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PubMed1993

Effects of synthetic trypsin inhibitors on the growth of Escherichia coli.

The inhibitory effects of various aromatic esters of trans-4-guanidinomethylcyclohexanecarboxylic acid (GMCHA), potent trypsin inhibitors, on the growth of Escherichia coli were examined and the effects were compared with those of well known synthetic trypsin inhibitors. Various GMCHA esters strongly inhibited the growth of E. coli and their effects were markedly affected by the species and position of substitution on the phenyl nucleus of the GMCHA phenyl esters. No correlation was observed between the effects on the growth of E. coli and Ki's for trypsin. Inhibitory effects of benzamidine, phenylmethane sulfonylfluoride and diisopropyl fluorophosphate were less than 10% at 200 microM. 4-tert-Butylphenyl ester of GMCHA (GMCHA-OPhtBu), a representative of various GMCHA esters, dose-dependently inhibited the growth of E. coli and the growth inhibition was preceded by a dose- and time-dependent inhibition of DNA synthesis. Tosyl-L-lysine chloromethyl ketone (TLCK) and pentamidine isethionate, potent trypsin inhibitors, also dose-dependently inhibited the growth of E. coli and the DNA synthesis. However, their effects were transient and disappeared after a short while. These results indicate that the effects of TLCK and pentamidine isethionate differ from those of GMCHA esters. GMCHA-OPhtBu and pentamidine isethionate also inhibited RNA and protein synthesis.

Bacterial Proteins↗
PubMed1998

[ETICS Study: Empirical therapy of idiopathic chronic singultus].

Idiopathic chronic singultus (ICS) describes recurring episodes of persistent hiccuping lasting longer than an arbitrary time limit (e.g. one month) for which no organic cause or consistently effective treatment can be found. It has been suggested that ICS may result from chronic stimulation of a supraspinal "hiccup center" by impulses originating from receptors in the gastrointestinaltract. This hypotesis implies the possibility of treating ICS by reducing gastric acid (via omeprazole), facilitating gastric emptying (via cisapride), or suppressing of the "hiccup centre" (via GABA-ergic offects of baclofen or gabapentin). 29 patients (28 male, one female; age 71 +/- 10 years) suffering from ICS for four to 564 months were treated with a combination of cisapride (30 mg/d), omeprazole (20 mg/d) and baclofen (45 mg/d) (COB). The patients rated the severity of hiccuping on a subjective assessment scale (SAS) that ranged from 0 (= no hiccuping) to 10 (= unbearable hiccuping). Hiccuping ceased in 38% (11/29) of the treated patients and decreased in severity in an additional 24% (7/29). Mean SAS-scores following 20 to 24 weeks of therapy (3.7 +/- 3.4) were significantly lower compared to before therapy (8.8 +/- 1.3) (Mann-Whitney rank order test [p < 0.02]). In the patients that failed to respond to COB, gabapentin (1.200 mg/d) was substituted for baclofen. Hiccuping ceased in one and improved in two of these ten subjects. We conclude that COB is an effective empirical therapy in the majority of patients with ICS. It may be useful to substitute gabapentin for baclofen in those not responding to COB.

Acetates↗
PubMed2002

The effect of intrathecal gabapentin on mechanical and thermal hyperalgesia in neuropathic rats induced by spinal nerve ligation.

Gabapentin decreases the level of glutamate and elevates that of alpha-amino-butyric acid in the central nervous system. Gabapentin was shown to have antinociceptive effects in several facilitated pain models. Intrathecal gabapentin was also known to be effective in reducing mechanical allodynia in animals with neuropathic pain. In this study, we investigated to see whether intrathecal gabapentin produces antihyperalgesic effects on thermal and mechanical hyperalgesia in neuropathic rats and whether its effects are associated with motor impairment. To induce neuropathic pain in Sprague-Dawley rats, left L5 and L6 spinal nerves were ligated. After a week, lumbar catheterization into subarachnoid space was performed. Then, paw withdrawal times to thermal stimuli and vocalization thresholds to paw pressure were determined before and up to 2 hr after intrathecal injection of gabapentin. Also, motor functions including performance times on rota-rod were determined. Intrathecal gabapentin attenuated significantly thermal and mechanical hyperalgesia in neuropathic rats, but did not block thermal and mechanical nociception in sham-operated rats. Intrathecal gabapentin of antihyperalgesic doses inhibited motor coordination performance without evident ambulatory dysfunction. This study demonstrates that intrathecal gabapentin is effective against thermal and mechanical hyperalgesia, in spite of moderate impairment of motor coordination.

