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)

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.
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PMID:Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture. 238 52

The investigational amino acid antitumor agent, acivicin, has been reported to cause dose-related and reversible CNS toxicity in humans characterized by sedation, ataxia, hallucinations, personality changes, and other symptoms. In a series of studies aimed at characterizing this toxicity, we investigated several species as potential animal models, determined the effects of acivicin on neuronal action potentials, and measured drug effects on the brain content of several putative amino acid neurotransmitters. In mice, we were unable to demonstrate any effects of acivicin in a battery of tests used in identifying and classifying CNS-active agents of potential therapeutic utility. In rats, unlike phencyclidine and certain other psychotomimetic drugs, acivicin produced no impairment of shock avoidance or brightness discrimination in animals trained on an automated Y-maze. In contrast to the rodent species, acivicin effects were perceived as resembling those of cyclazocine by rhesus monkeys trained to discriminate between psychoactive drugs and saline by food reinforcement. Cats treated with acivicin exhibited dose-related symptoms of sedation, somnolence, and ataxia. Iontophoretically applied acivicin was shown to have no effect on the spontaneous firing rate of dorsal horn interneurones in spinal cats. At the time of peak CNS symptoms in cats treated with 100 mg/kg acivicin, content of gamma-aminobutyric acid (GABA; nmoles/mg protein) was elevated from 57-140% in cerebellum, diencephalon, midbrain, and corpus callosum compared to control animals. Brain contents of glutamate, glutamine, and aspartate were not altered in cats experiencing neurotoxicity. These studies have shown that some symptoms of acivicin CNS toxicity are shared by humans and higher non-human species such as the cat and the monkey but not by rodents. Acivicin itself is apparently not a CNS excitant or depressant, but metabolites of the drug could be. Acivicin may also cause increases in the GABA content of localized regions of brain.
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PMID:Animal behavioral and neurochemical effects of the CNS toxic amino acid antitumor agent, acivicin. 271 Oct 26

Acivicin, an L-glutamine antagonist, was administered to 37 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 67 evaluable 72-hr iv infusions were given at 3- to 4-week intervals. Doses ranged from 3.0 to 90 mg/m2/course. Reversible CNS toxicity was dose-limiting and included lethargy, somnolence, anxiety, hallucinations, and paranoid psychoses. Four of five patients experienced unacceptable CNS toxicity at 90 mg/m2. Three of eight patients experienced reversible diaphoresis and chills without fever at 75 mg/m2, and two had dizziness and ataxia. Hematopoietic toxicity, nausea, emesis, and diarrhea were mild and dose-related. One patient developed a blue-green discoloration of the infusion arm. Serial plasma and urine specimens from 13 patients were assayed for acivicin using a microbiologic method. Peak plasma levels at the end of the 72-hr infusions correlated with dose and ranged from 0.09 to 1.10 microgram/ml. When data from six patients were fitted to a two-compartment open model, alpha-half-life ranged from 1.1 to 63 mins, while beta-half-life ranged fro 338 to 629 mins. Renal clearance ranged from 6 to 24 mL/min, and nonrenal clearance accounted for 58%-83% of the total drug clearance. CNS toxicity correlated with plasma acivicin levels which exceeded 0.9 microgram/ml for greater than 16 hrs, but not with peak plasma levels or with the integrals of the concentration x time curves. Minor responses were seen in one patient with melanoma, in one with epidermoid pulmonary carcinoma, and in two with colon carcinoma. A starting dose of 60 mg/m2/course was recommended for phase II trials, with possible escalation to 75 mg/m2 in the second course if the drug was well-tolerated.
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PMID:Phase I trial and pharmacokinetics of acivicin administered by 72-hour infusion. 687 83