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PubMed2002

[Remission of nephrotic syndrome in patients treated with corticosteroids and other immunosuppressive agents].

INTRODUCTION: Glomerular diseases are hybrid group, mostly immunologically related kidney diseases where pathologic changes start in glomerules, but afterwards within their further process they grasp the other kidney structures. The most common clinical manifestation of the primary glomerulonephritis in the adults is nephrotic syndrome. Therefore, this elaboration aims are to estimate the therapy effect onto the different pathohistologic forms of the primary nephrotic syndrome. MATERIAL AND METHODS: Study has been conducted on 41 patients having the primary nephrotic syndrome, prior having normal kidney function. Different pathohistological forms of NS were verified by percutaneous kidney biopsy. Depending on the pathohistological finding the different therapeutic protocoles were applied. Each of the monitored patients were treated by giving steroids at least six weeks dosing them 2 mg/kg/bw/48 h, but not higher then 130 mg/48 h. In the cases of the patients having the given therapy, it did not lead them to the nephrotic syndrome remission, cyclophosphamid was induced in the dosage of 1.5-2.0 mg/kg/bw/48 h. According to the therapy reaction the patients were divided in three groups: the patients with the complete remission, with partial remission and the patients resistant to the treatment. THE RESULTS: 41 patients have been observed, 28 male and 13 female, aged between 16-69, average 32.3 years old. All patients had normal kidney function, and diseases duration from the moment of the pathohistomorphologic diagnosis had been lasting 0-2 years, from average 6.4 months. According to pathohistological diagnosis the patients were divided into four groups: a) "minimal changes" MCNS (n -11), b) focal--segmental glomerulosclerosis FSGS (n - 10) c) membraneous glomerulonephritis MGN (n-9) d) membranoproliferative MPGN (n-10). The best therapy effect had been resulted within the group with MCNS having 82% cases with the complete remission, while the group with MCNS had reacted the most adversely, 45% were resistant onto the therapy. 18 patients of the total 41 had the complete remission, 14 partial remission, and 9 of them were without remission. CONCLUSION: The patient having the minimal changes had the best response onto the steroids therapy, while the patients having the expressive proliferative changes did not respond with the complete remission.

Adolescent↗
PubMed1997

Assessment of dose proportionality, absolute bioavailability, and immunogenicity response of CTLA4Ig (BMS-188667), a novel immunosuppressive agent, following subcutaneous and intravenous administration to rats.

PURPOSE: The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. METHODS: A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. RESULTS: After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1-4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. CONCLUSIONS: The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.

Abatacept↗
PubMed1996

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20 alpha-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate. Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20 alpha-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.

Administration, Topical↗
PubMedDate not supplied

Comparative evaluation of dexamethasone with cyclophosphamide, chloramphenicol and cyproheptadine hydrochloride as immunosuppressive agents on skin homografts in rats and rabbits.

An experimental study on immunosuppressive action of cyclophosphamide, chloramphenicol and cyproheptadine hydrochloride in comparison with the control and dexamethasone was undertaken on skin homografts in rabbits and rats. The survival period of skin homografts in cyclophosphamide treated group was significantly increased (P less than 0.01) in rabbits, but there was insignificant increase in rats (P greater than 0.01). With chloramphenicol there was significant increase in survival period in both the species (P less than 0.01). Cyproheptadine did not show significant result in any of the species. The probable mechanisms of immunosuppressive action have been discussed.

Animals↗
PubMed1990

The effects of a new immunosuppressive agent, FK506, on the glomerular injury in rats with accelerated nephrotoxic serum glomerulonephritis.

