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Pharmacology

Pharmacology of Recombinant or Genetically Engineered Drugs

Kamal Kishore, Pawan Krishan1

Departments of Pharmacy, M.J.P. Rohilkhand University, Bareilly-243 006, Uttar Pradesh, 1Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147 002, Punjab, India

Address for correspondence: Dr. Kamal Kishore; E-mail: [email protected]

ABSTRACT

Recombinant technology or genetic engineering is a modern method used for the synthesis of therapeutic agents. The central theme of recombinant technology is the process of “gene cloning” which consists of the production of a deÞ ned fragment of DNA and its propagation and ampliÞ cation in a suitable host cell. Drugs developed by recombinant technology or genetic engineering are known as biologics, biopharmaceuticals, recombinant DNA expressed products, bioengineered, or genetically engineered drugs. A current list of various products developed by recombinant technology includes , coagulation modulators, enzymes, hormones, , , granulocyte colony-stimulating factors, anti-rheumatoid drugs, and various other agents like TNF, , hepatitis-B , antibodies etc. This article provides general as well as recent pharmacological information on different aspects of recombinant drugs that may be useful for their better understanding by users and health care professionals.

Key words: Biologics, erythropoietin, , interleukins, , thrombolytic enzymes

DOI: 10.4103/0975-1483.55747

INTRODUCTION fragment of DNA and its propagation and ampliÞ cation in a suitable host cell. Recombinant technology was only Drugs developed using living organisms with the help of possible after the discovery of restriction endonucleases, biotechnology or genetic engineering are known as biologics, the enzymes used as cutters for a desired segment[3] of biopharmaceuticals, recombinant DNA expressed genes known as recognition sequences. There are various products, bioengineered, or genetically engineered drugs. other enzymes that have great value in recombinant The recombinant technique was developed by Cohen in technology such as DNA polymerases, ligases, kinases, 1973.[1] The general procedure starts from the identiÞ cation alkaline phosphatases, and nucleases.[4] For thousands of of the gene responsible for the production of the desired years, living microorganisms have been used to produce product. The gene is isolated from human cells and gases, leaven bread, ferment alcoholic liquids, and for other inserted into other carrier or vector cells like bacteria desired by-products, but their use in recombinant DNA (Escherichia coli) or yeast (Saccharomyces cerevisiae, Hansenulla technology is often described as a relatively new science.[5] polymorpha, Pichia pastoris) that proliferate and produce large Recombinant technology, thus, is a new method for the amounts of the desired product.[2] The central theme of development of drugs and other life-saving products that recombinant DNA technology is the process of “gene involves the blending of discoveries in molecular cloning” which consists of the production of a deÞ ned biology, DNA alteration, gene splicing, immunology,

J Young Pharm Vol 1 / No 2 141 Kishore and Krishan. J Young Pharm. 2009;1(2):141-150 and immunopharmacology. Now a days, various human CLASSIFICATION OF RECOMBINANT PRODUCTS diseases are treated with the help of drugs developed by recombinant technology, such as erythropoietin, The following products or biologics are obtained by coagulation modulators, enzymes, hormones, interferons, recombinant or genetic engineering technology: interleukins, granulocyte colony-stimulating factors, anti-rheumatoid drugs, and various other agents like (I) Recombinant erythropoietin (TNF), becaplermin, hepatitis-B Epoetin-α vaccine, antibodies etc. This article provides general as Epoetin-β well as recent pharmacological information on different Epoetin-ω aspects like a brief description of recombinant products, Darbepoetin-α pharmacological actions, mechanism of action, adverse (II) Recombinant blood coagulation modulators effects, doses, contraindications, interactions and (a) Coagulants therapeutic applications. The pharmacological information Factor-VII A of bio-engineered products may be useful for better Factor-VIII understanding by users and professionals in the medical Factor-IX and health-related sciences. (b) Desirudin MANUFACTURING PROCESS FOR RECOMBINANT Drotecogin alfa PRODUCTS (III) Recombinant enzymes (a) Thrombolytic enzymes The following steps are involved in the production of [4] recombinant products: Duteplase Extraction of the DNA from a donor organism and the plasmid from bacteria ↓ Streptase or Cleaved with restriction endonucleases Tenecteplase ↓ Tissue Joined to form a recombinant DNA molecule or vector ↓ (b) Therapeutic enzymes Insert this vector into host cell or expression system Agalsidase beta (E. coli or Yeast) Aeromonas aminopeptidase ↓ Alpha-glactosidase-A Multiplication of recombinant DNA molecules Dornase alpha Imiglucerase or glucocerebrosidase or ↓ alglucerase Formation of clone Laronidase or alpha-L-iduronidase ↓ Galsulfase or N-acetylgalactosamine-4-sulfatase Scale-up (harvesting or fermentation) of cell to produce (IV) Recombinant hormones recombinant drugs (a) Insulin and its analogs ↓ Human insulin PuriÞ cation (centrifugation or Þ ltration) Insulin aspart ↓ Insulin glargine Preformulation Insulin lispro Insulin glulisine ↓ Insulin-like growth factor-I Preclinical studies (animal testing) Insulin-like growth factor-II ↓ (b) and its analogs Clinical studies (human testing) Growth hormone ↓ Growth hormone (ovine) Final product Growth hormone binding protein

