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PubMed2004

Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy.

PURPOSE: We investigated whether the preemptive use of gabapentin, a structural analogue of gamma amino butyric acid could reduce postoperative pain and fentanyl consumption in patients after single-level lumbar discoidectomy. METHODS: Fifty-six ASA I and II patients were randomly allocated into two equal groups to receive either gabapentin 300 mg or placebo two hours before surgery. After surgery, the pain was assessed on a visual analogue scale (VAS) at intervals of 0-6, 6-12, 12-18, and 18-24 hr at rest. Total fentanyl consumption in the first 24 hr after surgery was also recorded. Fentanyl 2 mug.kg(-1) intravenously was used to treat postoperative pain on patients' demand. RESULTS: Patients in the gabapentin group had significantly lower VAS scores at all time intervals of 0-6, 6-12, 12-18, and 18-24 hr than those in the placebo group (3.5 +/- 2.3, 3.2 +/- 2.1, 1.8 +/- 1.7, 1.2 +/- 1.3 vs 6.1 +/- 1.7, 4.4 +/- 1.2, 3.3 +/- 1.1, 2.1 +/- 1.2; P < 0.05). The total fentanyl consumed after surgery in the first 24 hr in the gabapentin group (233.5 +/- 141.9, mean + SD) was significantly less than in the placebo group (359.6 +/- 104.1; P < 0.05). CONCLUSION: Preemptive gabapentin 300 mg po significantly decreases the severity of pain postoperatively in patients who undergo single-level lumbar discoidectomy.

Adult↗
PubMed2003

entla, a novel epileptic and ataxic Cacna2d2 mutant of the mouse.

entla (ent) is a novel recessive phenotype of mice. The underlying mutation was mapped to chromosome 9 (60.1 centimorgans) and identified as an allele of the Cacna2d2 gene encoding the alpha2delta-2 subunit of voltage-gated calcium channels. The Cacna2d2entla allele harbors a 38-kb duplication comprising the 117 nucleotides of exon 3. The predicted duplication of 39 amino acid residues near the subunit's N terminus results in the expression of a full-length, membrane-associated protein. Western blot data were consistent with correct cleavage of the alpha2delta-2entla precursor into alpha2entla and delta2 proteins but indicated loss of the disulfide linkage between the two proteins. ent/ent mice develop ataxia by postnatal day 13-15, followed by paroxysmal dyskinesia a few days later. Two distinct types of cortical and hippocampal epileptic activity at 2 and 4 Hz were recorded, indicative of absence epilepsy. Homozygotes display reduced size and weight, increased mortality before weaning, and female infertility. No overt neuroanatomical abnormalities were detected. Ca2+ current densities recorded from acutely dissociated Purkinje cells of homozygous entla animals were reduced by 50% compared with wild type. Ligand binding assays using the antiepileptic drug [3H]gabapentin, a specific ligand of the alpha2delta-1 and alpha2delta-2 subunits, revealed a >60% reduced maximum binding to cerebellar membranes of ent/ent compared with unaffected littermates. entla is allelic to ducky and ducky2J, representing the third murine Cacna2d2 allele identified and so far the only one encoding an untruncated protein that is incorporated into membranes.

Acetates↗
PubMed1987

Inhibition of delayed hypersensitivity reactions by a new agent, cis-1-methyl-4-isohexylcyclohexane carboxylic acid (IG-10)--II. The mechanism regarding the action on lymphokines.

A newly synthesized anti-allergic agent, cis-1-methyl-4-isohexylcyclohexane carboxylic acid (IG-10), has the capacity to inhibit the effector phase of delayed hypersensitivity reactions. In the present paper, the effect of IG-10 was studied on the generation of superoxide anion (O2) from macrophages, on macrophage chemotaxis, and on the activity of lymphokines such as skin reactive factor (SRF), macrophage migration inhibitory factor (MIF) and monocyte/macrophage chemotactic factor (MCF) in guinea pigs. Oral administration of IG-10 (50-200 mg/kg) inhibited SRF-induced skin erythema in a dose-dependent manner. In vitro, this agent (10(-7) -10(-5) g/ml) did not inhibit the generation of O2- from macrophages. The agent (10(-7) -10(-6) g/ml) significantly inhibited the activity of MIF and this inhibition was not due to the facilitation of normal migration. For macrophage chemotaxis, IG-10 (10(-8) -10(-6) g/ml) significantly inhibited MCF-induced chemotaxis. The agent also depressed the macrophage chemotaxis induced by N-formyl-methionyl-leucyl-phenylalanine but not the chemotaxis induced by E. coli culture filtrate. The inhibitory action of IG-10 on MCF activity was not influenced by antiglucocorticoid agents such as 17 alpha-methyltestosterone and androstenedione which reverse significantly the inhibitory action of glucocorticoids. The inhibitory action of IG-10 was relatively dependent on exogenous Ca2+ and Mg2+, and was antagonized by dbc-GMP.

