Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures. OBJECTIVES: 1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years). SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement. MAIN RESULTS: There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). AUTHORS' CONCLUSIONS: Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.

The D2/D3-receptor antagonist tiapride impairs concurrent but not sequential taste aversion learning.

Taste aversion learning (TAL) is a learning modality in which the animals reject a gustatory stimulus associated with the administration of noxious visceral substances. This learning can be established by concurrent or sequential procedures that involve different anatomical and functional mechanisms and may constitute distinct learning modalities. The dopaminergic system has been related to various learning processes and goal-directed behaviours. The present study examined the effect of the administration of tiapride, a D(2)/D(3) dopaminergic antagonist, on concurrent and sequential TAL. Results obtained showed that pre-treatment with tiapride blocks the acquisition of concurrent TAL but does not affect sequential TAL, including reversal learning tasks. These results demonstrate the involvement of the D(2)/D(3) dopaminergic receptors in the former but not the latter learning process. The dopaminergic system appears to participate in concurrent TAL, an "implicit" learning modality, but not in sequential TAL, which is considered a relational/explicit acquisition process.

High-performance liquid chromatographic determination of tiapride and its phase I metabolite in blood plasma using tandem UV photodiode-array and fluorescence detection.

New bioanalytical SPE-HPLC-PDA-FL method for the determination of the neuroleptic drug tiapride and its N-desethyl metabolite was developed, validated and applied to xenobiochemical and pharmacokinetic studies in humans and animals. The sample preparation process involved solid-phase extraction of diluted plasma spiked with sulpiride (an internal standard) using SPE cartridges DSC-PH Supelco, USA. Chromatographic separation of the extracts was performed on a Discovery HS F5 250 mm × 4 mm (Supelco) column containing pentafluorophenylpropylsilyl silica gel. Mobile phase (acetonitrile-0.01 M phosphate buffer pH=3, flow rate 1 ml min(-1)) in the gradient mode was employed in the HPLC analysis. Tandem UV photodiode-array→fluorescence detection was used for the determination of the analytes. Low concentrations of tiapride and N-desethyl tiapride were determined using a more selective fluorescence detector (λ(exc.)/λ(emiss.)=232 nm/334 nm), high concentrations (500-6000 pmol ml(-1)) using a UV PDA detector at 212 nm with a linear response. Each HPLC run lasted 15 min. Lower limits of quantification (LLOQ) for tiapride (N-desethyl tiapride) were found to be 8.24 pmol ml(-1) (10.11 pmol ml(-1)). The recoveries of tiapride ranged from 89.3 to 94.3%, 81.7 to 86.8% for internal standard sulpiride and 90.9 to 91.8% for N-desethyl tiapride.

[A multicenter controlled study on aripiprazole treatment for children with Tourette syndrome in China].

OBJECTIVE: To evaluate the efficacy and safety of aripiprazole in the treatment of children with Tourette syndrome. METHOD: A prospective, multi-center, controlled clinical trial was conducted in 195 children aged 5-17 years with Tourette syndrome. The patients were assigned to two groups: aripiprazole group (n=98) and tiapride group (n=97), with the treatment dosage of 5-25 mg/d and 100-500 mg/d, respectively. After 12 weeks treatment, the clinical efficacy was assessed by the Yale Global Tic Severity Scale (YGTSS) score, and adverse reactions were observed by side effects symptoms scale, blood biochemical indexes, and electrocardiography. RESULT: Significant pre- and post-treatment differences were ascertained for motor tic, phonic tic, function damage and total scores of YGTSS in the both groups from the second week of treatment (P<0.0001). Compared with the tiapride group, the aripiprazole group showed a more significantly decreased function damage score of YGTSS by the second week of treatment (P<0.05). After 12 weeks treatment, total scores of YGTSS in the aripiprazole group decreased from 53.74±15.71 at baseline to 24.36±16.38, while in the tiapride group from 51.66±13.63 to 23.26±15.31. The mean reduction scores of YGTSS were 29.38 in the aripiprazole group and 28.40 in the tiapride group at the end of treatment, and the clinical response rates were 60.21% and 63.92%, respectively. There were no significant differences between the 2 groups (P>0.05). The incidence of adverse reactions was similar in the aripiprazole and tiapride groups, with 29.6% and 27.8% respectively. There were no significant differences in the incidence of adverse reactions between aripiprazole and tiapride groups and no severe adverse events were found in either group. CONCLUSION: The results showed that aripiprazole showed similar therapeutic effect to tiapride in treatment of children with Tourette syndrome. Aripiprazole was safe and well tolerated in Chinese population, and can be considered as a new valid option for the treatment of tic disorders.

