SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Our results demonstrate the potent immunosuppressive activity of combination MM and BQR therapy to prolong allograft survival. In addition, MM may provide a highly effective therapy for the prevention of chronic rejection.
The treatment of psoriasis and psoriatic arthritis by cyclosporin A, a new immunosuppressive agent believed to have a largely selective action on T lymphocytes, is described. Results in 4 cases show that cyclosporin A can bring about a most impressive improvement in psoriatic lesions of the skin and its appendages, but that its effect on the arthropathy is variable. There is still little certainty about the compound's mechanism of action in these conditions. Cyclosporin A may give rise to a whole range of side effects and its use--like that of other immunosuppressants--should therefore be contemplated only in severe and progressive forms of psoriasis and psoriatic arthritis resistant to other forms of treatment except cytostatic drugs.
Since the early 1980s, a 3-drug regimen that includes cyclosporine, azathioprine, and usually corticosteroids has been the mainstay of immunosuppression for patients undergoing cardiac transplantation. This regimen, however, has a variety of inherent toxicities and is not associated with any lesser incidence of graft coronary artery disease than the earlier regimen. For these reasons, there has been a widely perceived need for the introduction of improved immunosuppressive agents. Two such agents have thus far been introduced into clinical organ transplantation: mycophenolate mofetil and tacrolimus. Mycophenolate mofetil is used as a substitute for azathioprine and has been shown to result in significantly lower mortality rates and freedom from rejection in heart transplant recipients. Tacrolimus can be used as a substitute for cyclosporine but (at least in the short-term) seems to offer no important advantage in terms of survival or rejection. The combination of these 2 new agents seems to have no short-term disadvantage and longer-term follow-up is pending.
The effect of two immunosuppressive agents, azathioprine and cyclophosphamide, with and without UVB sunscreen protection on UV-induced skin carcinogenesis was studied in the albino hairless mouse. In a daily treatment regime spanning 9 weeks, groups of mice were immunosuppressed with either drug, and were exposed to minimally erythemal doses of a light source simulating the UV portion of the solar spectrum. The accumulated UV exposure alone induced skin tumours in 77% of mice. Azathioprine, but not cyclophosphamide, significantly enhanced the incidence of UV tumorigenesis. Photoprotection by topical application of one of two commonly used UVB sunscreens, 2-ethyl-hexyl-p-methoxycinnamate (2-EHMC) or octyl-N-dimethyl-p-aminobenzoate (o-PABA), reduced the UV tumour incidence to zero in immunologically normal mice and to 8-15% in immunosuppressed mice. Unexpressed latent tumour initiations were revealed in all sunscreen-protected groups by the subsequent application of a tumour promoter, croton oil. In immunologically normal mice 2-EHMC had allowed initiations in 39% of UV-irradiated mice, and o-PABA in 16.5%. However, in UV-irradiated mice immunosuppressed with azathioprine there had been initiations in 78% of mice protected with 2-EHMC and 65% of mice protected with o-PABA. Photoprotected mice immunosuppressed with cyclophosphamide did not show the same increase in UV-initiations (22% with 2-EHMC, 23% with o-PABA). These results provide evidence that azathioprine increases the susceptibility of the skin to UV carcinogenesis. However, UVB sunscreens afford effective protection from overt tumour expression in the absence of a tumour promoter.
The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.
OBJECTIVES: Transplantation of the small intestine would be an attractive therapeutic option for treatment of short bowel syndrome if effective, nontoxic immunosuppressive agents could be developed. This study examines the effect of three newly developed immuno-suppressive agents: rapamycin, deoxyspergualin, and mycophenolate mofetil, on the nutritional status and intestinal function of normal juvenile rats. DESIGN & METHODS: Rapamycin (2 mg/kg every second day), deoxyspergualin (2 mg/kg every second day) and mycophenolate mofetil (MM) (25 mg/kg every second day) were injected subcutaneously for six weeks. RESULTS: Rapamycin and deoxyspergualin caused significant reductions in weight gain without impairing feed intake. Both drugs caused small decreases in fat absorption; treatment with DSG induced an increase in permeability to 99Tc-DTPA. However, the permeability to other markers, such as mannitol and lactulose, was decreased in the rapamycin and mycophenolate mofetil-treated animals. Intestinal function in vitro was quantified using glucose flux (absorption). In the rapamycin group, there was a significant decrease in ileal uptake of glucose, with the net flux (absorption) being zero; there was an associated loss of villous size histologically. In the deoxyspergualin-treated groups, there was a decrease in the jejunal glucose flux. In the mycophenolate mofetil-treated animals, there was a decrease in jejunal with a compensatory increase in ileal glucose absorption. There were minor variations in intestinal morphology, but these were not consistent. CONCLUSIONS: Rapamycin and deoxyspergualin in these doses cause a significant reduction in weight gain in healthy juvenile animals, and all the drugs caused changes in the active transport characteristics of the intestine. Accordingly, the use of these drugs for intestinal transplantation should be evaluated carefully for their nutritional impact.
BACKGROUND: 2',2' -difluorodeoxycytidine (dFdC, gemcitabine) is a pyrimidine antimetabolite with antineoplastic activity against a wide range of solid tumors. The immunosuppressive activities of this compound have not been described to date. METHODS: The in vitro effects on activated T lymphocytes were studied with a lymphocyte colony-forming assay in a microagar culture system. Heart transplantations were performed in the fully allogeneic Lewis/ Brown Norway combination. dFdC was administered once daily at various dosages from the time of surgery until day 50. RESULTS: Phytohemagglutinin-induced lymphocyte proliferation was inhibited 50% by dFdC at a concentration of 3.25+/-0.9 nmol/L. Allografts of untreated animals survived for 7.5 (7-8) days and those with 25, 50, and 75 microg/kg body weight dFdC for 7.3 (7-8), 9.3 (8-10), and 16.3 (10-38) days, respectively. Treatment with 100 or 125 microg/kg body weight of dFdC, however, prolonged allograft survival until day 152.8 (129-178). Dose-dependent leukopenia was the main toxicity. CONCLUSIONS: DFdC is a new immunosuppressive agent that can successfully prevent cardiac rejection in a rat transplantation model.
BACKGROUND: Mycophenolate mofetil (MMF) has been approved as an immunosuppressive agent in kidney transplant recipients and may thus be used concomitantly with antiherpetic agents, the latter for the treatment of intercurrent herpesvirus infections. The parent compound of MMF, mycophenolic acid (MPA), is a potent inhibitor of inosine monophosphate dehydrogenase and causes depletion of the intracellular (deoxy)guanosine triphosphate [(d)GTP] pools. Lobucavir [1R(1alpha,2beta,3alpha)]-9-[2,3-bis(hydroxymethyl)cyc lobutyl]guanine (LBV) is a novel antiviral agent with activity against ganciclovir-resistant cytomegalovirus (CMV) strains, that is in phase II clinical trials for the treatment of CMV infections. LBV triphosphate inhibits the viral DNA polymerase competitively with dGTP. We present the results of our studies on the antiviral effects of the combinations LBV + MMF and LBV + MPA. METHODS: The antiviral effects of LBV either alone or in combination with MMF or MPA on the replication of CMV, herpes simplex virus type- (HSV) 1 (HSV-1), HSV-2, and thymidine kinase-deficient HSV-1 were studied by means of plaque or CPE reduction assays. RESULTS: When combined with LBV, MPA (at concentrations ranging from 0.25 to 10 microg/ml, which are readily attainable in human plasma) markedly potentiated the antiviral efficacy of LBV against HSV-1 and HSV-2, that is a 10- to 100-fold decrease in EC50. Moreover, the EC50 of LBV against TK- HSV-1 decreased up to 1400-fold upon combination with MPA. MPA by itself had little or no effect on the replication of these viruses. Moreover, MPA and MMF resulted in a marked increase in the anti-CMV activity of LBV minimal FIC (FICmin: 0.24 and 0.26, respectively). Exogenously added guanosine reversed the potentiating effect of MPA on the antiviral activity of LBV, which indicates that this potentiating effect results from a depletion of the endogenous dGTP pools, thus favoring the inhibitory action of the LBV-triphosphate on the viral DNA polymerase. Ribavirin, another inhibitor of inosine monophosphate-dehydrogenase, also caused a marked enhancement of the antiviral activity of LBV against HSV-1 (12-fold), HSV-2 (20-fold), and TK- HSV-1 (25-fold). CONCLUSION: MMF markedly potentiates the activity of LBV against HSV-1, HSV-2, TK- HSV-1, and CMV. This drug interaction may have important implications when using LBV in the treatment of intercurrent herpesvirus infections in transplant recipients under MMF therapy.
Induction of transplantation tolerance remains a much sought-after but elusive goal with a potential promise of rendering patients free of long-term immunosuppressive drugs while maintaining good organ transplant function indefinitely. All currently studied strategies toward transplantation tolerance include using immunosuppressive agents for a limited time period to achieve tolerance. There are a growing number of agents that lend themselves to tolerance induction and these agents are considered herein. Such agents generally fall into the categories of lymphocyte depletion, costimulation blockade, and adjunctive agents such as rapamycin. Preliminary data using donor stem cells suggests that embryonic stem cells may have substantial advantages over conventional donor bone marrow for tolerance induction. These preliminary results are briefly reviewed as well. Tolerance has been achieved in a small number of organ transplant patients and such successes suggest that progress in the clinical arena is happening and is an obtainable result.
