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Peter G Gibson - One of the best experts on this subject based on the ideXlab platform.
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Gabapentin for refractory chronic cough a randomised double blind placebo controlled trial
The Lancet, 2012Co-Authors: Nicole M Ryan, Surinder S Birring, Peter G GibsonAbstract:Summary Background Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as Gabapentin might be effective for refractory chronic cough. We established the efficacy of Gabapentin in patients with refractory chronic cough. Methods This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive Gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. Findings 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56–3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given Gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. Interpretation The treatment of refractory chronic cough with Gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. Funding National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.
Kenneth C. Cundy - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of Gabapentin enacarbil vs placebo in patients with postherpetic neuralgia and a pharmacokinetic comparison with oral Gabapentin.
Pain Medicine, 2011Co-Authors: Miroslav Backonja, Daniel M. Canafax, Kenneth C. CundyAbstract:Background. The efficacy of Gabapentin in some patients with postherpetic neuralgia (PHN) may be limited by suboptimal drug exposure from unpredictable and saturable absorption. Gabapentin enacarbil (GEn) was designed for absorption by high-capacity transporters expressed throughout the intestine and undergoes rapid postabsorption hydrolysis to Gabapentin. GEn extended-release tablets provide sustained, dose-proportional Gabapentin exposure. This study assessed the efficacy of GEn vs placebo and compared the pharmacokinetics of Gabapentin after oral dosing of GEn or Gabapentin in patients with PHN. Methods. In this double-blind, randomized study, 115 patients with PHN completed a 7-day baseline period and 11-day Gabapentin run-in period. Eligible patients were randomized and 101 received double-blind GEn 1,200 mg (624 mg-equivalents Gabapentin) ( n = 47) or placebo ( n = 54), twice daily for 14 days. We evaluated patient-reported pain, sleep, mood, global improvement, and adverse events, plus Gabapentin pharmacokinetics. Results. The improvement in mean weekly pain scores from baseline to the end of treatment (primary endpoint) was significantly greater for GEn (−2.1) vs placebo (−1.2), P = 0.0321. Significant improvements from GEn vs placebo were also seen in sleep, mood, and patient global assessment ( P < 0.05). With a 31% lower daily dose of Gabapentin equivalents, GEn tablets provided a significant increase in average steady state Gabapentin concentrations vs Gabapentin capsules in the same patients ( n = 42; P = 0.0050). Conclusions. GEn was effective in providing PHN pain relief, improved Gabapentin exposure compared with Gabapentin capsules, and was generally safe and well tolerated in patients with PHN.
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The effect of food with varying fat content on the clinical pharmacokinetics of Gabapentin after oral administration of Gabapentin enacarbil.
International journal of clinical pharmacology and therapeutics, 2010Co-Authors: Juthamas Sukbuntherng, F. J. Huff, Kenneth C. CundyAbstract:Gabapentin enacarbil, an actively transported prodrug of Gabapentin, provides sustained and dose-proportional exposure to Gabapentin. Objective: To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of Gabapentin enacarbil. Methods, materials and sub jects: A randomized, open-label, crossover study of 1,200 mg Gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 - 300 kcal total, ∼6% from fat), moderate-fat (500 - 600 kcal total, ∼30% from fat) or high-fat meals (1,000 kcal total, ∼50% from fat), separated by a washout period of > 5 days. Results: Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of Gabapentin from Gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC inf ) in fed conditions were 23% (low-fat meal), 31 % (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t max , but a trend for delayed Gabapentin enacarbil absorption was seen in t max ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. Conclusion: Administration of Gabapentin enacarbil with food enhanced Gabapentin exposure compared with fasted conditions, regardless ofthe fat or caloric content, and Gabapentin enacarbil was generally well tolerated.