The aim of the present work was to study the effects of a new immunosuppressive drug, FK506, in accelerated nephrotoxic serum glomerulonephritis. Glomerulonephritis was induced in female Wistar rats by the preimmunization with normal rabbit IgG (Day-4) and the subsequent intravenous injection of rabbit anti-GBM serum (Day 0). Without treatment with FK506, rats developed proteinuria at Day 6 and onward. Rat anti-rabbit IgG was strongly detected at Day 6 and the titer was maintained through Day 20. Moderate hypercellularity and focal crescent formation were observed at Day 20. Rats injected intramuscularly with 0.3 or 1 mg/kg of FK506 did not develop proteinuria and the anti-rabbit IgG titer was much less or was undetectable throughout the experiments. These data suggest that FK506 is effective in the present model of glomerulonephritis.

Animals↗
PubMed1993

Reversal of multidrug resistance in Chinese hamster ovary cells by the immunosuppressive agent rapamycin.

The ability of cyclosporin A, FK506, and rapamycin to overcome multidrug resistance was investigated in Chinese hamster ovary cells in vitro by growth inhibition experiments. 1-30 microM of immunosuppressant sensitized drug-resistant cells and their drug-sensitive parents in a dose-dependent manner to adriamycin (2-2000-fold), colchicine (2-260-fold), and vinblastine (2-120-fold). The multidrug resistance-reversing activity increased in the order rapamycin < FK506 < cyclosporin A, irrespective of whether the resistant cells overexpressed hamster or human P-glycoprotein. The interaction of the three macrolides with P-glycoprotein was characterized by their ability to competitively inhibit the photoaffinity labelling of plasma membranes of resistant CHRB30 cells by iodomycin. The three immunosuppressants bound with high affinity to P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1982

Synergism between immunosuppressive agents and uremia?

The susceptibility of uremic patients to infectious disease has been widely reported, but the host immune factors associated with the increased incidence of infection have not been clearly defined. In this study, the possibility of synergism between biologically active components that accumulate in uremia and immunosuppressive drugs used in the course of management was investigated. An animal model of chronic stable uremia was used in these experiments to assess the effect of cyclophosphamide, methotrexate, and azathioprine on antibody response in the uremic host. Chronic uremia did not affect the immunosuppressive activity of cyclophosphamide, methotrexate, or azathioprine, and synergism between these agents and uremic components is unlikely to complicate further the immune status of the host in renal failure.

Animals↗
PubMed1986

Prevention of graft-versus-host disease by immunosuppressive agents after transplantation of DLA-nonidentical canine marrow.

Dogs given 9.2 Gy of total body irradiation (TBI) followed by hematopoietic grafts from DLA-nonidentical unrelated or littermate donors and no postgrafting immunosuppression all develop acute graft-versus host disease (GVHD) and die within 3 weeks of grafting. Over a period of 10 years, the present study evaluated various immunosuppressive drugs either alone or in combination and compared their effectiveness to that of methotrexate (MTX) in preventing acute GVHD and prolonging survival. Among the single agents tested, 6-mercaptopurine and azathioprine resulted in a slight but significant prolongation of survival compared to controls, but they were less effective than MTX. Procarbazine and cytosine arabinoside were ineffective. Drugs tested in combination included MTX, cyclophosphamide, 6-mercaptopurine, azathioprine, cyclosporin, procarbazine, prednisone and antithymocyte globulin. Drug combinations, while effective in delaying the onset of GVHD, were associated with hematopoietic and other toxicities, which made their use impractical. Administration of MTX twice weekly proved to be no better than once weekly administration. Prednisone administered for the first 4 days after grafting in addition to MTX resulted in a modest improvement in survival. High-dose MTX (200 mg/kg) followed by leukovorin rescue resulted in severe early toxicity, both gastrointestinal and hematopoietic; however, some of those dogs which survived the early postgrafting period became stable long-term survivors. Most single agents tested in the present study proved to be either ineffective or were inferior to MTX in their ability to prevent GVHD. None of the drug combinations tested was as effective as the one involving MTX/cyclosporin reported previously.

Acute Disease↗
PubMed1990

FK506, a novel immunosuppressive agent, induces antigen-specific immunotolerance in active Heymann's nephritis and in the autologous phase of Masugi nephritis.

