Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurements of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chest and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on a weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.
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PMID:Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. 234 2

Mycophenolate mofetil (MMF) is a new immunosuppressive agent for the prevention of renal allograft rejection. MMF is a prodrug of mycophenolic acid (MPA), a fermentation product of several Penicillium species of fungus. MPA acts at a late stage in T and B lymphocyte proliferation by selective, uncompetitive and reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine nucleotide synthesis. The three large studies individually and the combined (pooled) 1-year patient efficacy data have shown that MMF, given in combination with cyclosporine and corticosteroids, significantly reduces the incidence of acute rejection episodes (by 50%), without detectable difference in patient mortality. Analysis of secondary efficacy endpoints revealed that patients treated with MMF required less additional immunosuppressive therapy for treatment of acute rejection episodes and showed better renal function. In another studies, the efficacy of MMF in the treatment of first acute rejection episodes and in the treatment of refractory, acute, cellular renal transplant rejections has been shown. The principal adverse events associated with MMF administration included diarrhea, vomiting, leukopenia and a higher frequency of certain types of infections. The efficacy of MMF for the treatment of chronic allograft nephropathy is controversial. The ability of MMF to reduce the occurrence of acute rejection episodes and improve allograft function may have significant implications for promoting the long-term survival of renal allografts, but we need long-term observations to prove this benefit.
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PMID:[Use of mycophenolate mofetil in kidney transplantation]. 1171 23

The management of nephrotic syndrome (NS) in children remains a clinical challenge for pediatricians and pediatric nephrologists. Especially, the treatment of patients with steroid-resistant (SR) and steroid-dependent (SD) nephrotic syndrome, because they are at risk for developing complications from prolonged exposure to steroids, CsA and alkylating agents. Mycophenolate mofetil (MMF) is a selective and reversible inhibitor of inosine monophosphate dehydrogenase used above all in transplantology and recently also in patients with nephrotic syndrome. The aim of this study was to tentatively assess the usefulness and the safety of MMF as an immunosuppressive agent in children with steroid-resistant NS, in whom remission was not obtained with previous treatment regimens, and those with steroid-dependent NS, in whom severe adverse reactions were observed in steroid and cyclosporine therapy. The study included 19 children with NS (11 girls, 8 boys) aged 7 to 19.5 years (a mean of 13.5), treated at the Deptartment of Pediatric Nephrology. The duration of disease was from 1 to 16 years (a mean of 9.3). The patients were divided into 3 groups: I--9 children with steroid-dependent NS; II--6 children with steroid-dependent NS and episodes of steroid-resistance; III--4 children with steroid-resistant NS. All patients in groups II and III required multi-drug therapy (prednisone, cyclosporine A, methylprednisolone, chlorambucil, cyclophosphamide) before MMF was introduced. MMF was administered orally: 180-600 mg/m2 body surface/dose, twice daily. The follow-up period lasted for 4 to 16 months (a mean of 7.7). The clinical outcome analysis included decrease or disappearance of proteinuria, clinical improvement and/or possibility of tapering therapy intensity, especially the dosage of steroids and/or CsA. Also, renal function was monitored with serum cystatine C concentration. Particular attention was paid to adverse effects of MMF upon the gastro- intestinal tract and/or opportunistic infections. All medication (apart from MMF) could be discontinued in 4 patients; in 15 cases, prednizone dose was reduced and in 9 cases CsA dose was reduced or discontinued. In group I (SD) steroid treatment could be reduced from a mean prednisone dose of 22.8 to 3.6 mg/m2/48 hours (p=0.018), in groups II and III, in spite of 50 % reduction of a mean prednisone dose, the difference did not reach statistical significance. During MMF therapy Csa treatment could be reduced from a mean CsA dose 4.3 to 2.9 mg/kg/24 hours (p=0.008). Improvement or preservation of stable renal function was observed in all patients--cystatin C levels decreased significantly from a mean 1.35 to 0.96 mg/l (p=0.007). Adverse reaction to MMF (abdominal pain) was observed in 2 patients (nausea, vomiting, diarrhoea in 1, CMV infection in 1). The initial clinical observation of MMF treatment in nephrotic patients shows its best effect in the group of patients with steroid-dependent NS. MMF can safely be used in children with NS. The introduction of MMF allows for reduction of other chronically used medications, especially CsA and steroids.
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PMID:[Mycophenolate mofetil in treatment of childhood nephrotic syndrome--preliminary report]. 1689 86

A main cause for gastrointestinal (GI) complications in graft recipients is the routinely administered inosine monophosphate dehydrogenase inhibitor mycophenolic acid (MPA). MPA is available in two formulations, the prodrug mycophenolate mofetil (MMF) and the enteric-coated sodium salt (EC-MPS). Clinical results point to a better GI tolerability of EC-MPS as compared to MMF. We performed an open surveillance study in 397 organ graft recipients to investigate the clinical tolerability of EC-MPS in renal graft recipients who were converted from MMF to EC-MPS (maintenance) or who received EC-MPS as a new component of their immunsuppressive regimen (de novo). Physicians recorded GI symptoms (nausea, emesis, anorexia, diarrhea, abdominal cramps) at the start of EC-MPS treatment (visit 1) and at the next two visits in the clinic (visits 2 and 3); general tolerability (very good/good/moderate/poor) was assessed at visit 2 and 3. Two hundred seventy-five patients were on maintenance treatment with MMF and were converted to equimolar doses of EC-MPS, and 122 patients received EC-MPS de novo. The mean time since transplantation was 4.2 +/- 4.4 years. Median time until visit 2 was 28 days and until visit 3, 65 days. In 63.0% of patients, tolerability was rated as very good at visit 2 and in 64.7% at visit 3. Most patients who had suffered from GI complications during preceding MMF treatment reported improvement or total disappearance of their symptoms after conversion to EC-MPS. In conclusion, EC-MPS is a useful means to reduce GI complications in MPA-treated patients.
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PMID:Enteric-coated mycophenolate sodium reduces gastrointestinal symptoms in renal transplant patients. 2000 59

MMF, the most commonly used adjuvant immunosuppressant in pediatric heart transplantation, has frequent GI adverse events. SNPs in inosine 5'-monophosphate dehydrogenase I (IMPDH1) may contribute to MMF GI intolerance. Phased haplotypes may have more utility than individual SNPs in candidate gene association studies for complex traits. This study defined common IMPDH1 haplotypes and investigated whether these haplotypes influence MMF GI intolerance in 59 pediatric heart recipients. Genotypes were assessed by Taqman analysis of IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294, and rs2228075, and haplotypes were inferred using Arlequin 3.01 software. GI intolerance was defined as diarrhea, vomiting, nausea, or abdominal pain requiring MMF dose holding for > 48 h or MMF discontinuation. GI intolerance occurred in 21 patients (35.6%). Ten IMPDH1 haplotypes were identified in this population. In univariable analyses, one haplotype was strongly associated with MMF GI intolerance with 59.1% of carriers of this haplotype experiencing MMF GI intolerance compared to 21.6% of non-carriers (p = 0.005). In this study, we identify a common IMPDH1 haplotype associated with MMF GI intolerance in a population of pediatric heart transplant patients. This haplotype of interest did not demonstrate stronger association with MMF GI intolerance than an individual IMPDH1 SNP.
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PMID:Inosine 5'-monophosphate dehydrogenase 1 haplotypes and association with mycophenolate mofetil gastrointestinal intolerance in pediatric heart transplant patients. 2064 57