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Clinical pharmacokinetic drug interaction studies of Gabapentin enacarbil, a novel transported prodrug of Gabapentin, with naproxen and cimetidine
British Journal of Clinical Pharmacology, 2010Co-Authors: Juthamas Sukbuntherng, Virna Vicente, Robin L. Blumenthal, Judy Ho, Kenneth C. CundyAbstract:AIM Gabapentin enacarbil, a transported prodrug of Gabapentin, provides sustained, dose-proportional exposure to Gabapentin. Unlike Gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, Gabapentin enacarbil is rapidly hydrolyzed to Gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug–drug interactions at these two transporters, the pharmacokinetics of Gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate).
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clinical pharmacokinetics of xp13512 a novel transported prodrug of Gabapentin
The Journal of Clinical Pharmacology, 2008Co-Authors: Kenneth C. Cundy, Srikonda Sastry, Tristen L Moors, Daniel M. CanafaxAbstract:Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose-dependent pharmacokinetics, high inter-patient variability, and potentially ineffective drug exposure. XP13512/GSK1838262 is a novel transported prodrug of Gabapentin that is absorbed throughout the entire length of the intestine by high-capacity nutrient transporters. In 4 studies of healthy volunteers (136 subjects total), the pharmacokinetics of XP13512 immediate- and extended-release formulations were compared with those of oral Gabapentin. XP13512 immediate-release (up to 2800 mg single dose and 2100 mg twice daily) was well absorbed (>68%, based on urinary recovery of Gabapentin), converted rapidly to Gabapentin, and provided dose-proportional exposure, whereas absorption of oral Gabapentin declined with increasing doses to <27% at 1200 mg. Compared with 600 mg Gabapentin, an equimolar XP13512 extended-release dose provided extended Gabapentin exposure (time to maximum concentration, 8.4 vs 2.7 hours) and superior bioavailability (74.5% vs 36.6%). XP13512 may therefore provide more predictable Gabapentin exposure and decreased dosing frequency.
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xp13512 1 alpha isobutanoyloxyethoxy carbonyl aminomethyl 1 cyclohexane acetic acid a novel Gabapentin prodrug ii improved oral bioavailability dose proportionality and colonic absorption compared with Gabapentin in rats and monkeys
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Kenneth C. Cundy, Thamil Annamalai, Lin Bu, Josephine De Vera, Jenny Estrela, Payal Shirsat, Allan Torneros, Ronald W Barrett, Mark A GallopAbstract:The absorption of Gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three or more times per day to maintain therapeutic levels. These deficiencies appear to result from the low capacity, limited intestinal distribution, and variable expression of the solute transporter responsible for Gabapentin absorption. Saturation of this transporter at doses used clinically leads to unpredictable drug exposure and potentially ineffective therapy in some patients. XP13512 [(±)-1-([(α-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of Gabapentin designed to be absorbed by high-capacity nutrient transporters located throughout the intestine. XP13512 was efficiently absorbed and rapidly converted to Gabapentin after oral dosing in rats and monkeys. Exposure to Gabapentin was proportional to prodrug dose, whereas exposure to intact XP13512 was low. In rats, >95% of an oral dose of 14C-XP13512 was excreted in urine in 24 h as Gabapentin. In monkeys, oral bioavailability of Gabapentin from XP13512 capsules was 84.2% compared with 25.4% after a similar oral Neurontin dose. Compared with intracolonic Gabapentin, intracolonic XP13512 gave a 17-fold higher Gabapentin exposure in rats and 34-fold higher in monkeys. XP13512 may therefore be incorporated into a sustained release formulation to provide extended Gabapentin exposure. XP13512 demonstrated improved Gabapentin bioavailability, increased dose proportionality, and enhanced colonic absorption. In clinical use, XP13512 may improve the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing efficacy, reducing interpatient variability, and decreasing frequency of dosing.
G N Woodruff - One of the best experts on this subject based on the ideXlab platform.
