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PubMed2002

Effect of gabapentin on the anticonvulsant activity of antiepileptic drugs against electroconvulsions in mice: an isobolographic analysis.

PURPOSE: The objective of this study was the isobolographic evaluation of the interactions between the novel antiepileptic drug (AED) gabapentin (GBP) and a number of other AEDs against electroconvulsion-induced convulsions in mice. METHODS: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point). Adverse effects were evaluated with the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of AEDs were measured by immunofluorescence or high-pressure liquid chromatography. RESULTS: GBP (< or =50 mg/kg) remained ineffective on the electroconvulsive threshold. According to the isobolographic analysis, GBP appears to act synergistically with carbamazepine, valproate, phenytoin, phenobarbital (PB), lamotrigine (LTG), and LY 300164. The pharmacokinetic events may be responsible for the interactions of GBP/PB and GBP/LTG, because only PB and LTG significantly elevated the plasma concentration of this AED. Conversely, GBP did not affect the plasma levels of other AEDs used in this study. No adverse effects were induced by combinations of GBP with these AEDs. CONCLUSIONS: The isobolographic analysis revealed that combinations of GBP with other AEDs generally results in synergistic (supraadditive) interactions.

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PubMed2003

Vigabatrin, but not gabapentin or topiramate, produces concentration-related effects on enzymes and intermediates of the GABA shunt in rat brain and retina.

PURPOSE: The antiepileptic drug (AED) vigabatrin (VGB), which exerts its pharmacologic effects on the gamma-aminobutyric acid (GABA) system, causes concentric visual field constriction in >40% of exposed adults. This may be a class effect of all agents with GABA-related mechanisms of action. We compared the concentration-related effects of VGB in rat brain and eye with those of gabapentin (GBP) and topiramate (TPM), both of which have been reported to elevate brain GABA concentrations in humans. METHODS: Adult male rats (n = 10) were administered 0.9% saline (control), VGB (250, 500, 1,000 mg/kg), GBP (50, 100, 200 mg/kg), or TPM (12.5, 25, 50, 100 mg/kg). At 2 h after dosing, animals were killed, a blood sample obtained, the brain dissected into eight distinct regions, and the retina and vitreous humor isolated from each eye. Samples were analyzed for several GABA-related neurochemical parameters, and serum and tissue drug concentrations determined. RESULTS: VGB treatment produced a significant (p < 0.05) dose-related increase in GABA concentrations and decrease in GABA-transaminase activity in all tissues investigated. This effect was most pronounced in the retina, where VGB concentrations were 18.5-fold higher than those in brain. In contrast, GBP and TPM were without effect on any of the neurochemical parameters investigated and did not accumulate appreciably in the retina. CONCLUSIONS: These findings corroborate a previously reported accumulation of VGB in the retina, which may be responsible for the visual field constriction observed clinically. This phenomenon does not appear to extend to other GABAergic drugs, suggesting that these agents might not cause visual field defects.

4-Aminobutyrate Transaminase↗
PubMed2003

Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells.

PURPOSE: Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the Ih substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the Ih were investigated in CA1 pyramidal cells of rat hippocampus. METHODS: CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique. RESULTS: GBP increased the Ih amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of Ih. The effects ranged from approximately 20% at 50 microM, approximately 25% at 75 microM, to approximately 35% at 100 microM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on Ih were similar to those obtained in the absence of cAMP. CONCLUSIONS: These results suggest that GBP increases the Ih through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.

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PubMedDate not supplied

Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons.

BACKGROUND AND OBJECTIVES: Neuropathic pain following injury to peripheral sensory neurons is a common clinical problem and frequently difficult to treat. Gabapentin (GBP), a novel anticonvulsant, has significant analgesic effects in clinical neuropathic states and in relevant preclinical models, but its mechanism of action remains unclear. Because calcium currents play a significant role in neuronal function, this study was designed to assess the effect of GBP on the membrane voltage-activated inward calcium currents (I(Ca)) in dorsal root ganglia (DRG) primary afferent neurons of neuropathic versus control rats. METHODS: Male rats were prepared according to the chronic constriction injury (CCI) model. The L4 and L5 dorsal root ganglia of those selected as CCI or control after appropriate behavioral testing were removed, and neurons were enzymatically dissociated. Fluorescent dye (DiI) placed at the injury site allowed identification of neurons projecting to that site. These were acutely studied using whole-cell, perforated (with beta-escin) patch-clamp recordings. Additionally, neurons from sham or nonoperated rats were also studied. RESULTS: Although there was marked variability among cells, concentrations of GBP ranging from 0.1 to 300 micromol/L decreased neuronal peak ICa in midsized neurons (30 to 40 microm) of both sham and neuropathic rats, in a fast, reversible, and concentration-dependent manner. Intergroup differences were not significant, however the concentration-response EC50s were 2.7 micromol/L for the sham and 16.5 micromol/L for the CCI neurons. The drug suppressed I(Ca) in nonoperated rats to a lesser degree, but changes did not differ significantly from the operated groups. Calcium currents in either small or large diameter neurons were also variably decreased by 10 micromol/L of GBP in sham and CCI neurons. Current inhibition by GBP was partly voltage dependent. CONCLUSIONS: GBP, at clinically relevant concentrations, results in significant reduction of I(Ca) in both sham and neuropathic neurons, while in nonoperated rats reduced I(Ca) to a smaller degree. Sensitivity to drug was not affected by neuropathy. This current inhibition is partly voltage dependent. Depression of I(Ca) may be partly related to the binding of the drug to the alpha(2)delta modulatory subunit of the voltage activated calcium channels (VACC). Analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca(2+)-dependent process.

