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PubMed1994

Limitation by gabapentin of high frequency action potential firing by mouse central neurons in cell culture.

The investigational anticonvulsant drug, gabapentin (GP; 1-(aminomethyl) cyclohexaneacetic acid) limited repetitive firing of sodium-dependent action potentials of mouse spinal cord and neocortical neurons in monolayer dissociated cell culture. The effect developed slowly over time with sustained exposure. The IC50 was 1.3 x 10(-4) M for exposure times < or = 60 s, 1.9 x 10(-5) M for 10-60 min, and 4.0 x 10(-6) M for 12-48 h. Hyperpolarization restored sustained firing in the continuing presence of GP. Blockade of action potential firing by GP was frequency (use)-dependent. After preincubation with 2.9 x 10(-5) M GP (5 micrograms/ml), trains of brief stimuli at > or = 50 Hz elicited fewer action potentials than in control solution. Also, at 150 Hz, maximal rate of rise of action potentials decreased progressively with repetitive firing in GP-containing, but not control, solution. After overnight incubation in 2.9 x 10(-5) M GP, the absolute refractory period was prolonged from 2.4 +/- 0.6 ms in control solution (n = 11) to 4.7 +/- 0.3 ms (n = 10; P = 0.02 vs. control), and complete recovery from inactivation was prolonged from 8.0 +/- 1.3 ms to 17.0 +/- 2.6 ms (P < 0.001 vs. control). These findings suggest that GP may alter function of voltage-activated sodium channels, but the mechanism is unproven and may be indirect. Limitation of firing was observed in > or = 50% of neurons at concentrations in the range of those found in plasma and cerebrospinal fluid of patients treated successfully with GP. These results suggest that limiting the rate of firing of sodium-dependent action potentials may contribute to the anticonvulsant efficacy of gabapentin.

Acetates↗
PubMed1996

The anticonvulsant gabapentin decreases firing rates of substantia nigra pars reticulata neurons.

Gabapentin is a novel anti-epileptic drug which enhances GABA (gamma-aminobutyric acid) turnover in certain brain regions, including substantia nigra. However, the functional consequences of GABA turnover increases in response to gabapentin and their potential involvement in the anticonvulsant action of this drug are not known. In the present study, we examined the effects of gabapentin on the extracellular, single unit activity of nondopaminergic (presumably GABAergic) neurons of the substantia nigra pars reticulata in rats. During the recordings, the animals were infused with the narcotic opioid analgesic fentanyl, associated with a skeletal muscle relaxant and artificial ventilation. The spontaneous firing of substantia nigra pars reticulata neurons was determined up to about 2 h after i.v. or i.p. administration of gabapentin at doses of 15-30 mg/kg. After both routes of administration, gabapentin markedly reduced neuronal firing when administered at a dose of 20-30 mg/kg, while 15 mg/kg were ineffective in this regard. The suppressive effect of gabapentin was rapid in onset (2 min after i.v. and about 20 min after i.p. injection), reached peak values of about 70% below predrug baseline after about 45-60 min, and remained at this level for at least 2 h. Vehicle administration had no effect on substantia nigra pars reticulata neurons. The ability of gabapentin to alter substantia nigra pars reticulata firing does correlate with its known ability to increase nigral GABA turnover. Since a substantial body of evidence suggests that the substantia nigra pars reticulata is a critical site at which decrease of neuronal firing by potentiation of GABAergic influences results in protection against various seizure types, the suppressive effect of gabapentin on substantia nigra pars reticulata activity may contribute to the anticonvulsant action of this drug.

Acetates↗
PubMed1998

SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo.

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFalpha) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFalpha production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFalpha production with an ED50 of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFalpha production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFalpha production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 microgram) inhibited intralesional concentrations of interleukin-4 (55%; P <.01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFalpha production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Effect of riluzole and gabapentin on cocaine- and methamphetamine-induced behavioral sensitization in mice.

