic SCT. Pharmacologic doses of IL-7 may have potent effects on mature T cells^{ref1, ref2}. IL-7 treatment may induce peripheral T-cell expansion and effectively enhance the response of mature T cells to alloantigen. These consequences may well predict enhancement of GVHD and graft rejection. Mackall’s group^ref utilized a murine model of parent stem cells into F1 progeny to study the effect of IL-7 on immune reconstitution and GVHD following allogeneic bone marrow transplantation (alloBMT). In this model, administration of IL-7 lowered the threshold dose of T cells required to induce clinical signs of GVHD as well as lethal GVHD. IL-7 administration was associated with a greater degree of inflammation and tissue damage at all T-cell doses employed. It was observed however, that in a setting of alloBMT in T cell–depleted hosts, IL-7 therapy enhanced thymic function although not to the degree noted with treatment of syngeneic BMT recipients. This study stands in contrast to that reported by Alpdogan et al^ref in which posttransplant administration of IL-7 to recipients of alloBMT enhanced lymphoid reconstitution without aggravating GVHD. It was noted that the alloreactive donor-derived T cells from the alloBMT recipients expressed little IL-7R. Resolution of these disparate results will require further examination of the respective variations in IL-7 dose and time and duration of IL-7 administration. In summary, the preclinical database, primarily in rodent models of myelosuppression or BMT with myeloablative conditioning, suggests a potentially effective role for IL-7 therapy for reconstituting the immune system of severely irradiated personnel. 2 recent studies in nonhuman primate models underscore this potential. Fry and colleagues demonstrated significant increases in peripheral blood CD4 and CD8 T cells after IL-7 treatment of moderately CD4-depleted SIV-infected rhesus macaques and suggested that a major component of its effect is peripheral homeostatic expansion of mature cells^ref. Storek et al showed that IL-7 administration after autologous BMT in baboons stimulated a significant expansion of peripheral blood CD4 T cells^ref. IL- 7is currently in phase I clinical trials to enhance T-cell function (local route)^ref.
• IL-8 / CXCL8 (-octakin)
• emoctakin
• IL-9 (-nonakin)
• IL-10 (-decakin) inhibits tumour antigen presentation (pending)^ref
• ilodecakin (Tenovil^®; source : Schering-Plough)
• IL-11 (-elvekin) :
• oprelvekin (Neumega^®) 50 mg/kg SQ qd.
• IL-12 (-dodekin) is currently in phase I-II clinical trials to enhance T_h1 immunity and cytotoxicity and inhibit angiognesis (systemic or local route)^ref
• edodekin alfa
• IL-13 inhibits cytotoxicity againt viral neoplasms (pending)^ref
• IL-15 enhances cytotoxicity (pending)^ref
• IL-18 enhances T_h1 immunity and cytotoxicity and inhibits angiogenesis^ref
• megakaryocyte growth and developmental factor (MGDF)
• thrombopoietin (TPO)^ref : a potent stimulator of platelet production that also primes platelets to aggregate in response to otherwise subthreshold levels of thrombin, collagen, or adenosine diphosphate by activating the PI3K signaling pathway in platelets^ref. In mice, elimination of the thrombopoietin gene or its receptor reduces the level of production of megakaryocytes and platelets to approximately 10% of normal^ref. In addition to stimulating megakaryocytopoiesis, thrombopoietin has an important and nonredundant role in the survival and expansion of HSCs. When tested alone or in combination with other cytokines in vitro, TPO supports the survival and proliferation of HSCs^ref. Moreover, genetic elimination of TPO or TPO-R in mice reduces by a factor of 7 to 8 the number of stem cells with the capacity to repopulate the bone marrow and decreases by a factor of 17 the expansion in the number of HSCs that occurs after transplantation^{ref1, ref2}. The effects of TPO on stem cells are mediated by enhanced expression or nuclear localization of several transcription factors — STATT, HOXB4, and HOXA9 — and by autocrine production of VEGF^ref. As a result of these studies, virtually every current attempt in the laboratory to expand HSCs includes TPO or a TPO mimetic in the culture medium, and current clinical trials of thrombopoietic agents are designed to detect the panhematopoietic effects that were seen in the preclinical trials of the hormone. Thrombopoietin levels in blood are inversely related to the number of platelets in the blood and megakaryocytes in the bone marrow^ref; unlike erythropoietin production, however, the regulation of thrombopoietin levels is multifaceted. At least 50% the production of TPO occurs in the liver^ref, but the kidney and skeletal muscles also produce the hormone. Mature platelets and megakaryocytes display TPO-R and are capable of removing the hormone from the circulation^ref. Thus, one mechanism of the inverse relationship between the platelet count and the TPO level is adsorption of the hormone from the circulation, a finding that can explain how platelet transfusions delay the rate of recovery from chemotherapy-related thrombocytopenia^ref. In addition to these steady-state mechanisms of TPO production and catabolism, stromal cells in the bone marrow increase production of the hormone substantially in states of severe thrombocytopenia^{ref1, ref2}. Furthermore, hepatic TPO production can be enhanced by inflammatory mediators such as IL-6^{ref1, ref2}, providing a molecular explanation for the common finding of reactive thrombocytosis in rheumatoid arthritis, Crohn's disease, and several other inflammatory and infectious conditions^ref. TPO gene has been cloned in 1994, but the protein has not yet been approved for clinical use

Indications :
• accelerate platelet recovery after moderately intensive chemotherapy^ref, but not after the intensive chemotherapy necessary for treating acute myelogenous leukemia, or at least with the use of the dosing strategies tested thus far^ref.
• augment the number of HSCs mobilized by G-CSF^ref
• increase the number of platelets available for apheresis from platelet donors.
Side effects : the potential for the clinical use of recombinant thrombopoietin was irreversibly altered by a study to determine whether the hormone could improve platelet yields from platelet donors. The thrombopoietin used in most of the clinical trials that were conducted between 1995 and 1998 was a truncated form of the protein produced in Escherichia coli and modified with PEG. Termed "megakaryocyte growth and differentiation factor (MGDF)", the recombinant protein and native thrombopoietin have important differences that probably explain an important adverse effect. Native thrombopoietin contains 3 sites of serine glycosylation, which are not present in the truncated recombinant protein produced in bacteria. Moreover, because MGDF is a truncated version of thrombopoietin, the C-terminal amino acid of MGDF is not normally a terminal residue. Hence, several nonnative structures (potential neoepitopes) were created in MGDF. When administered subcutaneously to platelet donors, some of the donors produced antibodies against MGDF that cross-reacted with endogenous thrombopoietin, thereby causing severe autoimmune thrombocytopenia^ref. This adverse event — an important lesson in the engineering of recombinant proteins meant for clinical use — led to the abandonment of the use of MGDF and full-length forms of thrombopoietin as therapeutic proteins. The experience with MGDF instigated a search for molecules that bind to and stimulate the thrombopoietin receptor on hematopoietic cells. Sophisticated screening techniques have led to the discovery of several small-molecule thrombopoietin mimics that bind and stimulate the thrombopoietin receptor. These agents are undergoing clinical testing. The results of a recent trial of a molecule carrying 4 copies of a TPOR–binding peptide on an Ig scaffold point to the potential clinical utility of a thrombopoietin-receptor agonist. The bone marrow of patients with ITP usually contains numerous megakaryocytes, reflecting an attempt to compensate for the thrombocytopenia. The abundance of megakaryocytes in these patients argued against an approach involving stimulation of the bone marrow to raise platelet levels. However, TPO levels are not elevated in patients with ITP, which raises the possibility that TPO therapy could be advantageous in such patients. In a recent phase 2 trial, nearly 80% of patients with refractory ITP had a response to the thrombopoietin agonist AMG531, a peptide mimic of the hormone (Bussel JB, Kuter DJ, George JN, et al. Long-term dosing of AMG 531 is effective and well tolerated in thrombocytopenic patients with immune thrombocytopenic purpura. Blood 2005;106:68a-68a). This observation is evidence that pharmacologic levels of growth factors can increase hematopoiesis above the levels attained in a maximal physiologic response.
• hybrid/synthetic cytokines :
• PIXY321 (a GM-CSF/IL-3 fusion protein)
• SC71858 / promegapoietin (a synthetic cytokine comprising mutated version of IL-3 and TPO)
• SCF : ancestim (Stemgen^®; cloned in Escherichia coli; source : Amgen, USA) (recombinant methionyl)
• hematopoietic colony stimulating factors^ref :
• G-CSF (-grastim) : cloned in 1987^ref; toxic granulation of neutrophils in the peripheral blood, which is a morphologic correlate of their heightened functional state, and a leftward shift (immaturity) in the leukocyte differential count. Activation of neutrophils in the bone marrow by G-CSF causes them to release matrix metalloproteases. This effect helps to explain the mobilization of hematopoietic stem cells out of the bone marrow^ref. Granulocyte function may be altered after in vivo G-CSF administration and this has been related to both an immaturity of mobilized cells and to a defect in F-actin polymerization. In resting filgrastim (non-glycosylated G-CSF)-pulsed cells, F-actin polymerization, membrane-linked RhoA and cell polarization are enhanced compared to those found in resting lenograstim (glycosylated G-CSF)-cells. The basal hyper-activation of RhoA could be responsible for the morphological and functional modifications of filgrastim-mobilized cells. Moreover, filgrastim-mobilized cells, but not lenograstim-mobilized cells, are unable to correctly respond to LPS stimulation, as demonstrated by minor further RhoA activation and cell elongation^ref. Neutrophil morphology is modified by treatment with filgrastim, while it is not affected by lenograstim. Little information is available about actin polymerization in neutrophils from subjects treated with the two types of rhG-CSF. In the current paper we evaluated two groups of donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. 10 subjects were treated with filgrastim and 10 with lenograstim to mobilize PBSC; 15 blood donors were evaluated as a control group. Actin polymerization (both spontaneous and fMLP-stimulated) was studied by a flow cytometric assay. A microscopic fluorescent assay was also carried out to evaluate F-actin distribution in neutrophils. Filgrastim induced an increased F-actin content in resting neutrophils, along with morphologic evidence for increased actin polymerization distributed principally at the cell membrane and frequently polarized in focal areas; in addition, fMLP was not able to induce further actin polymerization. On the contrary, treatment with lenograstim was associated with F-actin content, distribution, and polymerization kinetics indistinguishable from those displayed by control neutrophils^ref
• filgrastim^ref (Gran^® (Japan, Taiwan, Korea, China); Neupogen^® (Europe, USA, Canada, Australia; source : Amgen, Thousand Oaks, CA)) : recombinant methionyl protein produced in Escherichia coli (nonglycosylated) consisting of a 175–amino acid with a molecular weight of 18.8 kDa.

Side effect : systemic capillary leak syndrome (SCLS).
Schedule : initial dose: 6 mg/kg SC bid; adjust individually on basis of both clinical course and ANC; rarely, patients require doses >100 mg/kg/d; doses that increase ANC to >10,000/mm³ may not provide any additional clinical benefit
• pegfilgrastim (Neulasta^®; Neupopeg^®; source : Amgen) is composed of the protein filgrastim to which a 20-kDa polyethylene glycol (PEG) is covalently bound at the N-terminal residue resulting in decreased renal clearance and increased plasma half-life compared with filgrastim, allowing single-dose administration per chemotherapy cycle.

Indications and usage :
• decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.
• mobilization of peripheral hematopoietic stem cells in allogeneic donors^ref
Contraindications : Neulasta is contraindicated in patients with known hypersensitivity to E.coli-derived proteins, pegfilgrastim, Filgrastim, or any other component of the product.
Warnings :
• splenic rupture : rare cases or splenic ruptures have been reported following the administration of the parent compound of Neulasta, filgrastim. For PBPC mobilization in both healthy donors and patients with cancer, some of these cases were fatal. Neulasta has not been evaluated in this setting : therefore, Neulasta should not be used for PBPC mobilization. Patients receiving Neulasta who report left upper abdominal or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.
• adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis receiving Filgrastim, the parent compound of Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS, In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS, and patients should receive appropriate medical management for this condition
• allergic-type reactions, including anaphylaxis, skin rash, and urticaria, occurring on initial or subsequent treatment have been reported with the parent compound of Neulasta, Filgrastim. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Allergic-type reactions to Neulasta have not been observed in clinical trials. If a serious allergic reaction or an anaphylactic reaction occurs, appropriate therapy should be administered, and further use of Neulasta should be discontinued
• sickle cell diseases : severe sickle cell crises have been reported in patients with sickle cell disease (specifically homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle/b⁺ thalassemia) who received Filgrastim, the parent compound of pegfilgrastim, for PBPC mobilization or following chemotherapy. On eof these cases was fatal. Pegfilgrastim should be used with caution in patients with sickle cell disease, and only after careful consideration of the potential risks and benefits. Patients with sickle cell disease who receive Neulasta should be kept well hydrated and monitored for the occurrence of sickle cell crises. In the event of severe sickle cell crisis, supportive caree should be administered, and interventions to ameliorate the underlying event, such as therapeutic red blood cell exchange transfusion, should be considered.
Precautions :
• general :
• use with chemotherapy and/or radiation therapy : Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy because of the potential for an increase in sensitivity of rapidy dividing myeloid cells to cytotoxic chemotherapy. The use of Neulasta has not been studied in patients receiving chemotherapy associted with delayed myelosuppression (eg nitrosoureas, mitomycin C). The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has ot been evaluated in patients. Admnistration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival. The use of Neulasta has not been studied in patients receiving radiation therapy
• potential effect on malignant cells : pegfilgrastim is a growth factor that primarily stimulats neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for AML, important differences in remission rate between the 2 arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints
• information for patients : patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be considered on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts. If it is determined that a patient or caregiver can safely and effectively administer Neulasta at home, appropriate instruction on the proper use of Neulasta should be provided for patients and their caregvers, including caregul review of the informations for patients and caregivers" insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available
• laboratory monitoring : to assess a patient's hematologic status and ability to tolerate myelosuppressive chemotherapy, a CBC and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended
• drug interaction : no formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receving lithium and Neulasta should have more frequent monitoring of neutrophil couns.
• carcinogenesis, mutagenesis, impairment of fertility : no mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once-weekly subcutaneous injection of up to 1000 mg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mg/kg prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
• pregnancy category C : pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered SC every other day during  gestation at doses as low as 50 mg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mg/kg/dose. Pegfilgrastim doses of 200 and 250 mg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed t doses of 200 to 1000 mg/kg/dose, and decreased numbers of live rabbits fetuses were observed at pegfilgrastim doses of 200 to 1000 mg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation. Once-weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation though day 18 of lactation at doses up to 1,000 mg/kg/dose did not result in any adverse maternal effect. There were no deleterious effects on the growth and developmento of the offspring, and no adverse effects were found upon assessment of fertility indices. There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
• nursing mothers : it is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Neulasta is adminstered to a nursing woman.
• pediatric use : the safety and effectiveness of Neulasta in pediatric patients have not been established. The 6 mg fixed-dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg
• geriatric use : of the 465 subjects with cancer who received Neulasta in clinical studies, 85 (18%) were age 65 and over, and 14 (3%) were age 75 and over. No overall diffrences in safety or effectiveness were observed between these patients and younger patients; however, due to the small number of elderly subjects, small but clinically relevant differences cannot be excluded.
Adverse reactions :
• safety data are based upon 465 subjects with lymphoma and solid tumors (breast, lung and thoracic tumors) enrolled in 6 randomized clinical studies. Subjects received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most adverse experiences were attributed by the investigators to the underlying malignanciy or cytotoxic chemotherapy and occurred at similar rates in subjects who received Neulasta (n=465) or Filgrastim (n=331). These adverse experiences occurred at rates between 72% and 15% and included nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. The most common adverse event attributed to Neulasta in clinical trials was medullary bone pain, reported in 26% of subjects, which was comparable to the incidence in Filgrastim-treated patients. This bone pain was generally reported to be of mild-to-moderate severity. Approximately 12% of all subjects utilized non-narcotic analgesics, and less than 6% utilizes narcotic analgesics in association with bone pain. No patients withdrew from study due to bone pain. In clinical studies, leukocytosis (WBC counts > 100 x 10⁹/L) was observed in less than 1% of 465 subjects with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects. In subjects receiving Neulasta in clinical trials, the only serious event that was not deemed attributable to underlying or concurrent disease, or to concurrent therapy, was a case of hypoxia. Reversible elevations in LDH, alkaline phosphatase, and uric acid, which did not require treatment intervention, were observed. The incidences of these changes, preented for Neulasta relative to Filgrastim, were as follows: LDH (19% vs. 29%), alkaline phosphatase (9% vs. 16%), and uric acid (8% vs. 9% [1% of reported cases for both treatment groups were classified as severe]).
• immunogenicity : as with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Neulasta has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim or pegfilgrastim, the nature and specificity of these antibodies have not been adequately studied. No neutralizing antibodies have been detected using a cell-based bioassay in 46 patients who appraently developed binding antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the asssay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia, but this has not been observed in clinical studies
• overdosage : the maximum amount of Neulasta that can be safely administered in single or multiple doses has not  been determined. Single doses of 300 mg/kg have been administered SC to 8 normal volunteers and 3 patients with NSCLC without serioud adverse effects. These subjects experienced a mean maximum ANC of 55 x 10⁹/L, with a corresponding mean maximum WBC of 67 x 10⁹/L. The absolute maximum ANC observed was 96 x 10⁹/L, with a corresponding absolute maximum WBC, observed of 120 x 10⁹/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals.
• dosage and administration : the recommended dosage of Neulasta is a single SC injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be admnistered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg
• lenograstim (since 1991) (Neutrogin^® (Japan, China); Myelostim^® (source: Italfarmaco); Granocyte^® (Europe and Australia; source : Chugai Pharm Co, Japan and Rhone-Poulenc Rorer)) produced in Chinese hamster ovary (CHO) cells (O-glycosylated)
• (Naltoplastim^®; source : Kyowa Hakko)
• nartograstim (Neu-Up^®; Japan; source: KW-2228 , Kyowa Hakko Kogyo, Tokyo, Japan) non-glycosylated with 5 amino acids substituted at the N-terminal region of intact rhG-CSF produced in recombinant Escherichia coli
• pegnartograstim
• GM-CSF (-gramostim) is currently in phase II-III clinical trials to enhance tumour antigen presentation^ref. stimulates in vitro the proliferation and differentiation of haematopoietic precursor cells resulting in the production of granulocytes, monocytes/macrophages and T-lymphocytes. Studies on fresh tumour explants in the human tumour clonogenic assay have demonstrated that rHuGM-CSF neither stimulates nor inhibits tumour cell growth. rHuGM-CSF can enhance expression of MHC class II antigens on human monocytes and can augment antibody production. In addition, rHuGM-CSF exhibits marked effects on the functional activity of mature neutrophils, including enhanced phagocytosis of bacteria, enhanced cytotoxicity toward malignant cells and priming of neutrophils for enhanced oxidative metabolism, an important reaction related to host defense. In vivo studies performed in cynomolgus monkeys demonstrated that the intravenous or subcutaneous bolus administration of molgramostim results in significant increases in the WBC count. Serial differential counts indicate that this increase mainly concerns the neutrophilic granulocytes and, to a lesser extent, the lymphocytes and eosinophils.
• sargramostim (Leukine^® (USA; source : Berlex, Inc.), Prokine^® (source : Amgen, formerly Immunex Corp, Seattle, WA and Hoechst)) produced in Saccharomyces cerevisiae (O-glycosylated), differs from the natural human GM-CSF by substitution of Leu for Arg at position 23 (127 amino acids : APARSPSPSTQPWEHVNAIQEALRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLT

KLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE). M_r = 15,500, 16,800, and 19,500 (three bands on SDS-PAGE representing variation in glycosylation)^ref. Both lyophilized GM-CSF (Sargramostin) and reconstituted product should be stored at 2-8'C. Lyophilized product ma also be frozen at -20 or -70° C. Sargramostin exists as a major species (pI 5.2) and a minor species (pI 4.5-5.2). Sargramostin shows a specific activity of 5.6 x 10⁶ IU/mg as measured in a TF- I cell proliferation assay.
Side effect : eosinophilia, skin-associated events (77%)
Indications and usage :
• use following induction chemotherapy in older adult patients with AML to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy have not been assessed in patients with AML under 55 years of age
• use in mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and following transplantation of autologous peripheral blood progenitor cells for acceleration of myeloid reconsitution
• use in myeloid reconstitution after autologous bone marrow transplantation in patients with NHL, ALL, and HD, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response can be detected by CBC with diffrential performed twice per week
• use in myeloid reconstitution after allogeneic bone marrow transplantation from HLA-matched related donors, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization
• use in autologous or allogeneic bone marrow failure of engraftment delay, prolonging survival in the presence or absence of infection. Survivial benefit may be relatively greater in those patients who demonstrate one or more of the following chracteristics: autologous BMT failure or engraftment delay, no preveious total body irradiation, malignancy other than leukemia or a multiple organ failure score < 2. Hematological response can be detected with CBC differential performed twice per week
• [adjuvant for vaccination^{ref1, ref2}]
Contraindications :
• patients with > 10% leukemic myeloid blasts in the bone marrow or peripheral blood
• patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product
• for concomitant use with chemotherapy or radiotherapy : due to the potentital sensitivity of rapidly dividing hematopoietic progenitor cells, it should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with SCLS received sargramostin and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without it. The patients randomized to sargramostin had significantly higher incidence of adverese events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.
Warnings :
• pediatric use : benyl alcohol is a constituent of Leukine Liquid and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to bea ssociated with a afatal gasping syndrome in premature infants. Liquid solutions containig benzyl alcohol (including Leukine liquid) or lyophilized Leukine reconstituded with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates
• fluid retention : edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after Leukine administration. In 156 patients enrolled in placebo-controlled studies using Leukine at a dose of 250 mg/m²/day by 2-hor IV infusion, the reported incidences of fluid retention (Leukine vs.placebo) were as follows : peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%, and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies, based on other uncontrolled studies and reports from users of marketed Leukine, the incidence is estimated to be < 1%. In patients with preexisting pleural and pericardial effusions, administration of Leukine may aggravate fluid retention; however, fluid retention associated with or worsened by Leukine has been reversible after interruption or dose reduction of Leukine with or without diuretic therapy. Leukine should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.
• respiratory symptoms : sequestration of granulocytes in the pulmonary circulation has been documented following Leukine infusion, and dyspnea has been reported occasionally in patients displaying dyspnea during Leukine administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Leukine should be administered with caution in patients with hypoxia
• cardiovascular symptoms : occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Leukine administration, particulary in  patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Leukine. Leukine should be used with caution in patients with preexisting cardiac disease
• renal and hepatic dysfunction in some patients with preexisting renal or hepatic dysnfunction enroled in uncontrolled clinical trials, administration of Leukine has induced elevation of serum creatining or bilirubin and hepatic enzymes. Dose reduction or interruption of Leukine administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidence of hepatic and renal dysfunction were comparable between Leukine (250 mg/m²/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients dysplaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other wek during Leukine administration
Precautions :
• general : parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, Leukine therapy should immediately be discontinued and appropriate therapy initiated. A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of Leukine (sargramostin) in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment. Stimulation of marrow precursors with Leukine may result in a rapid rise in WBC count. If the ANC exceeds 20,000 cells/mm³ or if the platelet count exceeds 500,000/mm³. Leukine administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within 3 to 7 days following cessation of Leukine therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.
• growth factor potential : Leukine is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Leukine can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics. Should disease progression be detected during Leukine treatment, Leukine therapy should be discontinued. Leukine has been administered to patients with MDS in uncontrolled studies without evidence of increased relapse rate. Controlled studies have not been performed in patients with MDS.
• use in patients receiving purged bone marrow : Leukine is effective in accelerating myeloid recovery in patients receiving bone marow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to Leukine. When the bone marrow purging process preserves a sufficient number of progenitors (> 1.2 x 104/kg), a beneficial effect of Leukine on myeloid engraftment has been reported
• Use in patients previously exposed to intensive chemotherapy/radiotherapy : in patients who before autologous BMT have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of Leukine on myeloid reconstitution may be limited.
• use in patients with malignancy undergoing Leukine-mobilized PBPC collection : when using Leukine to mobilize PBPC, the limited in vitro data suggest that tumor cels may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive
• patient monitoring : Leukine can induce variable increases in WBC and/or platelet counts. In order to avoid otential complications of excessive leukocytosis (WBC > 50,000 cells/mm³, ANC > 20,000 cells/mm³), a CNC is recommended twice per week during Leukine therapy. Monitoring of renal and hepatic function in patients displaying renal or hahepatic dysfunction prior to initiation of treatment is recommended at least biweekly during Leukine administration. Body weight and hydration status should be carefully monitored during Leukine administration
• drug interaction : interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effect of Leukine, such as lithium and corticosteroids, should be used with caution
• carcinogenesis, mutagenesis, impairment of fertility : animal studies have not been conducted with Leukine. It is not known whether Leukine can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Leukine should be given to a pregnant woman only if clearly needed
• pediatric use : safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that Leukine does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with Leukine in clinical trials at doses ranging from 60-1,00 mg/m2/day intravenously and 4-1,500 mg/m2/day sybcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 240 mg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solution containing benzyl alcohol (including Leukine Liquid) or lyophilized Leukine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.
• geriatric use : in the clinical trials, experience in older patients (age > 65 years), was limited to the AML study. Of the 52 patients treated with Leukine in this randomized study, 22 patients with age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy and endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these 2 age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out.
Adverse reactions :
• autologous and allogeneic bone marrow transplantation : Leukine is genrally well tolerated. In 3 placebo-controlled studies enrolling a total of 156 patients after autologous BMT or PBSCT, no significant differences were observed between Leukine and placebo-treated patients in the type or frequency of laboratory abnormalities reported in at least 10% of patients, including renal and hepatic parameters. In some patients with preexisitn renal or hepatic dysfunctions enrolled in uncontrolled clinicl trials, administration of Leukine has induced elevation of serum creatinine or bilirubin and hepatic enzymes. In addition, there was no significant difference in relapse rate and and 24 months survival between the Leukine and placebo-treated patients. In the placebo-controlled trial of 109 patients after allogeneic BMT, there were no significant differences in the incidence or severity of GvHD, relapse rates and survival between the Leukine and placebo-treated patients. Adverse events reported in at least 10% of patients observed for the patients treated with Leukine in the historically controlled BMT failure study were similar to those reported in the placebo-controlled studies. In additions, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with Leukine in the graft failure study. In uncontrolled phase I/II studies with Leukine in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills, and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other unfrequent events reported were dyspnea, peripheral edema, and rash. Reports of events occurring with marketed Leukine include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities. In patients with preexisting edema, capiary leak syndrome, pleural and/or pericardial effusion, administration of Leukine may aggravate fluid retention. Body weight and hydration status should be carefully monitored during Leukine administration. Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.
• AML : nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Leukine and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Leukine group. No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Leukine- and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate. In a historically controlled study of 86 patients with AML, the Leukine treated group exhibited an increased incidence of weight gain (p = 0.007), low serum proteins and prolonged prothrombin time (p=0.02), when compared to the control group. 2 Leukine treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the bone marrow which reversed when Leukine was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), an neurocortical hemorrhagic events (p=0.025).
• overdosage : the maximum amount of Leukine that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mg/kg/day (4,000 mg/m²/day or 16 times the recommended dose) were administered to 4 patients in a phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, anusea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Leukine. In case of overdosage, Leukine therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
• molgramostim (Europe and Canada) : nonglycosylated protein produced in Escherichia coli with isoleucine at position 100. It contains 127 amino acids and has a molecular weight of 14,477 daltons; it appears to be associated with greater toxicity in clinical trials
• Leucomax^® (since 1991) source : Genetics Institute, Schering-Plough, Madison, NJ and Sandoz, E.Hanover, NJ (formerly Novartis) => Essex Italia => Novartis, Basel, Switzerland or Novartis-Pharma, Nürnberg, Germany => Schering-Plough
• Mielogen^®; source : Schering-Plough, Madison, NJ
• Te'erli^®
Schedule :
• for cancer immunotherapy to reduce severity of neutropenia : 5 to 10 mg/kg per day administered s.c.. Treatment should be initiated 24 hours after the last dose of chemotherapy and continued for 7 to 10 days. Dosing may be initiated at 5 mg/kg a day (300 mg per vial into 1.0 mL of diluent)
• for myeloid recovery after BMT : 10 mg/kg per day administered by i.v. infusion (reconstituted molgramostim solution must be further diluted in 25 mL, 50 mL or 100 mL infusion bags or bottles of either normal saline solution or 5% dextrose in water. The number and the strength of lyophilized powder vials required must be such that the above infusion admixture solution contains a final concentration of molgramostim > 7 mg/mL. The resulting infusion solution is stable for at least 24 hours when stored at refrigeration) over 4 to 6 hours, beginning the day after BMT, and being continued until the ANC is >= 1000/mm³.
The maximum duration of treatment is 30 days. It should not be used in patients with myeloid malignancies
Side effects : the most frequently reported undesirable effects across all indications were fever, nausea, dyspnoea, diarrhoea, rash, rigors, injection site reaction (with s.c. administration), vomiting, fatigue, anorexia, musculoskeletal pain and asthenia. Less frequently reported events include: non-specific chest pain, stomatitis, headache, increased sweating, abdominal pain, pruritus, dizziness, peripheral oedema, paraesthesia and myalgia. Serious reactions, which occurred rarely in clinical trials, include: anaphylaxis, bronchospasm, cardiac failure, capillary leak syndrome, cerebrovascular disorders, confusion, convulsions, hypotension, cardiac rhythm abnormalities, intracranial hypertension, pericardial effusion, pericarditis, pleural effusion, pulmonary oedema and syncope; development of exacerbation of autoimmune diseases. Since dosing with Leucomax has been associated with a decrease in serum albumin, drugs that are highly bound to serum albumin may require dosage adjustment. Animal studies have shown reproductive toxicity. In primate models, administration of molgramostim was associated with foetal death and spontaneous abortion at doses of 6 and 10mcg/kg a day. In all patient groups, the most frequently occurring changes in laboratory values were decreased platelet count, decreased haemoglobin level, and decreased serum albumin level. The causal relationship of these changes to Leucomax cannot be determined definitively. Increased eosinophil counts (absolute and percent) have also been observed. The frequency of antibodies that bind to molgramostim, measured by ELISA and bioassay, was determined to be 1% post treatment. No loss of activity of Leucomax was evident in these patients. In some patients receiving therapeutic doses of 20 or 30mcg/kg per day, tachycardia, hypotension and a flu-like syndrome have been observed; these symptoms abated quickly upon symptomatic treatment.
In a study of the kinetics of response, the effect of a single dose of molgramostim usually appeared within 1 to 4 hours and reached its peak within 6 to 18 hours after initiation of dosing. Results of a dose-response study in cynomolgus monkeys utilising i.v. bolus injections of molgramostim for 5 consecutive days indicate that maximal response can be achieved at 15mcg/kg a day. Molgramostim has also been shown to increase the WBC count in a leucopenic cynomolgus monkey treated previously with cyclophosphamide. Studies in rats showed that radioactivity was extensively distributed following i.v. administration of 125I-rHuGM-CSF. The drug appeared to be rapidly metabolised and excreted. The pharmacokinetic profiles of molgramostim were similar in monkeys, healthy male volunteers and patients. After s.c. doses of 3, 10 or 20mcg/kg and after i.v. doses of 3 to 30 mcg/kg, increases in the total area under curve (AUC) were dose-related. Maximum molgramostim serum concentrations were reached in 3 to 4 hours after s.c. administration. Molgramostim had an elimination half-life of 1 to 2 hours after i.v. administration and of 2 to 3 hours after s.c. administration. The slightly longer half-life observed after s.c. administration is probably due to prolonged absorption from the injection site.
• regramostim produced in Chinese hamster ovary (CHO) cells (fully glycosylated)
• ecogramostim (Leucotropin^®; source : Cangene) : nonglycosylated protein produced in Streptomyces lividans
Indications :
• in patients receiving chemotherapy, the administration of G-CSF can lessen the incidence and severity of neutropenia, and in some settings, it can reduce the mortality rate.
• HSC mobilization from the bone marrow into the peripheral blood has represented an important advance in HSCT^ref. As compared with transplantation of bone marrow cells, the use of G-CSF–mobilized stem cells that originate in the peripheral blood reduces the duration of neutropenia after the administration of the myeloablative preparatory regimen and the need for platelet and red-cell transfusions, reducing both the need for hospitalization and costs. However, the value of the use of the cytokine in recipients of stem-cell transplants to further shorten the duration of neutropenia has not been established^ref.
• primary prophylaxis against neutropenia : recommended only if the risk of febrile neutropenia historically exceeds 40% for the planned chemotherapeutic protocol^ref. Of the 200 most commonly used chemotherapeutic protocols, only 12 are associated with a risk of febrile neutropenia > 20%^ref. In populations in which the risk is > 40%, such as patients 65 years of age or older who are undergoing aggressive chemotherapy for lymphoma, patients with small-cell carcinoma of the lung or uroepithelial tumors, and patients of any age who have received chemotherapy for acute myelogenous leukemia, G-CSF therapy has proved effective in avoiding the risk of severe neutropenia^{ref1, ref2}
• secondary prophylaxis in patients with solid tumors who have had chemotherapy-induced febrile neutropenia and who continue to receive intensive chemotherapy, if a dose reduction will impair the antitumor response.
• the administration of G-CSF to patients with congenital neutropenia or cyclic neutropenia has revolutionized the care of children with these disorders, since these conditions were usually fatal before the advent of recombinant G-CSF. The number of neutrophilic progenitor cells is severely reduced in both conditions as a result of mutations of the neutrophil elastase gene^ref. Administration of G-CSF increases neutrophil levels substantially, allowing these children to remain free of life-threatening infections. Despite this progress, G-CSF has been found to increase the risk of acute myelogenous leukemia in patients with congenital neutropenia. Before recombinant G-CSF was available for clinical use, there were occasional reports of acute myelogenous leukemia or myelodysplasia in patients with congenital neutropenia who survived infancy. Since the introduction of G-CSF, patients with congenital neutropenia live longer, but a malignant myeloid disorder develops in approximately 10%^ref. The gene for the G-CSF receptor in the malignant bone marrow cells from these patients usually displays a somatic mutation that eliminates one or more growth inhibitory signals^ref, akin to the truncation in the EPOR in patients with familial erythrocytosis^ref. Therefore, it is likely that the administration of G-CSF to patients with congenital neutropenia selects for cells with a mutation in the G-CSF receptor that enhances the proliferation of myeloid cells.
Side effects : the use of G-CSF in patients undergoing chemotherapy has been linked to an increased risk of treatment-related acute myeloid leukemia. Initially, the increased risk was seen only after therapy with topoisomerase II inhibitors^ref, but more recent studies indicate that patients treated for breast cancer with cyclophosphamide and doxorubicin may have an increased risk of t-MDS/t-AML if they have also received G-CSF^ref. What might explain this association? Chemotherapy given for a specific cancer may induce otherwise lethal mutations in a myeloid stem cell or progenitor cell, but the antiapoptotic effect of G-CSF saves the mutant cell from destruction, thereby allowing it to develop into a myeloid cancer. Clearly, additional study is necessary to clarify the risk of AML in patients who receive G-CSF chemotherapy and to determine the mechanism of the association
• M-CSF (-mostim) : mirimostim is currently in phase I-II clinical trial to enhance macrophage fuction (systemic route)^ref
• Leukoprol^®
• Macrolin^®; source : Chiron and Cellular Products
• Macstim^®; source : Genetics Institute and Schering-Plough
• caristim ?
• pegcaristim ?
• conjugates of 2 different types of colony-stimulating factors (-distim) : milodistim
• FGF-2 / bFGF
• FGF-7 / KGF : palifermin (Kepivance^®; source : Amgen). The efficient, de novo, thymic-dependent production of naïve T cells takes place within a stromal microenvironment composed of a complex network of epithelial cells and humoral factors. High-dose irradiation may severely disrupt the structured milieu that is necessary for reconstitution of the immune system and development of a functional T-cell repertoire. Recently, several groups have approached the problem of diminished immune reconstitution through the use of KGF, to stimulate recovery of the radiation or chemotherapy-damaged thymic epithelium^{ref1, ref2, ref3}. KGF is produced by thymic epithelial cells in both the cortical and medullary regions. KGFR (FGFR2IIIb) is expressed on TECs and in turn, TECs respond in vitro to KGF and support thymocyte survival^{ref1, ref2, ref3, ref4}. Mice that are lacking either FGF10 or the FGFR2 splice variant have significant defects in thymopoiesis, hypoplastic thymic tissue and impaired thymic epithelial cell development^{ref1, ref2}. The rationale for use of KGF is further enhanced by the fact that IL-7 is produced by a subset of TECs and IL-7 is required for normal thymopoiesis^{ref1, ref2, ref3}. The literature documents the treatment efficacy of KGF in various murine models of bone marrow transplant in which KGF is administered prior to BMT. However, there are no published reports of KGF administered therapeutically in models of radiation- or chemotherapy-induced myelo- and immune-suppression. KGF has been shown to protect epithelial cells from chemotherapy or radiation-induced injury^{ref1, ref2}. Subsequent studies demonstrated that pretreatment of mice with KGF ameliorated GvHD and manifestations of idiopathic pneumonia following intensive chemotherapy-induced conditioning and alloBMT^{ref1, ref2} (Sorensen DK, Bond VP, Cronkite EP, Perman V. An effective therapeutic regimen for the hemopoietic phase of the acute radiation syndrome in dogs. Radiation Res. 1960;13: 669–685). Pretreatment with KGF reduced GVHD-induced weight loss as well as lesions in the skin and lungs of the long-term survivors resulting in significantly reduced morbidity and mortality (Sorensen DK, Bond VP, Cronkite EP, Perman V. An effective therapeutic regimen for the hemopoietic phase of the acute radiation syndrome in dogs. Radiation Res. 1960;13: 669–685). Blazar’s group extended these early studies and further demonstrated that KGF reduced GVHD, by mechanisms independent of repair of the conditioning-induced injury^ref. Murine GVHD could be ameliorated in the absence of conditioning in SCID recipients of allo T cells. KGF could be administered prior to (3-day course) or after (7-day course) T cell transfer with no difference in survival although the posttreatment schedule promoted higher body weights. Blazar and Weinberg extended these studies by determining the ability of KGF pretreatment to enhance immune reconstitution via its restorative/protective effect on TECs and consequent production of intrathymic IL-7^ref. In this report, the KGF-treated BMT recipients showed enhanced thymopoiesis and increased numbers of functional peripheral T cells. Furthermore, KGF pretreatment increased thymopoietic capacity of mice after congenic or alloBMT and after any of 5 different conditioning regimens that differed in radiation dose or cytotoxic therapy. Compared to PBS controls, KGF-treated groups had significantly increased thymic cellularity following radiation doses of 650, 1000, or 1400 cGy. KGF treatment increased thymocytes measured at 28 days after BMT by 3-fold over controls^ref. Of significant note is the fact that a brief course of KGF pretreatment sustained the rise in cellularity of the thymus for at least 3 months after BMT. These differences in cellularity were due to an increase in donor-derived thymocytes, not from survival of radiation-resistant host thymocytes. Increased production of TEC-derived intrathymic IL-7 was suggested as the mechanism of KGF-induced post-BMT immune reconstitution. The KGF-treated mice had an increased frequency of intrathymic cells expressing IL-7 transcripts. Min et al^ref substantiated this effect by analyzing the response to KGF treatment in IL-7^-/- mice. They noted that the thymuses of either PBS- or KGF-pretreated IL-7^-/- mice were hypocellular and consisted of only 20% donor-derived thymocytes. This suggests that IL-7 production by TECs is required for the observed effects of KGF on post-BMT thymopoiesis and immune reconstitution. Although the utility of pretreatment with KGF would be reserved for emergency first responders in the radiation accident scenario, its noted efficacy in BMT models and knowledge of its mechanism of action suggest its significant potential as a therapeutic.
• FGF-10 / KGF-2 : repifermin is an epithelial mitogen that reduces level or ROS by activating NRF-2^ref
• TNF-a : tasonermin (Beromun^®; cloned in Escherichia coli; source : Boehringer Ingelheim, Austria) is currently in phase III clinical trials to induce tumour-cell apoptosis and activate endothelium and granulocytes (systemic route)^ref. TNF-a may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. A study assessed the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. IHC analysis 2 hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens^ref. Chemotherapeutic drugs were tested alone and in combination with NGR-TNF (0.1 ng) in murine lymphoma, fibrosarcoma, and mammary adenocarcinoma models. Different administration schedules have been tested and the effects on tumor growth, animal weight, tumor perfusion, and cell cytotoxicity have been investigated. Pretreatment with NGR-TNF enhanced the response to all these drugs although to a different extent. The increased efficacy was not accompanied by increased toxicity at least as judged from the loss of animal weight. The synergistic effect was transient, maximal synergism being observed with a 2-hour delay between NGR-TNF and drug administrations in all models and with all drugs tested. NGR-TNF did not increase the in vitro cytotoxicity of chemotherapeutic drugs against tumor cells, suggesting that the in vivo synergism depends on NGR-TNF effects on host cells rather than on tumor cells^ref. Currently, NGR-TNF is being tested in clinical studies. Targeted delivery of low doses of NGR-TNF to the tumor vasculature can increase the efficacy of various drugs acting via different mechanisms. Optimal administration schedule requires 2 hours of pretreatment with NGR-TNF independently from the mechanism of drug cytotoxicity^ref.
• PDGF-BB : becapermin (Regranex^®; cloned in Saccharomyces cerevisiae; source : Chiron Corp, USA)
• TNFSF10 / TRAIL induces tumour-cell apoptosis (pending)^ref
• FLT3L is currently in phase I-II clinical trial to stimulate dendritic-cell and NK-cell function (systemic route)^ref. The pleiotropic FL acts at very early stages of hematopoietic and lymphoid development and appears essential in the development of a murine stem cell subset toward lymphoid-restricted progenitors in vivo and in vitro^{ref1, ref2, ref3, ref4}. Furthermore, FL, through its action on dendritic cell expansion, may augment antigen-driven peripheral T cell homeostasis^ref (Fry TJ, Sinhn M, Thomas EK, et al. Flt3 Ligand: a potential new immunorestorative agent [abstract]. Blood 2001;98:735a). Fry et al, utilizing FL in rodent models of BMT in both thymectomized and euthymic recipients, suggested that FL is capable of enhancing both thymic-independent homeostasis and thymopoietic pathways for T cell restoration (Fry TJ, Sinhn M, Thomas EK, et al. Flt3 Ligand: a potential new immunorestorative agent [abstract]. Blood 2001;98:735a). Additional studies using a class of engineered proteins called progenipoietins emphasized the potential of combination therapy^ref. Progenipoietin, a chimeric composed of both flt-3 and G-CSFR agonists, administered after high-dose myelosuppressive irradiation significantly enhanced neutrophil recovery over that noted with FL or G-CSF monotherapy. The combined administration of FL and G-CSF was as effective in enhancing neutrophil recovery as progenipoietin. These data suggest that the combination of FL and one of the granulocyte CSFs—G-CSF, GM-CSF, or peg-G-CSF—would be effective in stimulating both neutrophil and immune recovery after severe, high-dose irradiation. To evaluate the effects of Pichia pastoris secreted rhFL on the growth of mouse EL-4 lymphoma and C26 colon adenocarcinoma injected in syngeneic mice, mice were placed into one of two treatment groups. 2 x 10(5) EL-4 or C26 cells were injected subcutaneously (SC.) into mice on day 0. Group 1 received subcutaneous PBS injections from Day -7 to Day 14 and group 2 received subcutaneous rhFL injections at 30 microg/day from Day -7 to Day 14. Serial tumor areas were measured. On Day 22, mice from each group were sacrificed, and weight of tumors and spleens were evaluated. Data analysis used Student t tests. Pichia pastoris secreted rhFL resulted in tumor growth delay for both EL-4 lymphoma and C26 colon adenocarcinoma compared with control (P < 0.01). Tumors from rhFL-treated mice were smaller (P < 0.01) than controls while spleens larger (P < 0.01) than controls. Histological examination of tumor sections revealed an obvious increase in regions composed largely of infiltrating cells in the rhFL-treated tumors. Infiltrating cells could be detected in clusters among tumors from mice treated with rhFL whereas these cells were only occasionally detected in sections of control tumors. Treatment of rhFL expressed from Pichia pastoris resulted in an antitumor response against EL-4 and C26 tumors injected in syngeneic mice^ref.
• CCL19 : in a murine model of spontaneous bronchoalveolar cell carcinoma. These transgenic mice (CC-10 TAg) express the SV40 large T antigen under the Clara Cell promoter, develop bilateral, multifocal, pulmonary carcinomas and die at 4 months owing to progressive pulmonary tumour burden. To mimic therapy in late-stage disease, 3-month-old transgenic mice were treated with recombinant CCL19 (0.5 mg/dose) by intranodal (axillary lymph node region) injection three times per week for 4 weeks. CCL19 treatment led to a marked reduction in tumour burden with extensive mononuclear infiltration of the tumours compared to diluent treated controls. Flow cytometric analyses showed significant increases in CD4 and CD8T cell subsets as well as DC in the lungs of CCL19-treated mice. Lung tissue cytokine profiles showed a shift towards immune stimulatory molecules with a decrease in the immunosuppressive cytokine TGF-b. CCL19 may serve as a potential immune stimulator and provide a strong rationale for the evaluation of CCL19 in cancer immunotherapy^ref
• XCL1 / lymphotactin is currently in phase I clinical trial to enhance T-cell recruitment (local route)^ref
• TGF-b₁ inhibits T-cell effector function (pending)^ref
• neuron growth factors :
• CNTF : akokine
• GDNF (brain catheter with gastric pump). It is one of the few therapies for Parkinson's disease that attempts to preserve or pep up fading brain cells, rather than simply treating the symptoms of the disease. Hopes for the treatment soared in 2003 when it was announced that the first 5 people treated with GDNF experienced a dramatic recovery in their movements^ref. Of the 34 people in the study, 4 started producing antibodies to the GDNF protein. Although the patients appeared healthy, this raises fears that the antibodies might go on to trigger a dangerous immune reaction if treatment had continued. In addition, studies in monkeys have found that brain cells in 2 animals given GDNF began to break down.
• thymosin-a₁ : thymalfasin (SC Zadaxin^® and PO SCV-07^® by SciClone, Timosina^® by Sclavo, Tal-HLR^® by Hoffmann La Roche)
• thymopentin : Timunox^®
• lactoferrin : intratumoral injection reduces growth of murine squamous cell carcinoma and fibrosarcoma of the floor of the mouth : support for immunomodulation as a possible mechanism is the lack of any difference between controls and the experimental groups in vitro^ref
• osteoprotegerin (OPG) : for juvenile Paget's disease
To increase the half-life of a cytokine and target its activation specifically to disease sites, latent cytokines can be engineered using the latency-associated protein (LAP) of TGF-b₁ fused via a MMP cleavage site to IFN-b at either its N or C terminus. The configuration LAP-MMP-IFN-b resembles native TGF-b and lacks biological activity until cleaved by MMPs, whereas the configuration IFN-b-MMP-LAP is active. LAP provides for a disulfide-linked shell hindering interaction of the cytokine with its cellular receptors, conferring a very long half-life of 55 h in vivo. Mutations of the disulfide bonds in LAP abolish this latency. Samples of cerebrospinal fluid (CSF) or synovial fluid from patients with inflammatory diseases specifically activate the latent cytokine, whereas serum samples do not. Intramuscular injection in arthritic mice of plasmid DNA encoding these constructs demonstrated a greater therapeutic effect of the latent as compared to the active forms^ref.
Degrakine : fusion protein of a chemokine with the C terminal region of the HIV-1 protein Vpu (which physiologically has CD4 proteolytic targeting capability). The degrakine accumulates in the ER, trapping and functionally inactivating its target chemokine receptor(s) (CKR) via the host proteasome machinery.
• hormone replacement therapy (HRT) / endocrine, hormonal or hormone therapy / endocrinotherapy / hormonotherapy : see Homo sapiens physiology - Endocrinology
• organotherapy / Brown-Séquard's treatment : the treatment of disease by the administration of animal endocrine organs or their extracts
• glucagon (Glucagen^® (source : Novo Nordisk, Denmark), Glucagon^®) is used as a hypotonizing drug before small bowel enema
• GLP-1 is rapidly inactivated by dipeptidyl peptidase (DPP)-IV, limiting its therapeutic potential, although therapeutic effects can be shown when the peptide is administered by continuous infusion : so conjugation to albumin has been proposed. Albumin is a 67-kDa protein with 19-day half-life in humans, and albumin-binding of GLP-1 slows its absorption following subcutaneous administration, resulting in steady blood concentrations.
• fatty acid binding moiety :
• liraglutide (source : Novo Nordisk, Denmark) has completed phase 2 clinical trials and is now in phase III clinical trial. The compound has 97% homology with GLP-1, is released slowly from the injection site^ref. After a single injection the half-life of liraglutide is 11–15 h, with a decrease in glucagon, an increase in insulin, and lowering of 24-h glucose profiles in persons with type 2 diabetes following once-daily administration^ref. After 12 weeks of administration, HbA1c levels decrease to a similar extent to that seen with sulfonylureas but with weight loss rather than weight gain^ref. An important question for study is whether liraglutide reaches the same CNS binding sites as GLP-1. Liraglutide reduces blood glucose in a glucose-dependent manner, without effect in mice not expressing the GLP-1 receptor. When injected twice daily in a mouse model, the agent stimulates islet proliferation, again mimicking biological actions of GLP-1. Studies reported at the meeting suggested that liraglutide will be an effective therapeutic agent. Nauck et al. (abstract 356) administered 2 mg liraglutide s.c. daily versus placebo for 5 weeks in 144 persons with type 2 diabetes receiving 1 g metformin twice daily, leading to a 1.1% fall in HbA_1c. Compared with metformin plus glimepiride, patients treated with metformin plus liraglutide had a 2.9-kg greater weight decrease and a 22-mg/dl greater fall in fasting blood glucose. In an obese rat model using candy feeds, over 12 weeks, body weight decreased with liraglutide in association with a decrease in candy, but not chow, intake but did not show significant change with the DPP-IV inhibitor LAF237.
• covalent binding to albumin :
• CJC-1131, which is currently in phase 2 clinical trials, was developed by the research company ConjuChem based on their DAC (drug affinity construct) technology, leading to decreased clearance. The drug is not prebound to albumin before injection but binds covalently to endogenous albumin. A modification of the second COOH-terminal amino acid from L- to D-alanine renders the peptide resistant to DPP-IV, while not blocking binding to the GLP-1 receptors or reducing activation of GLP-1 receptor–dependent signal transduction pathways in vitro. After a single injection, the half-life is 10 days. In CJC-1131–treated persons with type 2 diabetes, evidence of a dose-response reduction was shown in a 7-point glycemic profile, with evidence of body weight reduction in animal models and in the human studies. CJC-1131 administered daily to 22 persons with type 2 diabetes for 14–20 days shows a dose-dependent lowering of fasting and postprandial glucose levels and a weight decrease. There is no evidence of immunogenicity of CJC-1131 after administration of 2 doses separated by 6 weeks.
• Albugon is a molecule covalently bound to albumin produced by the company Human Genome Sciences, exhibiting similar effects to those seen with exendin-4, although with less potent in vitro activation of the GLP-1 receptor. After intravenous or subcutaneous injection, albugon has a half-life of 11 h in mice and 2–4 days in cynomolgus monkeys. In the mouse model, it mimics the biological action of GLP-1 in decreasing glucose and glucagon and increasing insulin levels, and the molecule can be shown to act via the pancreatic GLP-1 receptor. Although less potent than exendin-4, there is definite effect in inhibiting gastric emptying in the mouse model, with no effect seen in mice lacking the GLP-1 receptor. These studies demonstrate that these larger albumin-bound molecules are able to access the neuronal pathways. Intraperitoneal albugon reduced food intake in the model, again without effect in mice lacking the GLP-1 receptor, with both albugon and exendin-4 increasing brainstem c-Fos in a similar fashion targeting the area postrema, further suggesting exhibition of at least some CNS effects similar to those of GLP-1. In response to a question regarding antibody production, Baggio noted that this has been shown in some patients treated with exendin-4, although not appearing to affect activity, and has not been shown at this point with either liraglutide or CJC-1131.
• islet amyloid polypeptide (IAPP) / amylin : pramlintide acetate (Symlin^®; source : Amylin Pharmaceuticals Inc.) for type 1 diabetes mellitus and type 2 diabetes mellitus
• insulin^ref : a protein corresponding to insulin elaborated in the human pancreas, derived from pork insulin by enzymatic action that changes its amino acid sequence or produced synthetically by recombinant DNA techniques (normally it aggregates into hexamers in subcutis, but absorbed only when dissociated in dimers or monomers). Human insulins have a more rapid onset and shorter duration of activity than pork insulins. 1 international insulin unit (IU) : 45 mg of the pure crystalline product of insulin, now adopted as the standard. Indications : type 1 diabetes mellitus and type 2 diabetes mellitus