FK506 is a new drug which has potent immunosuppressive activity. We studied its immunosuppressive effects on active Heymann's nephritis and the autologous phase of Masugi nephritis. The induction of active Heymann's nephritis was completely suppressed by FK506 injected simultaneously with the antigen (day 1) and then daily for 14 days at a dose of 0.64 mg/kg per day or more. With a lower dosage of this agent, antibody production and immune deposits in the glomerular basement membrane occurred despite the suppression of proteinuria. Similar results were obtained in rats on other treatment schedules (1-7 days or day 8-14 days duration). Rats that were prevented from developing Heymann's nephritis or the autologous phase of nephrotoxic antiserum nephritis by FK506 treatment exhibited a suppressed immune response to a second immunization of the same antigen even 4 weeks after cessation of drug administration: however, they developed antibodies when inoculated with other antigens. Rat peripheral leucocyte counts and serum creatinin were not remarkably influenced by the administration of FK506. These results indicate that FK506 has potent immunosuppressive activity, and it is suggested that it is able to induce an antigen-specific immunotolerance.

Animals↗
PubMed2006

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents.

Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively, and mediate a wide range of effects, including anti-inflammatory properties. However, cannabinoids that bind CB1 are also psychoactive thereby limiting their clinical use. In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2-selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.

Animals↗
PubMed2000

CTLA4-Ig: a novel immunosuppressive agent.

Activation of naive T-cells requires two signals: one is antigen-specific and based on T-cell receptor (TCR) recognition of a peptide-MHC complex and the second is antigen-nonspecific and delivered by specific T-cell receptors after ligation with their ligands (costimulatory molecules) expressed by antigen-presenting cells (APCs). Engagement of the B7 family of molecules on APCs with their T-cell associated ligands, CD28 and CTLA-4 (CD152), provides a pivotal costimulatoty signal in T-cell activation. The lack of costimulation after engagement of the T-cell receptor by antigen, results in a state of antigen-specific unresponsiveness, termed anergy. Manipulation of CD28/B7 pathway has therefore been envisioned as a potential strategy for achieving therapeutically useful immunosuppression or tolerance. CTLA4-Ig has been initially developed by Bristol-Myers Squibb as a competitive inhibitor of CD28/B7 pathway (BMS-188667). Thereafter, CTLA4-Ig was produced by Repligen and also in some individual laboratories. In various animal models, discussed in this paper, CTLA4-Ig has been shown to inhibit T-cell-dependent antibody responses, significantly prolong transplanted organ survival, induce long-term donor-specific tolerance in some models, slow progression of autoimmune disease and to have immunomodulatory function in several other immunological disease models. Recently, CTLA4-Ig has entered Phase I clinical trials for the treatment of psoriasis, a T-cell mediated skin disease and treatment of graft-versus-host disease in allogeneic bone marrow transplantation. Large clinical randomised trials on the use of CTLA4-Ig are missing, nevertheless, its immunosuppressive effects coupled with features such as specificity of interaction and low toxicity, make CTLA4-Ig a promising new therapeutic agent for induction of donor-specific immunological tolerance, the ultimate goal of clinical immunosuppression.

Abatacept↗
PubMed1989

Antihypertensive effect of an immunosuppressive agent, cyclophosphamide, in genetically hypertensive rats of the Lyon strain.

The effect of a pharmacological immunosuppression on the development of hypertension and the part played by hormonal secretions of the thymus in this disease were investigated in genetically hypertensive rats (LH) of the Lyon strain. For this purpose, systolic blood pressure (SBP) was measured in cyclophosphamide-treated LH rats and in neonatally thymectomized LH rats receiving thymostimulin, a thymus extract. Cyclophosphamide treatment delayed the onset and attenuated the full development of hypertension in LH rats whereas it had no effect on SBP in normotensive rats (LN). Thymectomized LH rats also exhibited a significantly decreased SBP as compared to sham-operated controls. Thymostimulin treatment slightly increased the SBP of thymectomized LH rats but did not restore it to the level seen in sham-operated animals. These results showed that thymic hormonal secretions did not seem to be involved in the initiation of hypertension. By contrast, the fact that a reduction of hypertension could be obtained either by thymectomy or cyclophosphamide treatment suggested that immune disorders, mediated by thymus-dependent cellular reactions, could be of pathogenic importance in the development of hypertension in LH rats.