RATIONALE: Recent studies have suggested the involvement of excitatory amino acid (EAA) and inhibitory gamma amino butyric acid (GABA) transmission in the effects of psychostimulants such as cocaine and amphetamines. OBJECTIVES: The present study was undertaken to investigate whether drugs that are considered to inhibit glutamate release (e.g., riluzole) or increase GABAergic transmission (e.g., gabapentin) attenuate the induction and expression of sensitization to cocaine and methamphetamine (METH) in Swiss Webster mice. METHODS: Sensitization to the psychomotor stimulating effect of cocaine and METH was rendered by five daily injections of cocaine (20 mg/kg) or METH (1.0 mg/kg). Locomotor activity was measured by infrared beam interrupts. RESULTS: Pretreatment with riluzole (2.5-20.0 mg/kg) affected neither the expression nor the induction of sensitization to cocaine. The pretreatment with riluzole (20 mg/kg) blocked the acute response to METH on day 1 and the expression of the sensitized response on day 5 but not the induction of sensitization to METH. Pretreatment with gabapentin (10 mg/kg and 30 mg/kg) affected neither the expression nor the induction of sensitization to cocaine. The pretreatment with gabapentin attenuated the acute response to METH on day 1 and the expression of the sensitized response on day 5, but it failed to block the induction of sensitization to METH. Psychostimulant-induced conditioned locomotion was affected neither by riluzole nor by gabapentin. CONCLUSIONS: Riluzole and gabapentin had no effect on the induction of sensitization to cocaine and METH; however, they attenuated the expression of sensitization to METH but not to cocaine. These findings suggest that riluzole- and gabapentin-mediated changes in EAA and GABAergic transmission, respectively, had no effect on mechanisms associated with the induction of sensitization, but they may affect the expression of the sensitized response to METH.

Acetates↗
PubMed2001

Metabolism of benzoate, cyclohex-1-ene carboxylate, and cyclohexane carboxylate by "Syntrophus aciditrophicus" strain SB in syntrophic association with H(2)-using microorganisms.

The metabolism of benzoate, cyclohex-1-ene carboxylate, and cyclohexane carboxylate by "Syntrophus aciditrophicus" in cocultures with hydrogen-using microorganisms was studied. Cyclohexane carboxylate, cyclohex-1-ene carboxylate, pimelate, and glutarate (or their coenzyme A [CoA] derivatives) transiently accumulated during growth with benzoate. Identification was based on comparison of retention times and mass spectra of trimethylsilyl derivatives to the retention times and mass spectra of authentic chemical standards. (13)C nuclear magnetic resonance spectroscopy confirmed that cyclohexane carboxylate and cyclohex-1-ene carboxylate were produced from [ring-(13)C(6)]benzoate. None of the metabolites mentioned above was detected in non-substrate-amended or heat-killed controls. Cyclohexane carboxylic acid accumulated to a concentration of 260 microM, accounting for about 18% of the initial benzoate added. This compound was not detected in culture extracts of Rhodopseudomonas palustris grown phototrophically or Thauera aromatica grown under nitrate-reducing conditions. Cocultures of "S. aciditrophicus" and Methanospirillum hungatei readily metabolized cyclohexane carboxylate and cyclohex-1-ene carboxylate at a rate slightly faster than the rate of benzoate metabolism. In addition to cyclohexane carboxylate, pimelate, and glutarate, 2-hydroxycyclohexane carboxylate was detected in trace amounts in cocultures grown with cyclohex-1-ene carboxylate. Cyclohex-1-ene carboxylate, pimelate, and glutarate were detected in cocultures grown with cyclohexane carboxylate at levels similar to those found in benzoate-grown cocultures. Cell extracts of "S. aciditrophicus" grown in a coculture with Desulfovibrio sp. strain G11 with benzoate or in a pure culture with crotonate contained the following enzyme activities: an ATP-dependent benzoyl-CoA ligase, cyclohex-1-ene carboxyl-CoA hydratase, and 2-hydroxycyclohexane carboxyl-CoA dehydrogenase, as well as pimelyl-CoA dehydrogenase, glutaryl-CoA dehydrogenase, and the enzymes required for conversion of crotonyl-CoA to acetate. 2-Ketocyclohexane carboxyl-CoA hydrolase activity was detected in cell extracts of "S. aciditrophicus"-Desulfovibrio sp. strain G11 benzoate-grown cocultures but not in crotonate-grown pure cultures of "S. aciditrophicus". These results are consistent with the hypothesis that ring reduction during syntrophic benzoate metabolism involves a four- or six-electron reduction step and that once cyclohex-1-ene carboxyl-CoA is made, it is metabolized in a manner similar to that in R. palustris.

Benzoates↗
PubMed1997

Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition.

BACKGROUND: Ornithine aminotransferase (OAT) is a 45 kDa pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of L-ornithine and 2-oxoglutarate to glutamate-delta-semialdehyde and glutamic acid, respectively. In humans, loss of OAT function causes an accumulation of ornithine that results in gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness. In an effort to learn more about the structural basis of this enzyme's function, we have determined the X-ray structures of OAT in complex with two enzyme-activated suicide substrates: L-canaline, an ornithine analog, and gabaculine, an irreversible inhibitor of several related aminotransferases. RESULTS: The structures of human OAT bound to the inhibitors gabaculine and L-canaline were solved to 2.3 A at 110K by difference Fourier techniques. Both inhibitors coordinate similarly in the active site, binding covalently to the PLP cofactor and causing a 20 degrees rotation in the cofactor tilt relative to the ligand-free form. Aromatic-aromatic interactions occur between the bound gabaculine molecule and active-site residues Tyr85 and Phe177, whereas Tyr55 and Arg180 provide specific contacts to the alpha-amino and carboxyl groups of L-canaline. CONCLUSIONS: The OAT-L-canaline complex structure implicates Tyr55 and Arg180 as the residues involved in coordinating with the natural substrate ornithine during normal enzyme turnover. This correlates well with two enzyme-inactivating point mutations associated with gyrate atrophy, Tyr55-->His and Arg180-->Thr. The OAT-gabaculine complex provides the first structural evidence that the potency of the inhibitor is due to energetically favourable aromatic interactions with residues in the active site. This aromatic-binding mode may be relevant to structure-based drug design efforts against other omega-aminotransferase targets, such as GABA aminotransferase.

Aminobutyrates↗
PubMed2003

The absorption of gabapentin following high dose escalation.

Gabapentins (GBP) is structurally similar to GABA yet its mode of action remains uncertain. It is water-soluble and GI tract absorption occurs via the L-amino acid transport system in the proximal small bowel. It has been suggested that this transportation is capacity limited, thus decreasing GBP bioavailability at higher doses. GBP is not protein bound, therefore, salivary levels might be expected to be similar to those in serum; also the drug does not induce hepatic enzymes and is excreted unmetabolised by the kidney. Within the dose-range normally prescribed, it is devoid of pharmacokinetic (PK) drug interactions with all other anti-epileptic drugs. This study assesses two things in patients with epilepsy: (a) bioavailability of higher doses of GBP (1200-4800 mg per day), and (b) the influence of high dose GBP on between-dose serum concentrations of co-prescribed anti-epileptic drugs. After stabilising at each dosage, a sequence of serum and saliva samples were collected within the dosage interval; GBP and co-medication concentrations were determined and the results subjected to PK modelling. Meaned results from 10 patients indicate that GBP continues to be absorbed in a reasonably linear manner relative to dose up to 4800 mg per day. The study also shows that GBP is transported into saliva, however, salivary concentrations are only 5-10% of those in plasma. Furthermore, the results indicate that GBP, in higher than recommended doses, did not change plasma concentrations of lamotrigine, carbamazepine, carbamazepine-epoxide, vigabatrin, primidone, phenobarbitone or phenytoin when added to treatment. It is concluded that larger than recommended doses of GBP can be efficiently absorbed by some patients and also that GBP plasma levels do not fluctuate greatly between dosage intervals, therefore, twice daily dosage is a possibility.

Absorption↗
PubMed1986

In vivo action of enzyme-activated irreversible inhibitors of glutamic acid decarboxylase and gamma-aminobutyric acid transaminase in retina vs. brain.