Acetates↗
PubMed1995

Gabapentin and lamotrigine: novel antiepileptic drugs.

The pharmacokinetics, efficacy, and adverse effects of gabapentin and lamotrigine, two new antiepileptic drugs (AEDs), are reviewed. Gabapentin and lamotrigine are promising advances in the treatment of epilepsy, which has not been satisfactorily controlled by available agents in 25-41% of patients. Gabapentin is chemically similar to gamma-aminobutyric acid, but it is able to pass into the central nervous system. It is effective for the treatment of partial-onset seizures that are refractory to other AEDs. It has no known drug-drug interactions and a relatively benign adverse effect profile, but its short half-life necessitates at least thrice-daily dosing. Lamotrigine is structurally unrelated to the other available AEDs. Its role is currently limited to add-on therapy in patients with partial seizures, with or without secondary generalization, that are resistant to current treatment. The efficacy of lamotrigine in patients with primary generalized tonic-clonic seizures, absence seizures, and Lennox-Gastaut syndrome remains to be validated. The adverse effect profile also remains to be determined. A rash may appear in up to 5% of patients, possibly necessitating discontinuation of the drug. Although lamotrigine does not seem to affect the pharmacokinetics of the other AEDs, the other AEDs affect lamotrigine pharmacokinetics. Lamotrigine can be given once or twice daily. Gabapentin and lamotrigine may be useful in treating patients whose epilepsy is not controlled by other available AEDs; however, further research is needed to confirm their roles in epilepsy treatment.

Acetates↗
PubMed1993

Effect of trans-4-guanidinomethylcyclohexanecarboxylic acid 4-tert-butylphenyl ester, a trypsin inhibitor, on the growth of various strains of Escherichia coli.

Similarly to Escherichia coli K-12 IAM 1264, trans-4- guanidinomethylcyclohexanecarboxylic acid 4-tert-butylphenyl ester (GMCHA-OPhtBu), a trypsin inhibitor, had a strong inhibitory effect on the growth of various strains of E. coli K-12, such as W 3350, AB 1157, JM 103, W 3110, C 600r-m- and C 600r+m+, preceded by suppressive effects of GMCHA-OPhtBu on DNA synthesis in these strains, although the inhibitory effects varied from strain to strain. These results suggested the possible involvement of a trypsin-like proteinase in DNA synthesis. A trypsin-like proteinase was partially purified from E. coli K-12 AB 1157 by ammonium fractionation and successive chromatographies on DEAE-cellulose, Sephadex G-100 and arginine-Sepharose 4B columns. The properties were compared with those of proteinase In, which instantly appears just before the onset of DNA synthesis and seems to participate in the initiation of DNA replication, and which was purified from E. coli K-12 IAM 1264. The proteinase from E. coli K-12 AB 1157 was identified with proteinase In. These results suggest that proteinase In must be widely distributed in various E. coli strains and plays a pivotal role in the onset of DNA replication.

Bacterial Proteins↗
PubMed1971

Regulation of tryptophan biosynthetic enzymes in Neurospora crassa.

The formation of enzymatic activities involved in the biosynthesis of tryptophan in Neurospora crassa was examined under various conditions in several strains. With growth-limiting tryptophan, the formation of four enzymatic activities, anthranilic acid synthetase (AAS), anthranilate-5-phosphoribosylpyrophosphate phosphoribosyl transferase (PRAT), indoleglycerol phosphate synthetase (InGPS), and tryptophan synthetase (TS) did not occur coordinately. AAS and TS activities began to increase immediately, whereas PRAT and InGPS activities began to increase only after 6 to 12 hr of incubation. In the presence of amitrole (3-amino-1,2,4-triazole), the formation of TS activity in a wild-type strain was more greatly enhanced than were AAS and InGPS activities. With a tr-3 mutant, which ordinarily exhibits an elevated TS activity, amitrole did not produce an increase in TS activity greater than that observed on limiting tryptophan. With tr-3 mutants, the increased levels of TS activity could be correlated with the accumulation of indoleglycerol in the medium; prior genetic blocks which prevented or reduced the synthesis of indoleglycerol also reduced the formation of TS activity. The addition of indoleglycerol to cultures of a double mutant (tr-1, tr-3) which could not synthesize indoleglycerol markedly stimulated the production of TS activity but not PRAT activity; the production of TS activity reached the same level with limiting or with excess tryptophan. A model explaining these and other related observations on enzyme formation in N. crassa is proposed.