Aging↗
PubMed1988

Prolongation of skin allograft survival in rats by a novel immunosuppressive agent, FK506.

FK506, an immunosuppresant, was isolated from Streptomyces tsukubaensis. Intramuscular administration of FK506 (0.32 mg/kg or more) 5 days a week for two weeks after grafting prolonged the acceptance time of F344 skin allograft to WKA rats. Similar results were obtained with cyclosporine at 32 mg/kg or more, but other immunosuppressives (i.e., prednisolone, azathioprine, and bredinin) gave only a marginal prolongation. The prolonging effect of FK506 was obtained in various donor-recipient combinations across a major or minor histocompatibility barrier. The agent also prolonged the acceptance time of mouse skin xenografts to rats. Furthermore, maintenance doses of 3.2 or 0.32 mg/kg twice a week after an initial 14-day treatment with the agent at 3.2 mg/kg gave graft survival as long as the treatment was continued for more than 120 days. Our findings show that FK506 has a potent immunosuppressive effect in rats and suggest that the agent merits further investigation.

Animals↗
PubMed1993

The effect of ion channel blockers, immunosuppressive agents, and other drugs on the activity of the multi-drug transporter.

The MDRI protein is an energy-dependent transport protein responsible for the multi-drug resistance seen in many tumors. A variety of drugs have been shown to inhibit the function of this pump, including compounds known to block various ion channels. The mouse lymphoma cell line L5178Y has been transduced with the human mdrI gene. Using this cell line, we have tested a number of compounds to determine whether there is a correlation between the ability to block a specific type of ion channel, or shift membrane potential, and the ability to act as an MDR-reversing agent using the fluorescent substrates Rhodamine 123 and daunorubicin as test compounds. Our results show no apparent correlation between the ability to block a specific ion channel and reversal of MDR transport ability. We have found active MDR inhibitors in compounds that affect K+, Na+, Ca++, H+, but not Cl- channels. Our data suggest that Cl- channel activity may be distinct from MDR activity. Several immunosuppressive compounds and analogs were also tested and found to be active reversing agents. Measurements suggest a significant difference in resting membrane potential between the L5178YvMDR line and the L5178Y parental cell line used in these experiments. No correlation was found between the ability of drugs to alter membrane potential and to inhibit MDR transport activity. Our results suggest that MDR transport function may be independent of the physiological movement of ions and show that a wide variety of compounds can inhibit MDR transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Other immunosuppressive agents for focal segmental glomerulosclerosis.

A prolonged course with corticosteroids represents the first therapeutic approach for nephrotic patients with focal segmental glomerulosclerosis (FSGS). In patients with contraindications to steroids or in those who do not respond to steroids or cyclosporine, cytotoxic agents, mycophenolate mofetil (MMF), plasmapheresis, and low-density lipoprotein (LDL) apheresis have been tried as alternative treatments. A short-term treatment with cytotoxic agents often is ineffective in steroid-resistant patients However, an aggressive and prolonged treatment with cytotoxic agents combined with corticosteroids proved to be effective in more than half of steroid-resistant children. In adults, the response to cytotoxic agents was good in steroid-responsive patients, but was poor in steroid-resistant patients. Better results were observed when cytotoxic therapy was prolonged for several months. The problem with these drugs is that long-term immunosuppression may be complicated by severe side effects including a major risk for cancer. Uncontrolled studies reported that MMF can induce some reduction of proteinuria, but complete remission of proteinuria was rare and no data on long-term follow-up evaluation with this drug are available. Good results have been reported with plasmapheresis, immunoadsorption, and lipopheresis. However, all the reports were uncontrolled, small sized, and with short-term follow-up evaluation. In conclusion, there are several therapeutic options for patients who respond to steroids and have further relapses of nephrotic syndrome, but how to treat steroid-resistant patients is still a matter of debate. Nevertheless, a 6-month trial with cytotoxic agents or MMF can be offered to steroid-resistant patients to identify the few patients who respond to these agents. The preliminary results with plasmapheresis or lipopheresis are promising but further studies are needed to assess the role of these treatments.