	trade name	retardant	onset (hrs)	peak (hrs)	duration (hrs)
rapid- or short-acting insulin  insulin injection / regular human insulin (RHI) : a rapid-acting insulin with an approximate time of onset of 1 hour and duration of action of 6–8 hours, consisting of crystalline bovine or porcine insulin dissolved in a clear fluid prompt insulin zinc suspension : a rapid-acting insulin with an approximate time of onset of 1 hour and duration of action of 14 hours, consisting of bovine or porcine insulin modified by the addition of zinc chloride to produce a suspension of amorphous insulin	Actrapid HM®	zinc and neutral buffer solution	20-30 minutes	2-4	5-8
	Humulin R® (cloned in Escherichia coli; source : Eli Lilly & Co, USA)  NovoInsulin® (cloned in Saccharomyces cerevisiae; source : Novo Nordisk, Denmark)  Novorapid® (source : Novo Nordisk, Denmark)
	Bioinsulin R®
intermediate-acting insulin : globin zinc insulin injection : an approximate time of onset of 2 hours and duration of action of 18 hours, consisting of bovine or porcine insulin reacted with zinc chloride and globin I (from bovine hemoglobin) to form a protein complex from which insulin is slowly released; now rarely used. isophane insulin suspension / neutral protamine Hagedorn (NPH) insulin :  time of onset about 2 hours after injection and duration of action of 24 hours, consisting of bovine or porcine insulin reacted with zinc chloride and protamine to form a protein complex with a ratio of free and bound insulin isophane insulin human suspension : insulin human reacted with zinc protamine sulfate to form a protein complex consisting of insulin human, protamine, and zinc. lente insulin / insulin zinc suspension : an approximate time of onset of 2 hours and duration of action of 24 hours, consisting of a stable mixture of prompt and extended insulin zinc suspensions yielding a 7:3 ratio of crystalline (ultralente) to amorphous (semilente) insulin in acetate buffer	Humulin I®	zinc and protamine in phosphate buffer	1-1.5 (1.5-3.0)	2-10 (6-12)	18-20
	Protaphane HM®
	Bioinsulin I®
	Humulin L®	zinc and acetate buffer	1.5	4-10	24
	Monotard HM®		2.5	7-15	22
biphasic (insulin preparations with a predetermined proportion of intermediate-acting insulin mixed with short- or rapid-acting insulin) 10/90 20/80 30-70 insulin : a combination of 30% regular insulin + 70% NPH insulin 40/60 50-50 insulin : a combination of 50% regular insulin + 50% NPH insulin 75% NPH insulin/25% insulin lispro / 3-to-1 insulin : a combination of regular insulin and protamine zinc insulin, having the activity of 3 parts of the former and 1 part of the latter	Actraphane®		0.5	1-7	14-16
	Humulin®
	Bio-Insulin®
ultrarapid-acting (replaces post-prandial incretion; lower risk of late hypoglycemia)	lispro (ILP) (Humalog®) : inversion between Pro28 and His29 on the insulin B chain reduces aggregation; cloned in Escherichia coli; source : Eli Lilly & Co, USA; available in Italy since November 1997)		5 minutes	1	2-4
	aspart (Novolog®, NovoRapid® outside USA; source : Novo Nordisk)
slow-acting insulin : an insulin preparation whose onset of action is more than 3 hours after injection and peak of action is between 10 and 30 hours after injection : protamine zinc insulin suspension : a long-acting insulin with time of onset about 7 hours after injection and duration of action of 36 hours, consisting of bovine or porcine insulin reacted with zinc chloride and protamine to form a protein complex from which insulin is slowly released. extended insulin zinc suspension : a long-acting insulin with time of onset about 7 hours after injection and duration of action of 36 hours, consisting of bovine or porcine insulin in the form of large zinc-insulin crystals. extended insulin human zinc suspension : a long-acting insulin consisting of insulin human reacted with a zinc salt to produce zinc-insulin crystals	Ultratard HM®		4	8-24	28
	Humulin U®
	Bioinsulin U®
long-acting insulin (replaces basal incretion)	glargine (Lantus®; addition of Arg in B31 and B32 (=> pI moves from 5.4 to 6.7) and Asp=>Gly in A21 (=> stable hexameric form); cloned in Escherichia coli; source : Aventis Pharma, Germany)	protamine zinc	1	no	23
	insulin detemir (Levemir™) : an amino acid is replaced with a fatty acid which binds to plasma albumin