Cell-Free System↗
PubMed1995

Optimized method for determination of gabapentin in serum by high-performance liquid chromatography.

The anticonvulsant drug gabapentin and its heptaneacetic acid analog-used here as an internal standard--are isolated from serum (pH 9) with an octyldecyl (C-18) solid-phase sorbent column. To enhance analytical detection, trinitrobenzene derivatives of these extracted compounds are prepared quickly within 10 min. To further improve chromatographic selectivity, the derivatives are concentrated on a thin C-18 solid-phase membrane and interferences are washed away. The retained purified derivatives are eluted from the membrane with a small volume of solvent and the eluate is directly injected onto an Ultrasphere C-18 high-performance liquid chromatography column with quantification at 340 nm. No evaporation-concentration steps are necessary. Recoveries (extraction) of gabapentin and the internal standard are 94.2 +/- 2.9% and 98 +/- 2.0%, respectively. Analytical responses are linear from lower limit of sensitivity of 0.05 mg/L up to at least 10 mg/L. Between-run coefficients of variation (CV) range from 2.3 to 2.9% through the concentration range 0.5-4.0 mg/L. To illustrate the rationale for selection of test parameters for a robust method, we present optimization graphs for these processes. Moreover, we discuss the advantage of the packed cartridge and membrane sorbens as companion extraction devices.

Acetates↗
PubMedDate not supplied

[Improvements in the symptoms of olivopontocerebellar atrophy with gabapentin].

INTRODUCTION: Olivopontocerebellar atrophy (OPCA) is a degenerative disease of the nervous system (NS) which currently has no known cure. The neuronal depopulation it brings about produces a number of neurochemical alterations, including a reduction in levels of gamma-aminobutyric acid (GABA) in tissues and in cerebrospinal fluid (CSF). The drug gabapentin (GBP) has proved to be capable of increasing the concentration of this neurotransmitter in the central nervous system, and of improving the cerebellar ataxia in other diseases with a similar neurochemical substrate. CASE REPORTS: We describe two sporadic cases of OPCA, who were administered GBP. In one of the cases, the ataxia was noticeably reduced after taking one 400 mg dose. In the other case, a considerable improvement was observed in a very intense cerebellar dysarthria, and there was less oscillopsia with better vision, following administration of GBP for a period of over 12 months. CONCLUSIONS: GBP has proved to be capable of slowing down the motor disorders reported by patients in the course of OPCA. We discuss how such effects are due to the increased levels of GABA in the NS triggered by the drug. Finally, we suggest that the administration of GBP could constitute an effective symptomatic treatment for the ataxia and the dysarthria caused by OPCA, and that the improvement in symptoms following single doses of GBP could be valuable in cases of OPCA, as well as other types of ataxia, that are ideal for taking advantage of the stimulus of the GABAergic neurotransmission.

Amines↗
PubMed2001

Anticonvulsant action and long-term effects of gabapentin in the immature brain.

The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.

Acetates↗
PubMed1979

Tranexamic acid in alveolar sockets in the prevention of alveolitis sicca dolorosa.

The effect of trans-4-amino-methyl-cyclohexane acid (AMCA) and a placebo preparation on the development of alveolitis sicca dolorosa (ASD) was investigated in a double-blind designed experiment. The preoperative registrations were age, sex, use of oral contraceptives, menstrual cycle, smoking, degree of impaction and operation time. The study included 120 healthy persons. Each person had bilateral impacted mandibular molars removed surgically at one session. AMCA (160 mg/extraction site) or placebor was applied in each socket after the operation. The postoperative course was evaluated on average 5 days later by the use of 13 different variables describing local and general discomfort. The incidence of ASD was 7.5% in the AMCA side and 5.0% in the placebo side. The result shows that a local inhibition of plasminogen activation by AMCA is insufficient to prevent the development of ASD. The occurrence of ASD and postoperative discomfort was not increased in women operated during the menstrual period. The usage of oral contraceptives is known to be associated with a high frequency of ASD. Women taking oral contraceptives may therefore postpone the operation to the withdrawal period of the pill, to reduce the risk of developing ASD. Postoperative pains and the consumption of analgetics were significantly increased in patients who were habitual smokers.

