Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.
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PMID:Comparative adverse effect profiles of platinum drugs. 857 96

1 A nomogram and a digital computer program have been developed to calculate dosage schedules of gentamicin for individual patients. The minimum input data consist of the patients' age, sex, body weight and serum creatinine concentration. 2 These prescribing aids have been evaluated in 36 patients with severe Gram negative infections. Renal function ranged from normal to complete anuria. Nomogram dosage schedules gave serum concentrations of gentamicin within the chosen therapeutic limits. Physician dosage schedules gave serum concentrations which sometimes exceeded and sometimes fell below these limits. The validity of the computer program was demonstrated by its ability to predict serum concentrations of gentamicin whatever the dosage schedule. 3 Half the patients recovered from the bacterial infection but seven remained infected and eleven died. Pseudomonas aeruginosa was the most difficult organism to eradicate. 4 Four of the patients who survived developed ataxia and two developed hearing loss at high frequencies. The risk of ototoxicity was a function of mean trough serum gentamicin concentration and duration of treatment. Ototoxicity was only detected in patients with serum creatinine concentrations above 3 mg/100 ml who tended to have higher trough concentrations. When treatment was prolonged beyond 8-10 days the risk of ototoxicity was increased without evidence of further substantial therapeutic benefit.
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PMID:Prescribing aids for gentamicin. 2245 68