Insulin is commercially available in concentrations of 100 or 500 units/ml (designated U-100 and U-500, respectively; 1 unit equals 36 µg of insulin). U-500 is only used in rare cases of insulin resistance when the patient requires extremely large doses. U-500, insulin lispro, insulin aspart, insulin glargine, and 75% NPL/25% insulin lispro require a prescription. Insulin preparations are sometimes formulated individually for use in infants (e.g., U-10) with diluents provided by the manufacturer. In these instances, special care must be taken to ensure that the correct dose of the diluted insulin is administered with an ordinary insulin syringe. Different types and species of insulin have different pharmacological properties. Human insulin is preferred for use in pregnant women, women considering pregnancy, individuals with allergies or immune resistance to animal-derived insulins, those initiating insulin therapy, and those expected to use insulin only intermittently. Insulin type and species, injection technique, insulin antibodies, site of injection, and individual patient response differences can all affect the onset, degree, and duration of insulin activity. Changing insulin species may affect blood glucose control and should only be done under the supervision of a health professional with expertise in diabetes. Human insulin manufactured using recombinant DNA technology is replacing insulin isolated from pigs. Future availability of animal insulin is uncertain. Pharmacists and health care providers should not interchange insulin species or types without the approval of the prescribing physician and without informing the patient of the type of insulin change being made. If an individual is admitted to a hospital, the type of insulin he or she has been using should not be changed inadvertently. If there is doubt about the principal species, human insulin should be administered until adequate information is available. When purchasing insulin, the patient should make sure that the type and species are correct and that the insulin will be used before the expiration date. In the event that a patient’s specific brand of insulin is temporarily unavailable, the same insulin formulation from another manufacturer may be substituted. Changing insulin types (e.g., long, intermediate, short, and rapid acting) from one formulation to another should always be done under medical supervision. The patient should be fully informed as to the reason for any change in insulin and the potential need for additional glucose monitoring.
• storage : vials of insulin not in use should be refrigerated (- 4°C). Extreme temperatures (<36 or >86°F, <2 or >30°C) and excess agitation should be avoided to prevent loss of potency, clumping, frosting, or precipitation. Specific storage guidelines provided by the manufacturer should be followed. Insulin in use may be kept at room temperature to limit local irritation at the injection site, which may occur when cold insulin is used. The patient should always have available a spare bottle of each type of insulin used. Although an expiration date is stamped on each vial of insulin, a loss in potency may occur after the bottle has been in use for >1 month at RT, especially if it was stored at room temperature. The person administering insulin should inspect the bottle before each use for changes (i.e., clumping, frosting, precipitation, or change in clarity or color) that may signify a loss in potency. Visual examination should reveal rapid- and short-acting insulins as well as insulin glargine to be clear and all other insulin types to be uniformly cloudy. The person with diabetes should always try to relate any unexplained increase in blood glucose to possible reductions in insulin potency. If uncertain about the potency of a vial of insulin, the individual should replace the vial in question with another of the same type.
• mixing insulin : administration of mixtures of rapid- or short- and intermediate- or long-acting insulins will produce a more normal glycemia in some patients than use of a single insulin. The formulations and particle size distributions of insulin products vary. On mixing, physicochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately. When rapid-acting and ultralente insulins are mixed, there is no blunting of the onset of action of the rapid-acting insulin. A slight decrease in the absorption rate, but not the total bioavailability, is seen when rapid-acting and NPH insulin are mixed. In clinical trials, however, the postprandial blood glucose response was similar when rapid-acting insulin was mixed with either NPH or ultralente. Mixing of short-acting and lente insulins is not recommended, except for patients already adequately controlled on such a mixture. Upon mixing, Zn²⁺ present in lente insulins) (e.g., lente and ultralente) will bind with the short-acting insulin and delay its onset of action. The degree and rate of binding varies with the ratio and species of the 2 insulins; binding equilibrium may not be reached for 24 h. Phosphate-buffered insulins (e.g., NPH insulin) should not be mixed with lente insulins. Zinc phosphate may precipitate, and the longer-acting insulin will convert to a short-acting insulin to an unpredictable extent. Mixing of insulins should follow these guidelines:
• patients who are well controlled on a particular mixed-insulin regimen should maintain their standard procedure for preparing their insulin doses.
• no other medication or diluent should be mixed with any insulin product unless approved by the prescribing physician.
• insulin glargine should not be mixed with other forms of insulin due to the low pH of its diluent.
• use of commercially available premixed insulins may be used if the insulin ratio is appropriate to the patient’s insulin requirements.
• currently available NPH insulin and rapid-acting insulin formulations when mixed may be used immediately or stored for future use.
• rapid-acting insulin can be mixed with NPH insulin, lente, and ultralente.
• when rapid-acting insulin is mixed with either an intermediate- or long-acting insulin, the mixture should be injected within 15 min before a meal.
• mixing of rapid-acting and lente insulins is not recommended except for patients already adequately controlled on such a mixture. If rapid-acting and lente mixtures are to be used, the patient should standardize the interval between mixing and injection.
• phosphate-buffered insulins (e.g., NPH insulin) should not be mixed with lente insulins.
• insulin formulations may change; therefore, the manufacturer should be consulted in cases where its recommendations appear to conflict with the American Diabetes Association guidelines.
Routes of administration :
• s.c. injections : syringes : conventional insulin administration involves subcutaneous injection with syringes marked in insulin units. There may be differences in the way units are indicated, depending on the size of the syringe and the manufacturer. Insulin syringes are manufactured with 0.3-, 0.5-, 1-, and 2-ml capacities. Several lengths of needles are available. Blood glucose should be monitored when changing from one length to another to assess for variability of insulin absorption. Regulations governing the purchase of syringes vary greatly from one state to another. Many different medical devices have been developed to reduce the risk of needle sticks and other sharps injuries using current OSHA standards. These devices incorporate features designed to reduce injury. Use of some currently available insulin syringes with engineered sharps injury protection (ESIP) may present barriers to effective insulin self-administration training. Use of a device for training that is different from the device to be used in practice is inconsistent with teaching/learning principles, and may compromise the success of the training process. Individualized patient assessment should guide the use of an ESIP insulin syringe during insulin self-administration instruction. (See AADE, Diabetes Educ 28:730, 2000). Syringes must never be shared with another person because of the risk of acquiring a blood-borne viral infection. Travelers should be aware that insulin is available in a strength of U-40 outside of the U.S. To avoid dosing errors, syringes that match the concentration of U-40 insulin must be used.
• disposal : recapping, bending, or breaking a needle increases the risk of needle-stick injury and should be avoided. Insulin syringes and pens, needles, and lancets should be disposed of according to local regulations. Some areas may have special needle disposal programs to prevent sharps from being in the main waste disposal stream. When community disposal programs are unavailable, used sharps should be placed in a puncture-resistant container. Local trash authorities should be contacted for proper disposal of filled containers. Care should be taken to keep these filled containers away from containers to be recycled. In areas with container-recycling programs, placement of containers of used syringes, needles, and lancets with materials to be recycled is prohibited.
• needle reuse : manufacturers of disposable syringes and pen needles recommend that they only be used once. One potential issue, which arises with reuse of syringes or needles, is the inability to guarantee sterility. Most insulin preparations have bacteriostatic additives that inhibit growth of bacteria commonly found on the skin. Nevertheless, syringe/needle reuse may carry an increased risk of infection for some individuals. Patients with poor personal hygiene, an acute concurrent illness, open wounds on the hands, or decreased resistance to infection for any reason should not reuse a syringe or pen needle. Another issue has arisen with the advent of newer, smaller (30 and 31 gauge) needles. Even with one injection, the needle tip can become bent to form a hook which can lacerate tissue or break off to leave needle fragments within the skin. The medical consequences of these findings are unknown but may increase lipodystrophy or have other adverse effects. Some patients find it practical to reuse needles. Certainly, a needle should be discarded if it is noticeably dull or deformed or if it has come into contact with any surface other than skin. If needle reuse is planned, the needle must be recapped after each use. Patients reusing needles should inspect injection sites for redness or swelling and should consult their healthcare provider before initiating the practice and if signs of skin inflammation are detected. Before syringe reuse is considered, it should be determined that the patient is capable of safely recapping a syringe. Proper recapping requires adequate vision, manual dexterity, and no obvious tremor. The patient should be instructed in a recapping technique that supports the syringe in the hand and replaces the cap with a straight motion of the thumb and forefinger. The technique of guiding both the needle and cap to meet in midair should be discouraged, because this frequently results in needle-stick injury. The syringe being reused may be stored at room temperature. The potential benefits or risks, if any, of refrigerating the syringe in use or of using alcohol to cleanse the needle of a syringe are unknown. Cleansing the needle with alcohol may not be desirable, because it may remove the silicon coating that makes for less painful skin puncture.
Extreme subcutaneous insulin resistance (SIR) is a rare syndrome characterized by severe resistance to subcutaneous insulin with normal intravenous insulin sensitivity. Its pathophysiology is unknown, though an increased insulin degrading activity has been suggested. Regarding treatment, surgical implantation of an intraperitoneal insulin pump appears to be the best solution^ref
• syringe alternatives : insulin can be given with jet injectors that inject insulin as a fine stream into the skin. These injectors offer an advantage for patients unable to use syringes or those with needle phobias. A potential advantage may be a more rapid absorption of short-acting insulin. However, the initial cost of these injectors is relatively high, and they may traumatize the skin. They should not be viewed as a routine option for use in patients with diabetes. Several pen-like devices and insulin-containing cartridges are available that deliver insulin subcutaneously through a needle. In many patients (e.g., especially those who are neurologically impaired and those using multiple daily injection regimens), these devices have been demonstrated to improve accuracy of insulin administration and/or adherence. Low-dose pens that can deliver insulin in half-unit increments are also available. Insulin delivery aids (e.g., nonvisual insulin measurement devices, syringe magnifiers, needle guides, and vial stabilizers) are available for people with visual impairments. Information about these products is available in the American Diabetes Association’s annual diabetes resource guide.
• injection technique :
• dose preparation : before each injection, the insulin label should be verified to avoid injecting an incorrect insulin. The hands and the injection site should be clean. For all insulin preparations, except rapid- and short-acting insulin and insulin glargine, the vial or pen should be gently rolled in the palms of the hands (or shaken gently) to resuspend the insulin. An amount of air equal to the dose of insulin required should first be drawn up and injected into the vial to avoid creating a vacuum. For a mixed dose, putting sufficient air into both bottles before drawing up the dose is important. When mixing rapid- or short-acting insulin with intermediate- or long-acting insulin, the clear rapid- or short-acting insulin should be drawn into the syringe first. After the insulin is drawn into the syringe, the fluid should be inspected for air bubbles. One or two quick flicks of the forefinger against the upright syringe should allow the bubbles to escape. Air bubbles themselves are not dangerous but can cause the injected dose to be decreased.
• injection procedures : injections are made into the subcutaneous tissue. Most individuals are able to lightly grasp a fold of skin, release the pinch, then inject at a 90° angle. Thin individuals or children can use short needles or may need to pinch the skin and inject at a 45° angle to avoid intramuscular injection, especially in the thigh area. Routine aspiration (drawing back on the injected syringe to check for blood) is not necessary. Particularly with the use of insulin pens, the needle should be embedded within the skin for 5 s after complete depression of the plunger to ensure complete delivery of the insulin dose. Patients should be aware that air bubbles in an insulin pen can reduce the rate of insulin flow from the pen; underdelivery of insulin can occur when air bubbles are present, even if the needle remains under the skin for as long as 10 s after depressing the plunger. Air can enter the insulin pen reservoir during either manufacture or filling if the needle is left on the pen between injections. To prevent this potential problem, avoid leaving a needle on a pen between injections and prime the needle with 2 units of insulin before injection. If an injection seems especially painful or if blood or clear fluid is seen after withdrawing the needle, the patient should apply pressure for 5–8 s without rubbing. Blood glucose monitoring should be done more frequently on a day when this occurs. If the patient suspects that a significant portion of the insulin dose was not administered, blood glucose should be checked within a few hours of the injection. If bruising, soreness, welts, redness, or pain occur at the injection site, the patient’s injection technique should be reviewed by a physician or diabetes educator. Painful injections may be minimized by the following:
• injecting insulin at room temperature.
• making sure no air bubbles remain in the syringe before injection.
• waiting until topical alcohol (if used) has evaporated completely before injection.
• keeping muscles in the injection area relaxed, not tense, when injecting.
• penetrating the skin quickly.
• not changing direction of the needle during insertion or withdrawal.
• not reusing needles.
Some individuals may benefit from the use of prefilled syringes (e.g., the visually impaired, those dependent on others for drawing their insulin, or those traveling or eating in restaurants). Prefilled syringes are stable for up to 30 days when kept in a refrigerator. If possible, the syringes should be stored with the needle pointing upward or laying flat, so that suspended insulin particles do not clog the needle. The predrawn syringe should be rolled between the hands before administration. A quantity of syringes may be premixed and stored. The effect of premixing of insulins on glycemic control should be assessed by a physician, based on blood glucose results obtained by the patient. When premixing is required, consistency of technique and careful blood glucose monitoring are especially important.
• injection site : insulin may be injected into the subcutaneous tissue of the upper arm and the anterior and lateral aspects of the thigh, buttocks, and abdomen (with the exception of a circle with a 2-inch radius around the navel). Rapid-acting insulin have to be injected  in abdomen one-hand far away from umbilicus (too vascularized) > in lateral external part of arms, thigh, hips (inaesthetism). Intermediate- and slow-acting insulins have to be injected in buttocks. Injection site has to be displaced by 1 cm every day. Intramuscular injection is not recommended for routine injections (syringe or pen needle has to be 8 mm long as i.m. injections would cause hypoglycemia). Rotation of the injection site is important to prevent lipohypertrophy or lipoatrophy due to autoimmune reactions. Rotating within one area is recommended (e.g., rotating injections systematically within the abdomen) rather than rotating to a different area with each injection. This practice may decrease variability in absorption from day to day. Site selection should take into consideration the variable absorption between sites. The abdomen has the fastest rate of absorption, followed by the arms, thighs, and buttocks. Exercise increases the rate of absorption from injection sites, probably by increasing blood flow to the skin and perhaps also by local actions. Areas of lipohypertrophy usually show slower absorption. The rate of absorption also differs between subcutaneous and intramuscular sites. The latter is faster and, although not recommended for routine use, can be given under other circumstances (e.g., diabetic ketoacidosis or dehydration).
• other considerations : whenever possible, insulin should be self-administered by the patient. In the case of children, the proper age for initiating this depends on the individual developmental level of the child as well as family and social circumstances. It should not be delayed beyond adolescence. In the case of the visually impaired, mechanical aids are available to ensure accuracy. Where this is insufficient, the syringes may be prefilled periodically by a relative, friend, home health aide, or visiting nurse and the dose may be self-injected. The latter strategy can also be applied to some individuals with borderline dexterity or arithmetical skills. For patients who are completely independent in insulin administration, it is still advisable to have a family member knowledgeable in the technique in case of emergency.
• patient management
• dosing : the appropriate insulin dosage is dependent on the glycemic response of the individual to food intake and exercise regimens (up to 40 IU). For virtually all type 1 patients and many type 2 patients, the time course of insulin action requires 3 or more injections per day to meet glycemic goals. Type 1 patients and some type 2 patients may also require both rapid- or short- and longer-acting insulins. A dosage algorithm suited to the individual’s needs and treatment goals should be developed with the cooperation of the patient. The timing of the injection depends on :
• blood glucose levels
• food consumption
• physical exercise increases blood flow and accelerates absorption from exercised areas
• skin thickness
• environmental temperature (hot baths, ...)
• smoking
• local massagetypes of insulin used. Variables in insulin action (e.g., onset, peak, and duration) must be considered. Rapid-acting insulin analogs should be injected within 15 min before a meal (30-40' in obese) or immediately after a meal. The most commonly recommended interval between injection of short-acting (regular) insulin and a meal is 30 min. Eating within a few minutes after (or before) injecting short-acting insulin is discouraged because it substantially reduces the ability of that insulin to prevent a rapid rise in blood glucose and may increase the risk of delayed hypoglycemia. Guidelines should be set by the physician for the suggested interval between insulin injection and meal time based on factors such as blood glucose levels, site of injection, and anticipated activity during the interval.
• self-monitoring : whenever possible, insulin-using patients should practice self-monitoring of blood glucose (SMBG). Insulin dosage adjustments should be based on blood glucose measurements. SMBG is extremely valuable in patients who take insulin because they experience day-to-day variability in blood glucose levels. This variability is influenced by differences in insulin absorption rates, insulin sensitivity, exercise, stress, rates of food absorption, and hormonal changes (e.g., puberty, the menstrual cycle, menopause, and pregnancy). Illness, traveling, and any change in routine (e.g., increased exercise and a different diet during vacation) may require more frequent SMBG under the guidance of a physician. Travel through >= 3 time zones requires special advice regarding insulin administration. During illness, it is important that insulin be continued even if the patient is unable to eat or is vomiting. When accompanied by hyperglycemia, a positive urine or blood test for ketones during illness indicates a need for extra, not less, insulin. Health professionals should obtain information regarding blood glucose values whenever patients need assistance in handling illness or stress.
• hypoglycemia : excess insulin is a common cause of hypoglycemia. Hypoglycemia may also result from a delayed or missed meal, decreased carbohydrate content of a meal, increased physical activity, or increased insulin absorption rates (e.g., as a result of increased skin temperature due to sunbathing or exposure to hot water). All insulin-requiring individuals should be instructed to carry at least 15 g carbohydrate to be eaten or taken in liquid form in the event of a hypoglycemic reaction. Family members, roommates, school personnel, and coworkers should be instructed in the use of glucagon in those with type 1 for situations when the individual cannot be given carbohydrate orally. All insulin users should carry medical identification (e.g., a bracelet or wallet card) that alerts others to the fact that the wearer uses insulin.
• intravenous (i.v.) administration in diabetic ketoacidosis or hyperosmolar hyperglycemia
• intraperitoneal (i.p.) administration to simulate hepatic first-pass effect
• nasal insufflations : inhaled insulin (INH) / HMR 4006 (Exubera^®; source : Pfizer, Sanofi-Aventis and Nektar Therapeutics (formerly Inhale Therapeutic Systems)). The rationale behind developing a pulmonary drug delivery system is to ensure that insulin powder is delivered deep into the lungs, where it is easily absorbed into the bloodstream, in a hand-held inhalation device. The device converts the insulin powder particles into an aerosol cloud for the patient to inhale. No propellants are used. The inhaler requires no power source and the clear chamber ensures that the patient knows immediately when all the insulin has been inhaled^ref. Early studies have shown promising results, and it has been demonstrated that the onset of action of inhaled insulin is faster than that of regular human insulin (RHI), resembling that of rapid-acting insulin analogs^{ref1, ref2, ref3, ref4, ref5}. RHI has several disadvantages when its use for controlling prandial glycemia is considered. A relatively slow onset of action and a prolonged duration of action results in a suboptimal time-action profile^ref. In addition, subcutaneous insulin injections are often considered inconvenient and cause anxiety for many patients^ref. Inhaled insulin may be a viable alternative to prandial insulin administration for patients with diabetes because of its more favorable pharmacokinetic profile and less invasive route of administration^ref. The assumed relative efficacy is 10% (i.e., 1 mg INH = 3 IU subcutaneous insulin).  Side effect : turbinate hypertrophy, low absorption during rhinitis
• pulmonary inhalation has absorption lower than s.c. route
• pumps for continuous subcutaneous insulin infusion (CSII) : as with any drug or medical device, professional staff and people with diabetes must be aware of the nature of insulin-pump therapy and its special requirements and be prepared to manage this therapy. Ideally, CSII therapy should be prescribed, implemented, and followed by a skilled professional team familiar with CSII therapy and capable of supporting the patient. Experience with insulin-pump therapy indicates that candidates for CSII must be strongly motivated to improve glucose control and willing to work with their health care provider in assuming substantial responsibility for their day-to-day care. They must also understand and demonstrate use of the insulin pump, self-monitoring of blood glucose, and use of the data so obtained. In many people, CSII or multiple insulin injections can provide equivalent improvements in control. Whereas some clinicians recommend CSII only when 3 or 4 daily injections fail to provide euglycemia, others consider CSII indicated for motivated patients whose daily schedule makes conventional therapy less effective. An insulin pump may provide great lifestyle flexibility, particularly with regard to meal schedules and travel but may be too demanding for some individuals. CSII can help improve metabolic control during pregnancy. The preferred meal planning approach used with patients on CSII is carbohydrate counting or carbohydrate equivalents. Factors to be considered in choosing an insulin pump should include safety features, durability, availability of service by the manufacturer, ability of the supplier to provide training, ease of use, clinically desirable features, and cosmetic attractiveness to the user. The nontechnical person may not be able to adequately evaluate the safety and dependability of the engineering of a new pump, so prescribers are cautioned to recommend or use pumps with field-proven reliability. Rapid-acting insulin analogs (such as lispro) are appropriate insulins for insulin infusion pumps. The stability of these insulins in pumps has been confirmed. Use of mixtures of insulins in pumps has not been evaluated and therefore is not recommended. 2 controlled trials demonstrated improved postprandial glucose control with rapid-acting insulin as compared to short-acting insulin (regular) when delivered immediately before a meal by CSII. Rapid-acting insulin analogs are not approved for use in pregnancy. Pump therapy is as safe as multiple-injection therapy when recom-mended procedures are followed. Potential complications peculiar to pump therapy, however, must be explained to users. Undetected interruptions in insulin delivery may result in ketotic episodes more often and more quickly with CSII, which is of particular concern in pregnancy. Infections or inflammation at the needle site may also complicate CSII therapy but can be minimized by careful hygiene and frequent site changes. Hypoglycemia can occur in pump users as with conventional treatments^{ref1, ref2, ref3, ref4}.
• NanoPump^® is a tiny silicon array on the skin in which dozens or hundreds of tiny, hollow pyramids, are set, barely detectable by the naked eye
Schemes of administration :
• intensive insulin therapy (to treat IDDM, gestational diabetes, unstable DM, or before surgery; therapeutical endpoints : fasting glycemia < 120 mg/dL, postprandial glycemia < 160 mg/dL, no ketonuria, HbA_1c < 7%) : biphasic insulin before breakfast (15%), lunch (30%), and dinner (30%), and intermediate-acting insulin before bedtime (25%). 4 self-checks a day under routine conditions
• conventional or nonintensive insulin therapy (to treat complicated diabetes, uneducated patients, elderlies, low insulin requirements; therapeutic endpoints : HbA_1c < 9%) : 30/70 biphasic insulin before breakfast and lunch. Number of controls = number of injections + 20% a day
Dosages :
• patients within 20% of IBW without infections or instability = 0.5-1 IU/kg/day, doubled during stresses, reduced (0.2-0.6 IU/kg/day) during relative remission in initial stages (moon wedding)
• 1 IU is enough to metabolize 15 g of carbohydrates introduced p.o. => 0.8-1.2 IUs/10 g carbohydrates ingested
• algorithms for adjustment of insulin dosage by patients who monitor blood glucose^ref
• preprandial modifications
• anticipatory
• compensatory (after the meals)
• glycemia < 50 mg/dl : reduce regular insulin by 2-3 IUs; delay injection until moment immediately preceding the beginning of the meal; include at least 10 g of fast-available carbohydrates in the meal
• glycemia = 50-70 mg/dl : reduce regular insulin by 1-2 IU; delay injection until moment immediately preceding the beginning of the meal
• glycemia = 70-130 mg/dl : intake the prescribed dose of preprandial regular insulin
• glycemia = 130-150 mg/dl : increase the preprandial dose of regular insulin by 1 IU
• glycemia = 150-200 mg/dl : increase the preprandial dose of regular insulin by 2 IUs
• glycemia = 200-250 mg/dl : increase the preprandial dose of regular insulin by 3 IUs; delay the meal by 15 minutes (45 minutes after injection)
• glycemia = 250-300 mg/dl : increase the preprandial dose of regular insulin by 4 IU; delay the meal by 20-30 minutes (40-60 minutes after injection)
• glycemia = 300-350 mg/dl : increase the preprandial dose of regular insulin by 5 IU; delay the meal by 20-30 minutes (40-60 minutes after injection). Evaluate urinary ketones. If the increase is moderate-important, increase fluid intake. Recheck glycemia and ketonuria after 2-3 hours
• glycemia = 350-400 mg/dl : increase the preprandial dose of regular insulin by 6 IU. Delay the meal by 20-30 minutes (40-60 minutes after injection). Evaluate urinary ketones. If moderate-important increase, increase fluid intake. Recheck glycemia and ketonuria after 2-3 hours
• glycemia > 400 mg/dl : increase the preprandial dose of regular insulin by 7 IUs. Delay the meal by 30 minutes (50-60 minutes after injection). Evaluate urinary ketones. If moderate-important increase, increase fluid intake. Recheck glycemia and ketonuria after 2-3 hours
• in prevision of abundant meal : increase regular insulin by 1-2 IU
• in prevision of light meal : reduce regular insulin by 1-2 IU
• in prevision of more intense physical activity : intake extra-carbohydrates and/or reduce regular insulin by 1-2 IU
• in prevision of sedentary physical activity : increase regular insulin by 1-2 IU
• correction supplements
• background :
• basal insulin (NPH or glargine) is the main insulin that acts during bedtime. Its effect is reflexted in results of sticks made at mid-night and awakening at the next morning
• the insulin before breakfast (regular or fast analogue) makes its maximal effect between breakfast and lunch. Its effect is reflected expecially in results of sticks before lunch
• the insulin before lunch (regular or rapid analogue) makes its maximal effect between lunch and dinner. Its effect is reflected expecially in results of sticks before dinner
• the insulin before dinner (regular or rapid analogue) makes its maximal effect between dinner and going at bed Its effect is reflected expecially in the results of sticks before going at bed.
• hyperglycemia not explained by diet, insulin or physical exercise
• if glycemia before breakfast is systematically > 130 mg/dl for 3-5 days, increase basal insulin (NPH, glargine bed-time) by 1-2 IUs. Before that verify that the lowest glycemia (around 3-4 a.m.) is > 70 mg/dl
• if glycemia before lunch is systematically > 130 mg/dl for 3-5 days, increase insulin before breakfast (regular insulin, rapid analogue) by 1-2 IUs
• if glycemia before dinner is systematically > 130 mg/dl for 3-5 days, increase insulin before dinner (regular insulin, rapid analogue) by 1-2 IUs
• increase only one component of insulin per time, beginning with the one which affects the first glycemia during daytime.
• hypoglycemia not explained by diet, insulin or physical exercise
• if glycemia before breakfast is < 70 mg/dl or there are proofs of hypoglycemic reactions during bedtime reduce basal insulin (NPH, glargine bed-time) by 1-2 IUs
• if glycemia before lunch is < 70 mg/dl or there is an hypoglycemia between breakfast and lunch, reduce insulin before breakfast (regular insulin, rapid analogue) by 1-2 IUs
• if glycemia before dinner is < 70 mg/dl or there is an hypoglycemia between lunch and dinner, reduce insulin before lunch (regular insulin, rapid analogue) by 1-2 IUs
• if glycemia before going at bed is < 70 mg/dl or there is an hypoglycemia between dinner and going at bed, reduce insulin before dinner (regular insulin, rapid analogue) by 1-2 IUs
• glycemic correction factor :
• 1 IU of lispro or aspart insulin reduces glycemia by 1800/total daily dose (TDD) mg/dl
• 1 IU of regular insulin reduces glucemia by 1500/TDD mg/dl
Side effects : hypoglycemia. Therapy :
• backgrounds :
• hypoglycemia needs to be corrected as soon as possible
• simple carbohydrates in liquid solution increase glycemia in 10-20 minutes
• 15 g of carbohydrates (half a coca-cola, 2 sugar dispensers, 1 fruit juice by 124 ml) increase glycemia by 30-50 mg/dl
• correction of mild hypoglycemia
• intake 15 g of simple carbohydrates
• check the stick after 15 minutes
• if hypoglycemia is not resolved intake additional 15 g of carbohydrates
• check stick again after 15 minutes
• thyroid hormones (thyroid or thyroxine replacement therapy / thyroidotherapy / thyrotherapy)
• L-T₃ : liothyronine sodium (Cytomel^®, Triostat^®)
• L-T₄ : levothyroxine sodium (Eutirox^®, Levoxyl^®, Levothroid^®, Synthroid^®,  ...)
• L-T₃ + L-T₄ : liotrix (Thyrolar^®)
• triiodothyroacetic acid / triac / tiratricol (Triax Metabolic Accelerator^®)
Schedules :
• healthy subjects :
• age < 40 years : 50-75 mg/die = 1.5 mg/kg
• 40 < age < 60 years : 25-50 mg/die
• age > 60 years : 25 mg/dL
• cardiopathics : 12.5-25 mg/dL
• pregnants : + 25-50% of the abovementioned doses
• hematopoietic growth factors (HGF)
• rHu-erythropoietin (EPO)^{ref1, ref2} : In 1906, Carnot (Carnot P, Deflandre C. Sur l'activité hematopoiëtique du sérum au cours de la régénération du sang. C R Acad Sci Med 1906;3:384-6) found that injecting healthy rabbits with serum from anemic animals prompted a rapid increase of erythrocytes in the recipients. The responsible humoral substance was first termed "hemopoietine" and was later named "erythropoietin." In 1957, Jacobson and colleagues^ref identified the kidney as the source of erythropoietin; in 1985, the factor was purified and its gene was cloned, thereby making it available for physiological study and therapeutic use^ref. Approved for use by the Food and Drug Administration in 1989^ref. Erythropoietin or its derivatives have been administered to treat anemia in over 3 million patients worldwide, including those in intensive care units, those about to undergo surgery, and those undergoing therapy for infection with the HIV or HCV^ref
• liver solution / liquid liver extract : a brownish liquid prepared from mammalian livers and containing the soluble thermostable fraction which stimulates hematopoiesis in patients with pernicious anemia
• epoetin is used for recombinant human erythropoietin preparations that have an amino acid sequence identical to the endogenous cytokine, followed by the appropriate Greek letter (spelled out); the words alfa, beta, gamma, etc, are added to designate preparations that differ in the composition and the nature of the carbohydrate moieties
• epoetin alfa (Epogen^®, Eprex^® (cloned in chinese hamster cells; source : Ortho Biotech/Janssen-Cilag; Ortho-Biologics Llc, Puerto Rico), Epoxitin^®, Epypo^®, Erypo^®, Espo^®, Globuren^®, Procrit^®; t_1/2 : 4÷8 hours; 1,000, 4,000, 10,000, 60,000 and 100,000 U formulations) for anemic patients with nonmyeloid malignancies on chemotherapy as hemoglobin plasma levels fall below 12 g/dL. Lower doses in patients with hemodyalsis due to risk of venous access thrombosis. Side effects : antibody-mediated pure red cell aplasia (PRCA)
• epoetin beta (Epogin^®, Marogen^®, NeoRecormon^® (source : Hoffman-La Roche), Recormon^® (cloned in chinese hamster cells; source : Boehringer Mannheim, T/A; Roche Diagnostics)
• epoetin gamma
• epoetin delta (Dynepo™ Gene Activated^® erythropoietin (GA-EPO)) (source : Transkaryotic Therapies (TKT), Inc. and Aventis Pharma). Shire Pharmaceuticals expects to launch the product in Europe in 2006, although patents held by the American biotechnology company Amgen, Inc. may preclude its sale in the USA. Unlike existing forms of pharmaceutical EPO manufactured in cultured animal cells, Dynepo is to be made in cultured human cells. It is therefore expected to have an authentic human form of sialic acid and other oligosaccharide residues. This characteristic may make it a longer-acting product than existing brands, but clinical data have not yet been made public. It should also make Dynepo undetectable in the existing urine test for EPO used to detect doping by athletes.
Schedule : 10,000-40,000 IU/week in 2 or more administrations (usually on Tuesday and Friday)
Indications : HGB < 10 g/dl (clinical indications if HGB = 10-12 g/dl). If HGB increase is < 1 g/dl after 6-8 weeks on therapy, the patient is considered a nonresponder. Discontinue when HGB > 12 g/dl. Monitor sideremia, transferrin saturation and ferritin
• darbepoetin alfa / novel erythropoiesis stimulating protein (NESP) (Aranesp^® SingleJect^® prefilled syringes (cloned in chinese hamster cells; source : Amgen, Inc., USA), Nespo^® SureClick^TM) : a hyperglycosylated analogue of recombinant human erythropoietin with 5 N-linked oligosaccharide chains and 2 times more (16 vs. 8) sialic acid residues, allowing 3.6 times longer serum half-life than epoetin => 10,000-40,000 IU once every 3 weeks. Indications : treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. Contraindications : uncontrolled hypertension. Erythropoietic therapies may increase the risk of thrombotic and other serious events; dose reductions are recommended if the hemoglobin increase exceeds 1.0 g/dL in any 2-week period. The most commonly reported side effects in trials were fatigue, edema, nausea, vomiting, diarrhea, fever, and dyspnea (Glaspy J et al. Novel erythropoiesis stimulating protein (NESP) exhibits a prolonged serum half-life in oncology patients. Proc.Am.Soc.Clin.Oncol. 200; 19:54a, Abstract)
Indications :
• evidence-based guidelines on the use of epoetin in patients with cancer have been published by the American Society of Hematology and the American Society of Clinical Oncology^ref and by the European Organisation for the Research and Treatment of Cancer^ref, and recent studies have reinforced the validity of a treatment threshold of 10 g/dl of hemoglobin. Treatment with epoetin is not risk-free, however. Intensive therapy in patients with head and neck or breast cancer has been associated with hypertension, bleeding, and an increased risk of thrombotic complications^{ref1, ref2}. Conversely, administration of the hormone does not ameliorate anemia in patients with hematologic cancer in whom the blood level of erythropoietin exceeds 500 mIU/ml^ref. Administration of epoetin is effective in patients undergoing myelosuppressive chemotherapy because chemotherapy induces apoptosis in both cancer cells and erythroid progenitors and epoetin blocks apoptosis of the erythroid progenitors^ref.
Side effects :
• induction of angioneogenesis => not recommended for cancer patients
• thrombosis may occur irrespective of an increase in hemoglobin. Recent research indicates that the erythropoietin receptor is expressed in several cancer cell lines, raising the concern of possible stimulation of tumor cell growth by these drugs^ref
• there had been almost no reports of adverse immunologic responses to epoetin for more than a decade, but between 1998 and 2003, antibody-mediated pure red cell aplasia (PRCA) developed in over 200 patients with end-stage renal disease who were treated with one preparation of recombinant erythropoietin^ref.62 Immunosuppressive therapy restored responsiveness to the recombinant hormone in about two thirds of the patients. Although the cause of the antierythropoietin antibodies in this condition continues to be explored, partial denaturation of the erythropoietin probably provoked the immune response
Erythropoietin was initially assumed to be an erythroid-specific hormone, but messenger RNA for erythropoietin and its receptor is readily detectable in neuronal and glial cells of the central nervous system and in the retina^{ref1, ref2}. Moreover, the hormone protects neurons from noxious stimuli^ref and induces the proliferation of neurons after neuronal injury^ref. Preclinical trials have shown that exogenously administered erythropoietin crosses the blood–brain barrier and exerts a protective effect on ischemic neurons. As compared with control treatment, erythropoietin was associated with an improvement in outcome scales and infarct size in experimental stroke^{ref1, ref2} and in a single clinical trial^ref. Should additional clinical studies confirm these results, an important new application for an "erythroid-specific" hormone will become available.
• bone morphogenic protein 7 (BMP7) : osteogenic protein 1 (Op-1 Implant^®; cloned in chinese hamster cells; source : )
• brain natriuretic peptide (BNP) : nesiritide (Natrecor^®; source : Scios) launched in the US for the treatment of acute decompensated congestive heart failure (CHF) (ADHF) in August 2001 and, recently, in Switzerland and Israel
• growth hormone releasing hormone (GHRH) : sermorelin acetate (Geref^®)
• growth hormone (GH) : childhood treatment leading to raised serum concentrations of both GH and IGF-1 has been associated with significant increase in the risk of developing colorectal cancer and Hodgkin's disease.