Adolescent↗
PubMed2003

Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome.

Dopaminergic agents such as ropinirole are the drugs of first choice in treating restless legs syndrome (RLS). Recently, gabapentin, a structural analogue of gamma-aminobutyric acid, has also been shown to improve sensorimotor symptoms in RLS. Therefore, the tolerability and efficacy of randomized treatment with either gabapentin or ropinirole in patients with idiopathic RLS was evaluated in this 4-week open clinical trial. Patients with idiopathic RLS were treated with either 300 mg of gabapentin (n = 8) or 0.5 mg of ropinirole (n = 8) as the initial dose, and the dose was up-titrated until relief of symptoms was achieved (gabapentin mean dosage 800 +/- 397 mg, range 300-1,200 mg; ropinirole mean dosage 0.78 +/- 0.47 mg, range 0.25-1.50 mg). In both groups, International Restless Legs Syndrome Study Group questionnaire scores improved significantly (p < or = 0.018), whereas the scores of the Epworth sleepiness scale remained unchanged within normal limits. Polysomnographic data showed a reduction of periodic leg movements during sleep (PLMS; p < 0.03) and PLMS index (p < 0.02) in both groups. Side effects were only mild and mostly transient. After 6-10 months of follow-up, in most patients, RLS symptoms were still improved. We conclude that gabapentin and ropinirole provide a similarly well-tolerated and effective treatment of PLMS and sensorimotor symptoms in patients with idiopathic RLS.

Acetates↗
PubMed2003

Different actions of gabapentin and baclofen in hippocampus from weaver mice.

The pre- and postsynaptic effects of baclofen, a broad-spectrum gamma-aminobutyric acid (GABA)B receptor agonist, and gabapentin, a selective agonist at GABA(B) receptors composed of GABA(B)(1a,2) heterodimers, were examined in CA1 pyramidal cells using whole-cell patch-clamp recordings in hippocampal slices from different strains of mice. In slices from C57BL/6 mice, by means of GABA(B) receptors, gabapentin and baclofen activated outward K+ currents at resting membrane potential. In weaver mice with a Kir3.2 channel mutation, baclofen and gabapentin failed to activate postsynaptic K+ currents. However, in littermate controls of weaver mice, gabapentin failed to evoke K+ currents, whereas baclofen activated currents in the same cells. Thus, postsynaptic actions of gabapentin and baclofen on K+ currents are different in this mouse strain. Via presynaptic GABA(B) receptors, baclofen significantly reduced GABA(A) inhibitory postsynaptic currents (IPSCs) in slices from C57BL/6 mice, as well as weaver and control mice. In contrast, gabapentin did not affect IPSCs significantly in any group of mice. These results indicate that although baclofen and gabapentin are agonists at postsynaptic GABA(B) receptors positively coupled to K+ channels, their mechanism of action differs in certain strains of mice, including the weaver wild-type mice, suggesting a dissociation in their signaling mechanism and coupling to K+ channels.

Acetates↗
PubMed1999

Crystal structure of 3-amino-5-hydroxybenzoic acid (AHBA) synthase.

The biosynthesis of ansamycin antibiotics, including rifamycin B, involves the synthesis of an aromatic precursor, 3-amino-5-hydroxybenzoic acid (AHBA), which serves as starter for the assembly of the antibiotics' polyketide backbone. The terminal enzyme of AHBA formation, AHBA synthase, is a dimeric, pyridoxal 5'-phosphate (PLP) dependent enzyme with pronounced sequence homology to a number of PLP enzymes involved in the biosynthesis of antibiotic sugar moieties. The structure of AHBA synthase from Amycolatopsis mediterranei has been determined to 2.0 A resolution, with bound cofactor, PLP, and in a complex with PLP and an inhibitor (gabaculine). The overall fold of AHBA synthase is similar to that of the aspartate aminotransferase family of PLP-dependent enzymes, with a large domain containing a seven-stranded beta-sheet surrounded by alpha-helices and a smaller domain consisting of a four-stranded antiparallel beta-sheet and four alpha-helices. The uninhibited form of the enzyme shows the cofactor covalently linked to Lys188 in an internal aldimine linkage. On binding the inhibitor, gabaculine, the internal aldimine linkage is broken, and a covalent bond is observed between the cofactor and inhibitor. The active site is composed of residues from two subunits of AHBA synthase, indicating that AHBA synthase is active as a dimer.

