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PubMed2001

Tremor associated with benign IgM paraproteinaemic neuropathy successfully treated with gabapentin.

We describe a 76-year-old patient with a severe tremor due to chronic demyelinating neuropathy associated with a benign IgM paraproteinaemia that was successfully treated with gabapentin. The patient reached the full dose of 1,200 mg/day of gabapentin without side effects and showed a significant therapy-related improvement of tremor and disability, as judged by the Fahn Tolosa Marin Rating Scale.

Acetates↗
PubMed2005

Gabapentin can improve postural stability and quality of life in primary orthostatic tremor.

Primary orthostatic tremor (OT) is characterized by leg tremor and instability on standing. High frequency (13-18 Hz) tremor bursting is present in leg muscles during stance, and posturography has shown greater than normal sway. We report on an open-label add-on study of gabapentin in 6 patients with OT. Six patients were studied with surface electromyography, force platform posturography, and a modified Parkinson's disease questionnaire (PDQ-39) quality of life (QOL) scale before and during treatment with gabapentin 300 mg t.d.s. If on other medications for OT, these were continued unchanged. Of the 6 patients, 4 reported a subjective benefit of 50 to 75% with gabapentin, 3 of whom showed reduced tremor amplitude and postural sway of up to 70%. Dynamic balance improved in all 3 patients who completed the protocol. QOL data from 5 patients showed improvement in all cases. No adverse effects were noted. Gabapentin may improve tremor, stability, and QOL in patients with OT, and symptomatic response correlated with a reduction in tremor amplitude and postural sway. The findings confirm previous reports of symptomatic benefit with gabapentin and provide justification for larger controlled clinical trials. Further work is required to establish the optimal dosage and to validate the methods used to quantify the response to treatment.

Aged↗
PubMed2006

Blinded placebo crossover study of gabapentin in primary orthostatic tremor.

Primary orthostatic tremor (OT) is a rare but disabling condition characterized by leg tremor and feelings of instability during stance. Previous studies have reported a reduction in OT symptoms with gabapentin treatment. In this study, we report on the benefits of gabapentin treatment in a double-blind placebo-controlled crossover study of 6 OT patients. First, the maximally effective gabapentin dosage (600-2,700 mg/day) for each patient was determined during an initial dose-titration phase. Patients were then studied 7 days after drug withdrawal and again after two 2-week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor. Other medications for OT were continued unchanged. Symptomatic response was assessed by a patient-rated severity scale and quality of life (QOL) questionnaire. All patients reported an increase in symptoms during the washout phase and symptom reduction (50%-75%) during gabapentin treatment. Tremor amplitude was reduced to 79% +/- 11% and sway area to 71% +/- 11% of the placebo state. QOL improved in all patients, no adverse drug effects were noted, and symptomatic benefit was maintained at follow-up (mean = 19 months). The findings confirm that gabapentin is an effective treatment for OT, reducing both tremor and postural instability and improving quality of life, and support its use as add-on or first-line therapy for OT.

Aged↗
PubMed1998

Double-blind controlled trial of gabapentin in essential tremor.

Gabapentin has been reported to be effective for essential tremor (ET) based on open-label trials. We studied gabapentin (1800 mg/day) and placebo in a double-blind crossover design in 20 ET patients. Eighteen patients completed the study and two patients dropped out as a result of adverse effects which resolved when the medication was discontinued. Tremor was assessed at baseline and after 2 weeks of gabapentin and placebo treatment. One patient was mildly improved and another was moderately improved with placebo. Similarly, one patient reported mild improvement and another patient had marked improvement with gabapentin. All the remaining patients either reported no change or were worse with both treatment arms. There was no significant difference for total tremor score, hand tremor score, handwriting scores, or pouring scores. Sickness Impact Profile scores were no different between placebo and gabapentin. Our results suggest that as an adjuvant therapy in ET, gabapentin has limited benefit.

Acetates↗
PubMed1998

Effective treatment of orthostatic tremor with gabapentin.

We report seven patients with orthostatic tremor (OT) who were successfully treated with the anticonvulsant gabapentin. Five of the patients had been previously tried on clonazepam, the most commonly used drug for OT, four without any benefit. The degree of improvement perceived by the patients with gabapentin varied from 60-80% (mean 73%). The effective dose of gabapentin ranged from 300-1800 mg/day (mean 1030 mg/day). The side effects were generally mild, transient, and dose-related. Duration of response has so far ranged from 2-22 months (mean 11 months) with all patients still currently benefiting from gabapentin. We conclude that gabapentin may be an effective treatment for OT. Further trials are indicated.

Acetates↗
PubMed2006

Isaacs' syndrome: clinical and electrophysiological response to gabapentin.