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PubMed2000

Gabapentin-induced mood changes with hypomanic features in adults.

We report two adults who received gabapentin (GBP) and subsequently developed behavioural side effects. Indications for GBP treatment were newly diagnosed epilepsy in one and painful paraesthesiae in the other. Both had no past history of psychiatric or behavioural disorder. Abnormal behaviour consisted of elevated mood, euphoria, and increased energy in both patients, and pressure of speech and decreased need for sleep in one of them. These symptoms were transient and fully reversible. One patient had to discontinue GBP. Behavioural changes were not related to seizure activity. They should be recognized as a possible side effect of GBP treatment in adults.

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PubMed2002

Mode of action of gabapentin in chronic neuropathic pain syndromes. A short review about its cellular mechanisms in nociceptive neurotransmission.

Gabapentin (GBP, CAS 60142-96-3) has anticonvulsant and antinociceptive properties; the latter relate especially to chronic neuropathic pain. The mode of action of GBP, possibly different in epilepsy and chronic pain syndromes, is only poorly understood. This minireview is aimed at compiling the different mechanisms by which GBP may diminish the nociceptive transmission in the dorsal horn of the spinal cord.

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PubMed2001

Determination of the antiepileptics vigabatrin and gabapentin in dosage forms and biological fluids using Hantzsch reaction.

A selective and sensitive method was developed for the determination of the anticonvulsants vigabatrin (I) (CAS 60643-86-9) and gabapentin (II) (CAS 60142-96-3). The method is based on the condensation of the drugs through their amino groups with acetylacetone and formaldehyde according to Hantzsch reaction yeilding the highly fluorescent dihydropyridine derivatives. The yellowish-orange color was also measured spectrophotometrically at 410 nm and 415 nm for I and II, respectively. The absorbance-concentration plots were rectilinear over the ranges 10-70 micrograms/ml and 20-140 micrograms/ml for I and II, respectively. As for the fluorescence-concentration plots, they were linear over the ranges 0.5-10 micrograms/ml and 2.5-20 micrograms/ml with minimum detection limits (S/N = 2) of 0.05 microgram/ml (approximately 2.1 x 10(-8) mol/l) and 0.1 microgram/ml (approximately 5.8 x 10(-7) mol/l) for I and II, respectively. The spectrophotometric method was applied to the determination of I and II in their tablets. The percentage recoveries +/- SD (n = 6) were 99.45 +/- 0.13 and 98.05 +/- 0.53, respectively. The spectrofluorimetric method was successfully applied to the determination of I and II in spiked human urine and plasma. The % recoveries +/- SD (n = 5) were 98.77 +/- 0.29 and 98.39 +/- 0.53 for urine and 99.32 +/- 0.74 and 98.90 +/- 0.96 for plasma, for I and II, respectively. No interference was encountered with the co-administered drugs: valproic acid (CAS 99-66-1), diphenylhydantoin (CAS 57-41-0), phenobarbital (CAS 50-06-6), carbamazepine (CAS 298-46-4), clonazepam (CAS 1622-61-3), clobazam (CAS 22316-47-8) or cimetidine (CAS 51481-61-9). A proposal of the reaction pathway is suggested. The advantages of the proposed methods over existing method are discussed.

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PubMed2006

[Gabapentin treatment in a female patient with panic disorder and adverse effects under carbamazepine during benzodiazepine withdrawal].

Despite their addictive potential, benzodiazepines belong to the most often prescribed drugs. We report on a patient with alprazolam dependence, who initially was treated with carbamazepine because of severe withdrawal symptoms. Due to liver enzyme elevation related to carbamazepine, we had to stop this treatment and instead of that started gabapentin treatment. Under this new therapy, the patient showed a dramatic relief of withdrawal symptoms and of the panic attacks recurring during withdrawal. Hence, due to their effectiveness and tolerability, newer anticonvulsants could be considered as medication for benzodiazepine withdrawal and as an alternative for benzodiazepine treatment in panic disorders.

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PubMed2002

Gabapentin treatment of multiple piloleiomyoma-related pain.

