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PubMedDate not supplied

[Acamprosate. From pharmacology to therapeutics].

Acamprosate is an homotaurine derivative, structural analogue of Gamma amino butyric acid and upper homologue of taurine. Its crossing through the blood brain barrier is facilitated by acetylation and calcium salification. Acamprosate has a very weak toxicity attributable to the ingested dose of calcium. Acamprosate is a GABAagonist showing pharmacological activity on direct and indirect tests of GABA activity and a high binding capacity with GABA receptors. Acamprosate also shows beta-adrenergic and serotoninergic activity, probably due to its GABAergic activity. Acamprosate is neither and antidepressant, nor a neuroleptic or a tranquillizer. In experimental alcohology, on different animal models (alcohol preferring or alcohol dependent) acamprosate induces a very clear and highly significant reduction of alcohol consumption. This effect is progressive and dose dependent, antagonized by bicuculine which is a GABA agonist. Besides, acamprosate reduces the intensity of the alcohol withdrawal syndrome. Clinical alcohology is a very difficult field for strict methodology in therapeutic trials: determination of inclusion characters, choice of judgment criteria, reduction of the number of drop out and lost subjects, length of evaluation... Different clinical controlled studies, most in double blind against placebo, on patients suffering from signs of physical or psychical alcohol addiction as well as biological modifications due to their ethylic consumption showed beneficial effects of acamprosate (in weaned alcoholics after withdrawal) according to clinical criteria (the number of abstinents after 3 months was doubled: 60% with active drug--30% with placebo) and for biological criteria (Normalization of Gamma Glutamyl Transpeptidase level in blood). The tolerance is good.(ABSTRACT TRUNCATED AT 250 WORDS)

Acamprosate↗
PubMed1992

Acamprosate modulates synaptosomal GABA transmission in chronically alcoholised rats.

Male Sprague-Dawley rats were pulmonary alcoholised for 30 days. Six were treated with acamprosate (400 mg/kg/day, PO) during alcoholisation. The control nonalcoholised group also received acamprosate (400 mg/kg/day, PO) during the 30 days. At the end of the experiment, brains areas (cortex, hippocampus, thalamus, striatum, and olfactory bulbs) were dissected for the study of synaptosomal 3H-GABA uptake. In another experiment, GABA levels were determined in the same areas using HPLC with electrochemical detection. Blood ethanol levels were also measured during alcoholisation. Acamprosate treatment did not modify blood ethanol levels. In cortex and olfactory bulbs, alcoholisation increased 3H-GABA uptake (Vmax) with an increase in the affinity (Km). 3H-GABA uptake was not affected by alcoholisation in other brain areas. In hippocampus and thalamus, acamprosate treatment enhanced 3H-GABA uptake (Vmax) only in alcoholised rats. Moreover, in thalamus, alcoholisation enhanced GABA levels. The effect of alcohol and acamprosate on GABA presynaptic events is discussed and it is concluded that the action of ethanol and acamprosate on GABA transport could be, in part, responsible for the modulation by acamprosate treatment of ethanol behaviour.

Acamprosate↗
PubMed1991

Acamprosate and diazepam differentially modulate alcohol-induced behavioural and cortical alterations in rats following chronic inhalation of ethanol vapour.

The effects of Acamprosate (the calcium salt of an acetylated form of homotaurine) and the benzodiazepine-receptor agonist Diazepam, were investigated on the alcohol-induced behavioural preference towards alcohol following chronic alcoholization by inhalation. We also examined the effects of Acamprosate and Diazepam on the blood alcohol level (BAL) and on the cortical microvascular network. Acamprosate (50, 100, 200 and 400 mg/kg daily per os during the alcoholization period) did not significantly reduce either BAL or alcohol-induced cortical hypervascularization. Increasing dosages of Acamprosate (i.e. 50, 100, and 200 mg/kg/day), however, progressively reduced preference for alcohol as expressed in a free choice beverage procedure, whereas 400 mg/kg/day of Acamprosate immediately stopped this behaviour. Acamprosate (50 mg/kg/day) also reduced the spontaneous activity of rats during the withdrawal syndrome. By contrast, Diazepam (5 mg/kg) induced inversion in the animals' choice (i.e. increased water consumption versus decreased alcohol intake) during the same experimental procedure, and potentiated the alcohol-induced hypermotility of the animals during the withdrawal syndrome without altering cortical hypervascularization. Taken together, our data provide evidence that both substances exert dose-dependent effects on preference towards alcohol, but display opposite profiles on spontaneous motor activity during the withdrawal phase without any modification of brain microvascularization or blood alcohol levels.

