Immunology

CONTENT 1. Introduction 2. History 3. Terms 4. Some definition 5. Classification & Mechanism 6. Drugs 7. Interaction 8. Side effect 9. Uses 10. Precaution 11. Special condition 12. Conclusion 13. References

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IMMUNOSUPPRESENT DRUGS Introduction:Immunosuppressant drugs are medicines that reduce the body's natural defensesagainst foreign invaders or materials. Used in transplant patients, these drugs help prevent their bodies from rejecting transplanted organs. When an organ, such as a liver, a heart or a kidney, is transplanted from oneperson (the donor) into another (the recipient), the recipient's immune system has the same response it has to any foreign material: It attacks and tries to destroy the organ. Immunosuppressant drugs help prevent this fromhappening by subduing the natural immune response. However, the drugs' actionalso makes the body more vulnerable to infection. For that reason, people who take these kinds of medicine need to be especially careful to avoid infections. In addition to being used to prevent organ rejection, immunosuppressant drugssometimes are used to treat severe skin disorders such as psoriasis and other diseases such as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss (alopecia areata). Immunosuppressant drugs are available only with a physician's prescription and come in tablet, capsule, liquid, and injectable forms. Commonly used immunosuppressant drugs include azathioprine (Imuran), cyclosporine (Sandimmune) and tacrolimus (Prograf). The physician will decide exactly how much of the medicine each patient needs. It is vital that the patient take this medicine exactly as directed. Nevertake smaller, larger or more frequent doses, and do not take the drug for longer than directed. Taking too much may increase the risk

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of side effects, while taking too little may not do any good. Nor should a patient stop taking the drug without checking with the physician who prescribed it. Seeing a physician regularly while taking immunosuppressant drugs is important. These regular check-ups will allow the physician to make sure the medicineis working as it should and to watch for unwanted effects. These medicines are very powerful and can cause serious side effects, such as high blood pressure, kidney problems and liver problems. Some side effects may not show up until years after the medicine is used. However, the good these drugs can do may outweigh the possible harm. Anyone who has been advised to take immunosuppressant drugs should thoroughly discuss the risks and benefits with his or herphysician Immunosuppressant drugs lower a person's resistance to infection and can makeinfections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the physician in charge knows about the medicine. Immunosuppressant drugs may cause the gums to become tender and swollen or tobleed. If this happens, check with a physician or dentist right away. Regular brushing, flossing, cleaning and gum massage may help prevent this problem. Ask the dentist for advice on how to clean the teeth and mouth without causing injury. People who have certain medical conditions or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before takingthese drugs, be sure to let the physician know about allergies, whether you are pregnant or on oral birth control pills, or who have shingles or chicken poxx People who take immunosuppressant drugs may be at higher than normal risk of developing certain kinds of cancer later in life. However, the drugs may be necessary to prevent the failure of a life-saving transplant. The possible harm must be carefully weighed against the drugs' benefits. Discussing the medicine's good and bad points with a physician will help a patient decideabout whether to take immunosuppressant drugs. The risk of cancer or infection may be greater when immunosuppressant drugs are combined with certain other drugs which also lower the body's ability to fight disease and infection. Anyone who takes immunosuppressant drugs should let the physician know all other medicines he or she is taking and should ask whether the possible interactions can interfere with treatment.

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History:A firestorm has erupted with the revelation on March 29, 2005 that a 3rd patient dosed with Tysabri had been discovered to have Progressive multifocal leukoencephalopathy (PML). PML is a demyelinating disease of the brain caused by the JC virus. This patient had 8 doses of Tysabri over the course of 18 months during a clinical trial for Crohn's disease, an autoimmune disorder that strikes the bowels. The doses were spaced out as follows: 3 months Tysabri, 9 months placebo, then 5 months Tysabri. The patient passed away in December of 2003, with his death originally attributed to a fatal brain tumor. The recent revelation of 2 cases of PML found in extended combination therapy of Avonex and Tysabri prompted a reinvestigation of this death. The new conclusion was that the patient had actually died of PML, not a brain tumor. This has been viewed by many as devastating the chances of Tysabri ever returning to market, given that it seems on the surface that Tysabri can cause PML even when used alone (monotherapy). However, This is MS became suspicious of the link between Tysabri and PML in this case, particularly given the low number of Tysabri doses that the patient had been exposed to, the spacing of those doses, and the mysterious mention of a past history of severe immunosuppresion. If PML were so "easy" to contract when exposed to Tysabri, why would we not see higher numbers of incidents in the multiple sclerosis Tysabri groups, who are more frequently dosed (monthly) over longer periods of time (over three years for the extended trial participants) with higher Tysabri circulation (when combined with Avonex, Tysabri clearance is reduced by ~30%). The investigation is enlightening, and we believe, shows that Tysabri cannot easily be considered the critical factor for this case of PML. As you will see, it is not a foregone conclusion that this patient could be considered to have been on Tysabri monotherapy, given the long-term effects of his previous therapies. To preface this article, note that this is an opinion piece based upon information in the public domain and written by non-medical personnel, so all conclusions are meant to serve as discussion points and not definitive answers. That being said, Elan disclosed the list of medications Patient 3 was treated with:

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•

Steroids no surprise here, and this relatively weak immunosuppressant is used commonly with most MSers.

•

Remicade, which is a powerful drug used to treat Crohn's disease. Now things get more interesting. A *partial* list of warnings for Remicade: "Many people with heart failure should not take REMICADE...There are reports of serious infections, including tuberculosis (TB), sepsis and pneumonia. Some of these infections have been fatal. ...REMICADE can lower your ability to fight infections, so if you are prone to or have a history of infections, or develop any signs of an infection such as fever, fatigue, cough, or the flu while taking REMICADE, tell your doctor right away...There have been rare cases of serious liver injury in people taking REMICADE, some fatal...Blood disorders have been reported, some fatal...Nervous system disorders have also been reported. Tell your doctor if you have or have had a disease that affects the nervous system, or if you experience any numbness, weakness, tingling, or visual disturbances while taking REMICADE. Reports of lymphoma (a type of cancer) in patients on REMICADE and other TNF blockers are rare but occur more often than in the general population. Tell your doctor if you have or have had cancer. Clearly, Remicade is not a treatment to be undertaken lightly and has a number of ways of causing fatalities.