Disease Progression↗
PubMed1997

Mycophenolate mofetil: a unique immunosuppressive agent.

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of mycophenolate mofetil are reviewed. Mycophenolate mofetil is used to prevent or treat allograft rejection after solid-organ transplantation. A prodrug, mycophenolate mofetil is rapidly hydrolyzed to mycophenolic acid after oral administration. Mycophenolic acid inhibits de novo purine synthesis, resulting in antiproliferative effects on T and B lymphocytes. The absolute bioavailability of mycophenolic acid is 94% for oral administration; the maximum plasma concentration occurs after two hours. Mycophenolic acid undergoes hepatic glucuronidation to an inactive salt that is renally excreted. Clinical trials of mycophenolate mofetil in renal transplant patients suggest that the drug is effective for the prevention of acute rejection and as rescue therapy. Clinical data on mycophenolate mofetil therapy in liver transplant patients are too limited to permit conclusions. Clinical trials of the drug for primary immunosuppression in heart transplant patients have not been conducted, but studies of this agent as rescue therapy suggest efficacy. Mycophenolic acid has proved useful for long-term management of psoriasis. The most common adverse effects of mycophenolate mofetil are gastrointestinal. Nephrotoxicity and overt hepatotoxicity have not been reported, but the drug may be linked to bone marrow suppression and certain malignancies. Mycophenolate mofetil is available as a 250-mg capsule for oral use. The recommended initial dosage is 1 g twice daily. Mycophenolate mofetil appears to be a useful addition to the armamentarium of immunosuppressive drugs, particularly for kidney transplant patients, but more study is needed to clarify its role.

Graft Rejection↗
PubMed2006

Mycophenolate mofetil as an immunosuppressive agent in refractory inflammatory eye disease.

PURPOSE: The aim of this study was to assess the role of mycophenolate mofetil (MMF) in refractory inflammatory eye disease. METHODS: Retrospective, noncomparative, interventional case series of all patients commenced on MMF between 1999 and 2005 for refractory inflammatory eye disease at St Paul's Eye Unit (Liverpool, UK). Main outcome measures noted were control of inflammation, steroid-sparing effect, and adverse effects of MMF therapy. RESULTS: Ten (10) patients (2 with sarcoid, 2 with intermediate uveitis, 1 with Vogt-Koyanagi Harada (VKH) syndrome, 1 with ankylosing spondylitis, 1 with juvenile chronic arthritis (JCA), and 3 with scleritis) who were unresponsive or intolerant to previous therapy and/or as a steroid-sparing agent, received 2-3 g of MMF per day for a mean period of 40.5 months (range, 3-67). Nine (9) patients had a favorable response, with diarrhea and insomnia being the main side-effects. MMF had to be withdrawn in 1 patient because of side-effects and in another because of active arthropathy (with stable uveitis). Average number of relapses was reduced from 3.1 per patient per year to 0.8 per patient per year (P < 0.005). A steroid-sparing effect was achieved in all patients. Visual acuity improved in 8 patients. CONCLUSIONS: MMF appears to be a safe and effective second- or third-line adjunct/alternative immunosuppressant in these difficult cases and works well in combination with cyclosporin A, tacrolimus, and antitumor necrosis factor (TNF) agents. It has potential as a firstor second-line agent and can be considered at a dose of 3 g/day in refractory cases.

Adult↗