Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PALA (N-phosphonoacetyl-L-aspartate) impairs de novo pyrimidine biosynthesis by inhibiting the enzyme aspartate transcarbamylase. During cancer chemotherapy trials the drug was given by weekly intravenous infusion. Seizures developed in 9 (11%) of the first 80 patients to receive a total dose of 9 gm/m2 or more. Seven of the affected patients had structural brain lesions; they developed seizures at a lower total dose (median of 16.4 gm/m2) than the 2 patients without clinically detectable brain lesions (115 to 130 gm/m2). Reversible encephalopathy was observed in 6 (7.5%) additional patients without clinically detectable cause other than PALA. Both seizures and encephalopathy began after the second dose of PALA or later. Experiments in rats demonstrated similar delayed-onset seizures after two or three combined systemic and intracerebral doses of PALA at 4-day intervals. Concurrent administration of uridine or carbamyl aspartate prevented the development of seizures in rats, indicating that pyrimidine starvation of the central nervous system was responsible for PALA neurotoxicity.
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PMID:Neurotoxicity of the pyrimidine synthesis inhibitor N-phosphonoacetyl-L-aspartate. 712 6

PALA was given iv on a weekly schedule to 32 patients with advanced malignant tumors. A course of treatment consisted of three weekly doses. Patients were treated at eight dose levels, ranging from 900 to 6750 mg/m2. Gastrointestinal toxicity (diarrhea) and skin rash were dose-limiting. No consistent myelosuppression occurred, and no renal or hepatic toxicity was observed. Two patients who did not have metastatic intracranial disease experienced episodes of encephalopathy and seizures. No major therapeutic responses were observed during this phase I trial; however minor responses (greater than or equal to 25% tumor decrease) occurred in three patients (one with adenocarcinoma of the lung and two with epidermoid carcinoma of the bladder). Doses of 4500 mg/m2/week for patients with a performance status greater than or equal to 70 and 3750 mg/m2/week for patients with a lower performance status are recommended for phase II studies.
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PMID:Phase I trial of PALA. 747 Nov 20