The pharmacokinetics of Cyclosporin A (CyA, Sandimmune) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9 +/- 4.9 hr to 11.9 +/- 4.9 hr (mean +/- SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2-0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5-3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.

On the dose dependency of cyclosporin A absorption and disposition in healthy volunteers.

Cyclosporin, a novel drug, exhibiting unique discriminatory action on the activation of helper lymphocytes without the undesirable side effects associated with conventional immunosuppressants, can well be considered as the prototype of a new generation of immunosuppressants. It is probably the first one to demonstrate that an immunopharmacologic approach to the modulation of the immune response by drugs is feasible. This enabled a decisive step forward to be made in transplantation surgery, particularly in the field of heart and kindney transplantation. Cyclosporin A exerts antifungal, antiparasitic and antiinflammatory activities also. There is considerable interest in the prospective value of this drug in the treatment of autoimmune disorders. Accolades are to be given for its role as a tool for studying mechanisms of the immune system. This review is an attempt to look into the various strides it had evolved before attaining the status of a unique drug, and also to assess critically the prospective value of this potent drug. The present modem era of antibiotic research is characterized by advanced screening procedures aiming specifically not only at antibacterials or antifungals but at compounds like enzyme inhibitors, immunomodulators and antitumor drugs. New sources of rare microorganisms are currently under exploitation. Development of microbial products with new medicinal activties has turned out to be a big research area, spearheaded by the success story of small molecular weight immunomodulators. Long accepted as the best way to prevent or treat rejection in patients undergoing organ transplantation, immunosuppressive therapy is attracting increased attention for its ability to treat a variety of diseases. One such potent agent, widely acclaimed as the first of a new generation of remarkable immunosuppressive agents, cyclospofin is being used in novel ways in a wide array of conditions. The cyclosporins are a group of over 25 closely related cyclic undecapeptides produced as secondary metabolites by two strains of fungi imperfecti, Cylindrocarpum lucidum BOOTH and Tolypocladium inflaturn CAMS, isolated from soil samples. Cyclosporin A is the main component of this family of cyclic peptides each containing 11 amino acids. This review is a survey of the works of a large team of chemists, biologists, clinicians, toxicologists and pharmacologists which lead to the development of a new drug of choice and the impact that this drug in particular is having and hopefully other similar ones will have in the field of immunopharmacology.

The panorama of cyclosporin research.

Although cyclosporine (CS) has been used for the treatment of patients with rheumatoid arthritis (RA) (3, 4, 5), we are not aware of any reports on CS treatment in juvenile rheumatoid arthritis (JRA). We describe here a patient with early onset of systemic JRA (1) who did not respond to therapy with systemic corticosteroids or cytostatic drugs (azathioprine, methotrexate, chlorambucil, cyclophosphamide). The patient recovered after CS treatment, and had no remaining signs of her illness.

Cyclosporin treatment of a patient with severe systemic juvenile rheumatoid arthritis.

All the studies so far performed indicate that CS treatment in RA is effective. But it is also clear that CS-induced nephrotoxicity is so far the main problem. However, nephrotoxicity can be minimized by lowering the CS dosage and by ensuring that RA patients subjected to CS therapy have a normal kidney function and no history of hypertension. Hypertrichosis due to CS therapy is also a considerable problem, since the majority of patients with autoimmune diseases are women. Malignant lymphomas are a minor problem as so far there have only been two reported cases among 2500 CS-treated patients with autoimmune diseases.

Cyclosporine and rheumatoid arthritis

All the studies so far performed indicate that Cyclosporine (CyA) treatment i RA is effective and one study indicates that it can also slow down radiological progression. But it is also clear that CyA induced nephrotoxicity is so far the main problem. However, nephrotoxicity can be minimised by lowering the CyA dosage and by ensuring that RA patients subjected to CyA therapy have a normal kidney function and no history of hypertension. I believe that CyA alone or in combination with other drugs will find its place in the treatment of RA and other autoimmune diseases in the near future.

Cyclosporine in rheumatoid arthritis: an overview.

Ciclosporin (CyA) is a potent immunosuppressive agent which acts selectively upon the immune response by inhibition of the lymphokine cascade, thus inhibiting cell-cell communication [1]. In addition, augmentation of the inflammatory response is attenuated by blockade of macrophage migration inhibition factor (MIF) and macrophage arming factor (MAF), limiting the delayed-type hypersensitivity response and immunologically nonspecific tissue injury [2]. By virtue of its efficacy and immunologic specificity, CyA is employed extensively in organ transplantation, and also appears to be of major potential importance in the area of auto-immunity.

Pharmacokinetics and Interactions of Ciclosporin

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Pharmacokinetics and Interactions of Ciclosporin