Animals↗
PubMed2004

Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels.

Gabapentin is a lipophilic analog of gamma-amino butyric acid (GABA) with therapeutic activity against certain forms of epilepsy and neuropathic pain. Despite its structural similarity to GABA, it does not bind GABAA or GABAB receptors and the mechanism, especially of its analgesic action, has remained elusive. Here, we have studied its effects on synaptic transmission mediated by the major spinal fast excitatory and inhibitory neurotransmitters, L-glutamate and glycine, in the superficial layers of the spinal cord dorsal horn, a CNS area, which is critically involved in nociception. Gabapentin reversibly reduced evoked excitatory postsynaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-EPSCs) and inhibitory postsynaptic currents mediated by glycine (gly-IPSCs). Inhibition of AMPA-EPSCs and gly-IPSCs occurred with similar potencies (approximately 10-50 nM) and by about the same degree (approximately 40% at 1 microM). Gabapentin did not affect membrane currents elicited by exogenously applied glutamate or glycine arguing against a postsynaptic site of action. Selective blockade of N-type Ca2+ channels with omega-conotoxin GVIA dramatically increased and blockade of P/Q-type channels with omega-agatoxin IVA strongly attenuated inhibition of evoked synaptic transmission by gabapentin. These results show that gabapentin affects both excitatory and inhibitory spinal neurotransmission via a presynaptic mechanism which preferentially involves P/Q-type Ca2+ channels.

Acetates↗
PubMed1998

Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin.

Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and spread of seizure activity. Low occipital lobe GABA was associated with poor seizure control in patients with complex partial seizures. Vigabatrin irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid (CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy. Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF increase. Doubling the daily dose from 3 to 6 g failed to increase brain GABA further. Increased GABA concentrations appear to reduce GABA synthesis in humans as it does in animals. With traditional antiepileptic drugs, remission of the seizure disorder was associated with normal GABA levels. With vigabatrin, elevated CSF and brain GABA was associated with improved seizure control. Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release of GABA during seizures may be mediated in part by transporter reversal that may serve as an important protective mechanism. During a seizure, this mechanism may be critical in stopping the seizure or preventing its spread.

4-Aminobutyrate Transaminase↗
PubMed2005

Novel role for gabapentin in neuroprotection of central nervous system in streptozotocine-induced diabetic rats.

AIM: To investigate the effect of gabapentin on neural [neuron-specific enolase (NSE)] and glial markers [glial fibrillary acidic protein (GFAP) and S100B] in different brain regions of diabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of streptozotocine (50 mg/kg body weight). Rats in one diabetic group received gabapentin (50 mg.kg(-1).d(-1)) and rats in the other diabetic group received vehicle only for 6 weeks. The levels of GFAP, S100B, and NSE were determined by immunoblotting in the hippocampus, cortex, and cerebellum. Lipid peroxidation (LPO as malondialdehyde+ 4-hydroxyalkenals) and glutathione (GSH) levels were also determined in the same brain parts. RESULTS: Total and degraded GFAP content and S100B protein expression in different areas of brain tissues significantly increased in diabetic rats compared to control rats. Similarly, NSE levels were also significantly elevated in hyperglycemic rats. In addition, there was a significant increase in LPO levels in the diabetic rat brain compared to control rat brains. Pretreatment with gabapentin prevented the upregulation of GFAP, S100B, and NSE in all brain regions of diabetic rats. The level of LPO was reduced, but not completely halted, by treatment with gabapentin. CONCLUSION: These results suggest that diabetes causes glial and neuronal injury, possibly as a result of elevated oxidative stress, and that gabapentin protects neurons and glial cells. Thus, we predict that gabapentin treatment will attenuate the hippo-campal and cortical neurodegeneration observed during diabetes mellitus in rats.

Amines↗
PubMed1995

Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure.

