Immunosuppression and antiinflammatory

Interleukin-2-inducible T cell kinase (ITK) is expressed mainly in T-lymphocytes and plays a major role in the activation of T-cells. Thus inhibitors of ITK should be useful as immunosuppressives and antiinflammatory agents. Snow et al. [67] describe a novel series of 2-aminobenzimidazole ITK inhibitors which is optimized... 

Janssen NM, Genta MS. The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med 2000 160 610-619. 

Immunosuppression and Antiinflammatory Effects In addition to its ability to suppress myometrial and endometrial prostaglandin formation, progesterone suppresses T-lymphocyte proliferation, interleukin-8 synthesis, and increases prostaglandin dehydrogenase activity, all of which contribute to preventing maternal rejection of the implanting conceptus (an allograft). 

A new generation of antiinflammatory agents having immunosuppressive activity has been developed. The appearance of preclinical and clinical reports suggest that these are near entry to the pharmaceutical market. For example, tenidap (CP-66,248) (12) has been demonstrated to inhibit IL-1 production from human peripheral blood monocytes in culture (55). Clinically, IL-1 in synovial fluids of arthritic patients was reduced following treatment with tenidap. Patients with rheumatoid or osteoarthritis, when treated with tenidap, showed clinical improvement (57,58). In addition to its immunological effects, tenidap also has an antiinflammatory profile similar to the classical NSAIDs (59). Other synthetic inhibitors of IL-1 production are SKF 86002 (20) andE-5110 (21) (55). 

Di-tert-butyl-4-hydroxyphenyl)-7//-triazolo [3,2-b][l, 2,4]triazin-7-one (HWA-131)is anon-immunosuppressive drug that effectively inhibited carrageenan-induced paw edema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effect of this new compound is most probably related to its antioxidative activity as well as inhibition of lipoxygenase... 

Type II, III, and IV allergic reactions are variants of physiologic defense mechanisms only relevant in special situations, which follow a common pathologic pattern. In general, treatment of these forms require antiinflammatory ( inflammation) or immunosuppressive strategies ( immunosuppression). Therefore, only therapy of Type I reactions will be described here. 

Corticosteroids have antiinflammatory and immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation. 

Thalidomide (Thalomid) is a derivative of glutamic acid that is chemically related to glutethimide. It exerts a number of biological effects as an immunosuppressive, antiinflammatory, and antiangiogenic agent, yet its mechanisms of action have not been fuUy elucidated. Thalidomide potently inhibits production of tumor necrosis factor (TNF) a and interleukin (IL) 12, and its effect on these and other cytokines may account for some of its clinical effects. 

Antiinflammatory and immunosuppressive effects Glucocorticoids suppress all types of inflammation, hypersensitization and allergic reactions. They suppress the edema, capillary dilatation, migration of leukocytes, capillary permeability in the inflamed area. 

Glucocorticoids are used primarily for their antiinflammatory and immunosuppressive effects to treat... 

Cyclosporins, produced by the filamentous fungus Tolypocladium niveum and by numerous strains of Fusaria and Neocosmospora, are a class of cyclic undecapep-tides which are composed of hydrophobic aliphatic amino acids [73-75], They exhibit antiinflammatory, immunosuppressive, antifungal, and antiparasitic properties [74], The main metabolite, cyclosporin A, is in clinical use worldwide under the trade name SANDIMMUN to prevent allograft rejection [77,78], Besides cyclosporin A, there are 24 naturally occuring cyclosporins which have substitutions of amino acids in positions 1, 2, 4, 5, 7, and 11 and/or contain unmethylated peptide bonds in positions 1,4,6,9,10, or 11 [79-82], Cyclosporin A contains three nonproteinogenic amino acids D-alanine in position 8, L-a-aminobutyric acid in position 2, and, in position 1, the unusual amino acid 4(R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt) (Fig. 8). All three amino acids have to be synthesized by a pathway independent of the primary metabolism. In addition, several peptide bonds of the cyclosporin molecule are A -mcthylated similar to the depsipeptides enniatin, beauvericin and PF1022A-related peptides. 

Corticosteroids have a range of activity. They have potent antiinflammatory and immunosuppressive activity. Many synthetic drugs are available as corticosteroids. In appropriate doses, these are used as replacement therapy in adrenal insufficiency. The topical application of corticosteroids is safer when compared with systemic use. Corticosteroids should be used in smaller doses for the shortest duration of time. A high dose may be used for life-threatening syndromes or diseases. A tapering pattern of withdrawal should be followed to avoid complications of sudden withdrawal. Systemic therapy is indicated in a variety of conditions. These are administered by intraarticular injections with aseptic conditions for rheumatoid arthritis and osteoarthritis. In skin diseases, such as eczema, contact dermatitis, and psoriasis, corticosteroids are used topically. In some cases, steroids are combined with antimicrobial substances such as neomycin. 

At an advanced stage (II, III) with AMA profile B, the combination of UDCA -I- prednisolone (maintenance dose 4-8 mg/day in the morning) should generally be administered as first medication. In the case of unsatisfactory therapeutic results or with AMA profiles C or D (= stages III or IV), we would recommend the additional administration of azathloprine as a triple therapy. A dosage of 1 x 50 mg (up to 2 x 50 mg) per day is well-tolerated and, like prednisolone at this dosage, has relatively few side effects. A maintenance dose of 50 mg every second day may be sufficient. (170) The immunomodulatory action of UDCA is thus combined with the immunosuppressive effect of azathioprine, while the antiinflammatory characteristics of the steroids are also included, i.e. the two-substance combination is extended to a triple combination if necessary, especially in profiles Cor D. 

Roubenoff R, Hoyt J, Petri M, Hochberg MC, Hellmann DB. Effects of antiinflammatory and immunosuppressive drugs on pregnancy and fertihty. Semin Arthritis Rheum 1988 18(2) 88-110. 

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