142 J Young Pharm Vol 1 / No 2 Pharmacology of recombinant drugs

Growth hormone-20K Recombinant albumin Somatrem Fc puriÞ ed recombinant protein Somatropin Becaplermin Sermorelin Beta- (c) Gonadotropins Bone morphogenetic protein-2 Recombinant follitropin-α Brain-derived neurotrophic factor Recombinant follitropin-β Ciliary neurotrophic factor Recombinant choriogonadotropin Chymosin Follicle-stimulating hormone Endostatin human Luteinizing hormone Enteropeptidase/Enterokinase (d) Other hormones Epidermal growth factors Calcitonin Glucagon Hepatitis-B vaccine (V) Recombinant interferons -2a Inß uenza A, nucleoprotein, recombinant protein Interferon alfa-2b Lung surfactant protein Interferon beta-1a Relaxin Interferon beta-1b TNF Interferon-gamma-1a Recombinant Interferon-gamma-1b α-antitrypsin Interferons-ω Consensus interferon PHARMACOLOGY OF INDIVIDUAL PRODUCTS (VI) Recombinant interleukins -1 alpha Recombinant erythropoietin Interleukin-1 beta [6] Interleukin-2 (aldesleukin) Erythropoietin is a 165 amino acid hormone Interleukin-3 that is synthesized naturally in the kidney and the liver but Interleukin-4 is now prepared by recombinant technology. It stimulates Interleukin-10 erythrocyte formation and is available as epoetin-α, Interleukin-11 () epoetin-β, and darbepoetin-α. Mechanism of action: It Interleukin-13 stimulates proliferation and differentiation of erythrocytes. Interleukin-15 Dose: 5-100 units/ kg/ s.c. or i.v./three times a week. Interleukin-17 Adverse effects: Allergic reaction, deÞ ciency of iron and folic acid, disorientation, encephalopathy, ß u-like symptoms, Interleukin-18 headache, mild hypertension, seizures, and thrombosis. (VII) Recombinant granulocyte colony stimulating Uses: It is preferred in cases of due to AIDS, cáncer factors , chronic renal failure, and anemia in premature babies. It is also useful in hematopoietic disorders and is used to increase the beneÞ ts of autologous blood transfusión. Recombinant blood coagulation modulators Regrasmostim PegÞ lgrastim Coagulants[7] (VIII) Recombinant anti-rheumatoid agents Factor-VII A is a unique hemostatic agent containing Inß iximab 406 amino acids[8,9] that is supposed to activate the extrinsic Adalimumab pathway of the coagulation cascade.[10] Dose: 150- 500 μg/ kg of body weight. Adverse effects: Factor VIIa may cause adverse effects such as pyrexia, hemorrhage, injection site reactions, arthralgia, headache, hypertension, nausea, vomiting, pain, , and rashes. Uses: It is preferred (IX) Miscellaneous agents in cases of hemophilia-A and B, and in patients with Recombinant antibodies congenital and acquired bleeding abnormalities.

J Young Pharm Vol 1 / No 2 143 Kishore and Krishan. J Young Pharm. 2009;1(2):141-150 Factor-VIII is an endogenous glycoprotein coagulating in bleeding, defective homeostasis, trauma, surgical factor that is necessary for blood clotting and hemostasis. procedures, , acute pericarditis, hypoglycemia and It is a cofactor essential for factor IX to activate in hyperglycemia. Dose: 100 mg/i.v. infusion. Adverse effects: the intrinsic pathway. It is a 1438 amino acid peptide that is Alteplase may cause adverse effects like nausea, vomiting, produced in CHO cells. DeÞ ciency of factor VIII causes , , allergy, , intracranial a common inherited bleeding disorder known as hemorrhage, and GIT bleeding. Uses: It is preferred in hemophilia-A.[11,12] ADME: It is administered intravenously; cases of angina pectoris, as an , intravascular its t1/2 is about 12 hours. Dose: 10-50 IU/ kg/ i.v./every thrombosis, ischemic diseases, , 2-3 days. Adverse effects: Factor VIII may cause adverse pulmonary embolism, and to dissolve thrombi. effects like febrile reactions, angioedema, flushing, Urticaria, -headedness, visual disturbances, nausea, Tissue plasminogen activator is Þ brin-selective but does and vomiting. Uses: It is preferred in cases of prevention not activate systemic plasminogen. It is synthesized by of bleeding during surgery in patients with hemophilia-A. recombinant technology and is also obtained from cultured human melanoma cells. Mechanism of action: It induces Factor-IX is a polypeptide containing 415 amino acids; Þ brinolysis of the formed thrombus by preferentially it is a vitamin K-dependent coagulation factor that is activating plasminogen bound to fibrin. Dose: 100 synthesized in the liver or by recombinant technology. mg/i.v ./3 hours. Uses: It is preferred in the treatment of Mechanism of action: Factor IX activated by factor IXa, in deep vein thrombosis. combination with factor VIII, activates factor X to Xa and [16] leads to the conversion of prothrombin to and Streptase or streptokinase is obtained from β-hemolytic the formation of a Þ brin clot. Dose: 75 IU/kg/i.v. infusion. Streptococci group-C. It combines with circulating Adverse effects: Factor IX may cause adverse effects like plasminogen to form an activation complex, which then headache, fever, chills, ß ushing, burning at injection site, causes limited proteolysis of other plasminogen molecules tingling, , lethargy, nausea, and vomiting. Uses: It is to plasmin. Antistreptococcal antibodies present due to the preferred in bleeding conditions such as hemophilia-B. initial dose of streptokinase make a loading dose necessary in the beginning. Mechanism of action: Streptokinase activates Anticoagulants the conversion of plasminogen (profibrinolysin) into Lepirudin[13] and Disirudin[14] are thrombin-inhibiting agents, plasmin (Þ brinolysin), which stimulates the conversion developed by recombinant technology and are also known as of fibrin (insoluble) into fibrin fragments (soluble). derivatives of . Precautions: used cautiously in patients Dose: 250,000 units followed by 100,000 units/hour for with renal failure. Mechanism of action: They directly bind to 1-3 days/i.v. Contraindicated in active internal bleeding, clot-bound and ß uid-phase thrombin. Dose: 30 mg/kg/ i.v./ bleeding diathesis, cerebral tumor. If hemostasis is day. Uses: They are preferred in cases of -induced important, pregnancy, previous cerebrovascular accident, thrombocytopenia and deep vein thrombosis. recent cranial trauma, surgery within ten days, and uncontrolled hypertension. Adverse effects: Streptokinase is a recombinant form of human activated may cause , bronchospasm, hypersensitivity, protein-C used as an anticoagulant and anti-inß ammatory fever, hypotension, and arrhythmias. Uses: It is preferred in agent. Mechanism of action: Inhibition of coagulation by cases of acute arterial thromboembolism, acute myocardial proteolytic inactivation of factors Va and VIIIa. Dose: infarction, acute thrombotic stroke, deep venous 24 mg/kg/h for a maximum of 96 hours. Adverse effects: thrombosis, local in the anterior chamber of Drotrecogin alfa therapy may cause bleeding. Uses: It is the eye, myocardial infarction, and unstable angina. preferred for the treatment of severe sepsis. Urokinase[17] is a proteolytic but not antigenic, Þ brin-selective, Recombinant enzymes thrombolytic, or fibrinolytic agent. It is developed by recombinant technology as pro-urokinase and is also derived Thrombolytic enzymes from the human kidney (is present in urine). It is converted Alteplase[15] is an enzyme that catalyzes tissue plasminogen to urokinase from pro-urokinase upon its binding to Þ brin. to plasmin and is commonly used to prevent clot-related Mechanism of action: It directly converts plasminogen into myocardial disorders. Mechanism of action: It dissolves blood plasmin. Contraindicated in bleeding risks, vascular aneurysm, clots by converting plasminogen into plasmin that digests endocardial thrombi, and allergy to streptokinase. Dose: Þ brin, Þ brinogen, and other proteins. Interactions: Its action 3,00,000 Units/h for 12 hours/i.v. Adverse effects: Urokinase accelerates in combination with heparin. Contraindicated may cause fever, bleeding, GIT bleeding, and hemolytic stroke.