•

Azathioprine (aka Imuran) - This is where things get extremely interesting. The patient was treated for approximately five years with this powerful drug commonly used for preventing the rejection of organ transplants and in lower doses, rheumatoid arthritis and other inflammatory diseases such as Crohn's. Quoting Medline: [Azathioprine] works by weakening the body's immune system so it will not attack the transplanted organ or the joints." It is not clear for what indication this patient took this drug, but it was likely taken off-label for what would obviously have to be a severe case of Crohn's disease. Let us examine this drug's mode of action and safety profile: "Imuran [is] used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months..." Note that Imuran is commonly prescribed in combination with another immunosuppressant AND the effect of the drug-- severe immunosuppression is often delayed. Continuing on with the litany of grave warnings: Rkdf college of pharmacy bhopal

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"Severe leukopenia [an abnormal decrease of white blood cells] and/or thrombocytopenia [abnormal decrease of blood platelets] may occur in patients on azathioprine. Macrocytic anemia and severe bone marrow depression may also occur...Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low leukocyte count or other evidence of bone marrow depression [Tysabri works by preventing leukocytes from crossing the Blood-Brain-Barrier, so if they are already severely reduced...]...Serious infections are a constant hazard for patients on chronic immunosuppression...Fungal, viral, bacterial and protozoal infections may be fatal and should be treated vigorously...Azathioprine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia [pre-cancerous cell growth]...acute myelogenous leukemia as well as solid tumors have been reported in patients...who have received azathioprine. Let us recap: Azathrioprine can be incredibly toxic, can decimate the immune system long after its dosing, and leaves the patient susceptible to potentially fatal infection. Could Imuran still have been exerting its effects during the Tysabri infusions? We don't have an answer to that, but if so, let us explore "the smoking gun": While looking at the reported adverse reactions for Azathioprine, we found this: "A case of progressive leukencephalopathy (PML) after a four year azathioprine therapy...was reported (Schnider,1991). That's right-- a case of PML linked directly with long-term administration of azathioprine. Patient #3 was actually on azathioprine for one year longer than this PML-azathioprine case. This is not the only case, here's another: "A 71-year-old woman receiving azathioprine and glucocorticoid therapy experienced onset of right-sided hemiplegia within a few days, became comatose, and died within a few days...postmortem examination showed PML. Simply put, we are aghast that this ravaged individual, exposed to years of dosing with a cocktail of potentially lethal drugs-- that among other things, can cause delayed immunosuppression, cancer, and even PML itself, was participating in a clinical trial with another experimental immunosuppresant. Maybe his case was so bad, he had no other hope, but in such an extreme situation, the fault of his death cannot be placed squarely on Tysabri. That he died is of course tragic, but quite frankly, a serious adverse event is not entirely surprising given his cumulative medical history. Rkdf college of pharmacy bhopal

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To conclude that Tysabri is the key factor for his contraction of PML and ultimate death, based on the post-mortem analysis of a patient that clearly was severely ill is to us, simply preposterous. While we are not doctors and so our opinion is purely non-medical, this situation cannot reasonably be viewed as akin to an otherwise healthy individual contracting PML after exposure to Tysabri monotherapy. In fact, given the latent effects of the Imuran treatment, without further information as to treatment start and stop dates, it cannot even be said definitively that this patient was on Tysabri monotherapy, as after five years of treatment, Imuran could still have been exerting its effects without being actively dosed. The contraindications for prescribing Tysabri are becoming clear, and coupled with the increased vigilance for PML that would be sure to accompany any Tysabri prescription, the risk factor would seem to be acceptable for many MSers anxious for a new treatment option. The fact that toxic drugs like Remicade and Imuran are tolerated but Tysabri would not be is at the very least extremely puzzling. Tysabri is extremely effective at what it does, and because of that potency, cannot be coupled with drugs that cause, or people who have, a history of immunosuppression, cancer and serious infections.

DEFINITIONS:

Immunosuppression:Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. In some cases the dosage can be reduced or even stopped without causing rejection. Other uses are in the treatment of certain autoimmune diseases and for prevention of erythroblastosis fetalis. Its main drawback is the increased risk of infection for the duration of treatment and of lymphoma in the case of long-term immunosuppression. The natural or induced active suppression of the immune response, as contrasted with deficiency or absence of components of the immune system. Like many other complex biological processes, the immune response is controlled by a series of regulatory factors. A variety of suppressor cells play a role in essentially all of the known immunoregulatory mechanisms, such as maintenance of immunological tolerance; limitation of antibody response to antigens of both thymicRkdf college of pharmacy bhopal

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dependent and thymic-independent types, as well as to antigens that stimulate reaginic antibody (antibodies involved in allergic reactions); genetic control of the immune response; idiotype suppression; control of contact and delayed hypersensitivity; and antigenic competition. All of the major cell types involved in the positive side of cellular interactions required for an immune response have also been found capable of functioning as suppressors in different regulatory systems.

 Suppressor cells:Some suppressor functions are antigen or carrier-specific. (A carrier is a molecule that can be chemically bound to another small molecule, called a hapten, in such a way that the combination induces an immune response that the hapten alone would not induce.) Others may not be carrierspecific, but may be specific for the type of response, such as immunoglobulin production but not delayed hypersensitivity. In the case of immunoglobulin production, the suppressor T cell may regulate the production of all immunoglobulin classes, a single class of immunoglobulins, or molecules that bind only a given antigen. Other suppressors may affect only cellular immunity and not humoral immunity. Suppressor cells are critical in the regulation of the normal immune response. Immunological tolerance refers to the ability of an individual's immune system to distinguish between its own and foreign antigens and to mount a response only to foreign antigens. A major role has been established for suppressor T lymphocytes in this phenomenon. Suppressor cells also play a role in regulating the magnitude and duration of the specific antibody response to an antigenic challenge. Reagin or IgE is the class of immunoglobulin that mediates allergic reactions such as asthma and urticaria. The reaginic antibody response depends heavily on nonspecific cooperator T cells and specific helper T cells as well as the B cells that produce the antibody. In a negative direction, IgG-blocking antibodies regulate the response, but antigen-specific and antigen-nonspecific suppressor T cells also play a critical role in regulating this response. See Allergy T cells are the major cells involved in immunosuppression, although activated phagocytic mononuclear cells are also significant as nonspecific suppressors in many systems. Helper T cells and suppressor T cells are different cell populations that are distinguished to a considerable

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extent by surface antigens that react with monoclonal antibodies or receptors for specific substances such as histamine. No single model explains the entire array of cellular suppressor phenomena. In different systems, other T cells, macrophages, or even B cells may be the immediate targets of the suppressor cells and their secretions. Some suppression requires direct cell-cell interaction, whereas other suppression may be mediated by suppressor lymphokines. Both antigen-specific and antigennonspecific factors are known, and they may be secreted to act upon other cells, or especially in the case of antigen-specific factors, they may be integral parts of the cell membrane. The soluble immune-response suppressor factor, produced by activated T cells and then activated by monocytes, inhibits B-cell proliferation and immunoglobulin production in response to antigens. Macrophages also secrete suppressor factors, including prostaglandins that act on T cells and other soluble factors that are B-cell-specific. There are a variety of disorders of immunoglobulin production in humans. In many cases these involve intrinsic defects in the bone marrow stem cells that normally mature into immunoglobulin-producing plasma cells. Defects in cell-mediated immunity occur in individuals who are infected with various fungal organisms. Suppressor T cells have been implicated; although it is not clear whether the appearance of suppressor cells is the initial event allowing development of the fungal infection or whether they develop secondarily after infection. Those individuals found to have suppressor T cells are at high risk for dissemination of the fungal infection and relapse following therapy. Although probably only one of many mechanisms, suppressor cells interfere with the host tumor-growth-inhibiting immune response to the foreign tumor-specific transplantation antigens that occur on malignant cells, thus allowing the tumors to progress. Both animal and human studies indicate a major role for both an activation of immunoglobulin-producing B cells as well as the absence or reduced numbers or function of suppressor T cells in autoimmune disorders such as Coombs-positive hemolytic anemia, systemic lupus erythematosus, rheumatoid disorders, and thyroid disorders in which antithyroid antibodies appear in the serum.

