Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.
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PMID:Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study. 1156 81

Myopathy is usually a non-fatal muscle disease involving skeletal muscle weakness, tenderness and pain with the possibility of the plasma creatinine kinase elevation. There are many different types of myopathies, some of which are genetic, inflammatory, or related to endocrine dysfunction. Also, numerous drugs have been reported to possess myotoxic effect. Myopathy is included among the potential side-effects and toxicities associated with the lipid lowering agents, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. However, the precise mechanism of statin-induced muscle toxicity remains unclear. The muscle-related side-effects reported with lipid-lowering drugs are significant but quite rare (0.1%), when used in monotherapy; while the incidence of steroid-induced myopathy has varied from 7 to 60%% and chronic alcoholic myopathy seems to be common complication of alcoholism affecting approximately 50% of patients, respectively. This review focuses on the differential pathophysiological grounds of these muscular injuries induced by statins, fibrates, as well as some other agents: corticosteroids or alcohol. A wide spectrum of possible mechanisms and hypotheses including muscle enzyme defects, changes in mitochondrial function and intracellular metabolism, the influence on the cell membrane stability and drug interactions involving P-glycoprotein or cytochrome P 450 system have been presented.
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PMID:Drug-induced myopathies. An overview of the possible mechanisms. 1584 74

Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.
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PMID:Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. 1738 88