The effects of low s.c. doses of gamma-acetylenic gamma-aminobutyric acid (GAG) on glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) activities, as well as of gamma-vinyl GABA (GVG) and gabaculine on GABA-T activities, were examined using preparations from retina and several other regions of rat central nervous system (CNS). GAG, in doses of 5 to 50 mg/kg, inactivated retinal GAD to a significantly greater degree than GAD from any other CNS region studied. Retinal GABA-T activities were also differentially inactivated by 1 to 50 mg/kg of GAG, 50 mg/kg of GVG, or 1 and 5 mg/kg of gabaculine. GAG, in doses of 25 and 50 mg/kg, more completely inactivated GAD and GABA-T in frontal cortex than in other brain regions. Frontal cortical GABA-T was not differentially inactivated by 10 and 50 mg/kg of GVG or 1 and 5 mg/kg of gabaculine. The effects of GAG on retinal GABA enzymes were long-lasting and not reversed by dialysis. The GAD and GABA-T activities from 1:1 mixes of control and GAG-treated retinal preparations were comparable to the means of the GAG-treated and control activities. The effects documented in this study, therefore, probably reflect irreversible in vivo changes. After peripheral administration, GAG, GVG and gabaculine might reach higher levels in the retina than in the brain. Alternatively, the differential effects of these compounds might be due to the relative proportions of catalytically active GABA enzymes in different CNS regions. On the basis of the foregoing results, the retina might be a particularly suitable region of the CNS for enzyme-activated irreversible inhibitors to label catalytically active enzymes of GABA metabolism.

4-Aminobutyrate Transaminase↗
PubMed1989

Reversal by apomorphine of the gabaculine-induced GABA accumulation in mouse cortex.

To test the assumption that in the mice cortex the rate of accumulation of gamma-aminobutyric acid (GABA) after irreversible inhibition of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) represents an index of GABA turnover, we examined whether the reversal of the gabaculine-induced accumulation of GABA elicited by apomorphine was due to a decrease in GABA turnover or to a modulation of the activity of the GABA-T inhibitor. Therefore, we simultaneously measured the action of apomorphine on gabaculine-induced accumulation of GABA and on GABA-T activity. In vitro, apomorphine (3 and 30 microM) did not alter the concentration-dependent inhibition of GABA-T by gabaculine. Ex vivo, apomorphine (2 x 0.5 mg/kg s.c.) markedly decreased (69%) gabaculine-induced (150 mg/kg i.p.) accumulation of GABA. This drug had no direct effect on GABA-T activity, but significantly reduced from 83 to 71% the inhibition of GABA-T by gabaculine. The linear correlation found between GABA levels and GABA-T activity allowed the quantification of the decrease in GABA turnover elicited by apomorphine. The results showed that apomorphine decreased significantly (P less than 0.001) the rate of GABA synthesis from 7.48 to 3.36 micromol GABA/g per h, if the partial reversal of gabaculine-induced inhibition of GABA-T is considered and 2.44 micromol/g per h if not. Apomorphine effect on GABA accumulation is mainly due to a decrease of the rate of GABA synthesis and to a lesser extent to a reversal of the inhibitory activity of gabaculine. Thus, inhibition of GABA-T by gabaculine is a sensitive and reliable method for the estimation of the rate of synthesis.

4-Aminobutyrate Transaminase↗
PubMed2003

Magnesium chloride and ruthenium red attenuate the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain.

BACKGROUND: Gabapentin, a gamma-aminobutyric acid analog anticonvulsant, has been shown to possess antinociceptive effects in animal models and clinical trials. An endogenous binding site of [3H]gabapentin has been revealed to be the alpha(2)delta subunit of voltage-dependent Ca2+ channels. Magnesium chloride, ruthenium red, and spermine have been shown to modulate [3H]gabapentin binding to this binding site in vitro. In this study, the authors examined whether intrathecal magnesium chloride, ruthenium red, or spermine could affect the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats received an incision over the plantar surface of the right hind paw to produce punctate mechanical allodynia. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before incision, 2 h after incision, and every 30 min after intrathecal coadministration of gabapentin with normal saline or different doses of magnesium chloride, ruthenium red, or spermine for 2 h. RESULTS: Intrathecal gabapentin (30, 100, 200 microg) dose-dependently reduced incision-induced allodynia. Hexahydrated magnesium chloride (5, 10, 20 microg) and ruthenium red (0.2, 2, 20 ng) noncompetitively inhibited the antiallodynic effect of gabapentin. Spermine at doses not inducing motor weakness (30, 60 microg) did not affect the antiallodynic effect of gabapentin. The antiallodynic effect of intrathecal morphine (1.5 microg) was not affected by hexahydrated magnesium chloride (20 microg), ruthenium red (20 ng), or spermine (60 microg). CONCLUSIONS: These results provide behavioral evidence to support that the alpha(2)delta subunit of Ca2+ channels may be involved in the antiallodynic action of intrathecal gabapentin in the postoperative pain model.