 Immunosuppressors:Suppression of the immune response may be specific to a particular antigen or may be a response to a wide range of antigens encountered. The whole immune response may be depressed, or a Rkdf college of pharmacy bhopal

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particular population of immunologically active lymphocytes may be selectively affected. In some cases, the effect may be preferentially on T cells rather than B cells. If B cells are affected, it

may

be

on

a

specific

subclass

of

antibody-producing

cells. Antigen-specific

immunosuppression may be the result of deletion or suppression of a particular clone of antigenspecific cells, or the result of enhanced regulation of the immune response by antigen-specific suppressor cells. It can also be the result of increased production of antiidiotypic antibody. Nonspecific suppression of the immune response occurs in a number of rare immunological deficiency diseases of childhood. Acquired deficiency states affecting mainly T-cell function occur in states of malnutrition and in the presence of tumors, particularly those of the lymphoreticular system. Acquired deficiencies may also occur secondary to a number of infectious diseases. The acquired immune deficiency syndrome (AIDS) is probably of similar origin; its manifestations are similar although more severe and more dramatic. There are a number of compounds capable of suppressing the immune response. The main stimulus for studies designed to identify these substances has been to devise means for controlling organ graft rejection. However, there has also been considerable activity in looking for compounds that will suppress the immune response and reduce the inflammatory process in experimental models of rheumatoid arthritis. The ideal immunosuppressive drug should fulfill five main requirements: (1) There should be a wide margin of safety between a toxic and a therapeutic dose. (2) The drug should have a selective effect on lymphoid cells and not cause damage to the rest of the body. (3) If possible, this effect should be only on those cells, which are involved, in the specific immune process to be suppressed. (4) The drug should need to be administered for only a limited period until the immunological processes become familiar with the foreign antigen and begin to recognize it as part of “self.’’ (5) The drug should be effective against immune processes once they have developed. The result of any immune response is a balance between the action of effector cells mediating the phenomenon and suppressor cells regulating the response. Anything that reduces the regulatory function of suppressor cells will functionally increase the immune response. As suppressor cells are derived from rapidly turning-over precursor cells, and effector cells of T-cell-mediated immunity are derived from slowly dividing precursors, it is possible preferentially to depress the action of suppressor cells without affecting effector cells. This may be done by the use of alkylating agents such as cyclophosphamide given before immunization. Cyclophosphamide Rkdf college of pharmacy bhopal

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used in this way can increase a normal cell-mediated immune response, reverse immunological tolerance caused by increased regulatory activity of suppressor cells, and even reverse antigenic competition. It is likely that the chemotherapeutic effect of alkylating agents which are used extensively in the treatment of cancer in humans is partially due to these agents modifying the biological response to the tumor, producing an immunopotentiating action.

Classification & Mechanism:Immunosuppressive drugs can be classified into four groups: •

Glucocorticoids

•

Cytostatics

•

Antibodies

•

Drugs acting on immunophilins

•

Other remedies 1 Glucocorticoids

1.1The mode of action 1.2Immunosuppressive effect 1.3 Antiinflammatory action 1.4 Glucocorticoid remedies 2 Cytostatics 2.1 Cytostatics and the immune system 2.2 Classification of cytostatics and major representatives 2.2.1 Alkylating agents 2.2.2 Antimetabolites 3.1 Polyclonal antibodies 3.2 Monoclonal antibodies Rkdf college of pharmacy bhopal

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3.2.1 Antibodies directed towards T-cell receptor 3.2.2 Antibodies directed towards IL-2 receptor 4 Drugs acting on immunophilins 4.1 Cyclosporine A 4.2 Tacrolimus (Prograf(TM), FK506) 4.3 Sirolimus (Rapamune (Tm), Rapamicin) 5 Other remedies 5.1 Interferons 5.1.1 The effect of interferons 5.2 Opioids 5.3 TNF-α binding drugs 5.4 Mycophenolic acid 5.5 Small biological agents 5.5.1 FTY120

Glucocorticoids Endogenous glucocorticoids are essential hormones the lack of which is not compatible with life. Their main effects are the maintenance of the appropriate level of glucose in the blood, the maintenance of blood pressure and the prevention of excessive immune response. Pharmacological or supraphysiological dosages are used in treatment of inflammatory and allergic disorders. They are also used as immunosuppressants after transplantations to prevent the acute transplant rejection by the receiver and also the immune response of the receiver to the receiver's antigens. However, they have many side effects: the gain of body mass, development or aggravation of diabetes, arterial hypertension and/or steroid induced osteoporosis. Therefore, the production of new glucocorticoid remedies is directed to the discovery of selective immunosuppressive drugs.

The mode of action Glucocorticoids bind to the cytosolic glucocorticoid receptor that is one of the receptors activated after ligand binding. After the hormone binds to the receptor, the receptor-ligand complex is translocated into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of target genes. The DNA bound receptor then interacts Rkdf college of pharmacy bhopal

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with basic transcription factors, which causes the increase in expression of specific target genes. This process is called transactivation. The transactivation mediates most of the main metabolic and cardiovascular side effects. The mechanism contrary to transactivation is transrepression. Here, the activated hormone receptor interacts with transcription factors that cooperate in the transcription of a specific gene and prevents it. Glucocorticoids are able to prevent the transcription of the IL-2 gene and all other immune genes . The ordinary glucocorticoids do not differentiate between transactivation and transrepression, therefore they influence the "wanted" genes and also "unwanted" ones. Currently, intensive research is focused on searching selective glucocorticoids. These will be able to transrepress the immune genes without affecting the metabolic and cardiovascular ones.

Immunosuppressive effect Glucocorticoids diminish the cell immunity: they act by inhibiting genes that code the following cytokines: IL-1, IL-2, IL-3 , IL-4 , IL-5 , IL-6, IL-8 and TNF-γ. Smaller production of cytokines causes reduced proliferation of T lymphocytes. This diminishes their effect and clone expansion of CD4+ cells (T-helper lymphocytes). Hereby, especially the IL-2 is important. Glucocorticoids also diminish the humoral immunity. Like T lymphocytes, B lymphocytes express smaller amounts of IL-2 genes and of genes coding for IL-2 receptors . This means reduced B lymphocyte clone expansion and consequentially, the diminished synthesis of immunoglobulins. Antiinflammatory action Glucocorticoids influence all types of inflammatory reactions independently of their cause. They induct the synthesis of lipocortin-1 (annexin-1) that binds to phospholipid membranes and prevents the activity of phospholipase A2, as the enzyme is not able to come into contact with its substrate. Phospholipase A2 is involved in the first step of the production of some eicosanoids. The expression of genes coding for cyclooxygenase (COX-1 and COX-2), which catalyzes further steps, also diminishes. Glucocorticoids also cause the release of lipocortin-1 in the extracellular space, where it binds to leukocyte membrane receptors and inhibits epithelial adhesion, emmigration, chemo taxis, phagocytosis, respiratory burst, release of lysosome enzymes, release of chemotactic substances, Rkdf college of pharmacy bhopal

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release of the activator plasminogen and of other inflammatory mediators from neutrophils and macrophages. By the action of lypocortin-1 it is also possible to explain the inhibitory effect of glucocorticoids on the release of histamine from tissue basophils. Glucocorticoids successfully soothe all signs of inflammation, however they do not prevent infection. They also inhibit later reparative processes . Glucocorticoid remedies There are many different glucocorticoids in use: cortisol, dexamethasone, hydrocortisone, methylprednisolone

Medrol

prednisone,

prednisolone

and

others.

