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.

[The benzamides tiapride, sulpiride, and amisulpride in treatment for Tourette's syndrome]. / Die Benzamide Tiaprid, Sulpirid und Amisulprid in der Therapie des Tourette-Syndroms. Eine Standortbestimmung.

The treatment of Tourette's syndrome is a challenge. Dopamine receptor antagonists are the drugs of first choice for the treatment of tics. Because large controlled trials are lacking, there is no consensus about which of the different neuroleptic drugs should be preferred. In Germany, tiapride seems to be used most often for the treatment of tics in children - although only one small controlled trial has been performed on it till now. In adults, other dopamine receptor antagonists such as risperidone, pimozide, and sulpiride seem to be more effective than tiapride. Today it is unknown whether new atypical neuroleptic drugs including the benzamide amisulpride are more effective than the older benzamides tiapride and sulpiride.

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).

[Carbamazepine intoxication. Complication of alcohol detoxification with combined carbamazepine and tiapride]. / Carbamazepin-Intoxikation. Komplikation der Kombinationsbehandlung aus Carbamazepin und Tiaprid zur Alkoholentgiftung.

The advantages of alcohol detoxification treatment with combined carbamazepine and tiapride compared to benzodiazepines or clomethiazole is a lower level of sedation and lack of addictive potential. We report a case of carbamazepine intoxication with serum levels up to 19 mg/l in an otherwise healthy 45-year-old alcohol-dependent male after treatment with 600 mg carbamazepine and 600 mg tiapride per day. Medication was discontinued immediately and a purgative was administered. We were able to combat the intoxication but the assumed good tolerance of the combined treatment with carbamazepine and tiapride for alcohol detoxification still has to be proven.

Tiapride pre-treatment in acute exposure to paraoxon: comparison of effects of administration at different points-in-time in rats.

INTRODUCTION: Accidental and suicidal exposures to organophosphorus compounds (OPC) are frequent. The inhibition of esterases by OPC leads to an endogenous ACh poisoning. Recently, the FDA approved, based on animal experiments, for military combat medical use oral pyridostigmine (PSTG) for pre-exposure treatment of soman; the concept is to block the cholinesterase reversibly using the carbamate pyridostigmine in order to deny access to the active site of the enzyme to the irreversible inhibitor (OPC) on subsequent exposure. We have shown previously that tiapride (TIA) is in vitro a weak inhibitor of AChE. We also have shown recently that in rats coadministration of TIA with the organophosphate paraoxon significantly decreases mortality without having an impact on red blood cell cholinesterase (RBC-AChE) activity. PURPOSE OF THE STUDY: To establish in a prospective, non-blinded study in a rat model of acute high dose OPC (paraoxon; POX) exposure the ideal point in time for TIA pre-treatment administration and to correlate it with measured TIA plasma levels. MATERIAL AND METHODS: There were six groups of rats in each cycle of the experiment and each group contained six rats. The procedure was repeated twelve times (cycles) (n = 72 for each arm; half male and half female). All substances were applied ip. All groups (1-6) received 1 microMol POX ( approximately LD(75)); groups 1-5 also received 50 microMol TIA at different points in time. Group 1 (G(1)): TIA 120 min before POX Group 2 (G(2)): TIA 90 min before POX, Group 3 (G(3)): TIA 60 min before POX, Group 4 (G(4)): TIA 30 min before POX, Group 5 (G(5)): TIA & POX simultaneously, Group 6 (G(6)): POX only. The animals were monitored for 48 hours and mortality/survival times were recorded at 30 min, 1, 2, 3, 4, 24 and 48 h. AChE activities were determined at 30 min, 24 and 48 h in surviving animals. Statistical analysis was performed on the mortality data, cumulative survival times and enzyme activity data. Mortality data was compared using Kaplan-Meier plots. Cumulative survival times and enzyme activites were compared using the Mann-Whitney rank order test. No Bonferroni correction for multiple comparisons was applied and an alpha < or= 0.05 was considered significant. RESULTS: Mortality is statistically significantly reduced by TIA pre-treatment at all points-in-time. Highest protection is achieved if TIA is given 90 to 0 min before OPC exposure. The reduction in mortality is not correlated to TIA plasma levels (C (max) approximately 120 min post ip-administration). TIA pre-treatment is not affecting AChE activity regardless of the timing of administration. CONCLUSION: The lack of correlation between TIA plasma levels and degree of mortality reduction as well as the lack of protective effect on enzyme activity seem to indicate that the site of action of TIA is not the blood. While our hypothesis that TIA would protect AChE in a pyridostigmine-like manner (via protection of the enzyme) could not be confirmed, the reduction in mortality with TIA pre-treatment is nevertheless of potential interest.