Acamprosate↗
PubMed1992

[Effect of acute administration of acamprosate on the risk of encephalopathy and on arterial pressure in patients with alcoholic cirrhosis].

To evaluate the risk of hepatic encephalopathy and arterial hypotension in cirrhotic patients after acute administration of acamprosate, a GABA mimetic drug used in the weaned alcoholic, a randomized double-blind trial was conducted in 24 cirrhotic patients with low or moderate hepatic insufficiency (Pugh grade A or B). Twelve patients received 666 mg (2 tablets) of acamprosate and 12 received placebo. The 2 groups were similar before treatment, except for a male predominance in the acamprosate group. Tested parameters were the P100 latency of visual evoked potentials using a checkerboard pattern reversal as stimulus, the number connection test and the arterial blood pressure in upright and recumbent positions. The two first parameters were studied before and 2 hours after treatment. Blood pressure was recorded every half hour during 6 hours. No significant effect on the development of subclinical hepatic encephalopathy was noted. Nevertheless, even if some authors disagree with the GABA hypothesis of hepatic encephalopathy, it is possible that the dose was too low to induce subclinical hepatic encephalopathy. A study with more prolonged treatment could be necessary to be sure of the drug's safety in these patients. On the other hand, a transient decrease of diastolic arterial blood pressure was observed without significant systolic blood pressure modification. These results suggest that a moderate dose of acamprosate does not induce subclinical encephalopathy, but transient diastolic hypotension.

Acamprosate↗
PubMed1990

Acamprosate appears to decrease alcohol intake in weaned alcoholics.

Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomotaurinate (CA), 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT), as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment, the patients in the CA group had significantly lower GGT (1.4 +/- 1.56 versus 2.0 +/- 3.19 times normal, P = 0.016). All significant differences (P less than 0.05) or trends (0.10 greater than P greater than 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo, P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months, in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism, not involving an antabuse effect, an antidepressant action, or conditioning.

Acamprosate↗
PubMed1991

[Modern drug therapy in alcoholism].

The recent investigations on biochemical and biophysical mechanisms of ethanol in acute intoxication, tolerance and physical dependence suggest that the cell membrane, intracellular metabolism and central neurotransmitters are involved. In acute intoxication ethanol increases the "fluidity" of the cell membrane and stimulates the central gabergic system. In alcoholics, the body adapts, and in the presence of ethanol, the cell membrane becomes more "rigid" and the gabergic system hypoactive. When alcohol intake is discontinued the hypoactivity of the gabergic system is unmasked and it is manifested as withdrawal syndrome. The alcohol intake compensates for the clinical symptoms of decreased gabergic activity and thereby continuously prevent the onset of withdrawal symptoms. On the other hand, intact central noradrenergic and 5-hydroxytryptaminergic systems as well as the neuropeptide vasopressin maintain the tolerance. After withdrawal syndrome, membrane alterations and the state of diminished gabergic activity gradually return to normal. This period of slow recuperation corresponds to the subacute withdrawal syndrome. In this period, there is a continuous desire for alcohol intake. Further, alcoholics, in this situation, are very vulnerable with feelings of insecurity, fragility and isolation. All these factors additionally induce a latent desire for ethanol. It follows then that a stimulation of decreased gabergic activity is a new approach in drug therapy of alcoholism. One of these new stimulants is acamprosate. The new substance is a structural analogue of GABA and acts as an agonist on gabergic receptors. Therefore, acamprosate improves the central gabergic activity. Alcoholics treated with acamprosate stated that they no longer felt a desire for alcohol intake. In this way, acamprosate maintains the abstinence for several months during the post-withdrawal phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1989

Application of an analytical method to calcium acetylhomotaurinate determination in urine.

After urine purification, plasma and urine concentrations of calcium acetylhomotaurinate (Acamprosate, CaAOTA) were determined with a high-performance liquid chromatography method following i.v. administration of the drug in two dogs. Results obtained in serum were in good agreement with those found previously. The CaAOTA urine determination is a promising method to be used in healthy volunteers.

Acamprosate↗
PubMed1989

Reinforcing and discriminative stimulus effects of Ca-acetyl homotaurine in animals.

Ca-acetyl homotaurine (Ca-AOTA) has been proposed as an adjunct for ethanol detoxification. The purpose of the present experiment was to determine whether Ca-AOTA would be predicted to have abuse potential. Rhesus monkeys that were experienced in the intravenous self-administration of cocaine (n = 2) or pentobarbital (n = 2) were given the opportunity to self-administer various doses of Ca-AOTA or its vehicle (0.9% saline). Ca-AOTA (1.0-10.0 mg/kg/injection, intravenously) was not self-administered above saline levels. The discriminative stimulus effects of Ca-AOTA were evaluated in a drug discrimination procedure in which animals were trained to make one response after a training drug and a different response after saline. Rhesus monkeys trained to discriminate d-amphetamine (n = 3) or pentobarbital (n = 3) from saline were tested with doses of Ca-AOTA ranging from 10 to 100 mg/kg (PO by nasogastric tube) and at 3 different pretreatment times (1, 2, or 4 hr). Ca-AOTA failed to engender drug-appropriate responding at any dose or pretreatment condition in either group of monkeys. In addition, Ca-AOTA was tested in 4 pigeons trained to discriminate pentobarbital from saline. Ca-AOTA administration did not result in pentobarbital-appropriate responding in doses ranging from 30-300 mg/kg (IM) and pretreatment times ranging from 30 to 240 min. The lack of both reinforcing properties and discriminative stimulus properties similar to d-amphetamine or pentobarbital suggests that Ca-AOTA has little or no abuse potential.

Acamprosate↗
PubMedDate not supplied

Dose-dependent suppression of the high alcohol intake of chronically intoxicated rats by Ca-acetyl homotaurinate.

The effect of taurine derivative, Ca-acetyl homotaurinate, on voluntary alcohol intake was investigated in ethanol-dependent and naive rats. A high 24 hr oral intake of a 10% ethyl alcohol solution (9-10 g/kg) was exhibited by rats following 15 days of intragastric infusions of ethanol (7-8 g/kg/day). In four groups, rats were IG injected by short pulses of isotonic saline or a daily dose of 200, 300 and 450 mg/kg respectively, distributed over six daily infusions during alternating 8 hr presentations of ethanol solution and water. Compared to their respective basal intakes during the first two days of injection, the rats demonstrated a dose-dependent 50 to 70% reduction in alcohol consumption with drug treatment. This suppression effect was specific to the ethanol solution and persisted during 4 days of post-treatment observation. In ethanol-naive rats similarly tested and drinking half the amount of alcohol drunk by their ethanol-dependent counterparts, only the highest dose of drug (450 mg/kg) significantly suppressed their alcohol intake. It is suggested that Ca-acetyl homotaurinate interacts with CNS mechanisms involved in the ethanol tolerance-dependence state, underlying an enhanced reinforcing property of ethanol oral intake. Opioid receptors could be the targets in this action.

Acamprosate↗
PubMedDate not supplied

Lack of effects of Ca-acetyl homotaurinate on chronic and acute toxicities of ethanol in rats.

