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

1-(2-o-Chlorobenzoyl-4-chlorophenyl)-5-glycyl-aminomethyl-3- dimethylcarbamoyl -1H-1,2,4-triazole hydrochloride dihydrate, (450191-S), exhibits pronounced central nervous system (CNS) activities similar to those of benzodiazepines, but it has only low affinity for benzodiazepine receptors. However, when 450191-S was administered to rats at a dose of 10 mg/kg, brain extracts markedly inhibited [3H]diazepam binding to the receptors. Thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), and radioreceptor assay (RRA) were used to isolate three metabolites that could inhibit [3H]diazepam binding prominently. These were identified by gas chromatography-mass spectrometry (GC/MS) as compounds having the triazolo-benzodiazepine skeleton. They showed high affinities for benzodiazepine receptors (Ki = 0.9 to 2.1 nM) and exerted potent pharmacological effects similar to those of 450191-S. In addition, their levels in the brain were sufficient to explain the pharmacological activity of 450191-S, which could not be detected in tissue extracts 15 min after administration. These results indicate that the pharmacological activity of 450191-S is largely due to the action of active metabolites, although some points remain to be elucidated to fully account for the large attenuation of the side effect (ataxia) compared with the major effects (anti-convulsant and hypnotic). We also determined the brain levels of metabolites following the administration of 450191-S and evaluated the extent to which each active metabolite contributes to the pharmacological activities of this drug.
 ...
PMID:Detection and determination of active metabolites of 1-(2-o-chlorobenzoyl-4-chlorophenyl)-5-glycyl-aminomethyl-3-dimethy l-carbamoyl-1H-1,2,4-triazole hydrochloride dihydrate, (450191-S), in rat tissues, using a radioreceptor assay for benzodiazepines. 614 19

In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline. 793 8

Gabapentin (GBP) is a antiepileptic drug (AED) indicated as adjunct therapy for treatment of partial seizures, with and without secondary generalization, in patients 12 and older with epilepsy. GBP (1-(aminomethyl) cyclohexaneacetic acid) is structurally related to gamma-aminobutyric acid (GABA), which readily crosses the blood-brain barrier. Radiolabeled GBP binds throughout the central nervous system in anatomic areas important in treatment of seizures. Its precise mechanism of action is unknown. An open-label, dose-ranging study of doses up to 1,800 mg produced > or =50% seizure reductions [responder rate (RR)] in 29% of patients with partial seizures. Three double-blind, placebo-controlled, parallel add-on trials at doses of 300-1,800 mg have produced RR of up to 28%, with a placebo RR of 8-10%. An active controlled, parallel group comparison of 600 mg to 2,400 mg in monotherapy conversion design showed no significant difference among the 600 mg, 1,200 mg, and 2,400 mg groups compared to a placebo group. An inpatient, active-controlled comparison of 300 mg and 3,600 mg in a parallel-design monotherapy trial showed that time to exit from the study was significantly longer for the 3,600-mg group and the completion rate significantly higher (53% vs. 17%) for patients receiving 3,600 mg/day vs. 300 mg/day of GBP. Successful double-blind, placebo-controlled trials in refractory childhood partial seizures and benign childhood epilepsy with centrotemporal spikes have been recently concluded. Absence was not successfully treated in one small double-blind trial. Open-label reports emphasize adjustments of patients to higher doses than those indicated in the package labeling. An open-label trial of GBP therapy in patients with partial seizures (n = 2,216) produced progressively greater seizure freedom rates as patients were titrated from > or =900 mg daily to > or = 1,800 mg daily (15.1% vs. 33.4%), with a similar effect on RR (18.1% vs. 44.9%). An add-on, open-label study treating partial seizures (n = 141) reported an RR of 71%, with 46% seizure-free in the last 8 weeks of treatment and doses up to 2,400 mg daily. A comparison trial of three doses of GBP to 600 mg of carbamazepine showed similar retention rates for 1,800 mg of GBP and 600 mg of CBZ. Another study reported 48% of patients experiencing 50% reduction, nine of whom had doses greater than 2,400 mg. Treatment in children has reported a 34.4% RR in 32 children with refractory partial seizures. A French open-label adjunctive trial documented a 33.9% RR; 13.4% were seizure-free during the evaluation period. Adverse experiences most commonly noted included somnolence, dizziness, and ataxia. Weight gain was sometimes reported with higher doses of GBP, and pediatric reports cite prominent behavioral changes, including hyperactivity, irritability, and agitation. GBP appears best used at doses at and potentially above those suggested in its package labeling. Although efficacy occurs at lower levels, increased GBP doses are associated with additional efficacy. Reports suggest that initiation at 2,400 mg or 3,600 mg may not be associated with increased adverse experiences. Titration to 900 or 1,200 mg on the first day of GBP therapy appear to be well tolerated.
 ...
PMID:Gabapentin. 1053 Jun 96

Pregabalin (S-[+]-3-isobutylgaba) was designed as a lipophilic GABA (gamma-aminobutyric acid) analogue substituted at the 3'-position in order to facilitate diffusion across the blood-brain barrier. It was originally developed as an anticonvulsant agent, however it has been shown to be effective in the treatment of several disorders including hyperalgesia and behavioural disorders. Although its exact mode of action remains unclear, pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor, gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the alpha(2)delta subunit of voltage-dependent calcium channels, widely distributed throughout the peripheral and central nervous system. Pregabalin appears to produce an inhibitory modulation of neuronal excitability. In healthy volunteers, it is rapidly absorbed with peak blood concentrations within 1 h and it has a bioavailability of approximately 90%. In preclinical trials of anticonvulsant activity, pregabalin is three to ten times more potent than gabapentin. It is well-tolerated and associated with dose-dependent adverse effects (ataxia, dizziness, headache and somnolence) that are mild-to-moderate and usually transient. There are no known pharmacokinetic drug-drug interactions reported to date. Preliminary animal and human studies showed beneficial effects in both ethological and conflict models of anxiety, as well as having some sleep-modulating properties. In Phase II and III trials, pregabalin shows promising anxiolytic action when compared to placebo in generalised anxiety disorder, social phobia and panic disorder.
 ...
PMID:Pregabalin: a new anxiolytic. 1266 21