144 J Young Pharm Vol 1 / No 2 Pharmacology of recombinant drugs

Uses: It is preferred in cases like central deep vein an exogenous alpha-galactosidase-A, and catalyzes the thrombosis such as superior vena cava syndrome and hydrolysis of glycosphingolipids including GL-3. Dose: ascending thrombophlebitis. It is also effective in acute 1 mg/kg/i.v. infusion/two weeks for 20 weeks. Adverse coronary thrombosis, myocardial infarction, and multiple effects: Agalsidase beta may cause nausea, vomiting, pulmonary emboli. abdominal pain, abnormal tear secretion, anemia, bradycardia, dizziness, drowsiness, edema, fatigue, fever, Anistreplase[18] or anisoylated plasminogen-streptokinase headache, hypersensitivity reactions, hypertension, injection activator complex is a human plasminogen and site pain, myalgia, palpitation, paraesthesia, proteinuria, streptokinase. The anisoyl group is removed in blood by a tachycardia, tremors, and visual disturbances. Uses: It is hydrolytic deacylation process. Dose: 30 units/i.v. infusion preferred in the treatment of Fabry’s disease. over 2-5 minutes. Adverse effects: Anistreplase may cause hypotension and allergy. Laronidase is an enzyme used for the treatment of non-neurological manifestations of mucopoly Tenecteplase[19] is developed by the recombinant technique saccharidosis-I, a lysosomal storage disorder caused by the and is a mutant of alteplase containing 527 amino acids. It deÞ ciency of alpha-L-iduronidase. Dose: 0.58 mg/kg/ i.v. is more Þ brin-selective and more resistant to plasminogen infusion/once a week. Adverse effects: Laronidase may activator inhibitor-1. It is given as a single bolus injection cause ß ushing, musculoskeletal pain, rashes, headache, and of 30-50 mg. It has a longer t1/2 and greater efÞ cacy. abdominal pain. Uses: It is preferred in non-neurological manifestations of mucopolysaccharidosis-I and to improve Saruplase[20] is a full-length, human, unglycosylated, pulmonary functions. single-chain polypeptide containing 411 amino acids, urokinase type plasminogen activator and also known as Dornase alpha[23] is an enzyme prepared from Chinese prourokinase. It is obtained by recombinant technology hamster ovary cells. It is a 260 amino acid, phosphorylated, from E. coli. It is a Þ brin-speciÞ c Þ brinolytic agent and is glycosylated, recombinant human deoxyribonuclease-1 effectively used for the treatment of thrombotic disorders (rhDNase) or is a genetically engineered product of a such as acute myocardial infarction. Dose: 20 mg/i.v. naturally occurring human enzyme that breaks extracellular bolus followed by a 60 mg infusion for 60 minutes. Uses: deoxyribonucleic acid or DNA. It is useful in the treatment It is preferred in thrombotic disorders and myocardial of cystic Þ brosis. Pharmacological actions: It reduces mucous infarction. viscosity in cystic Þ brotic patients. Mechanism of action: Cleaves extracellular DNA and reduces sputum viscosity. Precautions: Therapeutic enzymes[21] Breast feeding mothers. Dose: 2.5 mg/OD or BD/inhaled by Imiglucerase[22] is administered as enzyme replacement nebulizer. Adverse effects: Dornase alpha may cause chest pain, therapy in Gaucher’s disease, a familial disorder affecting conjunctivitis, laryngitis, pharyngitis, rashes, urticaria, and voice mainly the liver, spleen, bone marrow, and lymph nodes changes. Uses: It is preferred in the treatment of cystic Þ brosis. due to the deÞ ciency of beta-glucocerebrosidase activity, leading to the accumulation of glucocerebrosidase Recombinant hormones in many body tissues. It improves hematological abnormalities, hepatosplenomegalia and quality of life Insulin and its analogs[24] in patients of Gaucher’s disease. Mechanism of action: It Insulin is a protein hormone produced by the β-cells of catalyzes the hydrolysis of glucocerebrosidase to glucose the Islets of Langerhans of the pancreas. It regulates the and ceramide. Dose: 60 units/kg/i.v. infusion/two weeks. metabolism of carbohydrates, fats, and proteins. Lack Adverse effects: Imiglucerase may cause abdominal cramps, of insulin or resistance to its action may causes diabetes angioedema, diarrhea, dizziness, fatigue, fever, ß ushing, mellitus. It lowers the blood glucose concentration by headache, hypotension, nausea, vomiting, tachycardia, increasing the uptake of glucose into tissues, enhancing and urticaria. Uses: It is preferred in the treatment of glycogen synthesis from glucose, and inhibition of Gaucher’s disease. glyconeogenesis. Sources of insulin: Human insulin is prepared by enzymatic modiÞ cation of porcine insulin Agalsidase beta is an enzyme used for the treatment of or by recombinant technology using Escherichia coli. Routes Fabry’s disease; a lysosomal storage disorder caused by a for insulin administration: Intraperitoneally, implants, oral, deÞ ciency of alpha-galactosidase, leading to progressive nasal, rectal, and inhalation. Insulin delivery devices: External accumulation of glycosphingolipids, particularly GL-3 artiÞ cial pancreas, implantable pumps, insulin pumps, in many body tissues. Mechanism of action: It provides insulin syringes, jet injectors, and pen devices. Mechanism