In a previous study, it was shown that in rats Ca-acetyl homotaurinate suppresses or eliminates the high oral intake of ethanol induced by earlier chronic ethanol administration, and to a lesser degree the spontaneous ethanol intake of ethanol-naive rats. The present study examines the effect of the drug on the chronic and acute toxicity of ethanol as a possible mechanism in its alteration of the reinforcing properties of ethanol intake. In the first experiment, it was demonstrated that chronic administration of the drug (45 mg/kg per day) for 15 days, alone or combined with chronic intragastric administration of high doses of ethanol, did not significantly alter subsequent ethanol intake. In two other experiments, it was shown that the drug did not interfere with acute ethanol toxicity as tested by ethanol-induced hypothermia, motor impairment and taste aversion in ethanol-naive rats. It is concluded that the acute activity of Ca-AOTA on CNS mechanisms presumably involved in the state of tolerance-dependence, other than those concerned in ethanol-induced hypothermia, motor impairment and taste aversion, may explain its action on the reinforcing property of ethanol intake.

Acamprosate↗
PubMedDate not supplied

Ethanol effect on the ionic transfer through isolated human amnion. I. Preventive and antagonistic actions of some nutrients and of their synthetic congeners.

The inhibition of the placental transfer of nutrients was studied in the pathogenesis of the fetal alcohol syndrome. Ethanol reduces the ionic transfer through the human amnion. In this study, the preventive and antagonistic actions of natural nutrients (Mg2+, Ca2+, taurine, homotaurine, gamma-aminobutyric acid) and of their synthetic congeners (Ca2+-taurinate, Ca2+-acetyltaurinate, Ca2+-acetylhomotaurinate) were observed on the amniotic conductance which was modified by ethanol. All the molecules, except Mg, demonstrated protective actions on the fetal side. The effect varied with the molecule and its concentration. An absolute protective effect was obtained on the maternal side with Ca2+-acetylhomotaurinate and Ca2+-taurinate. Some molecules, which have protective actions, had no opposing actions (homotaurine), or inversely (Mg2+), only Ca2+-acetylhomotaurinate exhibited both a preventive and an opposing action against ethanol. These results show the interest of studying synthetic molecules for prevention of fetal alcoholism.

Acamprosate↗
PubMed1985

Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics.

After they had been weaned off alcohol in hospital 85 severe alcoholics (above 200 g alcohol/day) were included in a double-blind study of calcium bis acetyl homotaurine (Ca AOTA, 25 mg/kg/day), a new gamma-aminobutyric acid agonist, versus placebo. Patients were treated as outpatients during the 3-month study. The only other treatment that patients received was meprobamate, 800 to 1200 mg/day, in the first month. The criterion for success was abstinence at 3 months (with normal gamma-glutamyl transpeptidase being one of the criteria). Of the 70 patients who completed the study, 33 received Ca AOTA and 37 placebo. 20 patients on Ca AOTA did not relapse, compared with 12 on placebo (p less than 0.02 by X2 test). Side-effects were noted by 7 patients on Ca AOTA and 2 on placebo. The results suggest that Ca AOTA may be useful in helping severe alcoholics who have been weaned off alcohol not to relapse.

Acamprosate↗
PubMed1990

Determination of calcium acetylhomotaurinate in human plasma and urine by combined gas chromatography-negative-ion chemical ionization mass spectrometry.

A highly sensitive and specific assay has been developed for the determination of calcium acetylhomotaurinate and the internal standard (LM 3041) at the picomole level in human plasma and urine by gas chromatography-mass spectrometry with methane as the reagent gas. After a multiple-step extraction process, the cleaned-up organic extract was derivatized with pentafluorobenzoyl chloride at ambient temperature. Subsequently, chlorination followed by amidation of the sulphonic acid group led to the N-pentafluorobenzoyl di-n-butylamide derivatives. The mass spectrometer was set to monitor the abundant [M - HF]- ions (m/z 424 and 438), which were generated in the ion source switched in the negative-ion chemical ionization mode. This assay required 1 ml of plasma or 50 microliters of urine, and the detection limit was 1 ng/ml. The accuracy of the assay was tested day by day with quality control specimens spiked blind to the analyst. The mean difference between the theoretical and actual values was less than 8%.

Acamprosate↗