Acamprosate calcium

Acamprosate calcium is a synthetic drug for abstinence of patients with alcohol dependence [1].

Acamprosate administration can reduce alcohol intake. In rat model, oral acamprosate at dose of 50 to 400 mg/kg/day reduced voluntary oral ethanol consumption dose-dependently. However, the exact cellular target and mechanism of acamprosate is not clear. Acamprosate has a structure similar to that of GABA. It can specifically bind to GABAB receptors but not GABAA receptors. Besides that, acamprosate showed serotonergic properties. It increased 5-HT levels and the effects caused by 5-HT in rats exposed to ethanolvapour. Moreover, acamprosate was thought to have effects on inhibiting the excitatory activity of aminoacid and reducing Ca2+fluxes [1].

References:
1. Wilde M I, Wagstaff A J. Acamprosate. Drugs, 1997, 53(6): 1038-1053.

Pharmacokinetics and bioequivalence evaluation of acamprosate calcium tablets in healthy Chinese volunteers.[Pubmed:26360834]

Eur J Pharm Sci. 2015 Nov 15;79:67-72.

BACKGROUND: Few pharmacokinetic data of acamprosate were available in Chinese population and no medication is approved for alcohol dependence in China. PURPOSE: 1. Investigate the pharmacokinetic properties of Acamprosate calcium in healthy Chinese male volunteers on single- and multiple-dose administration. 2. Compare the bioequivalence of two formulations of Acamprosate calcium tablets both under fasting and fed conditions. METHODS: This open-label, randomized study included 3 stages. In each stage, a 2-way crossover bioequivalence study was conducted to study the pharmacokinetic properties and bioequivalence of Acamprosate calcium tablets on multiple dosing after standardized meals, single dosing under fasting conditions and fed conditions, respectively. The washout period between each treatment in a stage and between each stage was 1week. Plasma Acamprosate calcium was quantified by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Tolerability was evaluated by monitoring adverse events, physical examinations, 12-lead ECG, and laboratory tests. RESULTS: Totally, 36 male subjects were enrolled in the study and all of them completed the whole 3 study stages. Main pharmacokinetic parameters of test and reference formulations were as follows: multiple dosing, Tmax 9.94+/-6.59 and 9.47+/-5.47h, Cmax 435.74+/-348.10 and 346.54+/-155.66ng.mL(-1), AUC0-t 8600.52+/-5264.77 and 9315.10+/-6820.03ng.mL(-1).h, AUC0-infinity 8845.38+/-5838.18 and 9669.24+/-7326.53ng.mL(-1).h, t1/2 10.06+/-8.83 and 9.87+/-10.35h; single dosing under fasting conditions, Tmax 7.29+/-4.87 and 6.57+/-1.85h, Cmax 247.85+/-110.05 and 244.64+/-132.43ng.mL(-1), AUC0-t 3385.41+/-1418.92 and 3496.24+/-1767.29ng.mL(-1).h, AUC0-infinity 3781.53+/-1556.96 and 3829.56+/-1981.25ng.mL(-1).h, t1/2 13.07+/-17.24 and 10.26+/-7.78h; single dosing under fed conditions, Tmax 17.72+/-9.42 and 19.50+/-9.84h, Cmax 183.90+/-74.52 and 168.14+/-60.67ng.mL(-1), AUC0-t 3181.71+/-1368.24 and 3575.11+/-1416.39ng.mL(-1).h, AUC0-infinity3442.39+/-2002.53 and 3624.44+/-1418.12ng.mL(-1).h, t1/2 8.76+/-12.28 and 6.67+/-4.84h, respectively. In all three stages, 90% CIs for the test/reference ratio of AUC0-t and AUC0-infinity were located within 80%-125%, 90% CI for Cmax was within 70%-143%. CONCLUSIONS: Similar pharmacokinetic results of Acamprosate calcium tablets in healthy Chinese volunteers were found as those in Caucasic population. In all three stages, the two formulations met the regulatory criteria for bioequivalence. Chictr.org identifier: ChiCTR-TTRCC-14004853.

Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons.[Pubmed:10771287]

Eur J Pharmacol. 2000 Apr 14;394(2-3):221-31.

