Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004093 (asthenia)
 2,650 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis (RA) is a chronic disease affecting 0.8% of the population. Nonsteroidal anti-inflammatory drugs reduce the pain and inflammation of RA and improve mobility but do not slow the progression of joint damage. Disease-modifying antirheumatic drugs (DMARDs), which limit potentially irreversible joint damage, may influence the course of disease progression. This review describes the recently approved DMARD leflunomide, an isoxazole-based immunomodulator. Unlike other DMARDs, leflunomide arrests the growth of activated lymphocytes by inhibiting the enzyme dihydroorotate dehydrogenase, a critical link in the production of uridine monophosphate. Leflunomide is rapidly metabolized to the active major metabolite A77 1726, which is responsible for the drug's pharmacologic activity. Leflunomide has exerted inhibitory activity in animal models of RA. Its clinical efficacy has been demonstrated in a number of controlled trials. In two multinational 52-week studies and two 24-week studies, all leflunomide-treated patients received an initial loading dose of 100 mg for 3 days, followed by 20 mg/d. The effects on the signs and symptoms of RA were evaluated using the American College of Rheumatology (ACR) 20 responder index, tender and swollen joint counts and scores, patients' and physician's global assessments, and pain intensity index. Erosions and joint-space narrowing were assessed by radiography. Compared with placebo, leflunomide significantly improved the signs and symptoms of RA (41%-64% improvement) by ACR 20 responder criteria (P < 0.001). Leflunomide, methotrexate, and sulfasalazine were equally effective in terms of symptom outcomes. In terms of retarding the progression of disease, leflunomide was significantly superior to placebo, with no consistent difference from methotrexate or sulfasalazine. In a trial using a combination of leflunomide and methotrexate therapy, 53% of patients were responders by ACR 20 criteria. Adverse effects in RA patients receiving leflunomide included diarrhea, elevated liver enzymes, alopecia, and rash. Additional adverse events occurring with a frequency >5% included allergic reaction, asthenia, abdominal pain, back pain, and hypertension, among others. Thus leflunomide may be used in selected RA patients (ie, those starting RA therapy for the first time or failing earlier DMARD therapy). However, the product labeling requires monthly monitoring of liver enzymes until stable concentrations are reached. Other labeled warnings include a risk of immunosuppression and an increased risk of fetal death or teratogenic effects in pregnant women. Methotrexate, which is also hepatotoxic, is usually the initial DMARD recommended for use in patients with aggressive RA.
 ...
PMID:Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. 1089 Feb 56

SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.
 ...
PMID:UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. 1528 Sep 27