Acetates↗
PubMed2002

The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors.

The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a gamma-aminobutyric acid-B (GABA(B)) receptor agonist acting exclusively at a heterodimeric complex containing the GABA(B(1a)) splice variant (Mol Pharmacol 2001;59:144-152). In this study, we have investigated the effects of gabapentin on recombinant GABA(B(1a)) and GABA(B(1b)) receptors coexpressed with GABA(B(2)) in five different functional recombinant assays, its ability to inhibit [(3)H]GABA binding in a GABA(B) receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABA(B(1a,2)) or the GABA(B(1b,2)) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [(3)H]GABA from GABA(B) receptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA(B) receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA(B(1a)) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA(B(1a,2)) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA(B) receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA(B) receptor-independent mechanisms. This also implies that the first GABA(B) receptor splice variant-selective ligand remains to be discovered.

Acetates↗
PubMed1988

Inhibition of human platelet secretion and of Ca2+, calmodulin-dependent protein phosphorylation by the antiallergic agent GMCHA.

Calcium ion-dependent interaction with purified calmodulin (CaM), of a potent inhibitor of histamine release from mast cells, trans-4-guanidinomethylcyclohexanecarboxylic acid p-tertbutylphenylester (GMCHA), was investigated using 5-(dimethylamino)-1-naphthalenesulfonyl-calmodulin (dansyl-CaM). GMCHA undergoes a fluorescence increase with the Ca2+-dansyl-CaM complex but there is no significant change in the dansyl-CaM fluorescence with GMCHA, up to a 10 microM in the absence of calcium ion. This suggests that binding of GMCHA to CaM is Ca2+-dependent on the apparent Kd is approximately 1 microM. GMCHA suppressed the fluorescence of the hydrophobic probe 8-anilino-1-naphthalenesulfonate (ANS), in the presence of the Ca2+-CaM complex, with an IC50 value of 3 microM. [3H]N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) bound to the purified CaM was displaced, in a concentration dependent manner by GMCHA, the Ki value of GMCHA against the binding of W-7 to CaM was 2.3 microM, and there was a selective inhibition of the Ca2+-CaM induced activation of enzymes such as myosin light chain kinase. Increasing the CaM concentration in the presence of Ca2+ overcame the GMCHA-induced inhibition of myosin light chain kinase activation, with a Ki value of 2.7 microM. GMCHA at these concentrations is effective in inhibiting the release of histamine from mast cells. Moreover, this compound suppresses platelet secretion and relaxes vascular strips, at concentrations similar to those seen with the CaM interacting action and characteristic of CaM antagonists such as W-7. GMCHA also inhibits the Ca2+, CaM-dependent myosin light chain phosphorylation of human platelets. These results suggest that GMCHA, a potent inhibitor of histamine release from mast cells, suppresses platelet secretion, relaxes vascular smooth muscle and inhibits Ca2+, CaM-dependent protein phosphorylation, all at similar concentrations.

Adenosine Triphosphate↗
PubMed2000

Gabapentin use in neuropathic pain syndromes.