The N-methyl-D-aspartate (NMDA) receptor has been implicated as a putative sight of action for acamprosate, a novel drug that reduces craving for alcohol. The purpose of this study was to assess the effect of acamprosate on the function of native NMDA receptors expressed in primary cultured striatal and cerebellar granule cells, as well as ethanol inhibition and spermine modulation of these receptors, using whole-cell patch-clamp electrophysiological techniques. Under all circumstances, acamprosate (0.1-300 microM) did not alter NMDA- or glutamate-induced currents. Acamprosate did not alter the inhibitory effects of ethanol (10-100 mM) on receptor function. In a subpopulation of striatal neurons, acamprosate did reverse the potentiating effects of spermine. These findings indicate that although acamprosate may modify polyamine modulation of the NMDA receptor, acamprosate alone does not alter receptor function nor does it modify ethanol inhibition of this receptor expressed in primary cultured striatal and cerebellar granule neurons.

Acamprosate enhances N-methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABA(B) receptors in nucleus accumbens neurons.[Pubmed:9514305]

Alcohol Clin Exp Res. 1998 Feb;22(1):183-91.

Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N-methyl-D-aspartate (NMDA) and non-NMDA types of glutamatergic synaptic transmission in the NAcc. In the present study, we used voltage- and current-clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non-NMDA receptor-mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovalerate (d-APV), respectively. Bicuculline was also included to block GABA(A) receptors. Superfusion of acamprosate (5, 50, and 300 microM) did not alter the resting membrane properties of NAcc neurons. However, 300 microM acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 microM acamprosate had no significant effect on the non-NMDA receptor component of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 microM d-APV and 20 microM CNQX to block glutamatergic transmission and evoked monosynaptic GABA(A) receptor-mediated synaptic responses within the NAcc. Acamprosate (300 microM) did not change these monosynaptic GABA(A)-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABA(B) autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission. Like 0.5 microM CGP 34358 (a GABA[B] receptor blocker), acamprosate significantly decreased the paired-pulse inhibition (PPI) of GABA(A)-IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA-EPSP/Cs while blocking presynaptic GABA(B) receptor-mediated inhibition of GABA release. These results suggest that acamprosate's clinical efficacy in preventing relapse in weaned alcoholics could derive from its interactions with both the glutamatergic and GABAergic systems in the NAcc.

Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat.[Pubmed:8813529]

Eur J Pharmacol. 1996 Jun 3;305(1-3):39-44.

Acamprosate (calcium-acetyl homotaurinate) is a new compound in the treatment of alcoholism. Its efficacy has been proven in several clinical trials and registration is now pending in most European countries. The basic mechanisms by which acamprosate elicits its anti-craving action, thereby leading to reduced relapse rates, is not known at the moment. In the present study we describe a rat model of long-term alcohol-drinking which mimics relapse behavior in human alcoholics. The effect of acamprosate was studied in this model. Wistar rats had a free choice between water and alcohol solutions of different concentrations (5, 10, 20% v/v). After two months of continuous alcohol access, rats were deprived of alcohol for three days. Following this deprivation phase, all alcohol solutions were presented again. This procedure was repeated monthly for the following six months. The rats consumed 3.5 +/- 0.3 g/kg alcohol a day. After alcohol deprivation, alcohol intake rose to 5.2 +/- 0.3 g/kg per day resulting in blood alcohol levels of 30 +/- 6 mg/dl. Interestingly, the addition of quinine to the alcohol solutions or the additional presentation of a 5% sucrose solution did not affect the alcohol-deprivation effect after eight months of this intermittent alcohol exposure. However, when acamprosate (50-200 mg/kg i.p.) was administered twice daily, alcohol-drinking following an alcohol-deprivation phase was decreased dose dependently. Given at the highest dose alcohol intake even dropped significantly below baseline drinking. Together, these results show that acamprosate effectively diminishes the alcohol-deprivation effect. Furthermore, the described model seems to be a suitable animal model to screen compounds for their anti-relapse properties and subsequently for their anti-craving action.

Acamprosate calcium(Campral EC) is a GABA receptor agonist and modulator of glutamatergic systems; reduces alcohol consumption in animal models of alcohol addiction.

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