immunomodulator

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A SEMINAR ON IMMUNOMODULATORS IN ADVANCE PHARMACOLOGY & TOXICOLOGY FACILITATED BY: Mrs. MEENU SINGH, M. pharm. (Ph.D.) ASST. Professor, Department of Pharmacology PESCP , Bangalore-560050 PRESENTED BY: Shiva shanker rai 1 st M. Pharma Department of Pharmacology 3/24/2013 1 pfizer.mp4

IMMUNOMODULATORS:

IMMUNOMODULATORS Definition : Immunomodulator are the drugs which modify the immune response. OR Immunomodulators are drugs which either suppress the immune system – Immunosuppressant or stimulate the immune system – Immunostimulants 3/24/2013 2

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CLASSIFICATION OF IMMUNOSUPPRESSANTS Inhibitors of Lymphocyte Gene Expression Glucocorticoids Inhibitors of Lymphocyte Signaling Calcineurin Inhibitors mTOR Inhibitors Cyclosporine, Tacrolimus Sirolimus, Everolimus Cytotoxic Agents Antimetabolites Alkylating agents Azathiprine,Mthotrexate,leflunomid Cyclophosphamide Cytokine Inhibitors ( Anticytokine -Antibodies) TNF- α Inhibitors IL-1 Inhibitors IL-2 Inhibtors Etanercept, Infliximab,Adalimumab Anakinra Daclizumab , Basiliximab Antibodies Against Specific Immune Cell Molecules Polyclonal Antibodies Monoclonal Antibodies Antithymocyte Globulin (ATG) Alemutuzmab (AntiCD-52 Antibodies) Muromunab (Anti CD-3 Antibodies, OKT-3) Inhibitors of Immune Cell Adhesion Efalizumab Miscellaneous Rho (D) Immune Globulin 3/24/2013 3

Glucocorticoids:

Glucocorticoids Inhibits cytokine synthesis & release (IL-1,IL-2,IL-6 &TNF- ɑ) Inhibts the activation of cytotoxic T-lymphocytes function & proliferation Glucocorticoids also decreases neutrophils & monocytes chemotaxis & the lysosomal enzyme release 3/24/2013 4

Glucocorticoids contd..:

Therapeutic Uses: Acute transplant rejection, graft-versus-host disease in bone marrow transplantation. In autoimmune disorders like Rheumatoid arthritis, SLE, psoriasis. Asthma and other allergic disorders, inflammatory bowel disease, inflammatory ophthalmic diseases Adverse Effects: Growth retardation in children Avascular necrosis of bone, osteopenia cataracts, hyperglycemia, and hypertension Glucocorticoids contd.. 3/24/2013 5

CALCINEURIN INHIBITORS:

CALCINEURIN INHIBITORS Calcineurin is a protein phosphatase activates the T-cells of the immune system and can be blocked by drugs. Cyclosporine Bind to the cytosolic protein cyclophilin (an immunophilin) of T-lymphocytes. This complex of cyclosporine and cyclophilin inhibits the phosphatase calcineurin , which under normal circumstances induces the transcription of IL-2. The drug also inhibits lymphokines production and interleukin release, leading to a reduced function of effector T-cells 3/24/2013 6 Calcineurin, protein phosphatase 2B.flv

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Cyclosporine contd.. :

Cyclosporine contd.. Pharmacokinetics: Orally , oral bioavailability is low (about 30%) or I.V. Food decreases its absorption. Metabolized by CYP3A. Inactive metabolites are excreted mainly in bile and then in feces but minimally in urine. Plasma t½ is about 24 hrs. 3/24/2013 8

Cyclosporine contd..:

Uses Kidney, Liver, Heart transplantation Rheumatoid arthritis, IBD Psoriasis Aplastic anemia Dermatitis Adverse effects: Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia , Diabetogenic,nephrotoxicity Cyclosporine contd.. 3/24/2013 9

Tacrolimus:

Tacrolimus Pharmacokinetics : Given orally or I.V. 99% metabolized in liver by CYP3A and has a plasma t½ of 7-8 hrs. Use Prophylaxis of solid-organ allograft rejection Dermatitis, psoriasis. Adverse effects: Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension,Hyperglycemia 3/24/2013 10

Sirolimus (Mammalian Target of Rapamycin(mTOR) inhibitors:

Sirolimus (Mammalian Target of Rapamycin ( mTOR ) inhibitors Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus . Uses Prophylaxis of organ transplant rejection with other drugs Adverse effects: Increase in serum cholesterol, Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects 3/24/2013 11

Azathiopurine:

Azathiopurine 3/24/2013 12 Exposure to Nucleophiles (glutathione) Suppress T &B cell function Ig production & IL-2 secretion