A combination of levetiracetam and tiapride for outpatient alcohol detoxification: a case series.

OBJECTIVES: Optimal pharmacotherapy of the alcohol withdrawal syndrome (AWS) in outpatient settings is still a matter of discussion. The aim of this evaluation was to examine the efficacy and tolerability of a combination of levetiracetam and tiapride for outpatient alcohol detoxification. METHODS: This was an open-label evaluation. After screening eligibility for outpatient detoxification, 9 alcohol-dependent patients received levetiracetam and tiapride in a flexible dosage regimen up to 2500 and 300 mg/d, respectively, for a maximum of 7 days. Severity of alcohol withdrawal was assessed daily using the Alcohol Withdrawal Syndrome Scale (AWSS). RESULTS: All patients completed the treatment successfully. The mean initial doses of levetiracetam and tiapride were 2166.7 and 300 mg/d, respectively. AWS as indicated by the AWSS score decreased clearly over 5 days. The combination of levetiracetam and tiapride was well tolerated. Neither treatment discontinuations because of side effects of the medication nor serious medical complications were observed during the detoxification. CONCLUSIONS: The results of this evaluation provide first evidence that the combination of levetiracetam and tiapride might be an effective and safe treatment option for mild to moderate AWS in outpatient settings. Further randomized controlled trials are warranted to confirm these preliminary results.

Differential pulse anodic voltammetric determination of tiapride hydrochloride in pharmaceutical preparation and human urine using carbon paste electrodes.

The anodic voltammetric behavior of tiapride hydrochloride (TiapCl) was studied at carbon paste electrodes in 0.04 M Britton-Robinson buffer pH 7.0 using cyclic and differential pulse voltammetric techniques. The oxidation of TiapCl is an irreversible diffusion-controlled process. A differential pulse anodic voltammetric procedure has been developed for determination of the drug over the concentration range 0.36 - 19.35 µg/ml with detection and quantification limits of 0.12 and 0.40 µg/ml, respectively. The proposed method was successfully applied for the determination of the drug in commercial tablets and in spiked human urine samples.

Liquid chromatography-tandem mass spectrometry quantification of levosulpiride in human plasma and its application to bioequivalence study.

An improved method for determining levels of levosulpiride in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated. The protein precipitation method was used for plasma sample preparation. Levosulpiride and an internal standard (IS) were isocratically separated on a UPLC BEH C(18) column with a mobile phase of ammonium formate buffer (1mM, adjusted to pH 3 with formic acid) and acetonitrile (60:40, v/v). MS/MS detection was performed by monitoring the parent-->daughter pair of levosulpiride and the IS at m/z 342-->112 and 329-->256, respectively. The method was linear from 2.5 to 200ng/mL and exhibited acceptable precision and percent recovery. The method was successfully demonstrated in pharmacokinetic and bioequivalence studies of two levosulpiride oral formulations administered to healthy volunteers. When compared to the previous LC-MS methods, the proposed method is faster, well-validated, and uses lesser plasma volume and a similar sensitivity. The use of UPLC allowed rapid and sensitive quantification of levosulpiride, making this method suitable for high-throughput clinical applications.

[A control study of aripiprazole and tiapride treatment for tic disorders in children].

OBJECTIVE: To evaluate the efficacy and safety of aripiprazole in the treatment of tic disorder when tiapride is used as a control. METHODS: Sixty-five children aged 6-14 years old with tic disorders were randomly assigned to two groups: aripiprazole (2.5-10 mg/d) and tiapride treatment (25- 400 mg/d). After 12 weeks treatment, the clinical efficacy was assessed by the Yale Global Tie Severity Scale (YGTSS) score and the adverse reactions were observed. RESULTS: The YGTSS score in both groups decreased from the second week of treatment. Compared with the tiapride treatment group, the aripirazole treatment group showed a more decreased YGTSS score (29+/-13)% vs (16+/-14)%; P<0.01 by the second week of treatment. The overall effective rate in the aripiprazole and tiapride treatment groups was 91% and 84%, respectively (P>0.05) 12 weeks after treatment. There were no significant differences in the incidence of adverse reactions between the aripiprazole and tiapride treatment groups and no severe adverse events were found in either group. CONCLUSIONS: Low dose aripiprazole is safe and effective for treatment of tic disorders in children, suggesting that it represents a new valid option for the treatment of tic disorder.

Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi-centre, randomized, single-blind comparison trial.

INTRODUCTION: The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of psychiatric symptoms were the secondary end-points. METHODS: One hundred and ninety subjects affected by current alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin 450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised (SCL-90-R)] and quality of life (QL-index) rating scales were applied. RESULTS: On the CIWA-Ar score, all the groups showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01) on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the SCL-90-R and QL-index (P < 0.001). DISCUSSION: All the medications in the trial showed evidence of safety and efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin was superior to that of tiapride, used largely in research trials and, for some measures, to that of the 'gold standard', lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation.

Oxcarbazepine in combination with Tiaprid in inpatient alcohol-withdrawal--a RCT.

INTRODUCTION: Oxcarbazepine (OXC), a derivative of Carbamazepine (CBZ), may represent a solution to metabolic and side effects of CBZ treatment due to the fact that renal excretion is its major route of elimination. The goal of the study is to compare the efficacy and tolerability of OXC/Tiaprid (TIA) combination therapy to the well established Clomethiazole (CLO) therapy in an inpatient setting. METHODS: To investigate the efficacy of OXC/TIA in terms of lower alcohol withdrawal symptoms and better tolerability, 56 alcohol-dependent patients participated in a randomized open-label trial, where OXC/TIA and CLO treatments were compared. RESULTS: Following admission, we observed that severity of alcohol withdrawal syndrome was comparable between OXC/TIA and CLO-patients. Overall tolerability was good. However, significantly more patients in the OXC/TIA-group (48.1%) displayed no AE compared to the CLO-group (24.1%). We found no significant differences between groups regarding total number of recorded adverse events (AEs). DISCUSSION: OXC/TIA inpatient therapy proved to be as effective and participants demonstrated the same tolerance as with CLO. In medication-based alcohol withdrawal, OXC/TIA could have the potential to become a promising alternative for alcohol dependent patients unable to undergo inpatient withdrawal therapy with CLO. Our findings further indicate that it could be worthwhile testing OXC/TIA in alcohol withdrawal in daily care units and outpatient settings. This is an important question for national health care services, since outpatient therapy is more and more asked for as alternative to inpatient settings.

[Tiapride with the horn of saiga tatarica in the treatment of hemifacial spasm].

OBJECTIVE: Tiapride has been used effectively in the clinic for the treatment of dyskinesias and tic disorders including Tourette syndrome. The purpose of the retrospective study is to evaluate the effectiveness of tiapride with the horn of saiga tatarica in treatment of hemifacial spasm. METHOD: Twenty-eight patients with idiopathic hemifacial spasm, who were previously treated with carbamazepine, or acupuncture, or botulinum toxin injection, but refused to continue the previous therapies, were treated with tiapride, at a dosage of 50 mg/time once to thrice per day, combined with the horn of saiga tatarica at a dosage of 0.15 g to 0.30 g/time once per day. The dosage of tiapride can been up to 100 mg/time once to thrice per day in some cases if necessary. The effectiveness of the therapy was evaluated from the time of three months after the beginning of the treatment. The main efficacy parameter was the degree of spasm reduction, that is, the classification of spasm before versus after the treatment. RESULT: The duration of following up is between 3 months and 12 months. Twenty-five cases out of 28 patients have demonstrated a significant reduction of spasm. Of which, eight cases were completely relieved, 12 cases marked relieved and 5 cases partially relieved. The effective rate is 89.29%. CONCLUSION: Tiapride combined with the horn of saiga tatarica was effective and safe in reducing hemifacial spasm. However, further data from blinded trials and long-term following up are required before this treatment can be considered to be one of the main medical treatment options for hemifacial spasm.

[Case of enzyme-linked immunoglobulin with persistent elevation of lactate dehydrogenase activity in serum by administration of an anti-psychotic drug].

We presented a case, who showed extremely high activity of lactate dehydogenase (LD) and confirmed the presence of the LD linked immunoglobulin in her serum. The maximum activity of LD was 6830 IU/L, and the electrophoretic pattern of LD isozymes showed the broad spectrum from isozyme LD2 to LD5. Analysis by counter immuno electrophoresis revealed that immunogloblin was attached to the M subunit of LD and its subtype was an IgG, lambda-chain. The cause, which produced the complex, might be thought to be the side effects by tiapride administrated for her mild dementia. After discontinuance of this drug, the LD activity in serum had gradually reduced. The serum creatinine also increased gradually after administration of tiapride, and did not reverse to normal level by discontinuance of it. The patient died from acute renal failure, which aggravated from sporadic urinary tract infection. It was suggested that her basal renal dysfunction might be due to the LD IgG complexes. We propose a rapid disruption of suspicious drug for the course of the production of LD linked immunoglobulin, because very high titer of these complexes might suffer irreversible damage to the kidney, which chance to become acute renal failure.