Human GH :
• somatropin (Serostim^®, Genotropin^® (cloned in Escherichia coli; source : Pharmacia AB, Sweden), Humatrope^® (cloned in Escherichia coli; source : Eli Lilly & Co., USA), Norditropin (source : Novo Nordisk, Denmark), Nutropin^®, Nutropin Depot^®, Saizen^® (cloned in Escherichia coli; source : Laboratories Serono, Switzerland), Scitropin^® (cloned in Escherichia coli; source : Biotechnology General, Israel), Zorbtive^®) for short bowel syndrome (SBS)
• somatrem (Protropin^®) is a derivative of human GH with an additional Met at the N-terminus
The som- prefix and the -bove suffix are required for bovine somatotropin derivates, eg :
• somidobove
• sometribove (Posilac^®)
• somagrebove
The som- prefix and the -por suffix are required for porcine somatotropin derivatives, eg:
• somalapor
• somenopor
• sometripor
• somfasepor
• somatostatin :
• gonadotropin releasing hormone (GnRH) : gonadorelin hydrochloride (Factrel^®) or acetate (Lutrepulse^®), Fertagyl^®
• human chorionic gonadotropin (hCG) : Lepori^©, Pregnyl^©, A.P.L.^©, Profasi^© HP, ...
• luteinizing hormone (LH) and follicle stimulating hormone (FSH) : Pergonal^© 500, Humegon^©, Repronex^©
• menotropins / human FSH / human menopausal gonadotropin : an extract of human postmenopausal urine containing both FSH and LH. In females, it has the property of stimulating growth and maturation of ovarian follicles. In males, it has the properties of maintaining and stimulating testicular Leydig's cells related to testosterone production and of being responsible for full development and maturation of spermatozoa in the seminiferous tubules
• follicle stimulating hormone (FSH) :
• human menopausal gonadotrophin (HMG)
• purified by immunodepletion of LH : urofollitropin / uFSH (Metrodin^©, Fertinex^©)
• immunoconcentrated with mAbs : Metrodin HP^©
• recombinant :
• follitropin a (Gonal-F^©; cloned in CHO cells; source : Laboratories Serono, Switzerland)
• follitropin b (Puregon^© (cloned in CHO cells; source : Organon Netherlands), Follistim^©)
• TSH :
• bovine TSH was used to test thyroid function and to augment the uptake of radioiodine in patients with thyroid cancer. Bovine TSH has been largely abandoned as a clinical agent because of adverse immune reactions.
• recombinant human TSH (rhTSH) (Thyrogen^©) has a specific activity of approximately 4 IU/mg. Thyroid cancer patients who have been treated by thyroidectomy and radioiodine ablation but are at risk of harbouring residual thyroid cancer are candidates for Thyrogen administration to prepare them for whole body iodide scans and serum Tg measurements. In thyroidectomised thyroid cancer patients who are unable to secrete pituitary TSH upon thyroid hormone withdrawal, Thyrogen is the only acceptable method to prepare them for these procedures. Thyrogen has been used on a compassionate basis to prepare patients for radioiodine ablation. rhTSH, in addition to being useful in the management of patients with thyroid cancer, is potentially useful to test thyroid reserve and to aid in thyroid-related nuclear medicine procedures. In the future, TSH analogues that have superagonist or antagonist properties may become available as therapeutic agents.
• leptin crosses the blood-brain barrier and stimulates hypothalamic neurons to secrete GnRH, indicated in hypothalamic amenorrhea
• estradiol : Estrace^®, Estraderm^®, Vivell^®, Alora^®, Estring^®, ...
• natural estrogens
• human estrogens : only estriol can be administered orally (17b-estradiol and estrone have high first-pass effect)
• estradiol matrix patch : Dermestril^®, Tradelia^®, Dermatrans^®, Epiestrol^®, Armonil^®
• conjugated equine estrogens (CEE) (Premarin^®)
• synthetic estrogens
• esterified esters (Estratab^®)
• mixture of conjugated estrogens prepared from plant-derived sources (Cenestin^®) : these are hydrolyzed by enzymes present in the lower gut that remove the charged sulfate groups and allow absorption of estrogen across the intestinal epithelium
• estrone solubilized as the sulfate and stabilized with piperazine : estropipate (Ortho-Est^®, Ogen^®)
Allen-Doisy mouse unit : in the Allen-Doisy test, the least amount of estrogen that causes cornification of vaginal epithelium in a spayed laboratory mouse
• progesterone: Prometrium^®, Crinone^®, Progestasert^®. Side effect : drug-triggered pemphigus.Corner-Allen unit : a unit of activity of progestational agents
• estradiol and progesterone : Prempro^®
• ACTH (sudanophobic unit : the smallest amount of ACTH that will cause the disappearance of the sudanophobic zone of the adrenal cortex in at least 2 of 3 hypophysectomized rats when they are injected morning and evening on 8 consecutive days) : Corticotropin^®, ACTHar^®. Used for West syndrome and Landau-Kleffner syndrome (LKS)
• androstenedione : Androstene-50^®, Androstene-100^®, Androstenedione-100^®, Androforte^®, Androgen^®, Tetrabol^®, Androstene^®, Libidione^®
• androstenediol (5AD-Androstenediol^®, 5 AD^®, Pentabol^®, 5-Androdiol^®, 5-Andro^®, 4-AD^®, Androdiol^®, 4-androstenediol^®, Diol-4^®)
• DHEA : DHEA^®
• testosterone : Anatest^®, Andriol^®, Androderm^®, Androgel^®, Andronate^®, Andropository 100^®, Climacteron^®, Delatest^®, Delatestryl^®, Depotest^®, Everone 200^®, Heifer-aid^®, Histerone^®, LibiGel™ (gel), Opterone™ (SEPA^®) (gel), Synovex-H^®, Testamone-100^®, Testaqua^®, Testex^®, Testoderm^®, Testoderm TTS^®, Testos-100^®, Testrin-P.A.^®, Tostrelle™ (gel), Tostrex™ (transdermal gel), Virilon IM^®
• dihydrotestosterone (DHT) : Stanolone^®, Anabolex^®, Andractrim^®
• 1a,25-(OH)₂-vitamin D₃ / calcitriol :  Calcijex^®, Rocaltrol^® (see also precursors)
• DN-101, a high-dose oral calcitriol formulation (source : Novacea)^ref
• oxytocin (OT) (unit of oxytocin : a USP unit expressing the uterus-stimulating activity of preparations of synthetic oxytocin; 1 unit is approximately equivalent to the strength of 2 mg of pure hormone) : Pitocin^©, Syntocinon^©, ...