Fifty-one renal and marrow graft recipients have been treated with whole, absorbed rabbit anti-human-lymphocyte serum. Such sera are potent nontoxic immunosuppressive agents. Preexisting sensitivity can be erased, and early rejection episodes are essentially eliminated. Prolonged treatment is necessary and safe, and it ensures a sustained depression in circulating T cells. Adaptation between kidney graft and host then occurs, so that the combination of prednisone and Imuran alone can sustain graft viability.
The spectrum of uveitis constitutes one of the major causes of blindness. Advances in our understanding of the underlying mechanisms have altered the diagnostic and therapeutic approaches. The most notable development is the increasing usage of several immunosuppressive agents. A systematic approach in making accurate diagnosis is central to employment of specific, more effective treatment. One should be cognizant of the potential benefits and risks of each of these agents before exposing the patients to these very potent drugs.
A novel macrolide antibiotic, FK-506, isolated from Streptomyces tsukubaensis, has been shown to be a potent immunosuppressive agent in vivo and in vitro. FK-506 shares a number of immunosuppressive properties with the cyclic peptide, cyclosporin A (CsA), although 10 to 100 times more potent in this regard. These similarities suggest that both agents may share a similar mechanism(s) of action at the biochemical level. We have identified a cytoplasmic binding protein for FK-506 in the human T cell line, JURKAT, using [3H]FK-506. The FK-506 binding protein has a mr of 10 to 12 kDa (as determined by gel filtration), is heat stable and does not bind CsA. This contrasts with the CsA binding protein, cyclophilin, in that cyclophilin is heat labile and has a mr of 15 to 17 kDa. Our data suggest that FK-506 binds to a low m.w. protein(s) in JURKAT cells, which is distinct from cyclophilin. This protein may mediate the immunosuppressive effects of FK-506 in T cells. In addition, our results suggest that the immunosuppressive activity of FK-506, as with CsA, is mediated by an intracellular mechanism.
BACKGROUND: Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental immunosuppressive agent effective in the prevention/control of acute and chronic rejection in animal models and currently in phase I clinical trials in human transplant recipients. This agent is also effective in the control of graft-versus-host disease, autoimmune reactions, and the growth of certain tumors. The importance of the endothelium in these disease processes led us to hypothesize that leflunomide might act directly upon the endothelial cell (EC). METHODS AND RESULTS: Assay of human EC colony formation demonstrated dose-dependent, leflunomide-mediated inhibition of EC proliferation. In addition, the organization of EC into capillary-like networks, which occurs during 18 hr of incubation on Matrigel, was progressively disrupted with increasing concentrations of leflunomide. Finally, fibrin-embedded transverse sections of murine aorta, which sprout numerous microvessels during an 11-day incubation, were inhibited from doing so in the presence of this agent. All drug concentrations used in these experiments were nontoxic and pharmacologically relevant, and none of these effects were reversible by exogenous uridine, implying that inhibition of these processes was not due to intracellular pyrimidine depletion. Furthermore, neither cyclosporine nor tacrolimus exerted inhibitory activity in any of the experiments described above. CONCLUSIONS: Data generated by these studies distinguish leflunomide among immunosuppressants as uniquely capable of inhibiting angiogenesis-related endothelial functions and suggest additional mechanisms by which this agent might intervene in the diverse array of disease processes against which it has shown therapeutic potential.
Four patients with rapidly progressive glomerulonephritis and pulmonary hemorrhage (Goodpasture's syndrome) induced by circulating anti-glomerular basement membrane (GBM) antibodies were treated with immunosuppressive agents and varying amounts of plasma exchange. All four patients showed progressive decreases in circulating anti-GBM antibody during therapy. Two patients with established renal failure before therapy showed no improvement in renal function but had a remission from pulmonary disease. In two other patients, renal failure developed early in the course of therapy and required maintenance hemodialysis. Later, their renal function improved coincident with a decrease in circulating anti-GBM antibody. Aggressive measures to reduce the levels of circulating anti-GBM antibody may have a salutory effect on the clinical course of the disease, particularly when undertaken early.