J Young Pharm Vol 1 / No 2 145 Kishore and Krishan. J Young Pharm. 2009;1(2):141-150 of action: Insulin interacts with insulin receptors located on women)-Recombinant follitropin-α and follitropin-β, the liver and the fat cells, and enhances the transport of (iii) Urofollitropin or menotropin (Pure FSH), and (iv) glucose from the blood into cells by increasing the activity Human chorionic gonadotropin (obtained from urine of of glucose transporters. ADME: Insulin is administered pregnant women). Recombinant choriogonadotropin-α and subcutaneously, degraded by proteolytic enzymes in the luteinizing hormone. Uses: They are preferred in reproductive liver, kidney, and muscles, and its t1/2 is 5-9 min. Interactions: endocrinology, to restore fertility in males and females, and Alcohol and β-blockers produce a synergistic hypoglycemic diagnosis of pregnancy, time of ovulation and several male effect. Contraindicated with β-blockers which mask the and female reproductive disorders. hypoglycemic effect in diabetic patients who are on insulin therapy. Adverse effects: Insulin may cause hypoglycemia, local Follicle-stimulating hormone[27] is secreted from the irritation, local hypertrophy, hypersensitivity, and weight anterior pituitary under the inß uence of the hypothalamic gain or obesity. Uses: It is preferred in diabetes due to gonadotropin-releasing factor. It is mainly released in the pancreatic disease, diabetes, ketoacidosis or diabetic coma, Þ rst phase of the menstrual cycle wherein it induces the hyperkalemia, improving appetite and body weight, and growth and maturation of graaÞ an follicles by acting on schizophrenia. It can also be used to test the completeness the ovaries. Adverse effects: Follicle stimulating hormone may of vagotomy, in the treatment of diabetes mellitus, cause adverse effects like gynecomastia. Uses: It is preferred particularly IDDM, and an insulin + glucose infusion may in cryptorchidism, and for the maturation of prepubertal be used in-cyclic vomiting, hyperemesis gravidam, anorexia, testes, and spermatogenesis. and acute alcoholism. Other hormones Growth hormones and their analogs[25] Calcitonin is a polypeptide hormone containing 32 amino Growth hormones and their analogs are synthesized acids. It is prepared by recombinant technology and is also by recombinant technology, and are commonly used secreted by c-cells of the thyroid gland in mammals and as growth-promoting agents. These agents are not the cells of ultimobranchial bodies in lower vertebrates. Its effective in bone disorders, cardiac diseases, cartilage synthesis and release depend on calcium present in the body. disorders, Down syndrome, families of short stature, It is involved with parathyroid hormone in the regulation of GIT problems, and renal complications. They are available bone turnover and hence, in the maintenance of the calcium as somatrem, somatropin, and sermorelin. These agents balance and homeostasis. It is used to reduce plasma calcium are recommended for the treatment of complications levels in hypercalcemia. Mechanism of action: Prevents bone due to the deficiency of growth hormone. Growth resorption by inhibiting the action of bone osteoclasts. hormone deÞ ciency may occur due to skull fracture, Interactions: Enhances the release of calcitonin glucagon, excessive exposure to radiation, cancer disease, and due adrenergic agents, gastrin, , serotonin, and thyroxin. to intracranial infections like tuberculosis or meningitis. Adverse effects: Calcitonin may cause effects allergic reactions, Pharmacological actions: Stimulate the growth of connective alteration in taste, abdominal pain, diarrhoea, dizziness, facial tissues and skeletal muscles and enhance protein synthesis ß ushing, nausea, vomiting, rashes, and tingling sensation and fatty acid metabolism. They also decrease the use of in the hands. Uses: It is preferred in hypercalcemic states glucose in the body. Contraindicated in severe obesity, severe associated with hyperparathyroidism, osteoporosis, Paget’s respiratory syndrome, and after renal transplantation. disease, and vitamin-D intoxication. Adverse effects: Growth hormones may cause acromegaly, antibody formation, arthralgia, atherosclerosis, diabetes Recombinant interferons[25,28] mellitus, ß uid retention, gigantism, glucose intolerance, headache, hypertension, hypoglycaemia, hypothyroidism, Interferons are naturally occurring, inducible, small insulin resistance, myalgia, nausea, vomiting, pain and or , host-speciÞ c, broad-spectrum, pruritis at injecting point, paraesthesia, and visual potent, synthetic antiviral agents. They may also be disturbances. Uses: They are preferred in anti-aging produced by all body cells in response to inducers such and performance enhancers, chronic renal deÞ ciency, as attenuated measles, microbial extracts, viruses, and dwarÞ sm, gonadal dysgenesis, growth hormone deÞ ciency, anionic polysaccharides. They induce protein kinases, idiopathic short stature, and Sheehan’s syndrome. oligoisoadenylate synthetase, and phosphodiesterase enzymes. They can now be prepared by recombinant and Gonadotropins[26] cell culture techniques. They are nonspeciÞ c replication (i) Recombinant human growth hormone, (ii) Menotropins inhibitors of DNA and RNA viruses. The following types (FSH+LH) (obtained from urine of menopausal of interferons have been developed: Interferon alfa-2a,