Gabapentin, an anticonvulsant agent designated chemically as 1-(aminomethyl)-cyclohexaneacetic acid, was evaluated in a 2-year tumor bioassay in male Wistar rats. Three groups of 50 rats were fed gabapentin at 250, 1000 and 2000 mg/kg in the diet for 104 weeks. A fourth group was fed diet without drug. All rats were subjected to full histopathological evaluation. Body weight gain suppression occurred at 1000 and 2000 mg/kg. Survival was comparable across all groups. There was a treatment-related increase in the number of pancreatic acinar cell carcinomas; 0, 4, 3 and 8 of these carcinomas were observed in the control, 250, 1000 and 2000 mg/kg groups, respectively. There were no other increases in other tumor types, and there were no tumor increases in female rats. The frequency of pancreatic acinar cell hyperplasia was similar in treated and control groups. Biologically, the pancreatic carcinomas were not invasive, did not metastasize, were of late onset and did not compromise survival. Thus, gabapentin was a carcinogen in male Wistar rats. However, the tumorigenic response was of low-grade because it constituted a late tumor response which required very high doses. We reported recently that mice treated with gabapentin had no increase in pancreatic tumors. Therefore, neoplastic development was confined to the pancreas in a single sex and species of rodent. Consequently, gabapentin at therapeutic doses poses a low carcinogenic risk to humans.

Acetates↗
PubMedDate not supplied

Does gabapentin act as an agonist at native GABA(B) receptors?

Gabapentin, a novel anticonvulsant and analgesic, is a gamma-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABA(A) or GABA(B) receptors. It was recently reported to be a selective agonist at GABA(B) receptors containing GABA(B1a)-GABA(B2) heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native GABA(B) receptors using a rat model of postoperative pain in vivo and periaqueductal gray (PAG) slices in vitro; PAG contains GABA(B) receptors, and their activation results in antinociception. An intrathecal injection of gabapentin or baclofen, a GABA(B) receptor agonist, induced antiallodynia in this postoperative pain model. Intrathecal injection of GABA(B) receptor antagonists CGP 35348 and CGP 55845 antagonized baclofen- but not gabapentin-induced antiallodynia. In ventrolateral PAG neurons, baclofen activated G-protein-coupled inwardly rectifying K(+) (GIRK) channels in a manner blocked by CGP 35348 or CGP 55845. However, gabapentin displayed no effect on the membrane current. In neurons unaffected by gabapentin, baclofen activated GIRK channels through GABA(B) receptors. It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro.

Amines↗
PubMed1988

Determination of plasminogen activator inhibitor (PAI) capacity of human plasma in presence of oxidants: a novel principle.

A new functional assay of PAI-activity in human plasma is described. Hitherto known assays for fast acting PAI have some disadvantages: predilution and/or acidification steps of the sample to afford the required inactivation of alpha-2-antiplasmin (A2-PI). This approach in contrast implicates test performance in presence of chloramine T (CT), an oxidant that destroys plasma antiplasmin activity without impairing significantly the activity of urokinase (u-PA) or plasmin. The following reaction conditions were found optimal: 50 microliter of undiluted plasma, anticoagulated with citrate or EDTA, were first incubated with 1 IU u-PA in a Tris-buffer, pH 8.4 and then with Glu-plasminogen (0.85 mumol/l final), CT (2.5 mmol/l final), tranexamic acid (0.9 mmol/l final) for 5 min. at 37 degrees C. After addition of 0.3 mmol/l of the chromogenic plasmin substrate H-D-Nva-CHA-Lys-pNA (pNA = para nitroanilide) and of NaCl (250 mmol/l final) a linear kinetic with delta A405/t in the range of 0.2/min for normal plasma was recorded. In an endpoint version of the test the chromogenic substrate can be added together with plasminogen resulting an A/t2-kinetic. Dilution studies showed a linear calibration curve from 0 to 14 arbitrary u-PA inhibiting units (AU)/ml plasma. By means of PAI-standard plasmas PAI-capacity values of 20 healthy volunteers (10 males/10 females) (x = 26 years, sigma = 4.2) were determined. They ranged from 0.4 - 6.9 (x = 1.3, sigma = 0.9) AU/ml plasma. Plasma samples containing more than 14 AU/ml were prediluted with PAI-deficient plasma. Intra- and inter-assay coefficients of variation (CV) were determined to be 1.3 +/- 0.6 and 4.3 +/- 0.5%, respectively. The values of this assay correlate well with those obtained by acidification of the samples. However, the possibility of measuring plasma PAI (and PA) activities by means of a simple and direct approach can be considered as an important progress with regard to routine hospital practice. The presented oxidative inactivation of A2-PI mimics the leukocyte attack phase, suggesting that activated leukocytes create a microenvironment of uncontrolled plasmin activity.

Adult↗
PubMed2000

Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients.

