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PubMed1990

Gabapentin in partial epilepsy. UK Gabapentin Study Group.

Gabapentin is an analogue of gamma aminobutyric acid (GABA) which has anticonvulsant properties in animals. In a multicentre, double-blind, placebo-controlled, parallel-group study of 1200 mg/day gabapentin as additional therapy in 127 patients with drug-resistant partial epilepsy, 25% of patients who received gabapentin had the number of partial seizures at least halved, compared with 9.8% of patients given placebo. The median reduction in partial seizure frequency during 12 weeks' treatment was 29.2% with gabapentin compared with 12.5% with placebo. The mean adjusted response ratio for gabapentin (-0.192) was significantly better than the ratio of -0.060 for placebo by analysis of variance. 62% of patients who received gabapentin reported mostly mild or moderate adverse effects compared with 41% on placebo; no interactions were observed between gabapentin and other standard anticonvulsants. Gabapentin is an effective additional treatment for patients with partial epilepsy refractory to standard therapy, is fairly well tolerated, and appears to have a favourable efficacy-to-toxicity ratio.

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PubMed1992

Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin.

Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.

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PubMed1991

Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin.

Twelve subjects received a single oral dose (300 mg) of gabapentin and serial blood and urine samples were collected for drug measurements. Oral phenobarbitone (30-90 mg/day) was then administered to steady-state, and the gabapentin single dose study was repeated on day 42. Gabapentin was administered from days 49 to 52 to achieved steady-state, and further blood and urine samples were collected for drug measurements. Trough plasma phenobarbitone concentrations were monitored at frequent intervals. No statistically significant differences were observed in gabapentin Cmax, tmax, AUC, t1/2 or urinary drug recovery following single doses of gabapentin alone or combined with phenobarbitone. Phenobarbitone did not alter the disposition of gabapentin at steady state. Mean trough steady-state phenobarbitone concentrations were not significantly affected by concomitant gabapentin administration.

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PubMed1986

Pharmacokinetics and metabolism of gabapentin in rat, dog and man.

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, Gö 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.

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PubMed1991

Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain.

Gabapentin exerts anticonvulsant effects in different animal models of seizure states and in epileptic patients with different seizure types, but the mechanism of action of these effects is unknown. In the present study, the gamma-aminobutyric acid (GABA) accumulation induced by aminooxyacetic acid (AOAA) was used as a method to study the effects of gabapentin on regional turnover of GABA in the rat brain. Gabapentin was administered at a dose of 23 mg/kg i.p. (the ED95 against tonic electroconvulsions in rats) 1, 2 and 8 h prior to injection of AOAA, 100 mg/kg, i.p. Gabapentin significantly increased the AOAA-induced GABA accumulation in most of the 12 brain regions examined, but the time course of the increases in GABA accumulation differed from region to region. Regions in which the time course of the increase in GABA accumulation was similar to the anticonvulsant time course of gabapentin included substantia nigra, amygdala and thalamus. The data suggest that an effect of gabapentin on GABA synthesis might be involved in its mechanism of anticonvulsant action.

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PubMed1985

Gabapentin decreases monoamine release without affecting acetylcholine release in the brain.

Superfused rat brain cortex slices preincubated with 3H-noradrenaline or 3H-serotonin and superfused rabbit caudate nucleus slices preincubated with 3H-choline were used to examine the effects of gabapentin (an amino acid chemically related to gamma-aminobutyric acid, GABA) on the electrically evoked 3H overflow. Gabapentin inhibited the electrically (3 Hz) evoked 3H overflow from slices preincubated with the 3H-monoamines in a concentration-dependent manner (at 1 mmol/l by 20-30%), but did not affect the evoked overflow from slices preincubated with 3H-choline. The following drugs did not modify the inhibitory effects of gabapentin: bicuculline, RS-baclofen, GABA, phentolamine, metitepin, cocaine, and the inhibitor of serotonin uptake, 6-nitroquipazine. Gabapentin did not modify the inhibitory effect of GABA on the evoked 3H overflow from slices preincubated with 3H-serotonin. In slices preincubated with 3H-noradrenaline the inhibitory effect of gabapentin was still observed when the stimulation frequency was 10 instead of 3 Hz. In conclusion, gabapentin mimics GABAB receptor activation, but it appears to act by a GABA receptor-independent, as yet unidentified mechanism.