146 J Young Pharm Vol 1 / No 2 Pharmacology of recombinant drugs interferon alfa-2b, interferon beta-1a, interferon beta-1b, headache, anemia, dyspnea, hypokalemia, atrial , interferon-gamma-1a, interferon-gamma-1b, interferons-ω, fatigue, immunogenicity, myalgia, palpitations, and and consensus interferon. Mechanism of action: They block peripheral edema. Uses: It is preferred in the treatment of viral replication by inhibiting the translation of viral chemotherapy-induced thrombocytopenia. mRNA into viral proteins and suppress cell proliferation. ADME: They are administered i.m. or s.c, have a half Recombinant granulocyte colony- stimulating [30-31] short t1/2, and a small amount have been found to enter factors cerebrospinal ß uid. Dose: 3-10 MU/i.v. infusion/TDS/ week. Adverse effects: Interferons may cause alopecia, These are naturally occurring or synthetic gylcoproteins anemia, bone marrow depression, cardiovascular disorders, that stimulate the multiplication, differentiation, and actions depression, fatigue, fever, GIT disturbances, headache, of neutrophills, monocytes, and macrophages. They are hepatotoxicity, hyperglycemia, hypersensitivity reactions, useful in the treatment of aplastic anemia and AIDS. hypotension, influenza-like symptoms, leucopenia, myalgias, myelosuppression, nephrotoxicity, , Filgrastim[32] is a 175 amino acid, recombinant, human suicidal behavior, thrombocytopenia, and weakness. Uses: granulocyte colony-stimulating factor that enhances the α-interferon is used in hepatitis, AIDS, herpes simplex, synthesis of . Pharmacological actions: It enhances herpes zoster, and certain types of cancers, hairy cell functions and production, increases phagocytosis, leukemia, and viral infections. β-interferons are used in cytotoxic and antibody-dependent killing effect of sclerosis (hardening of blood vessels). Interferon-γ has neutrophils, and enhances bone marrow repopulation been used in rheumatoid arthritis, chronic granulocytosis, after high doses of chemotherapy, radiotherapy, and bone hepatitis, leishmaniasis, leprosy, and psoriasis. Consensus marrow transplants. It also mobilizes hematopoietic stem interferon is used in hepatitis-C, neoplastic disorders, and cells into peripheral blood. Mechanism of action: It stimulates infectious complications. proliferation and differentiation of neutrophils. ADME: It is administered as an s.c or i.v. infusión, 20 μg/kg for

