Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.
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PMID:Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group. 896 Jul 15

Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).
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PMID:A summary of mechanistic hypotheses of gabapentin pharmacology. 955 85

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
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PMID:Mechanisms of action of gabapentin. 968 47

Glutamate excitotoxicity seems to play an important role in the aetiopathogenesis and progression of Amyotrophic Lateral Sclerosis (ALS). Gabapentin is a modulator of the glutamatergic system and has been shown to prolong survival in the transgenic model of familial ALS. It has also been demonstrated to slow the decline of arm strength in human sporadic cases. The aim of our study was to assess the effects of different dosages and duration of treatment of gabapentin on the natural history and survival of ALS patients. A total of 110 patients affected by definite ALS entered the study. After a 6-12 month period of observation, patients were randomly assigned to receive oral gabapentin 500 mg/day (Group A) or 1000 mg/day (Group B) for 6 months. In addition a group of patients received gabapentin 500 mg/day for 6 months and 1000 mg/day for a further 6 months (Group C). A group of 121 patients referred to our Institute, who received only symptomatic treatment, was considered as the control group (Group D). Each patient was seen at entry and every 3 months. All average slopes were negative but the comparison of all slopes showed a trend toward a slower rate of decline of muscle strength loss in all treated groups of patients compared with the control group. The differences were statistically significant. Analysis between the pretreatment and treatment period showed a statistically significant decrease of the decline of muscle strength and Norris score during the treatment period. Survival analysis showed a significantly longer survival in treated patients of Groups B and C. Our study suggests that gabapentin may be an effective drug for ALS; hence a controlled trial involving a sufficient large number of patients is warranted.
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PMID:The natural history and the effects of gabapentin in amyotrophic lateral sclerosis. 985 51