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PubMed1998

Clinical application of immunosuppressive agents in renal transplantation.

The availability of a number of new immunosuppressive drugs has resulted in significant improvements in the outcome of kidney transplantation. Currently 1-year graft survival rate for cadaver kidney transplants is approximately 85%. A number of new agents are presently in clinical studies. This article reviews the currently available agents and examines various aspects of induction and maintenance immunosuppressive therapy, and the treatment of acute rejection episodes. In addition, the agents currently in clinical trials and future directions in immunosuppressive therapy are discussed.

Acute Disease↗
PubMed2005

Sirolimus as primary immunosuppression agent in kidney transplant recipients: Akdeniz University experience.

OBJECTIVES: Recently usage of sirolimus as the primary immunosuppressant is widening among kidney transplant recipients. We reviewed the clinical follow-up of patients transplanted at our center using sirolimus protocols. METHODS: Sirolimus including primary immunosuppressive treatment protocols were begun in February 2002. Among the 21 patients (15 men, six women) who received sirolimus, six patients were prescribed sirolimus + prednisolone; seven, sirolimus + mycophenolate mofetil + prednisolone; and eight, sirolimus + cyclosporine + prednisolone. The mean age of the patients was 32.9 +/- 7.3 years and the mean posttransplantation follow-up, 13.2 +/- 4.5 months. RESULTS: Three patients experienced acute rejection episodes, which were treated successfully with steroids. None of the patients had either hematologic or wound healing problems. Lymphoceles developed in eight patients. Serum creatinine level was 1.4 +/- 0.5 mg/dL at 12 months. There was a serious increase in serum cholesterol and triglyceride levels starting from the first month posttransplant (total cholesterol levels pretransplant and at 1 month, respectively: 159.3 +/- 29.5 and 255.7 +/- 52.3 mg/dL, P = .0001; triglycerides pretransplant and at 1 month, respectively: 146.9 +/- 89.5 and 215.1 +/- 102.5 mg/dL, P = .001). Despite routine antihyperlipemic treatment those high levels were maintained for 12 months. CONCLUSIONS: We achieved 100% graft and patient survival rates for 1 year among patients who were using sirolimus. But the most important role in defining the morbidity and mortality in this group of patients is cardiovascular events; for this reason the abnormalities in the lipid profile must be taken seriously.

Cyclosporine↗
PubMed1996

Pharmacokinetics and pharmacodynamics of CTLA4lg (BMS-188667), a novel immunosuppressive agent, in monkeys following multiple doses.

The dose proportionality and multiple dose pharmacokinetics of CTLA4Ig, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4Ig in suppressing the immunoresponses to sheep red blood cell (SRBC) was also assessed. Two monkeys per gender were randomly assigned to one of the three dose levels, 1.0, 2.9, and 8.7 mg/kg of CTLA4Ig. The monkeys in each dose level received the assigned intravenous dose of CTLA4Ig by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4Ig on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4Ig on day 18 (last dose). In addition, predose blood samples were obtained on days 1, 4, 8, 11, 15, and 18. Serum samples were analyzed for the concentrations of CTLA4Ig using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4Ig attained steady state by day 11 regardless of the dose levels. The mean AUC0-720 values of CTLA4Ig increased in a dose proportional manner. The mean values of Cmax increased in a ratio of 1:3:3:8:5 while the dose administered increased in a ratio of 1:3:9. Predose serum concentrations (Cmin) of CTLA4Ig increased in a dose proportional manner. The mean T1/2 values were not significantly different among the dose groups, suggesting that the elimination characteristics of CTLA4Ig were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4Ig (78-98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4Ig exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0-8.7 mg/kg in monkeys.

Abatacept↗
PubMed2004

Synthesis and evaluation of disubstituted N1- and N3-imidazolidin-2-ones acting as potential immunosuppressive agents.

New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive activity have been discovered. Among the 17 synthesized and tested compounds, five of them showed maximal inhibition of proliferation of concanavallin A (Con A)- stimulated splenocytes at 90 microM, identical to that obtained with cyclosporin A (CsA) at 5 microM, an optimal concentration.

Animals↗
PubMed1994

Effect of combination of deoxypyridoxine with known anti-proliferative or immunosuppressive agents on lymphocyte serine hydroxymethyltransferase.

Measurements of serine hydroxymethyltransferase (SHMT) in resting lymphocyte cultures showed that the level of activity of this enzyme is very low. Under the influence of mitogenic stimuli serine hydroxymethyltransferase activity is induced 5-20-fold. Addition in the cultures of 4-deoxypyridoxine (dB6), a potent antagonist of vitamin B6 coenzymes, concurrently with the mitogen, inhibits the induction of SHMT. Separate addition in the cultures of four anti-proliferative (AP) and immunosuppressive (IMS) agents, namely actinomycin, cytarabine, asparaginase and cyclosporine, led to the following observations. (1) The AP and IMS agents produce a decrease in the mitogen-induced activity of SHMT. The higher the concentration of the AP/IMS compound, the greater the decrease of enzymatic activity. (2) When a AP/IMS agent is combined with dB6 its effect on SHMT is considerably greater. (3) Ineffective concentrations of AP/IMS agents become effective when combined with dB6. (4) The observed changes in SHMT activity are not, as one would expect, the same in the case of all four drugs. (5) The combination makes it possible to use much smaller doses of these agents with much better results, at least as far as the decrease of enzymic activity is concerned. This is very promising for clinical use of AP agents in cancer chemotherapy and IMS agents in transplantation especially of the heart and lungs, because combining these compounds with dB6 will make possible to use smaller doses over a longer period of time with greater effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