Recombinant interleukins 30 minutes, t1/2 is 3.5 hours. Contraindicated in severe Aldesleukin[29] is an interleukin-2 obtained from cultures congenital neutropenia. Dose: 5 μg/kg/s.c. or i.v./day. of E. coli and is available in two forms: Alpha and beta. Adverse effects: Filtrate may cause anemia, bone tenderness, Mechanism of action: It stimulates the natural killer cells, T and pain, breathlessness, cutaneous vasculitis, disuria, and B cells, TC cells, and enhances cellular immunity. Dose: epistaxis, exacerbation of rheumatoid arthritis, fever, 600,000 units/kg/eight hourly for five days. Adverse ß ushing, hepatomegaly, hypotension, increased uric acid, effects: Aldesleukin may cause nausea, vomiting, diarrhea, lethargy, mialgia, nausea, vomiting, osteoporosis, pericardial fever, capillary leak syndrome, hypotension, arrhythmias, effusions, lowering of BP, skin rashes, splenic enlargement, peripheral edema, prerenal azotemia, thrombocytopenia, tachycardia, thrombocytopenia, and urinary abnormalities. decreased tissue perfusion, confusion, and can reduce Uses: It is preferred in bone marrow suppression concomitant infection. Uses: It is preferred in the treatment or myelosuppression during cáncer chemotherapy, of metastatic renal cell carcinoma and melanoma. chemotherapy-induced neutropenia, cytotoxic-induced neutropenia in AIDS patients during zidovudine therapy, Oprelvekin is a recombinant human interleukin-11 leucopenia, to increase neutrophil counts, to prevent , consisting of 177 amino acids. It stimulates infections, and to treat congenital, cyclic, and aplastic and their precursors in the bone marrow anemia-induced neutropenia. and thus, prevents severe thrombocytopenia and decreases the need for transfusions in cancer patients Molgramostim is an unglycosylated, 127 amino receiving highly myelosuppressive chemotherapy. acid, recombinant, human granulocyte macrophage colony-stimulating factor that is derived from E. coli. Pharmacological actions: It stimulates the growth of multiple Mechanism of action: It stimulates the production of lymphoid and myeloid cells and consequently, enhances granulocytes and monocytes. Dose: 5-10 μg/kg/s.c./day. platelet and neutrophil counts. Mechanism of action: Adverse effects: Molgramostim may cause hypotension, Suppresses chemotherapy-induced thrombocytopenia by flushing, bone pain, fever, musculoskeletal pain, and stimulating megakaryocytes and their precursors in the GIT disturbances. Uses: It is used to reduce the severity bone marrow. ADME: It is administered subcutaneously of neutropenia in patients on immunosuppressive therapy and its t1/2 is seven hours. Dose: 25-50 μg/kg/s.c./day. and to accelerate myeloid recovery in patients with bone Adverse effects: Oprelvekin may cause arthralgia, dizziness, marrow transplantation.

J Young Pharm Vol 1 / No 2 147 Kishore and Krishan. J Young Pharm. 2009;1(2):141-150 Sargramostim is a 127 amino acid glycoprotein that is of action: Inhibition of interleukin functions by blocking produced in a yeast expression system. It enhances myeloid interleukin receptors. Precautions: In asthma patients. engraftment in autologous bone marrow transplantation, Interactions: Risk of infection transmission when given decreases the duration of antibiotic administration, and with live vaccines and also produces risk of infections reduces the incidence of infections. It also enhances the and neutropenia when given with TNF antagonists. Dose: proliferation and differentiation of neutrophils, eosinophils, 100-150 mg/day/s.c. Adverse effects: Anakinra may cause monocytes, and macrophages. ADME: It is administered redness, rashes, ß u-like symptoms, pain, and itching at subcutaneously or intravenously, t1/2 is 2-3 hours. Dose: 125- the injection site. Other reactions like headache, nausea, 500 μg/m2/day/s.c or i.v. infusion. Adverse effects: Sargramostim diarrhea, abdominal pain, URTIs, and neutropenia. Uses: may cause pleural and , fever, hypotension, It is preferred in the treatment of rheumatoid arthritis. tachycardia, rigors, flushing, malaise, nausea, vomiting, diarrhea, dyspnea, alopecia, bone pain, myalgia, rashes, and Adalimumab is a human, recombinant, monoclonal mucositis. Uses: It is preferred in bone marrow suppression antibody to TNF-alpha. It is similar to inß iximab but less or myelosuppression during cáncer chemotherapy. antigenic as it does not contain any foreign component. Pharmacological actions: It blocks the tumor necrosis factor and PegÞ lgrastim[33,34] is a pegylated polyethylene glycol-substituted also modulates leukocyte migration. Interactions: Enhances filgrastim, recombinant human granulocyte colony- the risk of infections and cancer. Dose: 40 mg/0.8 ml/s.c./ stimulating factor. It has a longer duration of action than OD for two weeks. Uses: It is preferred in the treatment Þ lgrastim and enhances WBCs production. Dose: 6 mg/s.c. of rheumatoid arthritis. or i.v./OD/chemotherapy. Uses: It is preferred in febrile neutropenia and infections in chemo patients. Inß iximab is a chimeric monoclonal antibody that inhibits the pro-inß ammatory cytokine, TNF-α. Mechanism of action: Recombinant antirheumatoid agents[5,31] Inhibits T-cell and macrophage functions and the release of pro-inß ammatory cytokines by occupying the membrane- Etanercept is a genetically engineered, modiÞ ed fusion bound TNF-alpha receptors. ADME: It is administered protein that resembles the cell surface receptor to which intravenously, t1/2 is 200 hours. Precautions: Caution may TNF-alpha normally binds to exert its actions. It is thus, be taken when used in cases of hepatic impairment, a cytokine-inhibiting agent, inhibiting tumor necrosis renal impairment, and demyelinating CNS factor-alpha, and is hence, used in the treatment of disorders. Interactions: Better results with methotrexate and idiopathic arthritis. Mechanism of action: Inhibition of live-attenuated vaccines. Contraindicated in severe infections inß ammatory and immunoregulatory actions of TNF-alpha like tuberculosis, pregnancy and breast feeding. Dose: by blocking its interaction with cell surface receptors. 5 mg/kg/ i.v . infusion/every eight weeks. Adverse effects: ADME: It is administered subcutaneously, t1/2 is about Inß iximab may cause effects like agitation, alopecia, amnesia, 115 hours. Interactions: Etanercept enhances the action of anxiety, arrhythmias, arthralgia, bradycardia, cholecystitis, methotrexate. Contraindicated in active infections, pregnancy, confusion, constipation, demyelinating disorders, diarrhea, and breast feeding. Dose: 25 mg/twice/s.c./week. Adverse diverticulitis, dizziness, drowsiness, dyspepsia, ecchymosis, effects: Etanercept may cause abdominal pain, aplastic endophthalmitis, fatigue, flushing, GIT hemorrhage, anemia, anemia, leucopenia, sepsis, asthma, cholecystitis, hematoma, hepatitis, hyperkeratosis, insomnia, interstitial dyspepsia, dizziness, GIT hemorrhage, headache, pneumonitis or Þ brosis, myalgia, palpitation, peripheral hypertension, hypotension, myocardial or cerebral ischemia, rashes, seizures, skin pigmentation, sweating, ischemia, esophagitis, opportunistic infections, pancreatitis, syncope, vaginitis, and vasospasm. Uses: It is preferred in pruritis, venous thromboembolism, nausea, tuberculosis, Þ stulating Crohn’s disease, rheumatoid arthritis, and severe optic neuritis, vomiting, and worsening heart failure. Uses: active Crohn’s disease. It is preferred in ankylosing spondylitis, idiopathic arthritis, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, Basiliximab and daclizumab are immunosuppressive, sarcoidosis, scleroderma, and Wegener’s granulomatosis. chimeric, monoclonal anti-CD50 antibodies produced by recombinant DNA technology. Mechanism of action: Block Anakinra[35,36] is a recombinant form of interleukin-1ra the alpha-chain of the interleukin-2 receptor located on the which inhibits the interactions of interleukin-1 with surface of activated T-cells. Interactions: Better results when immune cells and is used for the treatment of rheumatoid given with glucocorticoids, cyclosporine, or azathioprine. arthritis. Pharmacological actions: It inhibits proinß ammatory Dose: 20 mg/two hours before transplantation surgery and and immunomodulatory effects of interleukin-1. Mechanism 20 mg again on day 4 following transplantation. Uses: It is