Weak inhibitors protect cholinesterases from strong inhibitors (paraoxon): in vitro effect of tiapride.

Weak and reversible inhibitors of cholinesterases, when administered before potent organophosphorus inhibitors (pretreatment), have the ability, to a certain extent, to protect enzymes from inhibition. Such a protective effect was demonstrated in vitro for metoclopramide and ranitidine. The putative mode of protective action of these substances is, when administered in excess, competition for the active site of the enzyme with the more potent organophosphate. The present paper presents results using another benzamide with weak cholinesterase inhibitory properties: tiapride (TIA). The purpose of the study was to quantify in vitro the extent that TIA conferred protection, using paraoxon (POX) as an inhibitor, and to compare the results with existing data obtained using TIA as a protective agent against dichlorvos (DDVP). POX is a highly toxic non-neuropathic organophosphate. While the use of parathion (the inactive prodrug which is metabolically converted to POX) has been restricted in most countries, the organophosphate is still responsible for a large number of accidental or suicidal exposures. DDVP is a moderately toxic, non-neuropathic organophosphate. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different POX and TIA concentrations and the IC(50) was calculated. Determinations were repeated in the presence of increasing TIA concentrations. The IC(50) of POX increases with the TIA concentration in a linear manner. The protective effect of tiapride on cholinesterase could be of practical relevance in the pretreatment of organophosphate poisoning. It is concluded that in vivo testing of TIA as an organophosphate protective agent is warranted.

Early administration of tiapride to young rats without long-lasting changes in the development of the dopaminergic system.

BACKGROUND: The benzamide tiapride, a selective dopamine D2/D3-receptor antagonist, can be used effectively in children to treat tic disorders and stuttering. Tiapride is a clinically safe substance (even during long-term treatment and when given to young children). Unfortunately, its probable effects on general brain development and the maturation of the dopaminergic system have not been investigated. Thus, important information for drug treatment in children is missing. Therefore, this study in rats describes tiapride's effects on several parameters of dopaminergic activity (dopamine transporter, D2 receptor, dopamine, DOPAC, and homovanillic acid in the striatum) seen after tiapride administration (30 mg/kg/day) to prepubertal (from day 25-39) and postpubertal (from day 50-64) rats. METHODS: Three groups of rats (n = 6) received tiapride within their drinking water for 14 days. Two groups were treated before puberty; one of those was killed at day 50, the other at day 90. The group treated after puberty was measured at day 90. A fourth group (n = 6) was treated from day 50 to day 53 and measured under tiapride at day 53. Changes were measured by ligand-binding assays (KD and Bmax values of dopamine transporter by [3H]-GBR binding and D2 receptor by [3H]- spiperone binding) and by HPLC (concentrations of dopamine, DOPAC, and homovanillic acid). RESULTS: The density of dopamine transporters and D2 receptors remained unaffected after early (day 25) and late (day 50) tiapride administration. Only during the treatment period could a significant reduction of D2-receptor binding (displacement of spiperone) and of dopamine and DOPAC levels be stated. CONCLUSIONS: These data suggest that tiapride treatment during postnatal brain development causes no long-lasting changes in the development of the central dopaminergic system and is in line with clinical experience in children.

A combination of carbamazepine/tiapride in outpatient alcohol detoxification. Results from an open clinical study.