Azathiopurine contd..:

Therapeutic Uses: Allogeneic kidney transplantation, organ transplant rejection. Adverse effects: Bone marrow suppression including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon), Increased susceptibility to infections (especially varicella and herpes simplex viruses), hepatotoxicity , alopecia, GI toxicity, pancreatitis. Azathiopurine contd.. 3/24/2013 13

Mycophenolate Mofetil:

Mycophenolate Mofetil Prodrug  Mycophenolic acid Inhibits IMPDH (Inosine monophosphate dehydrogenase – enzyme in guanine synthesis. T, B cells are highly dependent on this pathway for cell proliferation Selectively inhibits lymphocyte proliferation, function , Antibody formation, cellular adhesion, migration. 3/24/2013 14

Mycophenolate Mofetil contd..:

Mycophenolate Mofetil contd.. Uses: Prophylaxis of transplant rejection Combination: Glucocorticoids + Calcineurin Inhibitors Adverse effects: GI, Hematological Diarrhea Leucopenia Risk of Infection 3/24/2013 15

Cyclophosphamide:

Cyclophosphamide Mechanism of Action: Alkylating agents introduce alkyl groups by forming covalent bonds with nucleophilic moieties such as phosphate, sulfhydryl, hydroxyl, carboxyl, amino and imidazole groups present in DNA or RNA. By cross linking in between the strands of DNA they prevent the cell division and protein synthesis. It is a unique immunosuppressant as it suppresses B-lymphocyte proliferation but can enhance T-cell responses. 3/24/2013 16

Cyclophosphamide contd..:

Therapeutic Uses: Autoimmune disorders (including systemic lupus erythematosus), In patients with acquired factor XIII antibodies and bleeding syndromes, autoimmune hemolytic anemia, antibody induced pure red cell aplasia . Adverse effects: Pancytopenia and hemorrhagic cystitis, Graftversus -host disease syndrome, nausea, vomiting, Cardiac toxicity and electrolyte disturbances Cyclophosphamide contd.. 3/24/2013 17

Cytokine inhibitors(Anticytokine-antibodies):

Cytokine inhibitors( Anticytokine -antibodies) TNF- α Inhibitors Activated cytotoxic TH1 cells, macrophages and cells secrete TNF-α that to TNF receptors (TNFR1 or TNFR2) present on fibroblasts, neutrophils and vascular endothelial cells. Besides these, there are soluble form of TNF-α receptor present in serum and synovial fluid. Activation of TNF-α result in the release of cytokines IL-1, IL-6 and adhesion molecules that promote leukocyte activation and trafficking (migration). 3/24/2013 18 Anti - TNF agents.flv

Etanercept:

Etanercept It is genetically engineered fusion protein composed of two soluble TNFp75 receptors moieties linked to Fc portion of human IgG1. The drug serves as an exogenously administered soluble TNF-α receptor and provides artificial binding sites to TNF-α. This prevents TNF-α from binding to membrane bound TNFR1 and TNFR2. The drug is used primarily to treat rheumatoid arthritis, and psoriatic arthritis. 3/24/2013 19

Infliximab & Adalimumab:

Infliximab & Adalimumab It currently used in Cronh’s disease and rheumatoid arthritis . 3/24/2013 20

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3/24/2013 21 prevent the release IL-1, IL-6 and IL-8 along with collagenase & metalloproteinases

1.Polyclonal Antibodies Antithymocyte Globulin (ATG):

1.Polyclonal Antibodies Antithymocyte Globulin (ATG) Antithymocyte globulin is a purified gamma globulin from the serum of rabbits immunized with human thymocytes . Mechanism of Action: Antithymocyte globulin contains cytotoxic antibodies that bind to CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class I and II molecules on the surface of human T lymphocytes. The antibodies deplete circulating lymphocytes by direct cytotoxicity (both complement and cell-mediated) and block lymphocyte function by binding to cell surface molecules involved in the regulation of cell function. 3/24/2013 22

1.Polyclonal Antibodies Antithymocyte Globulin (ATG) contd..:

Therapeutic Uses: Acute renal transplant rejection, recovery from ischemic reperfusion injury. Adverse effects: Fever and chills, Hypotension, Serum sickness, Glomerulonephritis , leukopenia and thrombocytopenia, Increased risk of infection and malignancy 3/24/2013 23 1.Polyclonal Antibodies Antithymocyte Globulin (ATG) contd..