Membrane sensors for the selective determination of tiapride in presence of its degradation products.

The construction and electrochemical response characteristics of polyvinyl chloride (PVC) membrane sensors for determination of tiapride in presence of its degradation products are described. The sensors are based on the ion association complexes of tiapride cation with sodium tetraphenyl borate (Tia-TPB) [sensor 1]) or ammonium reineckate (Tia-R) [sensor 2] counter anions as ion exchange sites in PVC matrix. The performance characteristics, sensitivity and selectivity of these electrodes in presence of tiapride degradation products were evaluated according to IUPAC recommendations. It reveals a fast, stable and linear response for tiapride over the concentration range 10(-5)-10(-2) M with cationic slopes of 28.997 and 30.580 mV per concentration decade with sensors 1 and 2, respectively. These sensors exhibit fast response time (20-30 s), low quantitation limit (4.5x10(-6) and 3.6x10(-6), respectively), and good stability (6-8 weeks). The direct potentiometric determination of tiapride hydrochloride using the proposed sensors gave average recoveries of 99.95+/-0.678 and 99.92+/-1.157 for sensors 1 and 2, respectively. The sensors are used for determination of tiapride hydrochloride, in pure form, in presence of its degradation products in tablets, and in plasma. Validation of the method shows suitability of the proposed sensors for use in the quality control assessment of tiapride hydrochloride and for routine analysis as stability indicating method. The developed method was found to be simple, accurate and precise when compared with a reference company spectrophotometric method.

[The analysis of tiapride in cadaveric material].

To optimize conditions of tiapride isolation from cadaveric organs, we compared the results of conventional methods by Stas-Otto, A.A. Vasilyeva and V.F. Kramarenko which provide tiapride isolation up to 50% and a new precise and reproducible method providing 60 +/- 2% tiapride isolation. Identification of tiapride isolated from cadaveric material was made with thin-layer chromatography and high performance liquid chromatography. The latter assay employed the method of external standard. The original techniques proposed identify and measure tiapride in hepatic samples in the presence of unidentified endogenic compounds. The techniques are rapid, selective, sensitive and reproducible.

Stability-indicating methods for determination of tiapride in pure form, pharmaceutical preparation, and human plasma.

Four different stability-indicating procedures are described for determination of tiapride in pure form, dosage form, and human plasma. Second derivative (D2), first derivative of ratio spectra (1DD), spectrofluorimetric, and high-performance column liquid chromatographic (LC) methods are proposed for determination of tiapride in presence of its acid-induced degradation products, namely 2-methoxy-5-(methylsulfonyl) benzoic acid and 2-diethylaminoethylamine. These approaches were successfully applied to quantify tiapride using the information included in the absorption, excitation, and emission spectra of the appropriate solutions. In the D2 method, Beer's law was obeyed in the concentration range of 1.5-9 microg/mL with a mean recovery of 99.94 +/- 1.38% at 253.4 nm using absolute ethanol as a solvent. In 1DD, which is based on the simultaneous use of the first derivative of ratio spectra and measurement at 245 nm in absolute ethanolic solution, Beer's law was obeyed over a concentration range of 1.5-9 microg/mL with mean recovery 99.64 +/- 1.08%. The spectrofluorimetric method is based on the determination of tiapride native fluorescence at 339 nm emission wavelength and 230 nm excitation wavelength using water-methanol (8 + 2, v/v). The calibration curve was linear over the range of 0.2-3 microg/mL with mean recovery of 99.66 +/- 1.46%. This method was also applied for determination of tiapride in human plasma. A reversed-phase LC method performed at ambient temperature was validated for determination of tiapride using methanol-deionized water-triethylamine (107 + 93 + 0.16, v/v/v) as the mobile phase. Sulpiride was used as an internal standard at a flow rate of 1 mL/min with ultraviolet detection at 214 nm. A linear relation was obtained over a concentration range of 2-30 microg/mL with mean recovery of 99.66 +/- 0.9%. Results were statistically analyzed and compared with those obtained by applying the reference method. They proved both accuracy and precision.

The efficacy of the dopamine D2/D3 antagonist tiapride in maintaining abstinence: a randomized, double-blind, placebo-controlled trial in 299 alcohol-dependent patients.