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PubMed1988

Gabapentin augments whole blood serotonin in healthy young men.

It has been previously demonstrated that gabapentin, a gamma-amino butyric acid analogue, inhibits monoaminergic neurotransmitter release from rabbit caudate nucleus slices and from rat cortex. In humans this drug has been shown to have anti-epileptogenic activity. Serotonin may act as an inhibitory neurotransmitter and its interaction with blood platelets is thought to reflect its central actions. We investigated sleep stages, whole blood serotonin levels, and serum melatonin in healthy men after the administration of gabapentin. With increasing serum gabapentin levels six healthy subjects showed an increase in sleep stages 3 and 4 and in whole blood serotonin (P less than 0.05) Serum melatonin levels were not influenced. On account of these results we speculate that gabapentin modulates the release of serotonin from blood platelets. The increase in peripheral serotonin points paradigmatically to an increase in the bioavailability of serotonin which may account for the increase in sleep stages 3 and 4.

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PubMed1991

Intestinal absorption of gabapentin in rats.

Gabapentin (1-aminomethyl-)cyclohexaneacetic acid, Gö 3450, CI-945; CAS 60142-96-3) is a new gamma-aminobutyric acid (GABA) analogous compound that has shown an anticonvulsive effect as well as low toxicity in preclinical and clinical studies. The substance is well absorbed after oral administration and penetrates the blood-brain barrier. The aim of experiments was to study the mechanism of intestinal absorption, the relationship between the absorption rate and the applied concentration and whether the absorption rate differs between different parts of the intestine. For this purpose, isolated intestinal segments of rats (everted sac preparations) were used. Due to the fact that gabapentin is not metabolized in the intestine, its concentration in the mucosal and serosal compartments could be determined by scintillation counting of 3H-gabapentin. The results showed that gabapentin was absorbed by simple diffusion because neither indications for an uphill nor for a carrier-mediated transport could be demonstrated. The absorption rate was linearly related in the concentration range from 0.001 to 100 mmol/l. There was no significant difference between the absorption rate in the three parts of the small intestine at 1 and 10 mmol/l, while the absorption rate was significantly (p less than 0.01) lower in the colon.

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PubMed1992

Long-term treatment with gabapentin for partial epilepsy.

Gabapentin was studied as an open-label 'add-on' antiepileptic drug in 35 patients with partial seizures. Follow-up at 6 months, 12 months, 18 months, and 24 months is reported. There was a trend toward improvement in simple (SPS) and complex partial seizures with it reaching significance for SPS at 12 and 24 months and for the weighted combination of seizures at 3 months. Five of nine patients were subsequently successfully converted to gabapentin monotherapy. Of those five, one is now seizure free and three are significantly improved since baseline. One remains with unchanged seizure frequency compared to baseline, but is experiencing less toxicity than at that time. This long-term observation suggests that the short-term effect demonstrated in blinded studies continues and that indeed some patients with refractory epilepsy can be maintained on gabapentin alone. Based on these findings, double-blind monotherapy trials of this drug are presently being conducted.

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PubMed1992

Stability studies of gabapentin in aqueous solutions.

Gabapentin is a gamma-aminobutyric acid analogue, which has been shown to be an effective antiepileptic. The solution stability of gabapentin in buffered systems was studied in order to facilitate the formulation of a liquid product. The degradation of the drug was followed as a function of pH, buffer concentration, ionic strength, and temperature. The results indicated that the rate of degradation was proportional to the buffer concentration and temperature. The pH-rate profile of gabapentin degradation showed that the rate of degradation was minimum at an approximate pH of 6.0. Further, the data suggested a slower solvent-catalyzed degradation rate for the zwitterionic species compared to the cationic or anionic species in the pH range of 4.5 to 7.0. There was no influence of ionic strength on the rate of degradation. Arrhenius plots of the data indicated that a shelf life of 2 years or more at room temperature may be obtained in an aqueous solution at a pH value of 6.0.