Side effects : systemic arterial hypotension, uterine tetany, water intoxication, fetal distress, anaphylactoid reactions
• calcitonin : salmon calcitonin (Calcimar^®, Miacalcin^®, Sical^®, Bionocalcin^®) is 10-fold more potent than natural one in humans
• calcitonin-salmon [rDNA origin] (Fortical^®; Unigene Laboratories, Inc.)  nasal spray for the treatment of osteoporosis in women > 5 years after menopause
• r-parathyroid hormone (PTH) :
• teriparatide / rhPTH (1-34) (Forteo^®)
• ALX 111 / rhPTH (1-84 : full-length) (Preos^®)
• antidiuretic hormone (ADH) / vasopressin (VP) : Diapid Lypressin Injection BP 1993^®, Lypressin Nasal Solution USP 23^®, Neo-Lidocaton TM^®, Postacton^®, Postacton TM^®, Syntopressin^®, Vasopresina^®, Vasopressin^®, Vasopressin TM^®, Vasopressine^®, and Vasopressine^©
• cholecystokinin (CCK)
• secretin
• enzyme replacement therapy (ERT)
• coagulation factors :
• clotting factor VIIa (rFVIIa) : eptacog alfa (activated) : recombinant human
• Niastase^®
• NovoSeven^® (cloned in CHO cells, human plasma- and albumin-free; source : Novo Nordisk, Denmark) : 92% response rate in joint, muscle and mucocutaneous hemorrhages. Most common adverse events are fever (4%), hemorrhage (3%), decreased plasma fibrinogen (2%), hamarthrosis (3%) and hypertension (2%). Patients with DIC, advanced atherosclerotic disease, crush injury, or septicemia may have a potential risk of developing thrombotic events
rFVIIa has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, may also likely be of benefit in providing hemostasis in other (non-approved) situations characterized by profuse bleeding and impaired thrombin generation^ref, such as patients with thrombocytopenia and in those with functional platelet defects^{ref1, ref2}. Additionally, it has been used successfully in a variety of less well-characterized surgical bleeding situations^{ref1, ref2} (Goodnough LT. Treatment of bleeding in the intensive care unit. In Goodnough LT, ed. Recombinant Factor VIIa: Potential Treatment of Critical Bleeding in the Future ICU. Int Care Med. 2002;28:A5) as well as in patients with impaired liver function^ref. To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa usage in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. The decision to use rFVIIa for patients with uncontrolled bleeding continues to be one that is made by individual physicians, assisted by their hospital pharmacotherapeutics or transfusion committees^ref. Recombinant factor VIIa (rFVIIa) dosing policies (Goodnough LT. Recombinant Factor 7a. Washington University Laboratory Medicine Newsletter 2003;9:1–4) :
• currently approved clinical settings :
• patients with factor VIII or IX inhibitor (factor VIII deficiency / hemophilia A / classical or true hemophilia and factor IX / PTC deficiency / hemophilia B / Christmas' disease)
• vigorous bleeding, impending compartment syndrome, or bleeding in critical location: 90 µg/kg q 2–3 hours until patient hemostasis is achieved, then less frequently thereafter.
• persistent bleeding, not life or limb threatening: titrate both dose and interval to obtain adequate hemostasis.
• prior to invasive procedures: 90 µg/kg initially, subsequent doses, interval, and duration of treatment titrated to bleeding risk.
• no signs of bleeding, stable Hgb: rFVIIa not indicated.
• currently nonapproved clinical settings
• qualitative, quantitative platelet disorders and life threatening bleeding unresponsive to platelet transfusion.
• correct coagulopathy and anemia with platelets, FFP, cryoprecipitate, and red cell transfusions.
• administer desmopressin acetate (DDAVP) and e-aminocaproic acid
• dialyze if uremic
• rFVIIa 4.8 mg vial (50–100 µg/kg for 100–50 kg patient). If clinical response, titrate dose and interval to maintain adequate hemostasis.
• prolonged INR requiring rapid reversal in patients receiving oral anticoagulant therapy : one report describes the use of rFVIIa in 7 adult patients with prolonged INR, 3 of whom required surgery. The doses administered ranged from 20 µg/kg to 90 µg/kg, and all patients were reported to have a positive outcome (Deveras RAE, Kessler CM. Recombinant factor VIIa (rFVIIa) successfully and rapidly corrects the excessively high international normalized ratio (INR) and prothrombin times induced by warfarin [abstract]. Blood. 2000;96:638a). These observations indicate that rFVIIa may be used to reverse the effect of warfarin or other vitamin K-antagonist therapy in cases in which the administration of vitamin K alone has been found to be insufficient. Two published reports of 15 total patients treated with rFVIIa for reversal of excessive anticoagulation with coumadin support a dosage of 20 µg/kg, or 1.2 mg for an adult patient^{ref1, ref2}. A recent review of 19 patients with acute warfarin-associated intracranial hemorrhage over this same time period at our institution, who received rFVIIa (30–135 µg/kg) as well as vitamin K (10 mg/D x 3) and FFP (1307 ± 652 mL) for treatment, found that treatment was associated with rapid correction of INR and that single doses appeared safe in this high-risk population^ref
• minimal or no active bleeding
• 10 mg Vitamin K IV or SQ
• life or limb at risk
• 1.2 mg vial rFVIIa (currently available in vials of 1.2 mg, 2.4 mg, and 4.8 mg), and
• FFP 15–20 mL/kg, and
• 10 mg vitamin K, IV infused over 20 minutes
• *20 µg/kg for a 70 kg patient; subsequent doses of rFVIIa indicated for clinical signs of persistent bleeding, not to maintain a normal PT/INR.
• uncontrollable hemorrhage associated with trauma, surgery, and liver failure in patients with acquired hemophilia A
• replace consumed/diluted hemostatic factors with FFP, cryoprecipitate, platelet transfusion, red cell transfusions.
• periodically monitor PT, aPTT, fibrinogen, platelet count, hemoglobin.
• if excessive bleeding continues without apparent response to adequate blood components and no identifiable surgical source has been found, 4.8 mg vial rFVIIa (50–100 µg/kg for 100–50 kg patient). If bleeding does not diminish in 30–60 minutes, consider one more dose or surgical exploration.
• use rFVIIa with caution in patients at increased risk for thrombotic complications:
• after cardiac surgery
• patients with history of coronary artery disease
• patients with history of venous or arterial thrombosis
• patients with disseminated intravascular coagulation (DIC)
• patients on extracorporeal membrane oxygenation (ECMO) or vincristine, doxorubicin, and dexamethasone (VAD)
• patients with cerebral vascular disease : treatment with rFVIIa within 4 hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events^ref.
A hemostatic effect has been demonstrated following the administration of rFVIIa in a limited number of patients after trauma and bleeding^ref (Goodnough LT. Treatment of bleeding in the intensive care unit. In Goodnough LT, ed. Recombinant Factor VIIa: Potential Treatment of Critical Bleeding in the Future ICU. Int Care Med. 2002;28:A5).7 trauma patients treated with rFVIIa after failure of conventional measures to achieve hemostasis^ref reported cessation of diffuse bleeding and correction of abnormal coagulation assays; 3 of the 7 patients died of reasons other than bleeding or of thromboembolism. Anecdotal case reports have been published that describe the successful use of rFVIIa in patients with substantial perisurgical bleeding^ref. A prospective, randomized study of rFVIIa (20 µg/kg or 40 µg/kg) versus placebo perioperatively in 36 patients undergoing radical retropubic prostatectomy found that the cohorts receiving rFVIIa had substantially less median operative blood loss compared to placebo (1235 mL, 1089 mL, and 2688 mL, respectively)^ref. 9 patients with coagulopathy and urgent neurosurgical intervention were reviewed after receiving preoperative rFVIIa (40–90 µg/kg)^ref. Post-rFVIIa coagulation parameters normalized as early as 20 minutes after infusion, with no noted procedural or operative complications. No associated thromboembolic complications were observed. The experience of rFVIIa use in trauma with excessive bleeding as well as in postoperative profuse bleeding, based largely on case reports, indicates a hemostatic effect of rFVIIa given in doses of 20–120 µg/kg. Initial dosage approval for administration is recommended to be a 4.8 mg vial, which for an adult patient is a dose range of 50–100 µg/kg for a body weight range of 100–50 kg. 1-2 administrations seem to be enough to decrease the bleeding significantly. Controlled randomized studies are, however, required to prove any beneficial effect of rFVIIa in these patients.
Patients with impaired liver function : a hemostatic effect of rFVIIa has been proven in a limited number of liver disease patients^ref In one clinical trial, 10 cirrhotic patients whose PT did not correct to within 2 seconds above the control reference value were given three successive dosages of rFVIIa (5, 20, or 80 µg/kg) during a 3-week period in a randomized study^ref. The PT transiently corrected to normal in all 3 dosage groups. A multicenter trial studied 71 patients with advanced liver disease who were undergoing laparoscopic liver biopsy^ref. The patients were randomized to receive one of four doses (5, 20, 80, or 120 µg/kg); 48 (74%) of 65 patients achieved hemostasis within 10 minutes. One thrombotic event and one case of disseminated intravascular coagulation (DIC) were reported, not felt by the authors to be related to rFVIIa therapy. Despite these complications, the authors concluded that laparoscopic liver biopsy can be performed safely and reliably by using rFVIIa in patients in whom the standard procedure might be contraindicated because of coagulopathy.
• congenital factor VII deficiency / Alexander's disease : in a randomized study^ref, 17 FVII-deficient patients were treated with rFVIIa^ref, ranging from 21 to 27 µg/kg based on the dose capable of normalizing the prothrombin time (PT) 15 minutes after injection. The treatment resulted in excellent resolution of all hemarthroses treated. An infant with severe FVII deficiency and massive intracranial hemorrhage was evaluated after administration of rFVIIa at three dose levels: 15 µg/kg, 22 µg/kg, and 30 µg/kg^ref. FVII levels were > 100% between 30 and 180 minutes after each infusion, with mean trough levels above 25% at all 3 dose levels. The recommended dosage at the Transfusion Medicine Service at Washington University for rFVIIa replacement therapy in congenital FVII deficiency is therefore 20 µg/kg.
• factor VII activity > 25%, expectant management except neurologic, cardiothoracic, or ophthalmologic surgery/trauma.
• factor VII activity < 25% and minor trauma/surgery:
• initial treatment: 10–15 mL/kg FFP
• repeat 3–6 mL/kg at 6–8 hour intervals until hemostasis is achieved.
• factor VII activity < 25% and at risk for neuro, cardiothoracic, ophthalmologic bleeding:
• initial treatment: rFVIIa 1.2 mg vial (20 µg/kg for 70 kg patient) q 2 hours until hemostasis is achieved.
• titrate dose and interval to ongoing bleeding risk.
• combined treatment with FFP and rFVIIa at lower doses is a consideration, in patients who can tolerate volume infusions.
Safety : of the > 170,000 standard doses of rFVIIa given after its approval (almost all to patients with hemophilia and inhibitors), only rare (< 1:11,300) thrombotic events have been reported^ref. 5 patients with thromboembolic events have been reported. 6 patients developed acute myocardial infarction in association with rFVIIa treatment. 5 out of the 6 patients were over 70 years old, and 2 hemophilia patients had a history of cardiovascular disease, which also was the case in 2 patients with acquired hemophilia. Cerebrovascular disorders were reported in 4 patients, 3 of whom were more than 55 years old, 1 with hemophilia, and the others having acquired hemophilia. Thrombotic complications have also been reported with rFVIIa therapy in patients without inhibitors to FVIII or FIX. An acute cerebral vascular accident and death occurred in a clinical trial of rFVIIa (90 µg/kg) before and after minor surgery or dental procedures in patients with FXII deficiency^{ref1, ref2}. The last of 10 patients enrolled in an open-label, dose-escalation trial to prevent rebleeding after subarachnoid hemorrhage developed middle cerebral artery thrombosis after receiving rFVIIa^ref. In a high-risk trauma population, 3 of 40 (7.5%) patients who were deemed at high risk for thrombosis developed thrombotic complications after receiving rFVIIa^ref. We reported a patient who had a fatal thrombosis after administration of activated prothrombin complex concentrate (APCC), who had also received 2 doses of rFVIIa > 6 hours earlier, while supported by extracorporeal membrane oxygenation^ref. Because of this experience, we recommend that patients should not receive combination therapy with both APCC and rFVIIa. On the basis of these reports, use of activated factor concentrates should be used with caution in patients with known hypercoagulability (e.g., history of thrombotic complications, established thrombotic disorders like factor V Leiden, antiphospholipid syndrome, etc.) or who have excessive bleeding in the setting of DIC or other states of generalized activation of the hemostatic system (e.g., after cardiac surgery, patients on extracorporeal membrane oxygenation [ECMO] or ventricular assist devices) based on the potential for development of localized or systemic intravascular thrombosis.
Utilization : a review of our transfusion service for 2002 to 2004 indicated that 122 patients received rFVIIa therapy for non-approved indications. The mean dose administered for all of these patients was 8.3 ± 7.7 mg (range 1.2–60 mg) at a mean cost of $7215 per patient. Over this same interval, 8 patients with hemophilia and inhibitors received a mean dose of 75.7 ± 80.8 mg at a mean cost of $60,800 per patient :