They

differ

in

pharmacokinetics absorption factor, their half-life, the volume of distribution, clearance and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; They are primarily administered per os (by mouth), as they are well absorbed in the intestines, and topically on skin, but also by other ways. The majority (more than 90 per cent) of glucocorticoids bind different plasma proteins, however, they differ in their binding specificity. Endogenous glucocorticoids and some synthetic corticoids bind with high affinity the protein transcortin (also CBG, corticosteroid binding protein), while all of glucocorticoids are able to bind albumin. They are metabolised quickly in the liver, where they conjugate with a sulfate or glucuronic acid, and are secreted in urine.

Cytostatics Main article: Cytostatics. Cytostatics are drugs that inhibit the cell division and therefore damage or destroy cells. They are especially used in cancer therapy. However, because they are not only specific for cancer cells, they also affect all other quickly dividing cells. This can most often be observed as the chemotherapy side effects. It is nonetheless reasonable to use them, as the cancer cells divide faster than normal ones and are therefore more sensitive.

Cytostatics and the immune system Quickly dividing cells are also T-lymphocytes and B-lymphocytes. As they recognize the specific antigen, they quickly proliferate to secure the adequate number of clones for the immune response. However, this makes them a suitable target of cytostatics. Therefore, we can use cytostatics whenever the immune response is not wanted. As immunosuppressants, cytostatics

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are used in smaller dosages as in the treatment of malign diseases. Their antiproliferative effect is in general not limited and it includes both T-lymphocytes and B-lymphocytes.

Classification of cytostatics and major representatives On the basis of the site of action, cytostatics can be divided into four groups: •

Alkylating agents (e.g. cyclophosphamide)

•

Antimetabolites (e.g. methotrexate, azathioprine)

•

Cytotoxic antibiotics

•

Inhibitors of the mitotic spindle Mainly purine analogs are administered, as they are the most effective, while the others are less frequently used. Alkylating agents

Their main representative are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds etc. They act cytostatically by effecting the DNA. Cyclophosphamide is an alkylating agent and probably the most potent immunosuppressive substance. It inhibits the DNA replication by making covalent bonds with it. In small doses, it is very efficient in the treatment of systemic lupus erytematosus, autoimmune hemolytic anemia’s, Wegener's granulomatosis and other immune diseases. High doses of cyclophosphamide can cause pancytopenia and hemorrhagic cystitis. Antimetabolites Their main representatives are folic acid analogues (methotrexate), purine analogues (azathioprine, mercaptopurine), pyrimidine analogues, and protein synthesis inhibitors. They affect all nucleic acids. Methotrexate Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents the synthesis of tetrahydrofolate. This way, it inhibits the synthesis of DNA, RNA and proteins (as tetrahydrofolate is involved in the synthesis of serine and methionine). It is used in the treatment of autoimmune diseases, as rheumatoid arthritis, and in some transplantation. Azathioprine Azathioprine is the main cytotoxic substance, used in immunosuppression. It is widely used in transplantations to control rejection reactions. It is nonezymathically cleaved to 6Rkdf college of pharmacy bhopal

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mercaptopurine, which act as a purine analogue and the inhibitor of DNA synthesis. By preventing the clone expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and humoral immunity. It is also successful in the treatment of autoimmune diseases. Cytotoxic antibiotics Among these, dactinomycin is the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, and mitramycin. All these substances act on DNA to mediate their effects. Mitotic spindle inhibitors (Vinca alkaloids, e.g. vincristine, vinblastine; podophyllins) are used in the therapy of some autoimmune diseases. They repress the M phase of the cell cycle. Vincristine depolimerizes mitotic spindle. Antibodies. Antibodies are used in the induction therapy that by a quick and potent immunosuppression tries to prevent the acute rejection reaction. Polyclonal antibodies Heterologous polyclonal antibodies are obtained from the serum of different animals (e.g. rabbit, horse) that the pacient's thymocytes or lymphocytes have been injected to. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are used. They are a part of the treatment of steroidresistant acute rejection reaction and of the treatment of grave aplastic anemia. However, they are mostly used as additives to other immunosuppressives, which allows for the diminishment of the latter's dosage and their toxicity. The antibodies also allow the later transition to cyclosporine therapy. They are usually administered for five days intravenously in the appropriate quantity. Patient stays in the hospital for three weeks so the immune system recovers and there is no risk of serum sickness anymore. Polyclonal antibodies inhibit T lymphocytes and cause their lysis through the interaction with different cell surface markers (e.g. CD2, CD3, CD4, CD8, CD11a, CD18, CD45, CD3, CD4). The lysis is both complement mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. This way, polyclonal antibodies inhibit cell-mediated immmune reactions, including the graft rejection, the

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delayed hypersensitivity (i.e. tuberculin skin reaction), and the graft-versus-host disease (GVHD), however their effect on the thymus-dependent antibody production is smaller. Currently (March 2005) there are two preparations available, Atgam (R), obtained from horse serum, and Thymoglobuline (R), obtained from rabbit serum. Polyclonal antibodies act non-specifically on all the lymphocytes and cause general immunosuppression that can lead to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially with cytomegalovirus .Therefore, the therapy must necessarily be performed in a hospital, where adequate isolation from infection is available. As polyclonal antibodies are also highly immunogen, by almost all the patients an acute reaction develops in the first few days of the treatment. It is characterized by fever, sometimes rigor episodes and in some cases, even anaphylaxis develops. Later during the treatment, the serum sickness or by the immune complexes induced glomerulonephritis can develop. The serum sickness appears seven to fourteen days after the beginning of therapy. The patient suffers from fever, joint pain and erythema that can be soothed with the use of steroids and analgesics. Urticaria (hives) can also be present. Because of their immunogenicity, patients gradually develop a strong immune response against them, so these drugs cease to be effective. Their toxicity can be diminished by the use of highly purified serum fractions, intravenous application and their administration in the combination with other immunosuppressants, for example calcineurin inhibitors, cytostatics and cortisteroids. The most common combination is the simultaneous use of antibodies and cyclosporine. Monoclonal antibodies Monoclonal antibodies are much more specific, as they are directed towards exactly defined antigens and therefore, they cause fewer side effects. Especially important are antibodies against the IL-2 receptor (CD25) and against CD3, and probably new will appear. They are used to prevent rejection of transplanted organs, but also in the tracking of changes in lymphocyte subpopulations in immunosuppressive therapy. Antibodies directed towards T-cell receptor

Till now, OKT3 is the only approved anti-CD3 antibody. It is a mous anti-CD3 monoclonal antibody of the IgG2a type that acts by binding the T-cell receptor complex, which is present on all differentiated T cells. In this way, it prevents T-cell activation and proliferation. It is one of the most potent immunosuppressive substances and is clinically used to control episodes of acute Rkdf college of pharmacy bhopal