Actinobacteria↗
PubMed1989

Inhibitory effects of GMCHA-OPhBut on phospholipid methylation and histamine release in mast cells activated by concanavalin A, anti-IgE, and antigen.

[3H]Methyl group incorporation and histamine secretion in rat mast cells induced by anti-IgE and con A were strongly inhibited by trans-4-guanidinomethylcyclohexanecarboxylic acid 4-tert-butylphenyl ester (GMCHA-OPhBut), a strong and specific inhibitor for pH 7 tryptase (Muramatsu et al. (1988) Biol. Chem. Hoppe-Seyler 369, 617-625) which is present in rat mast cells. The IC50s for these events were of the order of 10(-6) M. Addition of GMCHA-OPhBut after the maximal increase in [3H]methyl group incorporation in rat mast cells activated by con A and anti-IgE induced rapid reduction of the methylated phospholipid, and the later histamine release was strongly suppressed. Mast cells were prepared with Mg2+-free Tyrode-HEPES solution, and challenged with anti-IgE with or without Mg2+. With Mg2+, [3H]methyl group incorporation was enhanced, and histamine was secreted time-dependently. Without Mg2+, [3H]methyl group incorporation fell to one-third, whereas histamine secretion was not affected. These results were incompatible with the above results. From these results it was strongly suggested that a trypsin-like protease, probably pH 7 tryptase, is involved not only in the early events, such as activation of phosphatidylethanolamine methyltransferase I and/or II, but also in the late events such as histamine release, and phospholipid methylation is not associated with histamine secretion.

Animals↗
PubMed1995

Absence of Ki-ras mutations in exocrine pancreatic tumors from male rats chronically exposed to gabapentin.

Human pancreatic malignancies originating from duct cells most frequently demonstrate activation of Ki-ras gene by G-to-A transition at codons 12 and 13. Rat pancreatic exocrine tumors more frequently and almost exclusively derive from acinar cells and thus differ morphologically from human pancreatic neoplasms. Male Wistar rats fed with 2% gabapentin (1-(aminomethyl)cyclohexane acetic acid) in diet for 2 years developed pancreatic exocrine adenomas and adenocarcinomas. To study the mutations in Ki-ras gene, rat pancreatic proliferative lesions induced by gabapentin were retrospectively analyzed by PCR amplification of DNA isolated from paraffin sections of formalin-fixed rat pancreatic adenomas and adenocarcinomas, using specific primers for regions encoding exon 1 (codon 12/13) and exon 2 (codon 61). The amplified 110-bp fragments of exon 1 and exon 2 were analyzed for mutations at codon 12/13 and 61. The results showed Ki-ras mutations at codon 12 in human pancreatic carcinomas. Novel mutations GGT-to-TGT and GGT-to-CGT were detected at codon 12 in 1/5 and 2/5 human pancreatic tumors. Rat adenomas or carcinomas induced by gabapentin expressed wild type sequences at codons 12, 13 and 61. These findings were confirmed by allele-specific oligonucleotide hybridization, single-strand confirmation polymorphism of exon 1 and direct sequencing of exon 1 and exon 2. The absence of mutations in these rat pancreatic tumors suggests that these tumors do not correspond to the human tumors, and that the pathogenesis of this rodent tumor formation may follow different molecular mechanisms.

Acetates↗
PubMed2006

Various GABA-mimetic drugs differently affect cocaine-evoked hyperlocomotion and sensitization.