This was an open, prospective study to examine the efficacy, practicability and medical safety of a combination of carbamazepine and tiapride in outpatient detoxification of alcohol-dependent patients. Patients were carefully screened for relevant neuropsychiatric disorders and then seen on a daily outpatient basis. Patients received medication if the initial CIWA-A score exceeded 16 points. Fifty consecutively admitted patients entered the program; 49 (98 %) successfully ended treatment. The mean initial dose for carbamazepine was 628 mg or 332 mg for tiapride. No serious medical complications or adverse events were observed. In general, medication was well tolerated. Withdrawal symptomatology as indicated by CIWA-A scores clearly decreased over time. Most frequently named side effects were sedation (63 %), hyperhidrosis (49 %), lack of drive (38 %), dry mouth (31 %) and orthostatic dysregulation or vertigo (22 %). Results from this study suggest that a combination of the anticonvulsant carbamazepine and tiapride is an effective and safe treatment for outpatient alcohol detoxification in patients with moderate severity of withdrawal syndrome.

The preclinical pharmacologic profile of tiapride.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D(2) (IC(50) = 110-320 nM) and D(3) (IC(50) = 180 nM) receptors in vitro but lacks affinity for dopamine D(1) and D(4) receptors and for non-dopaminergic receptors including H(1), alpha(1), alpha(2)-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED(50) approximately 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10-30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas. In behavioral experiments in rats, lower doses of tiapride (ED(50) = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED(50) = 60 mg/kg, ip) were required to block stereotyped movements. In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED(50) = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED(50) = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3-30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance. The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D(2) and D(3) receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

Clinical management of agitation in the elderly with tiapride.

Agitated behaviors such as uncooperativeness with necessary care, motor hyperactivity, and verbal or physical aggression are some of the most commonly reported complications in dementia and organic disorders in elderly subjects. These symptoms present greater clinical challenges and management issues than the cognitive deficits. Antipsychotics are the most commonly used psychotropic agents for treating these types of symptoms. The aims of this article are to review clinical studies with tiapride, a substituted benzamide, and more specifically to present recent data coming from two double-blind, randomized studies in elderly subjects. The first study versus melperone was conducted in Germany, with over 176 hospitalized demented patients, and indicated that tiapride was as effective and safe as melperone. More recently, a multicentre, international, double-blind, three-parallel group study compared a 21-day treatment of tiapride to haloperidol and placebo and included 306 demented elderly patients with agitation and aggressiveness. The results showed that tiapride and haloperidol were significantly effective in the treatment of agitation and aggressiveness compared to placebo. The tiapride safety profile was found to be better than haloperidol for clinical acceptability, particularly for significantly fewer extrapyramidal symptoms in the tiapride group.

Use of tiapride on stuttering in children and adolescents.

Reported here is the therapeutic efficacy of Tiapride with 10 10- to 17-yr.-old patients afflicted with severe stuttering problems. During the 20-wk. open, controlled study (baseline, low dose of Tiapride, high dose of Tiapride, follow-up observation without medication) the stuttering in various speech situations decreased markedly. No substantial change in different parameters of acoustic analysis and psychopathological characteristics accompanied the reduction in stuttering when group data were compared although positive effects concerning these variables could be seen in some cases. Several conclusions based on these results are presented. One assumed effect of the medication is improvement of central nervous regulatory mechanisms of speech motor coordination. Further, the value of the medication Tiapride in comprehensive stuttering therapy is discussed.

Tiapride in the prevention of relapse in recently detoxified alcoholics.