Familial leiomyomatosis cutis et uteri may present with numerous cutaneous leiomyomas, or piloleiomyomas, which can be painful. Pharmacologic agents have had limited efficacy in mitigating leiomyoma-associated discomfort. We describe a case of familial piloleiomyomas in which intermittent pain at the site of the lesions was substantially reduced by the administration of oral gabapentin. The unusual unilateral distribution of leiomyomas in this case is discussed.

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PubMed2002

Hyperhidrosis in pediatric spinal cord injury: a case report and gabapentin therapy.

Hyperhidrosis is a relatively common condition with a multitude of causes. Spinal cord injury may be complicated by hyperhidrosis. Many forms of therapy have been reported for this phenomenon but few have been demonstrated to be efficacious. We describe a case of a child with hyperhidrosis from a spinal cord injury and report the first therapeutic use, to our knowledge, of gabapentin for hyperhidrosis.

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PubMedDate not supplied

Asterixis induced by gabapentin.

We report the case of a patient with postherpetic neuralgia who developed asterixis while being treated with gabapentin. We discuss the possible mechanism of asterixis in this patient.

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PubMedDate not supplied

Gabapentin withdrawal syndrome.

Gabapentin (GBP) has gained wide acceptance in the treatment of pain, migraine, bipolar illness, and epilepsy. It has a relatively benign side effect profile, lacks significant drug interactions, is not liver metabolized, and is renally excreted. Herein three cases are presented that demonstrate withdrawal symptoms after abrupt discontinuation of GBP. Clinicians are encouraged to taper GBP dosage, especially when patients have taken high doses, and to warn patients of possible adverse effects of abruptly discontinuing GBP themselves.

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PubMed2000

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

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PubMed2002

Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity?

We evaluated effectiveness and predictors of response of gabapentin (GBP) as adjunctive treatment in a sample of 43 subjects with DSM-III-R bipolar disorder who were resistant to standard mood stabilizers. Diagnostic evaluation was performed by means of the Semistructured Interview for Mood Disorder. Clinical evaluation was performed at the beginning and end of the observation period by means of the Hamilton Rating Scale for Depression (HAM-D), the Young Mania Rating Scale, and the Clinical Global Impression Scale. GBP was administered as an adjunctive treatment for an 8-week period in combination with other mood stabilizers, benzodiazepines, antidepressants, and neuroleptics. Mean dosage +/- SD at week 8 was 1270 +/- 561.4 mg (range, 600-2400 mg). Adjunctive treatment with GBP was well tolerated by almost all the subjects; only three patients had to interrupt treatment before week 8, two because of inefficacy and one because of the appearance of side effects (ataxia and irritability); in other patients, the most frequent side effects were sedation, irritability, tremor, ataxia or motor instability, and nausea. Eighteen (41.9%) of 43 patients who began treatment were considered responders. Mean total HAM-D score showed a significant reduction during the 8 weeks of treatment. Analysis of the various HAM-D dimensions showed that the anxiety-somatization factor was the one with the greatest change. Seventeen of the 18 responder patients remained in remission for a period ranging from 4 to 12 months without clinically significant side effects or adverse events. One patient had to interrupt GBP treatment and be administered neuroleptics because of the reappearance of manic symptoms. Regarding response predictors, logistical regression analysis showed that the presence of panic disorder and alcohol abuse was associated with positive response. The results of the present study replicate prior studies indicating that GBP is an effective and well tolerated treatment in a large proportion of bipolar patients who are resistant to traditional mood stabilizers. More specifically, this drug appears to have antidepressant and anxiolytic properties. What is new in the present report is the suggestion that the utility of GBP in resistant bipolar disorder resides in its effectiveness against comorbid panic disorder and alcohol abuse.

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PubMed1997

Changes in body weight with chronic, high-dose gabapentin therapy.

The authors reviewed changes in body weight in 44 patients treated with Gabapentin (GPN) for a period of 12 or more months. All patients had a seizure disorder and the dose of GPN was increased aiming at complete seizure control or until side effects limited further increase. Twenty-eight patients were receiving GPN dosages of > 3000 mg/day. Observed changes in body weight were as follows 10 patients gained more than 10% of their baseline weight, 15 patients gained 5% to 10% of baseline, 16 patients had no change, and 3 patients lost 5% to 10% of their initial weight. Weight increase started between the second and the third months of GPN treatment in most patients and tended to stabilize after 6 to 9 months of treatment, although the doses of GPN remained unchanged. Weight gain occurred in patients taking GPN in combination with each of the major antiepileptic drugs including Felbatol and also occurred with GPN monotherapy.

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PubMed1999

A case of sustained massive gabapentin overdose without serious side effects.

Gabapentin is an antiepileptic agent that is indicated for use as adjunctive therapy for partial seizures. It has a relatively benign side effect profile, but little data exists on massive overdoses with this agent. The authors present a case of a patient who received a massive overdose of this agent but suffered no clinically significant toxicity.

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PubMed2003

Plasma gabapentin concentrations in children with epilepsy: influence of age, relationship with dosage, and preliminary observations on correlation with clinical response.

The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.

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