2.Monoclonal Antibodies:

2.Monoclonal Antibodies Muromunab (Anti CD-3 Antibodies, OKT-3) 3/24/2013 24

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Muromonab-CD3 also reduces function of the remaining T cells, as defined by lack of IL-2 production and great reduction in the production of multiple cytokines, perhaps with the exception of IL-4 and IL-10. Therapeutic Uses: Acute organ transplant rejection. Adverse effects: Cytokine release syndrome, high fever, chills/rigor, headache, tremor, nausea, diarrhea, abdominal pain malaise, myalgias, arthralgias, and generalized weakness,cardiovascular collapse, cardiac arrest. 3/24/2013 25

Efalizumab:

Efalizumab Efalizumab (LFA-1 Inhibitor) is a humanized IgG1 mAb targeting the CD11a chain of LFA-1 (lymphocyte function associated antigen). Mechanism of action: Efalizumab binds to LFA-1 and prevents the LFA-1-ICAM (intercellular adhesion molecule) interaction to block T-cell adhesion, trafficking, and activation. Therapeutic Uses: Survival of murine skin and heart allografts and monkey heart allografts , psoriasis, renal transplantation 3/24/2013 26 Tocilizumab action - video clip.flv

Rho (D) Immune Globulin:

Rho (D) Immune Globulin Rho (D) immune globulin is a concentrated (15%) solution of human IgG containing a higher titer of antibodies against the Rho (D) antigen of the red cell. Therapeutic uses: Hemolytic disease of the newborn. 3/24/2013 27

Immunostimulants:

Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines Interferons Interleukin-2 Other drugs inosiplex , azimexon , imexon , thymosin , methylinosine monophosphate Immunization Vaccines , Immune Globulin , Rho (D) Immune Globulin 3/24/2013 28

Levamisole:

Levamisole Antihelminthic Restores depressed immune function of B, T cells, Monocytes, Macrophages USES: Adjuvant therapy with 5FU in colon cancer Used to treat immunodeficiency associated with Hodgkins disease. Toxicity Agranulocytosis 3/24/2013 29

Thalidomide:

Thalidomide Enhanced T-cell production of cytokines – IL-2, IFN- γ NK cell-mediated cytotoxicity against tumor cells Birth defect Contraindicated in women with childbearing potential USE: Multiple myeloma 3/24/2013 30

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Live bacillus Calmette -Guerin (BCG) is an attenuated, live culture of the bacillus of Calmette and Guerin strain of Mycobacterium bovis . Mechanism of action: Induction of a granulomatous reaction at the site of administration. Therapeutic uses: Treatment and prophylaxis of urinary bladder’s carcinoma . Adverse effects: Hypersensitivity, shock, chills, fever, malaise, and immune complex disease Bacillus Calmette -Guerin (BCG) 3/24/2013 31

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Types Examples Mode of action Therapeutic uses Adverse effects Interferons Alpha, beta, gamma Induction of certain enzymes, inhibition of cell proliferation, and enhancement of immune activities, including increased phagocytosis by macrophages and augmentation of specific cytotoxicity by T lymphocytes. Hairy cell leukemia, malignant melanoma, follicular lymphoma, AIDS related Kaposi's sarcoma, chronic hepatitis B and Condylomata acuminata Hypotension, arrhythmias, and rarely cardiomyopathy and myocardial infarction, GI distress, anorexia, weight loss, myalgia and depression. Interleukins Aldesleukin , des-alanyl-1, serine-125 human IL-2 Cellular immunity is profoundly activated with lymphocytosis , eosinophilia , thrombocytopenia, and release of multiple cytokines (e.g., TNF, IL-1 and interferon-g). Metastatic renal cell carcinoma and melanoma. Capillary leak syndrome, Hypotension, reduced organ perfusion, and death. Colony stimulating factors Filgrastim ( rmetHuG - CSF) Increases the number and differentiation of myeloid progenitors. Leucopenia, ganciclovirinduced neutropenia . Myocardial infarction, anorexia, 3/24/2013 32 RECOMBINANT CYTOKINES

References:

References Sharma HL, Sharma K.K. Principals of Pharmacology. 1 st ed. Paras Medical Publishers, New Delhi; 2007: 428-453. Katzung GB, Trevor JA. Basic and Clinical Pharmacology 11 th ed. 2009; 363-435. Golan DE. Principles of Pharmacology. The Pathophysiologic Basic of Drug Therapy. 2 nd ed. Lippincott 2008; 795-809. Rang HP and Dale MM. Rang and dale Pharmacology. 6 th ed. Churchill Livingestone Elsevier 2007; 481-488, 538-541. Richar AH. And Pamela CC. Lippincott's Illustrated Reviews: Pharmacology. 4 th ed. 2009; 489-498. Parnham MJ, and Nijkamp FP. Principles of Immunopharmacology . 2 nd ed. Birkhauser Verlag 2005; 377-389. 3/24/2013 33 Immunosuppression in Transplantation - YouTube.MP4

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3/24/2013 34 Queries

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