BACKGROUND: The aim was to investigate the effect of tiapride (100 mg three times a day for at least one month) on outcome following detoxification. METHOD: The setting was a tertiary referral centre. The study design was randomised, double-blind, and placebo-controlled. One hundred routinely admitted alcohol-dependent patients were entered, and 54 completed the trial. Outcome was assessed by considering drinking status at three months and six months follow-up, and by comparing psychological status at intake and follow-up using the Crown-Crisp Experiential index, the Litman Self-esteem scale and a Satisfaction with Life Situations scale. We also compared performance over the six months before admission with the three and six months of follow-up on measures of health, social and drinking variables. RESULTS: Tiapride proved better (usually at statistically highly significant levels) than placebo at promoting: abstinence, self-esteem, and satisfaction with life situations; and at reducing: alcohol consumption, use of health service resources, and levels of neuroticism. CONCLUSIONS: Tiapride merits serious consideration in the longer-term treatment of alcoholic patients.

[Oral dyskinesis, facial dystonia].

Oral dyskinesia or orofacial dyskinesia is considered to be one of the most severe side-effects of a chronic treatment with neuroleptics or 1-dopa, although it has also been described in nontreated people. In oral or orofacial dyskinesia, involuntary spasms cause arrhythmic movements of the tongue, sometimes with protrusion and drooling, opening of the mouth, clenching of the teeth, or pursuing and retraction of the lips. Each spasm lasts seconds to a minute or two. In orofacial dyskinesia, lip smacking, chewing and tongue movements occur in a repetitive pattern interrupting speech. The pathophysiology of the orofacial dyskinesia has been still unknown. However, previous clinical observations and basic pharmacological studies have suggested that the dopaminergic receptors, especially of D1 type, play a crucial role in causing this condition. Based on this assumption, dopaminergic receptor antagonists have been introduced as medical treatments.

["Induced detoxification treatment" of opiate dependent patients--a new therapy concept]. / Die "induzierte Entzugsbehandlung" bei Opiatabhängigen--ein neues Therapiekonzept.

Induced detoxification treatment of opiate addicts by means of naloxone was developed at the intensive care unit of the Department of Psychiatry at the University of Vienna. Two methods were tested 1. Rapid opiate withdrawal by means of a staggered naloxone regimen. 2. Ultrashort opiate detoxification during general anaesthesia using high doses of naloxone. In an open trial 15 patients were treated with staggered doses of naloxone while under tiapride. The various discomforts were satisfactorily reduced, and the detoxification syndrome was limited to 50 hours. In a second open trial 6 patients were administered 10 mg naloxone under general anaesthesia. All naloxone induced withdrawal syndromes can be suppressed by barbiturate anaesthesia. They do not appear even after the effect of the anaesthesia wears off if the patient is kept on a naloxone regimen as long as opiates remain present in the circulatory system. Both methods shorten detoxification treatment and provide smooth transition to a naltrexone maintenance programme.

Effects of repeated tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat.

The substituted benzamides tiapride and sulpiride, and the classic neuroleptic haloperidol, were studied in the rat to assess their interaction with the anterior pituitary (AP) dopamine (DA) receptors both in vitro ([3H]spiperone binding) and in vivo prolactin-PRL-release). Tiapride weakly inhibited [3H]spiperone binding in both pituitary and striatal membranes with affinity 5-7 times lower than sulpiride and 400-300 times lower than haloperidol. All three drugs were more potent in displacing [3H]spiperone from striatum than from AP. In vivo, tiapride produced weak and transient stimulation of PRL release reaching a full effect at 2 mg/kg i.p. Similar doses of sulpiride produced longer-lasting effects. Haloperidol was more potent than both benzamides. In prolonged treatments (15 or 60 days), tiapride, given twice daily at 0.5 mg/kg i.p., did not modify [3H]spiperone binding in either AP or striatum, nor did it induce significant changes of basal PRL levels. The challenge with a low threshold dose of TIA (0.2 mg/kg ip) produced similar increases of PRL release in the group either treated with TIA or saline. The data indicate that the benzamides examined have low potency for interaction with DA receptors in pituitary and striatum. In particular, tiapride displayed weaker affinity for AP-DA receptors than the other drugs and induced only slight stimulation of PRL levels. Results from repeated tiapride administration indicate that the drug, at a clinically relevant dose, is unable to modify either kinetic characteristics of DA receptors in the pituitary or plasma PRL levels.