148 J Young Pharm Vol 1 / No 2 Pharmacology of recombinant drugs preferred for the prophylaxis of organ transplants like liver Recombinant products, biopharmaceuticals, biologics, and heart rejection reactions. or genetically engineered drugs are produced using this technology by inserting the desired product isolated from Miscellaneous agents human cells into other carriers or vector cells. Some of the products of recombinant technology are of human origin Becaplermin[21] is a recombinant human platelet-derived including erythropoietin, coagulation modulators, enzymes, growth factor for the treatment of full-thickness hormones, interferons, interleukins, granulocyte colony- neuropathic and diabetic ulcers. It is applied topically as a stimulating factors, antirheumatoid drugs, and various thin layer daily and covered with gauze dressing moistened other agents like TNF, becaplermin, hepatitis-B vaccine, with physiological saline for a maximum duration of antibodies etc. They are proteins and nucleic acids and are treatment 20 weeks. Precautions: Avoid on sites with very speciÞ c, safe and pure agents. infection, malignancy, peripheral arteriopathy, osteomyelitis. Dose: 0.01% gel/topically. Adverse effects: Becaplermin may cause irritation, bullous eruption, and edema. Uses: It is REFERENCES used for the treatment of diabetic pressure ulcers. 1. Cohen SN, Chang AC, Boyer HW, Helling RB. Construction of biologically functional bacterial plasmids in vitro. Proc Natl Acad Sci U S A 1973; Hepatitis-B vaccine[37] contains inactivated hepatitis-B virus 70:3240-44. 2. Bhopale GM, Nanda RK. Recombinant DNA expression products for surface antigen adsorbed on aluminum hydroxide. Dose: 1 human therapeutic use. Current Science 2005; 89:614-22. ml/i.m./repeated one month and six months later. Adverse 3. Kaplan NP, Colowick NP, Wu R. Recombinant DNA: Recombinant DNA effects: Hepatitis-B vaccine may cause abdominal pain or Part F: Methods in Enzymology. Academic Press;1980. p. 68. cramps, agitation, anorexia, arthralgia, asthma, back pain, 4. Glick BR, Pasternak JJ. Molecular biotechnology, principles and applications of recombinant DNA. Washington, DC: ASM Press; 1994. p.16-7. bronchospasm, chills weakness, constipation, disturbed liver 5. Ballington DA, Laughlin MM. Pharmacology, 3rd ed. New Delhi: CBS functions, dizziness, ecchymosis, erythema, fatigue, fever, Publisher and Distributors; 2008. p. 473-7. flushing, headache, hypersensitivity, hypotension, 6. Bhopale GM, Nanda RK. Recombinant human erythropoietin: An overview. influenza-like symptoms, insomnia, lymphadenopathy, Indian Drugs 2004; 41:2707-13. 7. Abshire T, Kenet G. Recombinant factor VIIa: Review of efÞ cacy, dosing malaise, myalgia, nausea, vomiting, pain, palpitation, pruritis, regimens and safety in patients with congenital and acquired factor VIII or rashes, soreness and induration at the injection site, stiffness IX inhibitors. J Thromb Haemostatis 2004; 2:899-909. in arms, sweating, tachycardia, tingling, and urticaria. Uses: It 8. Roberts HR, Eberst ME. Current management of haemophilia B. Hematol Oncol Clin North Am 1993; 7:1269-80. is used to immunize people who are directly involved with 9. Carr ME, Martin EJ. Recombinant factor VIIa: Clinical applications for an the blood or saliva of patients and for passive immunization intravenous hemostatic agent with broad spectrum potential. Expert Rev by vaccination with hepatitis-B immunoglobulin. Cardiovasc Ther 2004; 2:661-74. 10. Roberts HR. Thoughts on the mechanism of action of fVIIa, 2nd symposium on new aspects of haemophilia treatment. Denmark: Compenhagen; 1991. Thrombopoietin is a 332 amino acid, high molecular p. 153-6. weight glycoprotein produced by hepatocytes and is a 11. Berntrop PE. Modern treatment of haemophilia. Bull WHO 1995; 73:691-701. primary regulator of platelet production. It is available 12. Bhopale GM, Nanda RK. Blood coagulation factor VIII: An overview. J Biosci 2003; 23:783-9. in two forms: Human and development 13. Greinacher A. Lepirudin: A bivalent direct thrombin inhibitor for factor, and human thrombopoietin. Recombinant anticoagulation therapy. Expert Rev Cardiovasc Ther 2004; 2:339-57. human thrombopoietin also reduces the duration of 14. Matheson AJ, Goad KL. Desirudin: A review of its use in the management thrombocytopenia and the need for platelet transfusion in of thrombotic disorders. Drugs 2000; 60:679-700. cancer patients receiving carboplatin or cyclophosphamide. 15. Doggrell SA. Alteplase: Descendancy in myocardial infarction, ascendancy in stroke. Expert Opin Investig Drugs 2001; 10:2013-29. 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Saruplase modern method used for the synthesis of therapeutic is a safe and effective thrombolytic agent; observation in 1998 patients: Results of the pass study, practical applications of saruplase study. Thromb agents. The technique has provided the means to Thrombilysis 1999; 8:143-50. develop many biologically effective therapeutic agents. 21. BMJ Publishing Group Ltd. London. BNF for children, The essential