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the antiepileptic agent Gabapentin neurontin possesses anxiolytic like and antinociceptive actions that are reversed by d serine
Psychopharmacology, 1996Co-Authors: Lakhbir Singh, Mark J Field, P Ferris, John C Hunter, R J Oles, R G Williams, G N WoodruffAbstract:This report describes the activity of the antiepileptic agent Gabapentin (Neurontin) in animal models predictive of anxiolysis and analgesia. Gabapentin displayed anxiolytic-like action in the rat conflict test, the mouse light/dark box and the rat elevated X-maze with respective minimum effective doses (MEDs) of 3, 10 and 30 mg/kg. Furthermore, Gabapentin also induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with a MED of 30 mg/kg. In the rat formalin test of tonic nociception, Gabapentin dose-dependently (30–300 mg/kg) and selectively blocked the late phase with a MED of 100 mg/kg. However, it failed to block carrageenan-induced paw oedema. The intracerebroventricular (ICV) administration of the glycine/NMDA receptor agonistd-Serine, dose-dependently (10–100 μg/animal) reversed the antinociceptive action of Gabapentin (200 mg/kg, SC).d-Serine (30 μg/animal, ICV) also reversed the anxiolytic-like effects (in the light/dark box and the rat elevated X-maze) of Gabapentin (30 mg/kg). In contrast,l-Serine (100 μg, ICV) failed to block the antinociceptive action of Gabapentin. The antinociceptive action of (+)-HA-966 (25 mg/kg, SC), a partial agonist at the glycine/NMDA receptor, was reversed byd-Serine (100 μg/animal, ICV). However,d-Serine (100 μg/animal, ICV) failed to affect the antinociceptive action of a competitive NMDA receptor antagonist CGS 19755 (3 mg/kg, SC). Gabapentin has negligible affinity for the strychnine insensitive [3H]glycine binding site. This indicates that the interaction between Gabapentin andd-Serine may not involve the NMDA receptor complex. Gabapentin may represent a novel type of anxiolytic and analgesic agent.
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characterisation of 3h Gabapentin binding to a novel site in rat brain homogenate binding studies
European Journal of Pharmacology, 1993Co-Authors: N Sumanchauhan, Louise Webdale, David R Hill, G N WoodruffAbstract:Abstract The binding characteristics of [3H]Gabapentin, the radiolabelled analogue of the novel anticonvulsant Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) were studied using purified synaptic plasma membranes prepared from rat cerebral cortex. In 10 mM HEPES buffer [3H]Gabapentin bound to a single population of sites with high affinity (KD = 38 ± 2.8 mM) with a maximum binding capacity of 4.6 ± 0.4 pmol/mg protein, reaching equilibrium after 30 min at 20°C. This novel site was unique to the central nervous system with little or no specific [3H]Gabapentin binding being measurable in a range of peripheral tissues. Binding was potently inhibited by a range of Gabapentin analogues and 3-alkyl substituted γ-aminobutyric acid (GABA) derivatives although GABA itself and the selective GABAB receptor ligand baclofen, were only weakly active. Gabapentin itself (IC50 = 80 nM) and 3-isobutyl GABA (IC50 = 80 nM) which also has anticonvulsant properties, showed the highest affinity for the binding site. Of a wide range of other pharmacologically active compounds only the polyamines spermine and spermidine influenced [3H]Gabapentin binding, with both compounds producing a maximum of 50% inhibition of specific binding. Magnesium ions produced a similar pattern of inhibition but the effect of the polyamines and magnesium ions were not additive. The data provide evidence for the existence in brain of a novel binding site that may mediate the anticonvulsant effects of Gabapentin and other potential anticonvulsant compounds.