PURPOSE: Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has been used in the management of neuropathic pain. We reported that daily dosing increased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. This study was designed to determine how rapidly brain GABA and the GABA metabolites, homocarnosine and pyrrolidinone, increase in response to the first dose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (four women) were studied serially after the first oral dose (1,200 mg) of GBP. Five patients (three women) taking a standard daily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single high dose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by 1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did not change significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI, 0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM; 95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased median brain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the anticonvulsant effects of increased homocarnosine and pyrrolidinone with daily therapy.

Acetates↗
PubMed1987

The effects of in vivo inactivation of GABA-transaminase and glutamic acid decarboxylase on levels of GABA in the rat retina.

Gabaculine and gamma-vinyl GABA (GVG) are specific enzyme-activated irreversible inhibitors of GABA-transaminase (GABA-T). gamma-Acetylenic GABA (GAG) irreversibly inhibits both GABA-T and glutamic acid decarboxylase (GAD). Subcutaneous injection of any of those compounds rapidly elevated levels of GABA in the retinae of rats. After injection of 10 mg/kg gabaculine, levels of retinal GABA climbed 5-fold in 4 h, and peaked 16 h after injection at levels approximately 7 times those from water-injected control rats. They remained significantly elevated compared to control levels for at least 6 days after injection. The postgabaculine increase in levels of retinal GABA was linear with time between 0.5 and 4 h after injection. In contrast, retinal GABA levels peaked at less than 3 times control levels within 8 h of injection of 50 mg/kg GAG and returned to baseline levels within 4 days. GAG, upon coadministration with gabaculine, significantly attenuated the postgabaculine rise in levels of GABA in retinae. Neither the rate of rise, nor the maximum levels, of retinal GABA was so great after injection of GAG plus gabaculine, compared to those after injection of gabaculine alone. The degree to which postgabaculine GABA accumulation was inhibited in the retina by 50 mg/kg GAG closely corresponded with the extent to which that dose of GAG inactivated retinal GAD activity. The results of this study extend previous reports from this laboratory that systemically administered gabaculine, GVG and GAG all inactivate target enzymes more potently in retina than in other brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobutyrate Transaminase↗
PubMed1990

Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial aneurysms. A double-blind placebo-controlled study.

One hundred patients with a verified subarachnoid haemorrhage were studied in a double blind, placebo-controlled trial at a single centre to determine the value and relative risks of tranexamic acid (TXA) in the management of ruptured intracranial aneurysms. The incidence of recurrent haemorrhage between active and placebo groups was identical (12%) and the mortality from recurrent haemorrhage was 7% and 5%, respectively. The overall incidence of cerebral infarction before surgery, at discharge and at 6 months follow-up was greater in the TXA group (27%) than in the control group (11%). Post-operative cerebral ischaemia was significantly more frequent in the active, 18 of 29 as compared to 6 of 32 patients, in the placebo group. In a fifth of the patients in whom cerebral blood flow was estimated there was a significant reduction of cerebral blood flow (CBF) on the side of the ruptured aneurysm in the TXA treated group. It is suggested that this may be the cause of the increased incidence of cerebral ischaemia in this group. There was no significant difference in the incidence of cerebral vasospasm, hydrocephalus, visual disturbances and gastrointestinal disturbances. More fatalities were encountered from ischaemia and recurrent haemorrhage in the TXA group but these differences did not reach statistical significance at the 5% level. Given that disability was due to either vasospasm or recurrent haemorrhage than a patient under TXA treatment was significantly more likely to have disability due to vasospasm (p less than 0.04); the reverse was true for the placebo patient (p less than 0.05).

Adult↗
PubMed1991

Alpha 2u-globulin nephropathy without nephrocarcinogenesis in male Wistar rats administered 1-(aminomethyl)cyclohexaneacetic acid.

Alpha 2u-Globulin (alpha 2u) nephropathy is a male rat-specific condition caused by a diverse group of xenobiotics. Features of this nephropathy include hyaline droplet accumulation in proximal tubules, tubular epithelial necrosis and regeneration, exacerbation of spontaneous renal disease, and induction of renal epithelial tumors. Nephrocarcinogenicity of compounds that cause this nephropathy may be a consequence of increased proximal tubular proliferation resulting from cell injury. These studies document alpha 2u nephropathy without primary renal epithelial tumors in male Wistar rats administered 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), a therapeutic agent with antiepileptic/anticonvulsant properties. In a series of preclinical studies gabapentin was administered to rats at the following doses and durations: 50 and 2000 mg/kg for 2 weeks; 250, 1000, 2000, and 3000 mg/kg for 13 weeks; 250, 1000, and 2000 mg/kg for 52 and 104 weeks. Renal effects were evaluated by biochemical, immunocytochemical, histopathologic, and ultrastructural techniques. Reversible increases in size and distribution of hyaline droplets within proximal tubular epithelium occurred through 1 year of treatment at a severity that was dose-dependent. In males given 2000 mg/kg, alpha 2u accumulation, degeneration, and necrosis of the P2 segment and intraluminal cellular casts were seen after 2 days of treatment. In the 2-week study, the size and number of phagolysosomes containing alpha 2u and the renal tissue alpha 2u increased with increasing dose and time. By Day 7, polymorphic crystalline inclusions were abundant in phagolysosomes of 2000 mg/kg males. In subchronic and chronic studies, spontaneous glomerulonephrosis was exacerbated in males given 2000 mg/kg, and, interestingly, no drug-related effect on renal tumor incidence was observed. To the best of our knowledge, this is the first documentation of the absence of nephrocarcinogenic effect in male rats treated for up to 104 weeks with a compound that causes acute and chronic lesions of alpha 2u nephropathy.