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rejection, where steroids and/or polyclonal antibodies are not effective. As it is more specific than polyclonal antibodies, it is also used preventively in transplantations. The exact mechanism of OKT3 (R) is not adequatly explained yet. It is known that it binds the T-cell receptor complex of antigen (TCR/CD3). In the first few administrations, this binding causes non-specific activation of T cells; therefore a serious syndrome develops 30 to 60 minutes after its application. It is characterized by the fever, myalgia, headache, and artralgia and can progress till the life-threatening reaction, that seriously affects cardiovascular system and the CNS and that a lengthy therapy is needed for. Later CD3 (R) blocks binding of TCR on antigen and causes change of conformation or the removal of the entire TCR3/CD3 from the T-cell surface. In this way, the CD3 antibodies lower the number of T cells, perhaps by sensitising them for the uptake by the reticular epithelial cells. The cross binding of CD3 molecules also provokes an intracellular signal, which causes the anergy or the apoptosis of T cells, if they do not receive another signal by one of more costimulatory molecules. CD3 antibodies also cause the shift in the balance of T cells from Th1 cells to Th2 cells. When making a decision about the use of OKT3(R) in the treatment, it is necessary to consider not only its great effectiveness, bu also its toxic side effects. These are the risk of excessive immunosuppression and the risk that the patient develops neutralizing antibodies against it, which would mean that the drug would not be effective anymore. Although CD3(R) antibodies are more specific than polyclonal antibodies, they significantly lower the cell-mediated immunity and predispose patient to opportunistic infections and malignancies. Antibodies directed towards IL-2 receptor Interleukin-2 is an important immune system regulator that is necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface receptor IL-2a, composed of α, β and γ chains. IL-2a (CD25, T-cell activation antigen, TAC) is expressed only on those T lymphocytes, that were previously activated in the interaction with a foreign antigen or with IL-2 and is the only IL-2 specific molecule. Therefore, it has a special significance in the selective immunosuppressive treatment. On the basis of these findings, research focused on the development of effective and safe anti-IL-2 antibodies. The modification of mouse anti-Tac antibodies with the recombinant gene technology enabled the presentation of two himeric mouse/human anti-Tac antibodies in the year 1998. One of these is basiliximab (Simulect (R)) and the other is daclizumab (Zenapax (R)). They work by binding the α chain of Rkdf college of pharmacy bhopal

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the IL-2a receptor on the activated T lymphocytes. This prevents the IL-2 induced clonal expansion of activated lymphocytes and shortens their survival. These two remedies are used as a profilaxis of the acute organ rejection in the patients, who have both kidneys transplanted. They cause few side effects and are similarly effective, as both of them decrease the frequency of the acute rejection for approximately a third.

Drugs acting on immunophilins:Cyclosporine A:Together with tacrolimus, cyclosporin is a calcineurin inhibitor. It has been in use since 1984 and is one of the most widely used immunosuppressive drugs. It is a fungal peptide, composed of 11 amino acids. When T-helper cell's receptor interacts with an antigen, the intracellular concentration of calcium in the cell rises. This increase activates the cytoplasmic phosphatase calcineurin. Calcineurin activates different transcription factors that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. This way, it directs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly. Cyclosporin is administered per intravenously. It reaches its highest concentration three to four hours later. Its tissue concentrations are to four times higher than in the plasma. In the tissue, it binds to the cytosolic immunophilin, named cyclofilin. The complex then binds to calcineurin and inhibits it. Cyclosporin is metabolized in the liver and secreted to the bile; its half time is about 24 hours. Cyclosporin is used in the treatment of acute rejection reactions, however because of its nephrotoxicity, it is substituted with newer immunosuppressants more and more. The nephrotoxicity affects 40 — 70% of patients. Especially the proximal tubules are destroyed.

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Other less frequent side effects are hypertension, venous thrombosis, tremor, headache, parestesias and hyperkalemia. Tacrolimus (Prograf(TM), FK506) Tacrolimus is a fungal product (Streptomyces tsukubaensis). It is a macrolide lactone and acts by inhibiting calcineurin. Tacrolimus is used particularly in the transplantation of kidney and liver. It can be administered per os or intravenously, and 99% of it degrades in the liver. Its half-life is approximately 12 hours. Tacrolimus binds an immunophilin, after which the complex binds to calcineurin and inhibits its phosphatase activity. In this way, it prevents the first phase of the T lymphocyte activation . Tacrolimus is more potent than cyclosporine and has less pronounced side effects. Among these, the most frequent are nephropathies, convulsions, tremor, hypertension, diabetes, hyperkalemia, insomnia, neuropathies and gout. Sirolimus (Rapamune (Tm), Rapamicin) Actinomycetes Streptomyces hygroscopicus produce it. Chemically it is a macrolide lactone. Sirolimus is used as an immunosuppresant in the transplantation. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects. It is administered solely per os in the form of tablets or a solution. It is metabolized in the liver by the CYP34A4 cytochrome, with the half time of about 62 hours. It is excreted particularly in feces, only 2% in urine. Contrary to cyclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, it affects the second one, namely the signal transduction and their clonal proliferation. It binds to the same receptor (immunophilin) as tacrolimus, however the produced complex does not inhibit calcineurin, but a special protein. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. Indirectly it inhibits several kinases and phosphates of T lymphocytes and prevents the transmission of signal into their activity and the continuation of the cell cycle from G1 phase to S phase. Similarly, it prevents B cell differentiation in the plasma cells, which means a lower quantity of IgM, IgG and IgA antibodies is produced. It acts immunoregulatory.

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Sirolimus' side effects are hyperlipidemia, leuko- and thrombocytopenia, anemia and hypokalemia. Its toxicity to the transplanted organ has not been proved, therefore it substitutes cyclosporin in kidney transplantations.

Other remedies:Interferons Interferons (IFNs) are cell proteins of the cytokine class and important antiviral factors, but they are synthesized also in response to other stimuli. Three major groups of interferons are known: IFN-α (leukocytic), IFN-β (fibroblastic) and IFN-γ (immune). These differ in their physical, chemical and biological properties. In a majority of cases, the production of interferons is induced by other cytokines, e.g. IL-1, IL2, TNF and CSF. IFN-α and IFN-β are synthesized in many cell types - macrophages, fibroblasts, endothelial cells, osteoblasts and others. Their synthesis is mainly caused by the appearance of viruses in the body. IFN-γ is produced in antigen-activated cells T in inflammatory and autoimmune conditions and has a central role in the immune response control. The effect of interferons All interferons have antiviral and antitumour effect and they cause fever. Beside this, IFN-β and IFN-γ have anti-inflammatory and immunosuppressive effects: •

IFN-γ is an inflammatory cytokine that by as yet unknown mechanism triggers apoptosis in lymphocytes

•

IFN-β inhibits the progression of multiple sclerosis. By an as yet unknown mechanism, it inhibits the production of Th1 cytokines and the monocyte activation. The production of IFN-γ during the infection is highly important to destroy foreign antigens and overcome the disease, however at the same time it can lead to autoimmune activity. Namely, IFN-γ has an exceptionally important immunoregulatory function. When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an intramuscular injection. Interferons hardly traverse the placenta and the blood-brain barrier. Their metabolism and excretion take place mainly in the liver and kidneys. The injection of interferons in the muscle, vein or under skin is generally well tolerated. The most frequent side effects are flu-like symptoms: raised body temperature, feeling ill, fatigue, headache, muscle pain, and convulsion. Erythema, pain and hardness on the spot of injection are Rkdf college of pharmacy bhopal

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also frequently observed. Rarely, patients experience their hair falling out, dizziness and depression. All known effects are reversible and disappear a few days after the therapy is finished. Opioids A prolonged taking of opioids (analgesics, illegal drugs) can cause immunosuppression, which means the risk of infection is increased. Their effects are not yet fully researched, however they cause diminished migration of leukocytes.

