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At least 397 records · Page 22Linked to original sources
PubMed1995

Tacrolimus: a new immunosuppressive agent.

The mechanism of action, pharmacokinetics, drug interactions, clinical efficacy, and adverse effects of tacrolimus, a newly approved immunosuppressant drug for use in the prophylaxis of organ rejection after transplantation, are reviewed. Tacrolimus prevents rejection of the transplanted organ by inhibiting the expression of interleukin-2 in T cells and inhibiting T-cell growth and proliferation. Bioavailability after oral administration is 5-67%, and the half-life is 4-41 hours. Tacrolimus is extensively metabolized by cytochrome P-450 3A4 isoenzyme, resulting in several known drug interactions. Most experience with tacrolimus has been at one institution, where clinical trials have been conducted in liver, kidney, heart, lung, and intestinal transplantation. Clinical trials have shown that tacrolimus is an effective alternative to cyclosporine for both primary immunosuppression and rescue therapy in liver transplant patients. Fewer reports have been published regarding tacrolimus use in other types of transplantation, but the results show that tacrolimus may be a useful alternative to cyclosporine. The major adverse effects of tacrolimus therapy are nephrotoxicity and neurotoxicity. Tacrolimus is an effective alternative to cyclosporine as a primary immunosuppressant in the prevention of organ rejection and may reduce the incidence of rejection after organ transplantation.

Clinical Trials as Topic↗
PubMed1994

Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent.

FK506, a macrolide antibiotic produced by Streptomyces tsukubaensis, is known as a potent T cell-specific immunosuppressant, and is effective against graft rejection after organ transplantation. Topical application of FK506 (0.03-1 mumol) to dorsal skin of CD-1 mice stimulated hair growth in a dose-dependent manner. Unlike topical application, oral administration of 30 mg/kg of FK506, a dose that induces marked immunosuppression, did not stimulate significant hair growth. Topical application of FK506 also stimulated hair growth of rats and Syrian golden hamsters. FK506 stimulated hair growth even in SCID mice that lack both B- and T-cell immunity. Therefore, it is unlikely that the hair growth-stimulatory effect of FK506 results from its immunosuppressive effect. FK506 (0.01-1 microM) stimulated both [3H]thymidine and [3H]glycine uptakes to cultured mouse vibrissae follicles in a concentration-dependent manner. Moreover, when the follicles were treated with FK506 (1 microM) for 16 d, the size of the follicles (length of hair plus follicle) increased slightly but significantly. On the other hand, the size of the non-treated follicles did not increase significantly. These results indicate that FK506 directly stimulates hair follicles. Long-term treatment of mice with FK506, i.e., topical application of 1 mumol FK506 twice a week for 6 months, did not affect body weight gain of mice, and the FK506-treated mice looked healthy. FK506 may be useful as a stimulant of hair growth.

Administration, Topical↗
PubMed1980

Immediate loss of cell-mediated immunity to murine cytomegalovirus upon treatment with immunosuppressive agents.

Splenic lymphocytes from cytomegalovirus-infected mice lost their in vitro proliferative responses to cytomegalovirus antigen within 3 h after in vivo treatment with antilymphocyte globulin and prednisolone. The response was inhibited when the agents were administered separately or together, and inhibition persisted through a 2-week course of immunosuppression. Circulating specific antibodies were depressed by multiple injections of antilymphocyte globulin alone or with prednisolone, but not by prednisolone alone. Mitogen-induced blast transformation was immediately depressed by immunosuppression with both agents. Although the response to lipopolysaccharide returned briefly, it declined with continuing treatment. Cytomegalovirus infection augmented the depressive effect of immunosuppression on the lipopolysaccharide proliferative response. Prednisolone treatment of infected animals did not affect the concanavalin A response, and lipopolysaccharide stimulation decreased more slowly and to a lesser extent than it did in mice treated with antilymphocyte globulin or both agents. Loss of specific cell-mediated immunity and simultaneous depression of humoral immunity indicated that immunosuppression immediately created an inability to respond to an active cytomegalovirus infection.

Animals↗
PubMed1998

Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.