In this investigation, the hypothesis was tested whether the selective dopamine D2/D3 receptor antagonist tiapride is effective in maintaining abstinence after detoxification in alcohol-dependent patients. The rationale of the study was based on the relevance of the dopaminergic system for addictive behaviour as well as some preliminary studies. A multi-centre, randomized, double-blind, placebo-controlled, parallel-group study was conducted. A total of 299 detoxified alcohol-dependent patients (ICD-10: F10.2) received either tiapride (300 mg/d) or placebo over a 24-wk study period. Subjects with severe comorbid psychiatric disorder such as schizophrenia or Wernicke-Korsakoff syndrome were excluded. Primary outcome variable was the time to first relapse with relapse defined as any alcohol consumption after detoxification. Data analysis was done with Kaplan-Meier estimates with log-rank test (one-sided, p<0.05). Tiapride was not superior to placebo in maintaining abstinence. The time to first relapse was 71 d in the tiapride group and 92 d in the placebo group (log-rank test, p=0.9895). Relapse rate was higher in the intervention group (54.4%) than in the control group (40.7%). Like the dopamine antagonist flupenthixol, tiapride was not effective in maintaining alcohol abstinence. Regarding the high success rate in the placebo group the influence of psychosocial treatment in studies investigating drug effects on the course of alcohol dependence has to be considered.

Comparison of two pre-exposure treatment regimens in acute organophosphate (paraoxon) poisoning in rats: tiapride vs. pyridostigmine.

Recently, the FDA approved the medical use of oral pyridostigmine as prophylactic treatment of possible nerve agent exposure: the concept is to block the cholinesterase transitorily using the carbamate (pyridostigmine) in order to deny access to the active site of the enzyme to the irreversible inhibitor (nerve agent) on subsequent exposure. We have shown previously that tiapride is in vitro a weak inhibitor of acetylcholinesterase and that in rats administration of tiapride before the organophosphate paraoxon significantly decreases mortality. The purpose of the present study was to compare tiapride- and pyridostigmine-based pretreatment strategies, either alone or in combination with pralidoxime reactivation, by using a prospective, non-blinded study in a rat model of acute high-dose paraoxon exposure. Groups 1-6 received 1 microMol paraoxon (approximately LD75) groups 2-6 received in addition: G(2)50 microMol tiapride 30 min before paraoxonG(3)50 microMol tiapride 30 min before paraoxon and 50 microMol pralidoxime 1 min after paraoxon G41 microMol pyridostigmine 30 min before paraoxon G(5)1 microMol pyridostigmine 30 min before paraoxon and 50 microMol pralidoxime 1 min after paraoxon G(6)50 microMol pralidoxime 1 min after paraoxon. Mortality data were compared using Kaplan-Meier plots and logrank tests. Mortality is statistically significantly influenced by all treatment strategies. Tiapride pretreatment followed by pralidoxime treatment (G3) is aux par with pyridostigmine pretreatment followed by pralidoxime treatment (G5). Tiapride pretreatment only (G2) is inferior to pyridostigmine pretreatment only (G4). The best results are achieved with pyridostigmine pretreatment only or pralidoxime treatment only (G4 and G6).

Anti-aggressive effects of GHB in OF.1 strain mice: involvement of dopamine D2 receptors.

Numerous studies indicate that gamma-hydroxybutyric acid (GHB) influences the endogenous dopamine system. Both GHB and most dopaminergic D(2) receptor antagonists are effective anti-aggressive agents in animal models. The present study aimed to investigate the effects of GHB on agonistic behaviour and to implicate D(2) dopamine receptor on these behaviours. For this purpose, the effects of GHB (80, 120 and 160 mg/kg, IP) and tiapride (60 mg/kg) administered alone or in combination were examined on agonistic behaviour elicited by 'isolation' in male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. The administration of 80 and 120 mg/kg of GHB reduced threat without impairing motor activity, but the administration of 160 mg/kg of GHB or the co-administration of GHB+tiapride (a selective D(2) receptor antagonist) significantly reduced threat and attack but concomitantly increased immobility. The co-administration of GHB+tiapride had different effects to those observed by the administration of these drugs separately. It is concluded that the anti-aggressive effect of GHB appears to be mediated, at least in part, by D(2) dopamine receptors. This anti-dopaminergic activity is an indirect effect, probably induced by the activation of GHB receptors of low affinity, and in this way, this compound would reduce levels of dopamine without blockading of D(2) postsynaptic dopamine receptors.