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localization of 3h Gabapentin to a novel site in rat brain autoradiographic studies
European Journal of Pharmacology, 1993Co-Authors: David R Hill, N Sumanchauhan, G N WoodruffAbstract:Abstract The autoradiographical distribution of [3H]Gabapentin, the tritiated analogue of the novel anticonvulsant Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) was measured in rat brain. Binding to sections was uniformly inhibited by non-radioactive Gabapentin and 3-isobutyl-γ-aminobutyric acid (3-isobutyl-GABA). Specific Gabapentin binding sites were unevenly distributed throughout the brain with the highest level being found in the outer layers of the cerebral cortex (38 ± 7 fmol/mm2; n = 3) and the lowest amounts in the white matter. In the hippocampus, the distribution of the binding site paralleled the excitatory neuronal input with the highest levels of binding being measured in the outer layers of the dentate gyrus and in the dendritic regions of the CA1 pyramidal cell layer. The binding site appeared absent from the cell body region of granule and pyramidal cells. Lesions performed unilaterally in the striatum using quinolinic acid resulted in a marked loss of [3H]Gabapentin binding sites as compared with sham-lesioned animals, suggesting the binding site was localized on neuronal cell bodies. These data complement and extend the results of experiments using [3H]Gabapentin with homogenates of rat brain and show the discrete localization of this novel binding site in regions associated with excitatory amino acid input. The data do not support previous indications of an association of the Gabapentin binding site and NMDA/glycine receptor complex.
Patrick J Flynn - One of the best experts on this subject based on the ideXlab platform.
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Gabapentin for hot flashes in 420 women with breast cancer a randomised double blind placebo controlled trial
The Lancet, 2005Co-Authors: Kishan J Pandya, Gary R Morrow, Joseph A Roscoe, Hongwei Zhao, Jane T Hickok, Eduardo Pajon, Thomas J Sweeney, Tarit K Banerjee, Patrick J FlynnAbstract:Summary Background Most women receiving systemic therapy for breast cancer experience hot flashes. We undertook a randomised, double-blind, placebo-controlled, multi-institutional trial to assess the efficacy of Gabapentin in controlling hot flashes in women with breast cancer. Methods 420 women with breast cancer who were having two or more hot flashes per day were randomly assigned placebo, Gabapentin 300 mg/day, or Gabapentin 900 mg/day by mouth in three divided doses for 8 weeks. Each patient kept a 1-week, self-report diary on the frequency, severity, and duration of hot flashes before the start of the study and during weeks 4 and 8 of treatment. Analyses were by intention to treat. Findings Evaluable data were available on 371 participants at 4 weeks (119 placebo, 123 Gabapentin 300 mg, and 129 Gabapentin 900 mg) and 347 at 8 weeks (113 placebo, 114 Gabapentin 300 mg, and 120 Gabapentin 900 mg). The percentage decreases in hot-flash severity score between baseline and weeks 4 and 8, respectively were: 21% (95% CI 12 to 30) and 15% (1 to 29) in the placebo group; 33% (23 to 43) and 31% (16 to 46) in the group assigned Gabapentin 300 mg; and 49% (42 to 56) and 46% (34 to 58) in the group assigned Gabapentin 900 mg. The differences between the groups were significant (p=0·0001 at 4 weeks and p=0·007 at 8 weeks by ANCOVA for overall treatment effect, adjusted for baseline values); only the higher dose of Gabapentin was associated with significant decreases in hot-flash frequency and severity. Interpretation Gabapentin is effective in the control of hot flashes at a dose of 900 mg/day, but not at a dose of 300 mg/day. This drug should be considered for treatment of hot flashes in women with breast cancer.
Nicole M Ryan - One of the best experts on this subject based on the ideXlab platform.
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Gabapentin for refractory chronic cough a randomised double blind placebo controlled trial
The Lancet, 2012Co-Authors: Nicole M Ryan, Surinder S Birring, Peter G GibsonAbstract:Summary Background Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as Gabapentin might be effective for refractory chronic cough. We established the efficacy of Gabapentin in patients with refractory chronic cough. Methods This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive Gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. Findings 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56–3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given Gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. Interpretation The treatment of refractory chronic cough with Gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. Funding National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.