TNF-α binding drugs TNF-α binding drugs are proteins or antibodies, that bind to TNF (tumor necrotising factor) and prevent its action, that is the production of IL-1 and IL-6 and the adhesion of molecules that activate lymphocytes. They are intravenously administered and are used in the treatment or inhibition of progression of rheumatoid arthritis, ankylosing spondylitis, Chron's disease etc. Besides respiratory and other infections, their side effects also include the edema on the spot of administration, pancytopenia and sometimes vasculitis develops. In prolonged therapy, the risk of lymphoma is increased. The representatives of this class of drugs are Etanercept (Enbrel (Tm)) and Infliximab (Remicade(TM)).

Mycophenolic acid Mycophenolic acid (MPA) is an active component produced from Mycophenolate mofetil (MMF) and a new substance Mycophenolate sodium (Myfortic(R)). It acts as a non-competitive, selective and reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH), which is a key enzyme in de novo gvanosin nucleotide synthesis. In contrast to other human body cells, lymphocytes B and T are much more dependent of the de novo synthesized gvanosin.

Small biological agents FTY120

FTY120 is a new synthetic immunosuppressor, a chemical modification of the ISP-1 metabolite of the fungus Iscaria sincaliri. It is a structural analogue of sphyngosine and gets phosphorylated with the sphyngosine kinase in the cell. It increases the expression or changes the function of Rkdf college of pharmacy bhopal

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certain adhesion molecules (α4/β7 integrine) in lymphocytes, so they accumulate in the lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants.

Drugs: Many of the currently available immunosuppressants were developed for use in oncology or transplantation. As this treatment is potentially life saving desperate measures can be justified. However, there are now over 80 autoimmune diseases and several common allergic conditions in which immunosuppressants could play a role although they may not be life saving. Some immunosuppressants act through immunodepletion of effector cells, while others are predominantly immunomodulatory, affecting the activity of cells, usually through cytokine inhibition. Immunosuppressants can be categorised as glucocorticoids, small molecules or proteins.  Glucocorticoids Corticosteroids are the mainstay of most immunosuppressive regimens in both the induction and maintenance phases. In high intravenous pulse doses . (methylprednisolone 250-1000 mg daily for 1-3 days) they are directly lymphocytotoxic. In smaller doses, they are immunosuppressive and anti-inflammatory by limiting cytokine production. The required dose and duration of treatment therefore tends to be disease specific. Some diseases, for example asthma, respond to a short course, which can be abruptly stopped, but most rheumatic diseases require the dose to be very slowly tapered over months, especially when single figure milligram doses of prednisone are reached. Abrupt cessation runs the risk not only of relapse of disease, but also hypoadrenocorticism. (Adrenal suppression can be confirmed by a one-hour synthetic ACTH stimulation test if there is clinical concern.) In the withdrawal phase, non-specific polyarthralgias and myalgias are common, but generally respond to a small dose.

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Second-line drugs, usually antiproliferative drugs such as azathioprine, mycophenolate or methotrexate, may have a steroid-sparing effect in the maintenance phase of treatment. However, they also have their own toxicities. Patients prescribed corticosteroids should be told to expect the common early adverse effects, such as sweatiness, hoarse voice, loss of diurnal sleep patterns, and appetite stimulation. Rarely, more serious acute psychiatric disturbances are seen such as agitation, aggression or psychosis. Long-term, and less reversible, adverse effects include

Cushingoid appearance, proximal myopathy, hypertension, hyperlipidaemia, diabetes, cataract formation, peptic ulceration, osteopenia and aseptic necrosis of bone. (Table1) The small molecule immunosuppressants include calcineurin inhibitors, such as cyclosporin, and antiproliferative drugs, such as sirolimus.

 Calcineurin inhibitors :-

Since the 1980s, calcineurin inhibitors have been the main contributors to the success of solid organ transplantation, especially kidneys. By blocking interleukin-2 synthesis, they prevent activation of T-lymphocytes and are therefore useful in disorders of cell-mediated immunity. Calcineurin inhibitors have a proven role in the prevention of acute cellular rejection of transplanted organs, in psoriasis and in nephrotic syndrome.

They have been used in many other autoimmune conditions but have a diminishing role in rheumatoid arthritis. While they are good at maintaining autoimmune diseases in remission, withdrawal often leads to relapse. In solid organ transplantation, combinations of calcineurin inhibitors, mycophenolate mofetil and prednisone give better results than monotherapy. Ironically, calcineurin inhibitors are nephrotoxic and may contribute to long-term renal failure, both in transplanted organs and normal kidneys. They also aggravate hypertension and hyperlipidaemia thereby inducing an unfavourable cardiovascular profile. There is also an increased risk of diabetes. Mycophenolate mofetil. Since it was introduced into Australia in 1996 mycophenolate mofetil has largely replaced azathioprine in organ transplantation. One advantage over azathioprine is that allopurinol can be Rkdf college of pharmacy bhopal

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used for gout prophylaxis without the need to reduce the dose of mycophenolate. Possibly because of its anti-B cell properties2 mycophenolate seems particularly effective in severe forms of systemic lupus erythematosus. It is also gaining favour as a steroid-sparing drug in the maintenance phase of a number of immune disorders, particularly the vasculitides.3 The main adverse effects are haematological and gastrointestinal. On higher doses a third of patients will develop diarrhoea. An enteric-coated formulation of mycophenolate has been developed to try and reduce gastrointestinal adverse effects. Therapeutic drug monitoring is available but not widely used. Sirolimus and everolimus These potent antiproliferative drugs have gained acceptance in renal transplantation as a strategy to minimise the use of calcineurin inhibitors in low immunological risk patients.4 They have a decreased likelihood of causing hypertension and glucose intolerance. Although these drugs are associated with less nephrotoxicity than calcineurin antagonists, they potentiate the renal toxicity of cyclosporin and regular monitoring of renal function is recommended. Sirolimus and everolimus are generally avoided perioperatively because they can severely delay wound healing. They are potent inhibitors of intimal hyperplasia in arteries, and sirolimus-eluting intraarterial stents are now used to reduce re-stenosis rates. However, they can increase serum cholesterol and lipids. The balance of the harm and benefit of continued treatment should be reevaluated in patients who develop severe refractory hyperlipidaemia. Therapeutic drug monitoring is essential because of the risk of toxicity such as anaemia, leucopenia and thrombocytopenia. Cyclophosphamide Cyclophosphamide is a cytotoxic drug. It is the drug of choice for Wegener's granulomatosis, but is also used in other vasculitides such as microscopic polyangiitis and systemic lupus erythematosus.5 Monthly intravenous pulses are as effective as daily oral use in systemic lupus erythematosus, but allow a reduced total dosage. Cyclophosphamide is also used to induce sustained remission in relapsing nephrotic syndrome. Marrow suppression with neutropenia is common after six weeks of treatment and continuing more than six months runs the risk of gonadal suppression and infertility in both sexes. Methotrexate

