Showing papers on "Mycophenolate published in 1994"

Mycophenolate mofetil Molecular mechanisms of action

Abstract: Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is investigated in clinical trials for the prevention of organ and tissue rejection in transplantation. Esterification of MPA to the prodrug MMF improves its bioavailability. MMF prolongs allograft survival and reverses ongoing rejection in animal studies, and has shown preliminary efficacy in human clinical trials in combination with established therapies for transplantation. The immunosuppressive activity of MPA results from the potent reversible inhibition of IMP dehydrogenase (IMPDH). Inhibition of IMPDH by MPA causes the depletion of intracellular GTP pools and inhibits proliferation of lymphocytes. IMPDH is the first enzyme in the committed pathway of de novo synthesis of guanine nucleotides. Two isoforms of human IMPDH are known. The type I enzyme is constitutively expressed, while the type II isozyme is induced in activated lymphocytes and other proliferating cells. MPA inhibits the type II enzyme with fivefold greater affinity than the type I enzyme (Ki=7 nM against type II IMPDH). Against the human enzymes, the kinetics of inhibition by MPA are uncompetitive with respect to both substrates IMP and NAD. Uncompetitive inhibition indicates that MPA preferentially binds to the enzyme after substrates, perhaps to an enzyme-IMP-NAD ternary complex or to an enzyme-XMP binary complex in the product side of the reaction. Uncompetitive inhibition by MPA cannot be overcome by increases in intracellular concentrations of the substrates. The immunosuppressive mechanisms of MPA are discussed in relation to lymphocyte proliferation, alterations of pools of other nucleotides coincident with GTP depletion, and inhibition of other GTP-dependent biochemical events.

Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo.

Abstract: Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 microM to 3.9 microM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Molt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (non-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B-cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experimental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK-Hep-1, a human hepatic endothelioma, or Hep-3B, a liver adenocarcinoma, at any of the doses tested.

Mycophenolate mofetil (RS-61443): preclinical, clinical, and three-year experience in heart transplantation.

Abstract: Mycophenolate mofetil (formerly known as RS-61443) is a morpholinoethyl ester of mycophenolic acid. Mycophenolic acid is a unique immunosuppressive agent because of its mechanism of action. By inhibiting the de novo pathway of purine synthesis, mycophenolic acid suppresses lymphocyte function much more than that of neutrophil, erythrocyte, and other rapidly dividing cell lines which can use the salvage purine synthesis pathway. Mycophenolate mofetil has been shown to be an effective immunosuppressive agent in both animal models and early human trials. This article describes the history, biochemistry, pharmacology, in vitro and in vivo effects, and clinical trials of myophenolate mofetil. In addition, previously unpublished 3-year follow-up of heart transplant recipients receiving mycophenolate mofetil is reported.

Treatment of recurrent heart rejection with mycophenolate mofetil (RS-61443): initial clinical experience

Abstract: Mycophenolate mofetil (RS-61443), a derivative of mycophenolic acid, is a new immunosuppressive agent that inhibits de novo purine synthesis in activated lymphocytes. In a clinical trial of mycophenolate mofetil in the treatment of recurrent or persistent heart rejection, 17 patients 0.6 to 104 months (median 5.4 months) after transplantation received a daily oral dose of mycophenolate mofetil of 3000 mg, with seven patients increasing to 3500 mg daily. Azathioprine was routinely discontinued at the start of mycophenolate mofetil treatment. One patient in shock from acute rejection required retransplantation before starting mycophenolate mofetil and died 68 days later of cytomegalovirus sepsis. Another patient died 72 days after mycophenolate mofetil of protracted multisystem failure (present before mycophenolate mofetil). One patient required early cessation of mycophenolate mofetil, and the other 14 patients were alive and well 5 to 10 months after initiating mycophenolate mofetil treatment. Three patients required transient dose reduction and one patient required discontinuation of mycophenolate mofetil because of nausea, diarrhea, or abdominal cramps. No other clinical side effects were noted. Frequency of rejection decreased from 0.67 rejection episodes per patient per month before mycophenolate mofetil to 0.27 rejection episodes per patient per month after mycophenolate mofetil (p < 0.0001). Frequency of infection was unchanged after mycophenolate mofetil (p = 0.9). Renal function was not affected by mycophenolate mofetil (creatinine clearance 1.8 mg/dl before mycophenolate mofetil vs 1.7 mg/dl after mycophenolate mofetil; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Mycophenolate mofetil high dose oral suspensions

Abstract: High dose, dry granulations and aqueous oral suspensions of mycophenolate mofetil or mycophenolic acid, contain: active compound (7.5-30 %), suspending/viscosity agent, sweetener, flavor, buffer (to a pH of 5-7), and optionally contain flavor enhancer, wetting agent, antimicrobial agent and color.

Derivatives of mycophenolic acid

Abstract: The disclosed derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents.

6-substituted mycophenolic acid and derivatives

Abstract: The disclosed 6-substituted derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil.

High dose ranolazine formulations

Abstract: Mycophenolate mofetil, mycophenolic acid, and ranolazine can be conveniently manufactured into high dose oral formulations by the hot melt filling of a supercooled mycophenolate mofetil, mycophenolic acid, or ranolazine liquid into a pharmaceutical dosage form High dose oral pharmaceutical formulations and manufacturing methods therefor are disclosed

high dose formulations

Abstract: Mycophenolate mofetil, mycophenolic acid, and ranolazine can be conveniently manufactured into high dose oral formulations by the hot melt filling of a supercooled mycophenolate mofetil, mycophenolic acid, or ranolazine liquid into a pharmaceutical dosage form. High dose oral pharmaceutical formulations and manufacturing methods therefor are disclosed.

4- amino derivatives of mycophenolic acid

Abstract: The disclosed derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents.

Method of using 4-amino derivatives of 5-substituted mycophenolic acid

Abstract: The disclosed derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents.

Method of using 4-amino 6-substituted mycophenolic acid and derivatives

Abstract: The disclosed derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents.