Tiaprida, una alternativa de tratamiento en el trastorno por uso de alcohol: a propósito de un caso / Tiapride, an alternative treatment in alcohol use disorder: a case report

Objetivo: Exponer a través de un caso clínico el uso de tiaprida para la desintoxicación de alcohol en un paciente con diagnóstico de trastorno por consumo de alcohol grave 303.90 (F10.20).Caso clínicoUna mujer de 50 años, en seguimiento en la Unidad de Conductas Adictivas desde septiembre de 2016 hasta la actualidad, con diagnósticos de trastorno de adaptación 309.4 (F43.25) con alteración mixta de las emociones o de la conducta, trastorno por consumo de alcohol grave 303.90 (F10.20) y descompensación maniforme, al cual se le instaura el tratamiento con tiaprida.ResultadosLos estudios consultados demuestran la eficacia y seguridad de tiapride para el síndrome de abstinencia a alcohol tanto en ámbito ambulatorio como hospitalario, en monoterapia o en politerapia con benzodiacepinas y/o antiepilépticos, siendo usado también en la agitación y/o la sintomatología psicótica.ConclusionesSe ha observado que en el síndrome de abstinencia a alcohol la tiaprida es eficaz, pudiendo incluso tenerlo en cuenta como tratamiento coadyuvante a benzodiacepinas o anticonvulsivantes. Con vistas a futuro, se deberían tener en cuenta la farmacogenética que afectan al trastorno por consumo de alcohol, con lo que se podría beneficiar de menores efectos adversos una terapia personalizada individualizada. (AU)

Objective: Present a clinical case report on the use of tiapride for alcohol detoxification in a patient with a diagnosis of severe alcohol use disorder 303.90 (F10.20).Clinical case report50 year-old female, under follow-up in the Addictive Behavior Unit from September 2016 to present, with diagnoses of adjustment disorder 309.4 (F43.25)Mixed disturbance of emotions or behavior, severe alcohol use disorder 303.90 (F10.20) and severe decompensation, who is treated with tiapride.ResultsThe studies consulted demonstrate the efficacy and safety of tiapride for alcohol withdrawal syndrome in both outpatient and inpatient settings, in monotherapy or in polytherapy with benzodiazepines and/or antiepileptics, being also used in agitation and/or psychotic symptomatology.ConclusionsIn alcohol withdrawal syndrome, tiapride has been found to be effective and can even be considered as an adjunctive treatment to benzodiazepines or anticonvulsants. With a view to the future, pharmacogenetics affecting alcohol use disorder should be taken into account, so that individualized personalized therapy could benefit from fewer adverse effects. (AU)

Contrasting effects of DOI and lisuride on impulsive decision-making in delay discounting task.

RATIONALE: The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). OBJECTIVES: The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. METHODS: Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. RESULTS: DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40 mg/kg). CONCLUSIONS: DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptors. DOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

The DA-antagonist Tiapride affects context-related extinction learning in a predictive learning task, but not initial forming of associations, or renewal.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride.

PURPOSE: Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. METHODS: Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. RESULTS: In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. CONCLUSIONS: This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).

Tiapride prevents the aversive but not the rewarding effect induced by parabrachial electrical stimulation in a place preference task.

The parabrachial complex has been related to the processing of both rewarding and aversive signals. This pontine area is activated after the gastrointestinal administration of rewarding nutrients, in taste aversion learning, and in response to the reinforcing and aversive effects of some drugs of abuse. Electrical stimulation of this region can induce, in different animals, preference or aversion behaviors towards a place in a rectangular three-chamber maze task. This study examined the effect of tiapride, a D2/D3 receptor antagonist, on the aversive or rewarding effects induced by electrical stimulation of the external lateral parabrachial subnucleus (NLPBe). As previously observed, administration of tiapride interrupted the aversive effect induced by NLPBe electrical stimulation. However, in contrast to the effects of dopamine antagonists on other rewarding systems, tiapride did not impair the place preference induced by NLPBe stimulation, an activation effect that is subject to tolerance. Tiapride administration also appeared to have no effect on the horizontal motor activity (crossings) of the electrically stimulated animals. We discuss the specific relevance of parabrachial reward with respect to other reinforcing brain components or systems, especially in relation to the preference effect of drugs of abuse, such as opiates, after dopamine antagonist administration.

Tiapride impairs the aversive effect of electrical stimulation of the parabrachial complex in a conditioned place task.

The parabrachial complex has been related to various rewarding or aversive behavioral processes, including taste aversion learning and conditioned place aversion. This study examined the effect of tiapride, an antagonist of D2/D3 dopaminergic receptors, on place aversion induced by electrical stimulation of the external lateral parabrachial (LPBe) nucleus. Results obtained show that brain-stimulated animals avoid the area of the maze associated with electrical stimulation but show no such behavioral rejection when they receive an injection of 30 mg/kg tiapride. Furthermore, tiapride did not appear to affect the horizontal motor activity (crossing) of the animals. These results are discussed in the context of the different natural and artificial modalities used to induce aversive behavior and their relationship with dopamine systems.

Estudio de la estabilidad de tiaprida en disolución para administración en perfusión intravenosa continua / Assessment of a Tiapride solution for its administration through continuous intravenous perfusion

Objetivo: La tiaprida es una benzamida sustituida clasificada como neuroléptica atípica. Ante la ausencia de datos publicados sobre su estabilidad en disolución para administración en perfusión continua intravenosa, este estudio analiza la estabilidad de la tiaprida en diferentes soluciones para infusión intravenosa, a diferentes concentraciones y durante 48 horas. Método: Se prepararon muestras de tiaprida por triplicado en cloruro sódico al 0,9% y en glucosa al 5% a concentraciones de 1 y 2 mg/mL. Estas muestras se conservaron en recipientes de cristal sin fotoprotección, a temperatura ambiente (25 ± 2oC). Los tiempos de muestreo a las 0, 1, 3, 6, 12, 24 y 48 horas incluyeron inspección visual y determinación del pH. Se cuantificó la concentración de tiaprida en las muestras mediante cromatografía líquida de alta eficacia acoplada a espectrometría de masas. A los valores de concentración a tiempo 0 se les asignó el valor de referencia del 100%. Se consideraron estables aquellas muestras con concentración de tiaprida superior al 90% de la inicial. Resultados: No se observaron cambios visibles en las muestras analizadas. El valor del pH varió en un rango de entre 0,1 y 0,4 unidades. A las 48 horas, la concentración remanente en cloruro sódico a 1 y 2 mg/mL fue 93,8% y 91,6%, respectivamente. En glucosa al 5%, a 1 y 2 mg/mL fue 96,8% y 94,1%, respectivamente. Conclusión: Las disoluciones de tiaprida en cloruro sódico al 0,9% y en glucosa al 5%, a concentraciones de 1 y 2 mg/mL, en recipientes de cristal sin fotoprotección, a temperatura ambiente, son estables física y químicamente durante 48 horas (AU)

Objectives: Tiapride is a substituted benzamide classified as an atypical neuroleptic. To our knowledge, there are no published data on its stability prepared as a continuous intravenous infusion. The current study analysed its stability in two different infusion solutions and concentrations over 48 hours. Method: Triplicate samples of tiapride were prepared in 0.9% sodium chloride and in 5% dextrose solutions at final concentrations of 1 and 2 mg/ml. Samples were collected in glass bottles without photoprotection and at room temperature (25 ± 2oC). Sampling times at 0, 1, 3, 6, 12, 24 and 48 hours included a visual inspection for colour changes and appearance of precipitation as well as pH determination. Tiapride was quantified at selected times by mass spectrometry using high-performance liquid chro-matography. Concentration values in the samples corresponding to 0 hours were given a reference value of 100%. Concentrations in subsequent samples greater than 90% were considered stable. Results: No colour change or precipitation was observed during the study period. pH values ranged between 0.1 and 0.4 units. At 48 hours, the concentration of remaining tiapride in sodium chloride 1 mg/ml and 2 mg/ml was 93.8% and 91.6%, respectively. That in 5% dextrose 1 mg/ml and 2 mg/ml was 96.8% and 94.1%, respectively. Conclusion: Dilutions of tiapride in 0.9% sodium chloride and in 5% dextrose solution, at concentrations of 1 mg/ml and 2 mg/ml, in glass bottles and at room temperature were stable both physically and chemically during 48 hours (AU)

Pretreatment for acute exposure to diisopropylfluorophosphate: in vivo efficacy of various acetylcholinesterase inhibitors.

Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors before exposure to organophosphorus compounds (OPCs) can reduce OPC-induced mortality. Pyridostigmine is the only FDA-approved substance for such use. The AChE-inhibitory activity of known AChE inhibitors was quantified in vitro and their in vivo mortality-reducing efficacy was compared, when given prophylactically before the exposure to the OPC diisopropylfluorophosphate (DFP). The IC50 was measured in vitro for the known AChE inhibitors pyridostigmine, physostigmine, ranitidine, tiapride, tacrine, 7-methoxytacrine, amiloride, metoclopramide, methylene blue and the experimental oxime K-27. Their in vivo efficacy, when given as pretreatment, to protect rats from DFP-induced mortality was quantified by determining the relative risk of death (RR) by Cox analysis, with RR = 1 for animals given only DFP, but no pretreatment. Physostigmine was the strongest in vitro AChE-inhibitor (IC50 = 0.012 µ m), followed by 7-methoxytacrine, tacrine, pyridostigmine and methylene blue. Ranitidine (IC50 = 2.5 µ m), metoclopramide and amiloride were in the mid-range. Tiapride (IC50 = 256 µ m) and K-27 (IC50 = 414 µ m) only weakly inhibited RBC AChE activity. Best in vivo protection from DFP-induced mortality was achieved when physostigmine (RR = 0.02) or tacrine (RR = 0.05) was given before DFP exposure, which was significantly superior to the pretreatment with all other tested compounds, except K-27 (RR = 0.18). The mortality-reducing effect of pyridostigmine, ranitidine and 7-methoxytacrine was inferior, but still significant. Tiapride, methylene blue, metoclopramide and amiloride did not significantly improve DFP-induced mortality. K-27 may be a more efficacious alternative to pyridostigmine, when passage into the brain precludes administration of physostigmine or tacrine.