Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)

/pdf/cyclosporin-a-review-of-its-pharmacodynamic-and-2wjzyh5l5a.pdf

Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.

Topical Cyclosporine in High-risk Corneal Transplants

Especially in western civilizations, immune diseases that are driven by innocuous (auto- or allo-) antigens are gradually evolving to become pandemic threats. A particularly poignant example is type 1 diabetes, where young children are confronted with the perspective and consequences of total pancreatic β-cell destruction. Along these disquieting observations we find ourselves equipped with impressively accumulating molecular immunological knowledge on the ins and outs of these pathologies. Often, however, it is difficult to translate this wealth into efficacious medicines. The molecular understanding, the concept of oral tolerance induction, the benefit of using recombinant Lactococcus lactis therein and recent openings towards their clinical use may well enable turning all colors to their appropriate fields on this Rubik's cube.

/pdf/recombinant-lactococcus-lactis-can-make-the-difference-in-5bfpqoxpu2.pdf

Recombinant Lactococcus lactis can make the difference in antigen-specific immune tolerance induction, the Type 1 Diabetes case

We have evaluated the effects of the novel immunosuppressant sodium fusidate (fusidin) in the non-obese diabetic (NOD) mouse and in D-galactosamine (D-Gal)-presensitized BALB/c mice challenged with the bacterial superantigen, Staphylococcus aureus enterotoxin B (SEB) or with the endotoxin, Escherichia coli lipopolysaccharide (LPS). The NOD mouse model has clinical and histoimmunological features similar to those of human insulin-dependent diabetes mellitus (IDDM). The SEB- and LPS-treated BALB/c mouse models exhibit pathogenic similarities with human septic shock conditions. In the NOD mouse, fusidin suppressed the spontaneous development of insulitis (mean inhibition 73%) and hyperglycaemia (IDDM incidence 25% versus 0%) when administered at 40 mg/kg five times weekly for 8 consecutive weeks from the fourth week of age; concurrently treated animals exhibited reduced percentages of splenic T lymphocytes. This anti-diabetogenic effect was confirmed in the accelerated model of diabetes induced in the NOD mouse with cyclophosphamide (CY) (IDDM incidence 55% versus 21-6% using dosages of fusidin from 40 to 80 mg/kg five times weekly); protection from IDDM development was achieved even when the drug (80 mg/kg/day) was first administered 7 days after CY challenge. In contrast, fusidin did not reverse hyperglycaemia when administered to CY-treated animals within 3 days of IDDM development. In the two models of septic shock, prophylactic treatment with fusidin, 80 mg/kg given three times for 2 days prior to D-Gal/SEB or D-Gal/LPS challenge, drastically reduced the lethality compared with D-Gal/buffer-treated mice. This effect may depend on the inhibitory action of fusidin on the secretion of cytokines such as interferon-gamma and tumour necrosis factor-alpha, the serum levels of which were greatly diminished in the fusidin-treated mice (mean inhibition 50-90%). These results demonstrate that fusidin may have a role in the treatment of cell-mediated autoimmune diseases and cytokine-mediated infectious diseases in humans.

Effects of sodium fusidate in animal models of insulin-dependent diabetes mellitus and septic shock.

Cyclosporin and other immunosuppressive agents have been proposed as a preventive treatment against the development of insulin-dependent diabetes mellitus (IDDM) in relatives at increased risk for the disease, based on the understanding that its etiology is an ongoing process of autoimmune beta-cell destruction. We used an epidemiological approach to evaluate several recent trials of cyclosporin in newly diagnosed IDDM patients to determine the degree of benefit that is to be expected. We assessed these and other studies to estimate the potential adverse effects of such treatment, were it to be used in the future, either in newly diagnosed subjects or healthy high-risk relatives. Standard sample-size calculations were used to quantify the number of study subjects necessary to allow adequate statistical power to test the positive and negative effects of a future treatment (alpha = 0.05, beta = 0.20). The estimates were based on the data available from published studies of cyclosporin treatment. The importance of conducting an adequate trial of such a therapy, both from an ethical and a practical viewpoint, is discussed. Five small immunosuppression trials were evaluated. Remission rates in treated subjects exceeded those in control subjects by 15-59%. Variability in defining remission may account for the differences in rates across the studies. Estimates of the major beneficial and adverse effects of cyclosporin were derived from these trials and studies of patients who have undergone long-term immunosuppression. Indicators of kidney damage associated with cyclosporin treatment were reported in 5-47% of treated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporin therapy for prevention and cure of IDDM. Epidemiological perspective of benefits and risks.

Effects of immunosuppression with cyclosporine in insulin-dependent diabetes mellitus of recent onset: the Canadian open study at 44 months.

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Effects of immunosuppression with cyclosporine in insulin-dependent diabetes mellitus of recent onset: the Canadian open study at 44 months.