The development of neuropathic pain involves a series of changes including primary and secondary hyperalgesia, peripheral and central sensitization, and wind-up phenomena. Neurotransmitters play a critical role in this process. For example, glutaminergic subtypes of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and neurokinin prime the N-methyl-D-aspartate (NMDA) receptor by triggering the release of intracellular calcium ions, thus unblocking the magnesium ion plug on the NMDA receptor and allowing Ca2+ influx into the cell. Ca2+ ions acting as secondary messengers initiate protein kinase C activation, phospholipase C and nitric oxide synthetase production, and proto-oncogene expression. The activation of the NMDA receptor thereby increases the responsiveness of the nociceptive system. Anticonvulsant drugs--including carbamazepine, phenytoin, and felbamate--have been used to treat neuropathic pain. Gabapentin is a novel anticonvulsant that may have a unique effect on voltage-dependent Ca2+ channel currents at postsynaptic dorsal horn neurons. Thus, gabapentin may interrupt an entire series of events, not just a single process, that lead to the development of neuropathic pain. Preclinical models of anti-inflammatory and neuropathic pain indicate that gabapentin effectively antagonizes the maintenance of this pain. Additionally, in preemptive surgical models, gabapentin has been shown to prevent the induction of pain. Gabapentin has been shown to be efficacious in numerous smaller clinical studies, case reports, and chart reviews in a variety of neuropathic pain syndromes. Two large multicenter studies, one in postherpetic neuralgia (PHN) and one in diabetic peripheral neuropathy (DPN), support preclinical findings. In the PHN study, patients treated with gabapentin demonstrated a significant difference (P<0.001) in their average daily pain score at endpoint compared to placebo patients. In the DPN trial, mean weekly pain was significantly (P<0.001) different for gabapentin-treated patients compared to placebo-treated patients at endpoint. Consistent with the known side-effect profile of gabapentin, the most common adverse events noted in both studies were dizziness and somnolence. Gabapentin should be considered an important addition to the management of neuropathic pain syndromes.

Acetates↗
PubMed2003

A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slices.

1 The mode of Ca(2+) channel blocking by gabapentin [1-(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca(2+) channel blockers, and the potential role of Ca(2+) channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. 2 mRNA for the alpha(2)delta subunits of Ca(2+) channels was found in rat cerebral cortex. 3 Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N- and P/Q-type Ca(2+) channels. Gabapentin blocked both types of Ca(2+) channels, and preferentially reversed the response to 30 mM K(+) stimulation compared with 50 mM K(+) stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K(+). 4 Gabapentin inhibited KCl-induced elevation of intracellular Ca(2+) in primary neuronal culture. 5 Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. omega-Conotoxin GVIA (omega-CTX) and omega-agatoxin IVA (omega-Aga) were effective in both models. 6 NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. omega-CTX and omega-Aga were effective in both the cases. 7 Therefore, the data suggest that gabapentin and verapamil cause activity-dependent Ca(2+) channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults.

Acetates↗
PubMed2003

A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.

1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.

Acetates↗
PubMed1981

Fibrinolytic activity of cerebral tissue after experimental subarachnoid haemorrhage: inhibitory effect of tranexamic acid (AMCA).

The influence of tranexamic acid (AMCA) on the fibrinolytic activity induced by plasminogen activators (PA) of the cerebral leptomeninges, arteries and choroid plexus after artificial subarachnoid haemorrhage (SAH) was studied in 90 rabbits. SAH was induced by injection of 1-2 ml autologous blood into the suboccipital cistern. Half of the rabbits were given AMCA, 200 mg per kg body weight, in daily single i.v. injections. The rabbits were sacrificed after 3-5, 8-10 and 14-15 days respectively. Part of the leptomeninges, basilar artery and choroid plexus were removed for assaying PA by the histochemical fibrin slide and fibrin plate methods, using thiocyanate for extraction of plasminogen activator from the tissues. Quantitative assays for the fibrin plate method showed high PA in the arterial and meningeal tissues from the untreated animals 3-5 days after SAH. The PA had decreased to normal levels 8-10 days after SAH but increased again 14-15 days after SAH. A lower PA in the choroid plexus followed the same pattern. The concentration of the primary plasmin inhibitor in plasma had decreased to half of the normal value 8 days after SAH when compared to the concentration in pooled plasma from normal rabbits. In AMCA treated animals the meningeal PA, assayed by both methods, was decreased 3-5 days after SAH while no or an insignificant decrease in PA was seen 8-10 and 14-15 days after SAH. The PA of the arterial vessel wall and choroid plexus in the AMCA treated animals, assayed by the histochemical method, was moderately decreased 3-5 days after SAH, while no significant differences between untreated and AMCA treated animals were seen after 8-10 or 14-15 days when the tissues were assayed by either method. These findings indicate that AMCA suppresses PA primarily in the leptomeninges during the first few days after SAH and presumably before the meningeal fibrosis has developed.