series	2002 Jan–June	2002 July–Dec	2003 Jan–June	2003 July–Dec	2004 Jan–June	total
all patients (n)	5	14	26	47	38	130
# of doses	18	45	121	121	78	383
mean total dose (mg) (range) (values expressed as means ± SD with range in parenthesis)	12.2 ± 9.1  (2.4–24)	12.0 ± 12.1  (2.4–48)	21.2 ± 50.5  (2.4–246)	10.4 ± 13.0  (1.2–60)	8.6 ± 13.5  (1.2–84)	12.5 ± 26.0  (1.2–246)
on-label – FVIII Inhibitors (n)	2	0	2	2	2	8
# of doses	9	0	79	12	26	126
mean total dose (mg) (range) (values expressed as means ± SD with range in parenthesis)	14.4 ± 6.8 (9.6–19.2)	-	125 ± 121  (4–246)	57 ± 2.5 (55.2–58.8)	43.2 ± 57.7  (2.4–84.0)	75.7 ± 80.8  (2.4–246)
off-label (n)	3	14	24	45	36	122
# of doses	9	45	42	100	52	248
mean total dose (mg) (range) (values expressed as means ± SD with range in parenthesis)	10.8 ± 11.6  (2.4–24)	12 ± 12.1 (2.4–48)	8.2 ± 4.8  (2.4–24.5)	8.3 ± 8.6  (1.2–60)	6.7 ± 5.2  (1.2–27.6)	8.3 ± 7.7  (1.2–60)