Acetates↗
PubMed1995

Antiepileptic drug mechanisms of action.

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.

Acetates↗
PubMed1998

Gabapentin reverses the allodynia produced by the administration of anti-GD2 ganglioside, an immunotherapeutic drug.

UNLABELLED: Systemically administered, the anti-GD2 antibody produces allodynia demonstrated by decreased mechanical withdrawal threshold. Electrophysiologic recordings indicate a probable neuropathic origin, as small-diameter sensory fibers develop continuous high-frequency discharge after antibody administration. Gabapentin (GBP) is a gamma-aminobutyric acid analog originally synthesized for its anticonvulsant actions. Several open-label clinical studies, as well as a wealth of anecdotal evidence, suggest that GBP may be beneficial for the treatment of neuropathic pain. This study examined the effects of GBP given as a posttreatment after induction of an anti-GD2-associated allodynia. Anti-GD2 (1 mg/kg intravenously [i.v.]) administered to Sprague-Dawley rats reduced the mean withdrawal threshold from 14.71 to 4.95 g (P < 0.001), as measured by using von Frey hairs. This was reversed by GBP in a dose-dependent fashion; the minimal effective dose was between 3 and 30 mg/kg i.v. The maximal percent analgesic effect of GBP was 76% and 93% at doses of 30 and 100 mg/kg, respectively (P < 0.001). With these doses, side effects were minimal and were manifested as slightly decreased spontaneous movement and startle response. No changes were seen in reflex responses to corneal or pinna stimulation, and no motor deficits were observed. These data support the use of GBP as an effective therapy for neuropathic pain. IMPLICATIONS: After the administration of anti-GD2 antibody, rats display an escape reaction to light touch, increased blood pressure, and aberrant firing in nerve fibers associated with pain transmission. Systemic gabapentin reduced or eliminated the escape response and reversed the hypertension with minimal side effects. This suggests that gabapentin blocked the antibody-associated (neuropathic) pain.

Acetates↗
PubMed2002

Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults.

BACKGROUND: Anticonvulsant drugs have multiple mechanisms of action. Recent in vivo MRS studies suggest that cerebral gamma-aminobutyric acid (GABA) increases occur with the administration of certain anticonvulsants in humans. OBJECTIVE: To investigate the effect of topiramate, gabapentin, and lamotrigine on cerebral GABA concentrations in healthy volunteers and correlate the GABA concentrations with serum drug levels. METHODS: Seventeen healthy adults were randomly assigned to receive topiramate, gabapentin, and lamotrigine and underwent GABA measurements using a 4.1-T magnet from a 13.5-mL volume over the occipital region. GABA concentrations and serum levels were measured at 3 and 6 hours following administration of an acute single dose of one of the drugs. Thereafter, drugs were titrated over 4 weeks to target doses, with GABA measurements performed at 2 and 4 weeks. RESULTS: Cerebral GABA concentrations rose 70% in the acute phase compared with baseline for topiramate. GABA rose 48% at 6 hours with gabapentin but not with lamotrigine. With long-term dosing and once target doses were achieved at 4 weeks, significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%). CONCLUSION: This study demonstrates that single doses of topiramate and gabapentin increase cerebral GABA concentrations acutely (hours) in healthy individuals, but all drugs at clinically utilized doses increase cerebral GABA at 4 weeks. These results suggest that the mechanisms of action of anticonvulsant drugs are more complex and are likely to be multiple in nature.

Acetates↗
PubMed2001

Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.

Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age.

Acetates↗
PubMed1993

A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma.

Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 +/- 18.3 to 35.7 +/- 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 +/- 0.05 to 0.12 +/- 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, Fabs = 1 - exp(-2Peff) by Amidon et al. (Pharm. Res. 5:651-654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