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This antimetabolite is used in some autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis and Crohn's disease. As a disease-modifying antirheumatic drug, its use in combination with tumour necrosis factor inhibitors (such as infliximab or etanercept) or leflunomide has been shown to markedly improve symptoms in rheumatoid arthritis.6 Proteins (Table 2) Polyclonal antilymphocyte (antithymocyte) antibodies have been used in Australia since the 1960s. More recently, hybridoma technology has produced a plethora of monoclonal antibodies against molecules expressed by human immune effector cells. T-lymphocyte depleting antibodies such as muromonab-CD3 have been widely used to prevent or treat acute rejection of organ transplants. The main drawback is a 'cytokine storm' reaction to the first dose, which can cause life-threatening pulmonary oedema. Basiliximab and daclizumab are monoclonal antibodies against the interleukin-2 receptor (CD25). They are used as induction drugs in transplantation as they significantly reduce the acute rejection rate, with little or no increase in morbidity. They are not yet significantly used in autoimmune diseases. The anti-B cell antibody (anti-CD20), rituximab, is licensed for use against B-cell lymphomata, but there are now published anecdotal reports of its effectiveness in 29 different autoimmune diseases.7 Randomised controlled trials are proceeding in systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and in renal transplantation of highly sensitised recipients. A new monoclonal antibody, alemtuzumab, is directed against a surface molecule (CD54), which is widely distributed on lymphocytes, macrophages and dendritic cells, thereby causing severe and long-lasting depletion of these cell lines. As a result, the risk of serious infection is increased. The use of this antibody is cautiously making the transition from immunoprophylaxis in transplant recipients to a wider use in immune diseases. Two monoclonal antibodies against tumour necrosis factor, infliximab and adalimumab, and etanercept, which prevents tumour necrosis factor binding to its receptor, are licensed for use in rheumatoid arthritis. They are also being used in ankylosing spondylitis, psoriatic arthritis and inflammatory bowel disease. Infusion reactions are common. Pooled intravenous immunoglobulin was introduced to restore immunocompetence to patients with congenital acquired immune deficiency syndrome. Paradoxically, the discovery of its ability Rkdf college of pharmacy bhopal

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to inhibit the production and binding of auto-and allo-antibodies means that it is now more widely used as an immunomodulatory drug in the treatment of debilitating autoimmune diseases and antibody-mediated allograft rejection.10 The fact that immunoglobulin also provides passive immunity means that it is regarded as having a low risk of infectious complications compared to other immunosuppressants. Consequently, it has been used in many conditions without good supportive evidence of efficacy, so the Australian National Blood Authority guidelines now restrict its use.11 Nevertheless, it is likely that immunoglobulin use will continue to rise as knowledge about its mechanisms of action accumulates. Using immunosuppressants - strategies and protocols Treatment protocols are designed to: (a) Remove suppress the predominant immune effectors (b) Resolve acute inflammation (c) Prevent relapse. To achieve (a) and (b), high doses are often used initially ('induction phase'). To achieve (c), lower doses of safer drugs are often chosen for the longer term ('maintenance phase'). Withdrawal of therapy is usually only considered after achieving clinical and laboratory evidence of sustained remission. Drugs are withdrawn gradually, one at a time and in the case of corticosteroids only after a long taper. Empiricism vs. controlled trials Many protocols have evolved empirically from an understanding of the putative immune mechanisms operating in a particular disease. Sometimes the protocols were derived from what had been seen to work in conditions with apparently similar immunopathology. Randomised controlled trials of immunosuppressive protocols are available in the more common conditions such as rheumatoid arthritis or organ transplantation, but as new drugs emerge, the combinations for comparison become bewildering. Today's 'gold standard' treatment can be very quickly outdated, perhaps even before it has been optimised. Tailoring of immunotherapy to the individual is desirable, but this approach makes protocol comparisons difficult. Similarly, the disease being treated may be so pleomorphic that finding like populations to compare in trials becomes very difficult. For example, lupus nephritis has five distinct histological subtypes, each with their own prognosis. Rkdf college of pharmacy bhopal

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Choosing immunosuppressive regimens In order to make sound judgements when choosing a treatment protocol the clinician has to consider the clinical trial evidence and then decide: •

Is the aim to pre-empt an anticipated immune response (for example, after organ transplantation) or to suppress an established immune-mediated inflammation (for example, acute glomerulonephritis)?

•

In the case of an immune disease, how much immunosuppression will be required and for how long (that is, an assessment of disease activity)? Consider:

•

The natural history of the untreated disease

•

Is the disease multiphase (for example, polyarteritis nodosa) or 'single shot'

•

(for example, microscopic polyangiitis)

•

The extent and severity of the disease in this particular patient

•

Is the affected organ beyond recovery

•

The likelihood of relapse

•

The ability to monitor disease parameters long term

•

Is this patient likely to withstand the treatment I will recommend (host fitness parameters)? Consider:

•

Age (older patients are easier to immunosuppress but have a greater risk of infection)

•

Sepsis risk

•

Cancer risk

•

Cardiovascular/diabetes risk

•

Presence of comorbidities

•

Patient compliance and availability for follow-up.

•

In choosing the dose and duration of immunosuppressive treatments, one must always weigh disease activity versus host fitness. For example, an elderly patient with perinuclear-ANCA positive microscopic polyangiitis, confined to the kidneys, with crescents in 10% of glomeruli, will not need as aggressive an approach as the same disease in a young patient, with 80% crescents, lung haemorrhage and mononeuritis multiplex.

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Managing and monitoring patients taking immunosuppressants Patients need to be under constant surveillance, usually by a partnership between the specialist and the general practitioner. Frequency of visits depends on perceived level of risk, but typical parameters to monitor are summarised in Table 3. Patients may need prophylaxis against the adverse effects of their treatment (Table 4). Therapeutic drug monitoring is available now for a number of drugs, for example cyclosporin, tacrolimus, sirolimus and mycophenolate. This allows for 'concentration-controlled' regimens. Some common drugs, for example corticosteroids, still have no good measure of individual bioavailability.  Infection risk Immunosuppression increases susceptibility to infections which can become life-threatening in a matter of hours. At first, common bacterial infections of wounds, chest or urine predominate, but after 1-2 months of therapy opportunistic infections emerge, particularly herpes viruses, pneumocystis pneumonia, fungi and atypical mycobacteria. Vaccinations against influenza (injected) and pneumococcus are recommended in chronically immunosuppressed patients.12 They are safe and reasonably effective when given in the stable maintenance phase. In general, live attenuated virus vaccines, such as varicella or measles, should not be given to immunosuppressed patients (or to close family contacts).

Interaction:Immunosuppressant drugs may interact with other medicines. When this happens, the effects of one or both drugs may change or the risk of side effects may be greater. Other drugs may also have an adverse effect on immunosuppressant therapy. This is particularly important for patients taking cyclosporin or tacrolimus. For example, some drugs can cause the blood levels to rise, while others can cause the blood levels to fall and it is important to avoid such contraindicated combinations. Other examples are: •

The effects of azathioprine may be greater in people who take allopurinol, a medicine used to treat gout.