OBJECTIVES: Ischemia-reperfusion injury affects posttransplant renal function, directly increases the probability of acute rejection, and is associated with chronic rejection and impaired long-term function. Animal studies suggest that ischemic preconditioning enhances resistance to ischemia and may be augmented by treating donors using immunosuppressant agents. This study sought to confirm the hypothesis that a combination of ischemic training and immunosuppression prior to renal harvest would maximize a transplanted kidney's resistance to ischemia-reperfusion injury. MATERIALS AND METHODS: Landrace pigs underwent either preharvest immunosuppression plus left kidney ischemic training (group 1, n=6) or ischemic training alone (group 2, n=6). Immunosuppression was composed of mycophenolate mofetil (20 mg/kg) and tacrolimus (0.1 mg/kg) administered intravenously 30 minutes before training. Training comprised 2 cycles of left renal pedicle occlusion for 5 minutes followed by release (reperfusion) for 10 minutes. Warm renal ischemia was then induced by clamping the left renal pedicle for 30 minutes, followed by heterotopic left kidney transplantation. Blood from the transplanted kidney renal vein was sampled directly at 0, 10, 20, 40, and 60 minutes posttransplantation for malondialdehyde (a reactive oxygen species marker), tumor necrosis factor-alpha (TNF-alpha), interleukins 6 and 8 (inflammatory cytokines), and erythrocyte-reduced glutathione (an antioxidant). Renal histology was graded on a 3-point scale. RESULTS: Reperfusion levels of malondialdehyde, TNF-alpha, and interleukin 6 were significantly lower in group 1 at both 40 and 60 minutes. None of the animals in group 1 (0/6) that received preharvest immunosuppression showed severe interstitial inflammation, compared with 4 of 6 animals in group 2 that did (P<.03). CONCLUSIONS: Preharvest immunosuppression with mycophenolate mofetil and tacrolimus significantly decreases immediate posttransplant reactive oxygen species and inflammatory cytokine production, enhances the protective effect of ischemic training, and should not only reduce ischemiareperfusion injury in transplanted kidneys but also should enhance immediate and long-term graft function while preventing acute rejection.
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium, everolimus, and FTY720. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and abstracts evaluating mycophenolate sodium, everolimus, and FTY720 in solid-organ transplantation were considered for evaluation. English-language studies and published abstracts were selected for inclusion. DATA SYNTHESIS: Mycophenolate sodium has recently been approved by the Food and Drug Adminstration for marketing in the United States; everolimus and FTY720 are immunosuppressive agents that may soon be available in the United States. These agents have proven efficacy in reducing the incidence of acute rejection in solid-organ transplantation. Clinical trials have shown that these newer agents are relatively well tolerated. The most common adverse events associated with these agents were gastrointestinal and hematologic effects (mycophenolate sodium); hyperlipidemia, increased serum creatinine, and hematologic effects (everolimus): and gastrointestinal effects, headache, and bradycardia (FTY720). CONCLUSION: Mycophenolate sodium has been approved in some European countries and the United States. Everolimus has been approved in some European countries and a new drug application has been submitted to the Food and Drug Administration. FTY720 is currently in phase III clinical trials and submission to the Food and Drug Administration for approval is a few years away. The approval of these agents will furnish the transplant practitioner with even more options for immunosuppression.
INTRODUCTION: Traditional Chinese Medicines (TCM) have been used for centuries in China to treat various immune-mediated disorders. METHODS: This review focuses on the clinical and experimental studies that have been performed with TCM as immunosuppressive agents for the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), atopic eczema and solid organ transplantation. RESULTS: The "thunder god" vine, Tripterygium wilfordii Hook F (TWHf), has been extensively used in China to treat SLE and RA. TWHf not only inhibited mitogen-stimulated lymphoproliferation, but its active derivatives have also been shown to inhibit production of proinflammatory cytokines by monocytes and lymphocytes, as well as prostaglandin E2 production via the cyclooxygenase, COX-2, pathway, a potential mechanism of action in patients with RA. Demethylzelasteral (TZ-93), a triterpenoid isolated from the root cortex of TWHf, the plant alkaloid berbamine, and the hydrophobic extract of a Chinese herbal decoction, CMX-13, were all shown to be active in prolonging allograft survival in experimental animal models of heart, skin and single lung transplants, respectively. There are few well-designed randomised placebo-controlled clinical trials demonstrating the efficacy of TCM in various diseases. Zemaphyte, a decoction of 10 herbs, has been shown to be efficacious in the treatment of atopic dermatitis in both children and adults in two randomised double-blind placebo-controlled trials. CONCLUSION: There is both laboratory and clinical evidence that the derivatives of many of these herbs may have significant beneficial immunosuppressive effects, however, concerns of toxicity must also be addressed, as exact dosing of the active derivatives is difficult to achieve with the current prescriptions of TCM.
We have previously shown that blood concentrations of tacrolimus, a new immunosuppressive agent, were greater when it was administered orally at 10 pm than when it was administered at 10 am in rats. The present study was undertaken to examine whether the toxic effects of tacrolimus show administration time-dependent variations. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Tacrolimus (1 and 4 mg/kg) was given orally at 10 am (day trial) or 10 pm (night trial) for 14 days. Blood samples were obtained at 24 hours after the final dosage of the agent. Weight gain was smaller in the night trial than in the day trial. Plasma concentrations of urea and creatinine increased significantly in the night trial while the elevations in these parameters were not observed in the day trial. These results suggest that the toxic effects of tacrolimus also vary with its time of oral dosage.