To substantiate the notion that cocaine behavioral effects may be influenced by gamma-aminobutyric acid (GABA) neurotransmission male Wistar rats were injected with gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (a GABA transaminase inhibitor) before acute or repeated treatment with cocaine evoking either locomotor hyperactivation or sensitization. Gabapentin (1-30 mg/kg), tiagabine (2.5-10 mg/kg) or vigabatrin (75-250 mg/kg) attenuated the cocaine (10 mg/kg)-induced hyperactivation and in the highest doses they also decreased basal locomotor activation. Vigabatrin (75-250 mg/kg) dose-dependently reduced the development of cocaine sensitization in rats treated repeatedly (days 1-5) with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) following 5-day withdrawal; the remaining drugs were ineffective. When injected acutely with a cocaine challenge dose, gabapentin (3-10 mg/kg) or vigabatrin (150 mg/kg), but not tiagabine, significantly attenuated the expression of cocaine sensitization. The present results show that enhanced GABA-ergic neurotransmission exerted inhibitory actions on acute responses to cocaine, however, only in a case of vigabatrin the inhibition seems to be unrelated to the inhibitory effect of the drugs on basal locomotor activity. The finding that vigabatrin protected against the development and the expression of cocaine sensitization further supports its therapeutic potential in the treatment of cocaine dependence.

Amines↗
PubMed1983

Effects of fibrinolytic treatment on rabbit Masugi nephritis.

We investigated the effects of administration of urokinase (UK) and trans-4-aminomethylcyclohexane carboxylic acid (t-AMCHA) on the development of experimental rabbit Masugi nephritis. Treatment with 1000 U/kg of UK, 5000 U/kg of UK and 100 mg/kg of t-AMCHA twice a day intravenously was initiated on the 7th and continued for 7 consecutive days. Concomitantly with the nephrotoxin injection, 5000 U/kg of UK was also given twice a day intravenously for 14 days. The administration of 5000 U/kg of UK twice a day for 7 days and 14 days suppressed the increases in BUN values and the decreases in urinary fibrinolytic activity. Fibrin-fibrinogen degradation products (FDP) were detected more frequently in the urine of rabbits given UK than in the control. Immunofluorescence microscopy showed a decrease in intra- and extra-glomerular fibrin deposition, and a decrease in fibrin or fibrinoid deposits in Bowman's space by 5000 U/kg of UK was demonstrated electron microscopically. Light microscopy revealed that the accumulation of fibrin in glomeruli, crescent formation, and progressive glomerular disorganization by 5000 U/kg of UK were prevented. On the other hand, treatment with t-AMCHA enhanced the increase in BUN values and there was a decrease in urinary fibrinolytic activity. Dense fibrin deposits in the glomeruli, were observed immunopathologically by treatment with t-AMCHA and histopathologic changes were found to be even more severe.

Animals↗
PubMed1995

Gabapentin.

The amino acid antiepileptic drug (AED) gabapentin (GBP) is indicated for adjunctive use in the treatment of partial seizures with or without becoming secondarily generalized in individuals older than 12 years. GBP was about as potent as phenytoin in the maximal electroshock test, but had a different profile of efficacy than standard antiepileptics in a range of animal models. Possible mechanisms of action include biochemical effects enhancing the ratio of gamma-aminobutyric acid (GABA) to glutamate, ion-channel actions (direct or indirect), and/ or enhancement of nonsynaptic GABA release. The anticonvulsant effect appears to depend on concentration of gabapentin in neurons, presumably by the L-system amino acid transporter that has been implicated in absorption from the gut. Data from studies for U.S. Food and Drug Administration (FDA) approval suggested a direct relationship of clinical response to dose and efficacy did not plateau at the doses used. The maximally effective dose, relationship of efficacy to blood level, and maximum tolerable dose are not yet known conclusively. Lack of significant binding to plasma proteins and lack of liver metabolism contribute to the absence of known limiting drug-drug interactions, particularly with other AEDs. Excretion intact in the urine affords dose adjustment on the basis of creatinine clearance. A half-life of approximately 7 h necessitates multiple doses daily for many individuals. The medication is well tolerated, in general. Side effects tend to be mild to moderate in intensity, most frequently affect the central nervous system, and resolve with time in many individuals. GBP has been prescribed for approximately 70,000 individuals worldwide without untoward incidence of severe systemic toxicity to date. Safety data continue to accumulate. GBP has been labeled category C on the basis of effects on rodent fetuses. Experience with use in pregnant women is limited and human teratogenic effects have not been reported. Data from ongoing monotherapy trials will help to clarify the range of clinical utility of gabapentin.

Acetates↗