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resource for clinical use of medicines in children. 2005. p. 635-36. 30. Armitage JO. Emerging application of recombinant human granulocyte 22. Whittington R, Goad KL. Alglucerasae: A review of its therapeutic use in macrophage colony stimulating factor. Jam Soc Hematol 1998; 22:4491-508. Gaucher’s disease. Drugs 1992; 44:72-93. 31. Sharma HL, Sharma KK. Principles of Pharmacology, 1st ed. Paras Medical 23. Bryson HM, Sorkin EM. Dornase alpha: A review of its pharmacological Publishing House, Hydarabad: 2008. p. 915-9. properties and therapeutic potential in cystic Þ brosis. Drugs 1994; 48:894-906. 32. Frampton J. Filgrastim: A review of its pharmacological properties and 24. Vazquez-Carrera, Silvestre JS. Insulin analogues in the management of therapeutic efÞ cacy in neutropenia. Drugs 1994; 48:731-60. diabetes. Met Find Exp Clin Pharmacol 2004; 26:445-61. 33. Crawford J. Neutrophil growth factors. Curr Hematol Rep 2002; 1:95-102. 25. Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s: The 34. Waladkhani AR. PegÞ lgrastim: A recent advance in the prophylaxis of Pharmacological Basis of therapeutics. 11th ed. New York: McGraw-Hill; chemotherapy induced neutropenia. Eur J Cancer Care 2004; 13:371-4. 2006. p. 1433-42. 35. Fleischmann RM, Tesser J, Schiff MH. Safety of extended treatment with 26. Lathi RB, Milki AA. Recombinant gonadotropins. Curr Womens Health anakinra in patients with rheumatoid arthritis. Ann Rheumat Dis 2006; Rep 2001; 1:157-63. 65:1006-12. 27. Hugues JN. Recombinant human follicle-stimulating hormone: A scientiÞ c 36. De smedt T, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute step to clinical improvement. Reprod Biomed Online 2001; 2:54-64. gout. Arthritis Res Ther 2007; 9:R-28. th 28. Tripathi KD. Essentials of Medical Pharmacology. 6 ed. New Delhi: Jaypee 37. Sharma VN. Essentials of Pharmacology, 3rd ed. New Delhi: CBS Publishers Brothers Medical Publishers (P) Ltd; 2008. p. 778-9. and Distributors; 2007. p. 623. 29. Jeal W, Goa K. Aldesleukin (recombinant interleukin-2): A review of its pharmacological properties, clinical efÞ cacy and tolerabilityin patients with Source of Support: Nil, Confl ict of Interest: None declared. renal cell carcinoma. Biodrugs 1997; 7:285-17.

OTHER ACTIVITIES - INPHARM

• Young Pharmacists Group of India – InPharm is the main association of young pharmacists in India (Age upper limit - 35 yrs) and aims at improving the knowledge of young Pharmacists. YPGI - InPharm exists to stimulate the exchanges and networking between young Pharmacists, to foster the co-operation and the sharing of best practices amongst them, particularly in the Þ eld of pharmaceutical education and research.

• Global Pharmacy Students Federation (GPSF) is one of the non - proÞ t global network that enables students and youth to interact with students of other countries to collaborate on projects/studies that enhance pharmaceutical learning and make a difference in the world.

• The mission of the Women Pharmacists Group (WPG-InPharm) is to help & develop outstanding women pharmacists, who impact with knowledge and integrity. The WPG-InPharm group is dedicated to support women through education and research. In addition, WPG-InPharm provides an atmosphere for personal growth and social networking for women pharmacists. WPG-InPharm recognizes, and works to eliminate, the multiple levels of oppression that act in society.

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