A patient with Isaacs' syndrome had generalized muscle spasms, twitching, and progressive muscle stiffness for 21 years. Electrodiagnostic study showed continuous spontaneous motor-unit activity and the presence of M-wave afterdischarges. He responded dramatically to treatment with carbamazepine but developed a drug rash; his treatment was changed to gabapentin with continued improvement. Subsequent nerve conduction studies showed decreased amplitude and later an absence of M-wave afterdischarges. Gabapentin thus appears to be an effective treatment for Isaacs' syndrome.

Action Potentials↗
PubMed2004

Treatment with the antiepileptic drugs phenytoin and gabapentin ameliorates seizure and paralysis of Drosophila bang-sensitive mutants.

Drosophila bang-sensitive (bs) mutants exhibit a stereotypic seizure and paralysis following exposure to mechanical shock. In a physiological preparation, seizures and failures corresponding to the defective behavior are observed in response to high frequency stimulation. The amplitude of the stimulus necessary to produce bs behavior, or seizure threshold, varies with bs mutant and its gene dosage. In many respects, the bs defects are similar to those observed in mammalian seizure disorders. Antiepileptic drugs (AEDs) were administered by feeding to easily shocked(2) (eas(2)), a representative bs mutant. The mean recovery times of treated flies were examined in comparison to control cultures. Some of the drugs administered, including carbamazeprine, ethosuximide, and vigabactrin, had little or no effect on the bs behavior of eas(2). Gabapentin, however, showed a reduction in mean recovery time with chronic drug exposure. Phenytoin also had a significant effect on the bs behavior of treated flies. There was a reduction of both mean recovery time and the percentage of flies that displayed bang-sensitive behavior with both acute and chronic treatment. The adult giant fiber preparation was used to examine the effects of phenytoin physiologically. Treated eas(2) flies showed changes in their response to normal stimulation as well as alterations in seizure threshold in response to high frequency stimulation. Gabapentin was also effective against two other bs mutants, bangsenseless(1) and slamdance(iso7.8), at strain-specific concentrations, while phenytoin also reduced bang-sensitive behaviors in bangsenseless(1) in a dose dependent manner. AEDs, therefore, can be used to dissect aspects of bs behavior and this model may be useful in understanding the underlying basis of seizure disorders.

Acetates↗
PubMed2006

Determination of gabapentin in human plasma using hydrophilic interaction liquid chromatography with tandem mass spectrometry.

A rapid, sensitive and selective method for the determination of gabapentin in human plasma was developed using hydrophilic interaction liquid chromatography/tandem mass spectrometry (HILIC/MS/MS). The devised method involved protein precipitation with acetonitrile followed by separation on an Atlantis HILIC silica column using an acetonitrile/ammonium formate mobile phase (100 mM, pH 3.0) (85:15, v/v). Analytes were detected using an electrospray ionization mass spectrometer in the multiple-reaction monitoring mode. The standard curve was linear (r = 1.000) over the concentration range of 50.0-10000 ng/mL. The lower limit of quantification for gabapentin was 50.0 ng/mL (ca. 20 pg gabapentin) using a 10-microL plasma sample. The coefficients of variation and relative errors for intra- and inter-assay at four QC levels (i.e., 50.0, 125, 750, and 7500 ng/mL) were 4.7 to 9.4% and -4.1 to 1.6%, respectively. Absolute and relative matrix effects for gabapentin and metformin were practically absent. Gabapentin and metformin recoveries were 98.5% and 99.0%, respectively. This method was successfully applied to a bioequivalence study of gabapentin in humans.

Amines↗
PubMed2003

Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells.

Gabapentin is a clinically effective anticonvulsant with an unclear mechanism of action. It was described as a GABA(B(1a,2)) receptor subtype-selective agonist, activating postsynaptic K(+) currents and inhibiting postsynaptic Ca(2+) channels in CA1 pyramidal cells, but without presynaptic actions. These activities appeared controversial and we therefore sought to further clarify gabapentin actions in rat hippocampal slices by characterizing K(+) currents and Ca(2+) channels targeted by gabapentin using whole-cell recording and multiphoton Ca(2+) imaging. 1) We found that gabapentin and baclofen induced inwardly rectifying K(+) currents (K(Gbp) and K(Bac), respectively), sensitive to Ba(2+) and Cs(+). 2) A constitutively active K(IR) current, independent of GABA(B) receptor activation and sensitive to Ba(2+) and Cs(+) was also present. 3) K(Gbp), K(Bac), and K(IR) currents showed some differences in sensitivity to Ba(2+) and Cs(+), indicating the possible activation of distinct Kir3 currents, independent of K(IR), by gabapentin and baclofen. 4) Gabapentin inhibition of Ca(2+) channels was abolished by omega-conotoxin GVIA, but not by omega-agatoxin IVA and nimodipine, indicating a predominant action of gabapentin on N-type Ca(2+) channels. 5) Gabapentin actions were linked to activation of pertussis toxin-sensitive G-proteins since N-ethylmaleimide (NEM) blocked K(Gbp) activation and Ca(2+) channel inhibition by gabapentin. 6) Finally, gabapentin reduced epileptiform discharges in slices via GABA(B) receptor activation. The anticonvulsant actions of gabapentin in hippocampal cells may thus involve GABA(B) receptor coupling to G-proteins and modulation of Kir3 and N-type Ca(2+) channels. Moreover, gabapentin and baclofen activation of GABA(B) receptors may couple to distinct cellular targets.