Immunotoxins (ITs) are potent cytotoxic agents used in the treatment of cancer, autoimmune disease, and graft-versus-host disease. Results from clinical trials demonstrate that many IT-treated patients, especially those with an intact immune system, develop anti-IT antibodies that may prohibit repeated IT dosing. We, therefore, evaluated a panel of novel immunosuppressive (IS) agents for their ability to inhibit the antitoxin immune response in mice receiving multiple courses of a ricin A chain (RTA)-containing IT and also assessed whether this suppression would result in an increase in IT-mediated antitumor activity. The results indicate that a 3-day pretreatment, plus one additional boost 2 weeks later, of a combination of hCTLA4Ig + anti-CD40L, virtually eliminated the anti-RTA response in normal mice receiving six weekly injections of an IT. When tested in BCL1 tumor-bearing mice, the concomitant use of a combination of hCTLA4Ig + anti-CD40L and six doses of the IT resulted in a 1.5-fold increase in tumor cell killing, as compared with treatment with IT alone. We conclude that a combination of IS + IT therapy should facilitate the administration of multiple courses of IT, as well as enhance its antitumor activity.

Animals↗
PubMed1989

Experimental investigations into the carcinogenic effect of antitumor and immunosuppressive agents.

In a comprehensive experimental study on rats, the carcinogenicity of various therapeutically important antitumor drugs was investigated. The influences of strain, sex, dose and time of administration were systematically varied. The tested compounds showed remarkable differences in their carcinogenic potential. These differences were particularly obvious, not only when the total tumor rate was analyzed, but also when the distribution of tumor rates to the various localizations was considered (tumor spectrum). Three classes of carcinogenic substances were identified: (1) Substances showing a specific carcinogenicity: they lead to tumorogenesis primarily in organs or organ systems that, in the untreated control animals, remain virtually tumor-free for life. One example of such a substance is chlormethine. (2) Substances with non-specific carcinogenicity: they lead to an increase in tumors in organs that are also stricken in the control animals, however, to a clearly reduced extent. Oxazaphosphorine carcinogenicity is typical for this class. (3) Substances of mixed-type carcinogenicity: this group shows non-specific carcinogenicity, as well as a carcinogenic action with marked organ specificity. One example of this class is procarbazine. The antimetabolites tested were shown to be practically non-carcinogenic. Characteristic differences occurred between the two rat strains used in the investigation, Sprague-Dawley and BD II, with regard to the spontaneous tumor spectrum and the organ-related extent of carcinogenicity under the influence of the substances tested. In an experiment involving short-term application (up to 17% LD50, five times i.v. at 14-day intervals), the carcinogenic effects were substantially lower than in an experiment involving long-term application (up to 7% LD50, once a week for 52 weeks, i.v.), although the strain- and substance-specific characteristics in both experiments were rather similar.

Animals↗
PubMed1999

[Treatment of myasthenia: role of corticoids and immunosuppressive agents].

OPTIMAL TREATMENT: Myasthenia is an autoimmune disease related to a recognized autoantigen. Treatment is aimed at providing symptomatic relief or a pathophysiological effect. The latter approach, with corticosteroid and immunosuppressor regimens, has proven to be effective, improving functional improvement, but at the cost of prolonged treatment over several years with the risk of major adverse effects. Indications and treatment modalities must be carefully weighed. INITIATING TREATMENT: The question is when to start corticosteroids or immunosuppressors. A regimen should be initiated when, after all aggravating factors have been eliminated, a well-conducted anticholinesterase treatment remains ineffective with persistent major muscular deficit and brain stem disorders (deglutition, ventilation). Corticosteroids and immunosuppressors are also indicated if acute episodes occur, even if they regress. TREATMENT REGIMENS: To date, no controlled study has validated any particular therapeutic protocol. Both corticosteroids and immunosuppressors are known to provide major improvement in 80% of patients. No one immunosuppressor has been found to be more effective, but azathioprine is prescribed preferentially because of its lower profile of adverse effects. IN CLINICAL PRACTICE: Response is relatively rapid to corticosteroids which are recommended in combination with azathioprine at treatment onset for more severe cases (brain stem signs or recurrent acute episodes) or secondarily in case of resistance to moderate dose corticosteroids. In all cases, treatment must be prolonged for several years. Relapses are frequent after treatment withdrawal.

Acute Disease↗