Animals↗
PubMed2000

Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability.

UNLABELLED: Gabapentin (GBP) is a non-metabolized, non-plasma protein bound, renally excreted antiepileptic drug that is actively absorbed via the system L amino acid transporter. Previous studies have demonstrated that gabapentin displays dose-dependent absorption. OBJECTIVES: These studies were conducted to determine inter- and intra-subject variability of gabapentin absorption. Two prospective clinical studies in healthy adult volunteers were conducted. Coefficient of variation (CV) was used to express variability of gabapentin absorption. METHODS: Study A: 400-mg single dose, randomized, cross-over study to assess bioavailability of four different gabapentin formulations (n=20, 9 males, 11 females; mean age and weight 41 years, 75.1 kg). Plasma was serially collected up to 48 h and bioavailability (F) calculated post-dose to determine concentration-time curves (AUC). All four formulations were bioequivalent, thus repeated measures analysis was performed to assess inter-and intra-subject variability. Study B: 600-mg single dose study (n=50, 15 males, 35 females; mean age and weight 31.1 years, 72.7 kg) was conducted to determine inter-subject variability in gabapentin F. Urine was collected over 48 h and bioavailability (F) calculated. Urine and plasma gabapentin concentrations were measured by HPLC-UV. RESULTS: Study A: Overall mean (CV) of GBP AUC values was 34.1+/-24 ug/h per ml. Inter-subject CV for AUC was 22.5% and intra-subject CV was 12.1%. Study B: Overall mean (SD) GBP F was 49.3+/-13.6%. Inter-subject CV of F was 27.6%. DISCUSSION: The inter-subject variability in gabapentin absorption is substantially less than that of the inter-subject variability. This indicates that one would expect a wide range in gabapentin absorption between subjects; however, a much smaller variability within a subject. The within subject variability of gabapentin is small enough that plasma drug monitoring may be used to assess gabapentin absorption for a given subject and the benefit of dose individualization.

Acetates↗
PubMed2004

The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation.

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) has a broad anticonvulsant spectrum and is currently in clinical development for epilepsy. The compound has an opening effect on neuronal KCNQ channels. At higher concentrations an augmentation of gamma-aminobutyric acid (GABA) induced currents as well as a weak blocking effect on sodium and calcium currents were observed. The goal of this study was to characterise the activity of retigabine in models of acute and neuropathic pain and to investigate if the potassium channel opening effect of retigabine contributes to its activity. Retigabine was tested in mice and rats in the tail flick model of acute pain and in the nerve ligation model with tight ligation of the 5th spinal nerve (L5) using both thermal and tactile stimulation. While retigabine like gabapentin had almost no analgesic effect in mice it showed some analgesic effects in rats in the tail flick model. These effects could not be antagonised with linopirdine, a selective KCNQ potassium channel blocker, indicating a different mode of action for this activity. In L5-ligated rats retigabine significantly and dose-dependently elevated the pain threshold and prolonged the withdrawal latency after tactile and thermal stimulation, respectively. In the L5 ligation model with thermal stimulation retigabine 10 mg/kg p.o. was as effective as 100 mg/kg gabapentin or 10 mg/kg tramadol. The L5 model with tactile stimulation was used to test the role of the KCNQ potassium channel opening effect of retigabine. If retigabine 10 mg/kg p.o. was administered alone it was as effective as tramadol 10 mg/kg p.o. in elevating the pain threshold. Linopirdine (1 and 3 mg/kg i.p.) had nearly no influence on neuropathic pain response. If we administered both retigabine and linopirdine the effect of retigabine was abolished or diminished depending on the dose of linopirdine used.In summary, retigabine is effective in predictive models for neuropathic pain. The activity is comparable to tramadol and is present at lower doses compared with gabapentin. Since the anti-allodynic effect can be inhibited by linopirdine we can conclude that the potassium channel opening properties of retigabine are critically involved in its ability to reduce neuropathic pain response.

Acute Disease↗