A retrospective review of 40 patients with coagulopathic bleeding in a variety of medical and surgical settings from 13 hospitals in a web-based database (excluding prior history of coagulopathy and trauma patients) who received rFVIIa (15180 µg/kg, with 38 patients receiving fewer than 5 doses) found that 32 (80%) achieved complete (n = 18) or partial (n = 14) cessation of bleeding^ref. Responses occurred in all dose ranges, without any evidence of a dose-response effect; the percentages of complete, partial, or no response were not different at doses of < 70 µg/kg, 70 to 90 µg/kg or > 90 µg/kg. Significantly fewer blood products were administered after rFVIIa therapy. 23 (58%) patients died, reflecting the unstable clinical status of the patients at the decision point for considering rFVIIa therapy.
Response to recombinant factor VIIa (rFVIIa) in each of 3 dose groups as assessed by the treating clinician. Number of patients per group: < 70 µg/kg/dose, n = 14; 70–90 µg/kg/dose, n = 10; > 90 µg/kg/dose, n = 16^ref.

Dose and timing of rFVIIa have yet to be defined in this diverse patient population, and formal prospective trials are needed; in the meantime, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutic or transfusion committees.
• clotting factor VIII/von Willebrand factor complex : for treatment of von Willebrand's disease
• antihemophilic factor (human) (Humate-P^®, Fandhi^®)
• antihemophilic factor (porcine) : a highly purified sterile freeze-dried concentrate of porcine factor VIII:C; it is less antigenic than human factor VIII:C and is used in the treatment of hemophilia in patients with circulatory antibodies to factor VIII:C and in patients with spontaneously acquired inhibitors to human factor VIII:C; administered by intravenous infusion
• solvent detergent treated— factor VIII concentrates are manufactured using combinations of the solvent, tri-n-butyl phosphate (TNBP), with a detergent, such as cholate, Tween 80 (polysorbate), or Triton-X-100, to inactivate lipid-enveloped potential viral contaminants (lipid-enveloped viruses include HIV, HBV, HCV). Alphanate and Koate DVI are solvent-detergent treated using TNBP and Polysorbate 80. Hemofil M and Monarc-M are solvent-detergent treated with TNBP and Triton X-100. A coagulation FIX product (AlphaNine SD) is solvent-detergent treated using TNBP and Polysorbate 80, as is the prothrombin complex concentrate Profilnine SD.
• clotting factor VIII for factor VIII deficiency / hemophilia A / classical or true hemophilia and acquired factor VIII inhibitors
• cryoprecipitated antihemophilic factor : a sterile, frozen concentrate of human antihemophilic factor prepared from the coagulation factor VIII–rich cryoprotein fraction of human venous plasma; used for autologous replacement of factor VIII in patients with hemophilia A, administered intravenously.
• hydrolized porcine : Hyate C^® (source : Porton International, Wrexham, Wales, UK), Vueffe^®ref
• octocog alfa : recombinant human
• Beriate P^®
• Bioclate^®
• Helixate^® (cloned in baby hamster kidney cells; source : Bayer Corp. USA)
• Helixate NexGen^®
• Kogenate^® (cloned in baby hamster kidney cells; source : Bayer Corp. USA)
• Recombinate^® (cloned in CHO cells)
• moroctocog alfa : a deletion rFVIII product that lacks the B domain and contains no albumin stabilizer
• ReFacto^® (cloned in CHO cells; source : Pharmacia AB, Sweden)
• recombinant antihemophilic factor, plasma/albumin-free (Advate^® ; source : Baxter)
• clotting factor IX for factor IX / PTC deficiency / hemophilia B / Christmas' disease
•  nonacog alfa :
• prepared from pooled human plasma and purified with a murine monoclonal antibody : Mononine^® (source : Aventis Behring LLC)
• recombinant human : BeneFix^® (cloned in CHO cells; source : Genetics Institute, Inc., USA)
• Fibrocaps™ (source : Quadrant Healthcare plc) a dry powder mixture of fibrinogen and thrombin for use as a fibrin sealant. A partner is sought to undertake full regulatory development
• non-activated prothrombin complex concentrates (PCC) : Prothromplex-T^®
• activated prothrombin complex concentrates (aPCC) : Autoplex^® or FEIBA^®
• bovine adenosine deaminase (ADA) in ADA-SCID
• b-glucosidase /b-glucocerebrosidase in Gaucher disease :
• alglucerase (Ceredase^®; human placental derived)
• imiglucerase (Cerezyme^®; cloned in CHO cells; source : Genzyme Corporation, USA). Side effects : anaphylactoid reaction to heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase)^ref
• acid a-glucosidase / acid maltase in GSD type IIa : Myozyme^®, Pompase^®, TBD^®
• a-mannosidosis after intravenous administration of lysosomal acid a-mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN^ref
• a-L-iduronidase in mucopolysaccharidosis type I (MPS I) / Hurler-Scheie syndrome : laronidase (Aldurazyme^®)^ref
• iduronate 2-sulfatase (I2S) (source : Transkaryotic Therapies, Inc.) for the treatment of patients with mucopolysaccharidosis II / Hunter syndrome (0.5 mg/kg of I2S on a weekly basis or every other week), improves forced vital capacity by 3.4% and 6-minute walk by 44 m
• arylsulfatase B (ARSB) : galsulfase (Naglazyme^®; source : Biomarin Pharmaceutical, Inc)
• recombinant human a-galactosidase A (r-haGalA) is now available for patients with Fabry disease
• agalsidase alfa produced in a human cell line
• agalsidase beta produced in CHO cells
• phenylketonuria (PKU)^ref
• phenylalanine hydroxylase (PAH)
• phenylalanine ammonia-lyase PAH
• pancreotherapy : therapeutic use of pancreas tissue or of extracts of the pancreas containing digestive enzymes (pancreatic lipase and protease); pancreatic replacement therapy, used in chronic pancreatic insufficiency with malabsorption (chronic pancreatitis and cystic fibrosis)
• conventional (uncoated) : Viokase^®, Cotazym^®, Kuzyme HP^®
• enteric coated : Cotazym-S^®, Pancrease MT 4^®, Pancrease MT 10^®, Pancrease MT 16^®, Creon 5^®, Creon 10^®, Creon 20^®, Ultrase MT 12^®, Ultrase MT 18^®, Ultrase MT 20^®.
• structural protein replacement therapy
• a₁-antitrypsin (AAT) / a₁-antiproteinase / a₁-antiplasmin (Aralast^® (source : Alpha Therapeutic Corporation), Prolastin^® (source : Bayer Corporation), Respitin^® (source : Alpha Therapeutic Corporation)) in pulmonary emphysema and cystic fibrosis
• C1-INH in hereditary angioneurotic edema (HAE)
• recombinant human type VII collagen : injected collagen localized to the basement membrane zone of both types of tissues, is organized into human anchoring fibril structures and reversed the features of dystrophic epidermolysis bullosa (DEB) disease in the DEB skin equivalent^ref
• DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein
• activated protein C (APC), recombinant human (rhAPC) : drotrecogin alfa (activated) (Xigris^®) has antithrombotic (inhibitor of factor Va and factor VIIIa inhibitors), antiinflammatory, and profibrinolytic properties and has been proposed for use in sepsis but clinical trials showed no benefit^ref
• antithrombin III (ATnativ^®, Thrombate III^®) for liver failure
• fibrinogen / factor I for congenital afibrinogenemia
• lactoferrin : bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented. Bovine lactoferrin is considered a promising option in treating oropharyngeal candidiasis^ref
• apoA-I Milano is a variant of apolipoprotein A-I identified in 1970s in 40 individuals in rural Northern Italy's Limone sul Garda in Italy who were healthy despite hyperlipidemia and very low levels of HDL. Intravenous infusion of recombinant apoA-I Milano-phospholipid complexes (ETC-216) for 5 doses at weekly intervals produces rapid regression of atherosclerosis^ref
• replacement therapy with other molecules
• glucuronic acid (Jetepar^®, Ietepar^®) is used as liver detoxicant
• bile acids for gallstone (Ø < 15 mm) dissolution, primary biliary cirrhosis,primary sclerosing cholangitis, cystic fibrosis, cerebrotendinous xanthomatosis.
• chenodeoxycholic acid (CDCA) / chenodiol ==epimerization==> ursodeoxycholic acid (UDCA) / ursodiol (Actigall^®, Urso^® in USA; Urdes^® in Italy; Destolit^®, Urdox^®, Ursofalk^®, Ursogal^® in UK; Ursotan^® in South Africa), originally in the form of bear bile (abundant there vs. only 5% in human bile), now synthetic
• clinical exogenous surfactants (ES)^ref endotracheally for hyaline membrane disease (HMD)
• natural surfactants prepared from mammalian lung : the presence of hydrophobic specific proteins (SP-B and SP-C) provides to natural ES better surface tension properties than artificial ES. The in vitro greater efficacy of natural ES has been confirmed in vivo in experimental models of surfactant deficiency, human pharmacodynamic studies, and comparative clinical trials. Furthermore, the excellent clinical tolerance and harmlessness of natural ES has been firmly established. A meta-analysis of the comparative clinical trials between natural ES and one artificial ES (enrolling as many as 4400 babies treated for HMD) suggests that the use of natural ES compared to this artificial ES significantly reduces the neonatal mortality by 20%^ref
• lavaged bovine lung surfactant (LS) : no longer recommended after the BSE affair
• beractant (Survanta^®, Abbott Ltd, Ross Laboratories, Columbus, OH). This is a modified natural surfactant prepared by lipid extraction of minced bovine lung then addition of DPPC, palmitic acid, and tripalmitin are added to specified concentrations.
• Surfactant TA: Similar to Survanta, it was the first surfactant used clinically. It is made and marketed only in Japan. It is a cow lung minced extract made by Tokyo Tanabe Co (Tokyo, Japan).
• calfactant (Infasurf^® is manufactured for Forest Pharmaceuticals, Inc, St Louis, MO, by ONY, Inc, Amherst NY. It is an chloroform-methanol extract of surfactant obtained from calf lung lavage.
• SF-RI 1 (Alveofact^®, Thomae GmbH, Biberach/Riss, Germany) is a chloroform-methanol extract of surfactant obtained by broncho-alveolar cow lung lavage. This surfactant is widely used in Germany.
• lavaged porcine lung surfactant : poractant alfa (Curosurf^®; Chiesi Farmaceutici, Parma, Italy) is a modified natural surfactant prepared from minced porcine lungs by washing, centrifugation extraction with 2:1 chloroform:methanol, and liquid-gel affinity chromatography. Curosurf was approved by the FDA on November, 1999
• artificial surfactants
• colfosceril palmitate (Exosurf Neonatal^®, Glaxo-Wellcome, Burgwedel, Germany). This surfactant is a synthetic protein-free surfactant that was invented by John Clements. It was the first surfactant approved for clinical use in the United States. It is a protein-free surfactant composed of 85% dipalmitoylphosphatidylcholine (DPPC), 9% hexadecanol, cetyl alcohol, and 6% tyloxapol. Mmarketing of this product is now limited to countries other than the United States.
• pumactant (ALEC^®) Made in England by Britannia, this is a synthetic surfactant composed of DPPC and PG. Marketing is currently suspended because of results summarized below.
• KL-4 is a synthetic surfactant composed of DPPC, palmitoyl-oleoyl phosphatidylglycerol, and palmitic acid combined with a 21 amino acid synthetic peptide that mimics structural characteristics of SP-B. Repeat subunits of one lysine and four leucines form an amphipathic helix.
• rSP-C (Venticute^®, Byk Gulden, Konstanz, Germany) surfactant contains DPPC, PG, and palmitic acid and 2 % rSP-C.
Lipid composition (%, g/g of total lipid) of surfactants :

Estimated average protein composition of surfactants (mg protein/mmol·L^-1 phospholipid) :

In vitro characteristics of surfactant with and without serum inactivation plus or minus polymers in a pulsating bubble surfactometer :

It is delivered endotracheally together with physiological solution.

Copyright © 2001-2005 Daniele Focosi. All rights reserved  |  Terms of use  | Legal notices
About this site  |  Site map  |  Acknowledgements | Open forum  |  Tell a friend about this site  |  Current link partners
 Abbreviations and acronyms  |  Medical terminology  |  Add a link  |  Translate this site into your favourite language  |  Softwares

---