Acetates↗
PubMed2005

Gabapentin fails to alter P/Q-type Ca2+ channel-mediated synaptic transmission in the hippocampus in vitro.

Gabapentin (Neurontin) has been successfully used in the treatment of both epilepsy and neuropathic pain. Despite its widespread clinical use, its mechanism of action is very poorly understood. Indeed, the only protein it is known to interact with is the alpha2delta subunit of the voltage-gated Ca(2+) channel complex. In a recent article, gabapentin was reported to inhibit synaptic transmission in the spinal cord through an inhibitory effect on presynaptic P/Q-type Ca(2+) channels in both glutamatergic primary afferents and glycinergic interneuones. To examine if such inhibition of P/Q-channel-mediated synaptic transmission by gabapentin generalised to other synaptic pathways, we tested the actions of gabapentin of P/Q-type Ca(2+) channel-mediated synaptic responses in the CA1 subfield of the hippocampus. We found that gabapentin was completely inactive on such synaptic responses even at 10 times the maximally effective concentration used in the spinal cord. A small ( approximately 10%) but consistent depression of control synaptic responses was elicited by 10 microM gabapentin. No greater response was observed at a 10 times higher concentration. From these data we conclude that gabapentin is not a generic inhibitor of presynaptic P/Q-type channels and its actions at the spinal level must represent a feature of the P/Q-type channel not present in the hippocampus. Given the known interactions of this compound, the best candidate for this is the presence, subtype, or state of the alpha2delta subunit.

Amines↗
PubMed1978

Teratogenicity testing in humans: a method demonstrating safety of bendectin.

We investigated the incidence of birth defects in the offspring of women who took Bendectin during pregnancy. Copies of all prescriptions issued for Bendectin in two Cities, Leeds and Liverpool, over periods of 12 and 14 months, respectively, were scanned and a record initiated for each patient. Birth notifications were later searched for matching with indexed patients. Births were traced for 2,298 patients and the incidence of major defects compared with those in the relevant populations. We found no evidence to suggest that Bendectin is teratogenic in humans.

Abnormalities, Drug-Induced↗
PubMed1988

Developmental toxicity evaluation of Bendectin in CD rats.

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

Abnormalities, Drug-Induced↗
PubMed1994

Developmental toxicity studies in mice, rats, and rabbits with the anticonvulsant gabapentin.

The developmental toxicity of the anticonvulsant agent gabapentin was evaluated in mice, rats, and rabbits treated by gavage throughout organogenesis. Mice received 500, 1000, or 3000 mg/kg on gestation days (GD) 6-15 and rats and rabbits received 60, 300, or 1500 mg/kg on GD 6-15 (rats) or 6-18 (rabbits). Additional groups received an equivalent volume of the vehicle, 0.8% methylcellulose, or remained untreated. All dams were observed daily for clinical signs of toxicity. In mice, body weights and food consumption were recorded on GD 0, 6, 12, 15, and 18 while in rats and rabbits these parameters were evaluated daily. Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) each female was euthanatized, necropsies were performed, and litter and fetal data were collected. Live fetuses were examined for external, visceral, and skeletal variations and malformations. No adverse maternal or fetal effects were observed in mice or rats given doses up to 1500 or 3000 mg/kg, respectively. No treatment-related maternal or fetal effects were apparent in rabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died, four others aborted, and reduced food consumption and body weight gain were observed. No other reproductive, litter, or fetal parameters were affected, except that the incidence of visceral variations in rat fetuses was slightly but statistically significantly increased at 1500 mg/kg due to a slight increase in the incidence of dilated renal pelvis. This finding was not considered biologically significant because this degree of variability has been seen in this strain of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed2000

Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog.

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT (12 mgkg(-1)i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB (60 mgkg(-1)) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mgkg(-1), i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n= 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug's kinetics, as evidenced by a 31% (P= 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life (t(1/2)), (P= 0.013) and area under the plasma PT concentration-time curve (AUC), (P= 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.

Acetates↗