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•

A number of drugs, including female hormones (estrogens), male hormones (androgens), the antifungal drug ketoconazole (Nizoral), the ulcer drug cimetidine (Tagamet) and the erythromycins (used to treat infections), may increase the effects of cyclosporine.

•

When sirolimus is taken at the same time as cyclosporin, the blood levels of sirolimus may be increased to a level where there are severe side effects. Although these two drugs are usually used together, the sirolimus should be taken four hours after the dose of cyclosporin.

•

Tacrolimus is eliminated through the kidneys. When the drug is used with other drugs that may harm the kidneys, such as cyclosporin, the antibiotics gentamicin and amikacin, or the antifungal drug amphotericin B, blood levels of tacrolimus may be increased. Careful kidney monitoring is essential when tacrolimus is given with any drug that might cause kidney damage.

•

The risk of cancer or infection may be greater when immunosuppressant drugs are combined with certain other drugs which also lower the body's ability to fight disease and infection. These drugs include corticosteroids such as prednisone; the anticancer drugs chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and mercaptopurine (Purinethol); and the monoclonal antibody muromonab-CD3 (Orthoclone), which also is used to prevent transplanted organ rejection. Not every drug that may interact with immunosuppressant drugs is listed here. Anyone who takes immunosuppressant drugs should let the physician know all other medicines he or she is taking and should ask whether the possible interactions can interfere with treatment.

Side effects:Increased risk of infection is a common side effect of all the immunosuppressant drugs. The immune system protects the body from infections and when the immune system is suppressed, infections are more likely. Taking antibiotics such as co-trimoxazole prevents some of these infections. Immunosuppressant drugs are also associated with a slightly increased risk of cancer because the immune system also plays a role in protecting the body against some forms of cancer. For example, long-term use of immunosuppressant drugs carries an increased risk of developing skin cancer as a result of the combination of the drugs and exposure to sunlight. Other side effects of immunosuppressant drugs are minor and usually go away as the body adjusts to the medicine. These include loss of appetite, nausea or vomiting, increased hair

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growth, and trembling or shaking of the hands. Medical attention is not necessary unless these side effects continue or cause problems. The treating physician should be notified immediately if any of the following side effects occur: •

unusual tiredness or weakness

•

fever or chills

•

frequent need to urinate

•

Uses:•

Used in conjunction with steroids

•

Used in autoimmune disorders

•

Used to reduce the immune response when foreign tissue is transplanted into the body

•

Older drugs depressed immune system; had unfortunate SE. Infections, cancer, hypertension and metabolic bone disease.

Precautions:Seeing a physician regularly while taking immunosuppressant drugs is important. These regular check-ups will allow the physician to make sure the drug is working as it should and to watch for unwanted side effects. These drugs are very powerful and can cause serious side effects, such as high blood pressure, kidney problems and liver problems. Some side effects may not show up

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until years after the medicine is used. Anyone who has been advised to take immunosuppressant drugs should thoroughly discuss the risks and benefits with the prescribing physician Immunosuppressant drugs lower a person's resistance to infection and can make infections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the treating physician knows about the immunosuppressant prescription. The prescribing physician should be immediately informed if signs of infection, such as fever or chills, cough or hoarseness, pain in the lower back or side, or painful or difficult urination, bruising or bleeding, blood in the urine, bloody or black, tarry stools occur. Other ways of preventing infection and injury include washing the hands frequently, avoiding sports in which injuries may occur, and being careful when using knives, razors, fingernail clippers or other sharp objects. Avoiding contact with people who have infections is also important. In addition, people who are taking or have been taking immunosuppressant drugs should not have immunizations, such as smallpox vaccinations, without checking with their physicians. Because of their low resistance to infection, people taking these drugs might get the disease that the vaccine is designed to prevent. People taking immunosuppressant drugs also should avoid contact with anyone who has taken the oral polio vaccine, as there is a chance the virus could be passed on to them. Other people living in their home should not take the oral polio vaccine. Immunosuppressant drugs may cause the gums to become tender and swollen or to bleed. If this happens, a physician or dentist should be notified. Regular brushing, flossing, cleaning and gum massage may help prevent this problem. A dentist can provide advice on how to clean the teeth and mouth without causing injury.

Special conditions:People who have certain medical conditions or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before taking these drugs, the prescribing physician should be informed about any of these conditions: Rkdf college of pharmacy bhopal

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 ALLERGIES  Anyone who has had unusual reactions to immunosuppressant drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.  PREGNANCY Azathioprine may cause birth defects if used during pregnancy, or if either the male or female is using it at time of conception. Anyone taking this medicine should use a barrier method of birth control, such as a diaphragm or condoms. Birth control pills should not be used without a physician's approval. Women who become pregnant while taking this medicine should check with their physicians immediately. The medicine's effects have not been studied in humans during pregnancy. Women who are pregnant or who may become pregnant and who need to take this medicine should check with their physicians.  BREASTFEEDING Immunosuppressant drugs pass into breast milk and may cause problems in nursing babies whose mothers take it. Breastfeeding is not recommended for women taking this medicine.  OTHER MEDICAL CONDITIONS People who have certain medical conditions may have problems if they take immunosuppressant drugs. For example: •

People who have shingles (herpes zoster) or chickenpox, or who have recently been exposed to chickenpox, may develop severe disease in other parts of their bodies when they take these medicines.

•

The medicine's effects may be greater in people with kidney disease or liver disease, because their bodies are slow to get rid of the medicine.

•

The effects of oral forms of this medicine may be weakened in people with intestinal problems, because the medicine cannot be absorbed into the body. Rkdf college of pharmacy bhopal

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Before using immunosuppressant drugs, people with these or other medical problems should make sure their physicians are aware of their conditions.

Conclusion:In addition to being used to prevent organ rejection, immunosuppressant drugssometimes are used to treat severe skin disorders such as psoriasis and other diseases such as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss (alopecia areata). Immunosuppressant drugs lower a person's resistance to infection and can makeinfections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the physician in charge knows about the medicine. People who have certain medical conditions or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before takingthese drugs, be sure to let the physician know about allergies, whether you are pregnant or on oral birth control pills, or who have shingles or chicken pox. Although corticosteroids and drugs such as azathioprine still have a role, there is increasing use of newer potent immunosuppressants. Many of these drugs act on T-lymphocytes. Tacrolimus is a calcineurin inhibitor which has a similar mechanism of action to cyclosporin, reducing T-cell differentiation. Sirolimus and everolimus bind to the same protein as tacrolimus, but have a different mechanism of action. As some of these drugs have a narrow therapeutic range, drug concentrations must be monitored. Mycophenolate is an inhibitor of purine synthesis. Another approach is to block the receptors on T-cells with immunosuppressant antibodies such as basiliximab, daclizumab and muromonab-CD3.

References: Abbas, A. K., and A. H. Lichtman. Basic Immunology: Functions and Disorders of theImmune System. Philadelphia: W. B. Saunders Co., 2001.  Sompayrac, L. M. How the Immune System Works. Boston: Blackwell Science, 1999. Rkdf college of pharmacy bhopal

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