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PubMed1986

Evaluation of encephalotropic and psychotropic properties of gabapentin in man by pharmaco-EEG and psychometry.

In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of gabapentin - a new gaba-analogue with anticonvulsant and antispastic properties penetrating the blood brain barrier easily - were studied in 10 normal subjects by means of quantitative pharmaco-EEG and psychometric analyses. They received randomized and in weekly intervals single oral doses of 50 mg, 100 mg, 200 mg and 400 mg gabapentin as well as placebo. EEG recordings and evaluation of pulse, blood pressure and side effects were carried out after 0, 1, 2, 4, 6 and 8 hours; psychometric tests were done at the same times except for the first hour. Computer-assisted spectral analysis of the EEG showed moderate though significant central effects of gabapentine in doses of 200-400 mg as compared with placebo, which were maximally pronounced in the 2nd hour post drug. These alterations were generally characterized by an attenuation of total power, augmentation of delta and theta activity and a decrease of alpha activity indicating CNS-inhibitory properties. Only at the late hours did the type of changes shift towards a vigilance-promoting one. Beta activity showed alternating changes. Psychometric and psychophysiological evaluations demonstrated subtle psychotropic effects as compared with placebo characterized mostly by an improvement in concentration, numerical memory, complex reaction and performance in the alphabetical reaction test while performance variability increased as well. Subjectively experienced well-being changed dose-dependently. CFF decreased after 100 mg as did pupil size after 50-200 mg. Evaluation of pulse, blood pressure and side effects demonstrated good tolerability of the drug.

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PubMed1991

Comparison of gabapentin with other antiepileptic and GABAergic drugs.

The effect of the experimental antiepileptic drug gabapentin (1-(aminomethyl) cyclohexane acetic acid; GPT) on the feline trigeminal complex was compared with the effect of established antiepileptic drugs and with the effect of GABAA and GABAB agonists and antagonists. Intravenous injection of 10-60 mg/kg GPT depressed the descending periventricular facilitation of trigeminal nucleus neurons, as well as segmental excitatory mechanisms. On the other hand, GPT usually facilitated, but sometimes depressed, both segmental and periventricular inhibitory mechanisms. GPT thus resembled carbamazepine and phenytoin in its action on excitatory mechanisms and on segmental inhibition, but differed in its effect on inhibitory pathways descending from the reticular formation. In agreement with our observations, GPT has been found to be effective against partial and generalized tonic-clonic seizures, similar to the spectrum of activity of carbamazepine and phenytoin. The action of GPT in our model also resembled that of the GABAB agonist baclofen in its facilitation of reticular and segmental inhibitory mechanisms and its depression of segmental excitatory mechanisms, but differed in its effect on excitatory mechanisms descending from the reticular formation. GPT has also been reported to mimic GABAB receptor activation in other experiments but appeared to act by a GABA-receptor independent mechanism.

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PubMedDate not supplied

Double-blind study of Gabapentin in the treatment of partial seizures.

Forty-three patients completed a double-blind, placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period, after which they were randomly allocated to receive either a placebo or 900 or 1,200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1,200 mg, in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.

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PubMed1987

Gabapentin as an antiepileptic drug in man.

Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, is a GABA analogue whose antiepileptic properties were tested in a double blind cross-over trial design as add-on therapy in a dose ranging study which compared 300 mg, 600 mg, and 900 mg/day (each dose given for 2 months) in 25 patients with severe partial and generalised epilepsies. A dose related antiepileptic effect was observed. All three doses were well tolerated and no psychometric impairment was noted. No significant drug interactions were seen. The drug appears worthy of further assessment.

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PubMed1990