Beneficial role of central anticholinergic agent in preventing the development of symptoms in mouse model of post-traumatic stress disorder.

Objectives The present study was designed to investigate the effectiveness of trihexyphenidyl, a central anticholinergic drug, in preventing the post-traumatic stress disorder (PTSD) symptoms in a mouse model. Methods Mice were subjected to underwater trauma stress for 30 s on day 1 followed by three situational reminders (3rd, 7th and 14th day). Thereafter, the behavioral alterations including freezing behavior were noted on 21st day. The serum corticosterone levels were measured as a biochemical marker of trauma. Elevated plus maze test was done on day 1 and day 2 to assess the memory formation following exposure to trauma. Results Trauma and situational reminders were associated with a significant development of behavioral changes and freezing behavior on the 21st day. Moreover, there was also a significant decrease in the serum corticosterone levels. A single administration of trihexyphenidyl (2 and 5 mg/kg) significantly restored trauma associated-behavioral changes and serum corticosterone levels. Moreover, it significantly increased the transfer latency time on day 2 following stress exposure in comparison to normal mice suggesting the inhibition of memory formation during trauma exposure. Trihexyphenidyl also led to significant reduction in freezing behavior in response to situational reminders again suggesting the inhibition of formation of aversive fear memory. Conclusion The blockade of central muscarinic receptors may block the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders. Central anticholinergic agents may be potentially useful as prophylactic agents in preventing the development of PTSD symptoms.

Misuse of Trihexyphenidyl (Artane) on Réunion Island.

BACKGROUND: Trihexyphenidyl (THP) is an anticholinergic drug misused to procure hallucination, sedation, and anxiolysis. The aim of this cohort was to show and describe, within a public health risk management policy, the risks of a long-standing but relatively unknown addiction: THP addiction. METHODS: On Réunion island, a cohort with systematic data collection has been set up by addictologists working in the Centres for Addiction Prevention and Treatment, in the university hospital, and in general practices who have active lists of patients misusing THP. Data collection included socioeconomic data and clinical data concerning addiction. RESULTS: This cohort included 69 patients during November 2016. The average age of the patients was 36 years; 97% were men; 93% had living accommodation but only 32 % were employed. In this cohort drug administration was exclusively oral. The most common reasons for use were anxiolytic (46%), stimulation (26%), and sedation (10%), the main effects described were dyskinesia and behavioral disorders. Over half (61%) of the patients reported a coaddiction, mainly to benzodiazepines, cannabis, tobacco, alcohol, and buprenorphine. CONCLUSIONS: This cohort describing the clinical characteristics of 69 patients is the largest cohort studied for THP addiction. Patients from the Centres for Addiction Prevention and Treatment were the youngest and most recently addicted, whereas general practice patients had been addicted for longer and were more socially integrated. This clinical description of THP addiction therefore enables us to identify the patients who are the most at risk, to set up an adapted care protocol.

Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dtsz) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics.

Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dtsz hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry. Tropicamide retarded the onset of dystonic attacks, as previously observed after acute systemic administration of trihexyphenidyl. Combined systemic administration of trihexyphenidyl (30mg/kg) and tropicamide (15mg/kg) reduced the severity in acute trials and delayed the onset of dystonia during long-term treatment. In contrast, acute striatal microinjections of trihexyphenidyl, tropicamid or the positive allosteric M4 receptor modulator VU0152100 did not exert significant effects. Receptor analyses revealed changes of M1 receptors in the dorsomedial striatum, suggesting that the cholinergic system is involved in abnormal striatal plasticity in dtsz hamsters, but the pharmacological data argue against a crucial role on the phenotype in this animal model. However, antidystonic effects of tropicamide after systemic administration point to a novel therapeutic potential of M4 preferring anticholinergics for the treatment of dystonia.

Efectividad de la terapia farmacológica oral utilizada para el tratamiento del control postural en niños con parálisis cerebral disquinética: una revisión sistemática / Effectiveness of oral pharmacologic therapy usedfor treatment of postural control in children withdyskinetic cerebral palsy (DCP): a systematic review

Objective: To evaluate the effectiveness of oral pharmacologic therapy in improving postural control and functionality in patients with DCP, with less than 20 years old, compared with any therapy or placebo. Methods: Randomized clinical trials and quasi-experimental with no restriction in publication date or language were included. The search was conducted in PubMed, EMBASE, The Cochrane Library (CENTRAL), Virtual Health Library (LILACS, SCIELO), ClinicalTrials.gov and Opengrey. The risk of bias was assessed according to the Cochrane Handbook for Interventions Systematic Reviews. Results: 3 cross over studies were included, according to the established criteria. The three drugs that were analyzed were: levodopa, and trihexyphenidyl and tetrabenazine, compared to placebo. No study had significant favorable results for the use of the drug over placebo. Conclusion: At the moment there is no evidence to support the use of oral medication in patients with DCP, based on the small number of high quality studies found, it is necessary to increase research on oral pharmacologic therapy in this group of patients.

Objetivo: Evaluar la efectividad del tratamiento farmacológico oral destinado a mejorar el control postural y la funcionalidad en pacientes con parálisis cerebral disquinética (PCD) menores de 20 años comparado con cualquier terapia o placebo. Métodos: Se incluyeron ensayos clínicos aleatorizados y cuasi experimentales sin restricción de fecha de publicación o lenguaje. La búsqueda se realizó en Pubmed, EMBASE, The Cochrane Library (CENTRAL), Biblioteca Virtual de la Salud (LILACS, SCIELO), ClinicalTrials.gov y Opengrey. El riesgo de sesgo fue evaluado de acuerdo al Manual Cochrane de Revisiones Sistemáticas de Intervenciones. Resultados: Se incluyeron 3 estudios cross-over de acuerdo a los criterios establecidos. Los tres fármacos analizados fueron: levodopa, tetrabenazina y trihexifenidilo, comparados con placebo. Ningún estudio tuvo resultados favorables de manera significativa para el uso del medicamento sobre placebo. Conclusión: Por el momento no existe evidencia que sustente el uso de la medicación oral en los pacientes con PCD en base al escaso número de estudios de alta calidad encontrados, siendo necesario que se aumente la investigación sobre el tratamiento farmacológico oral en este grupo de pacientes.

Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia.

OBJECTIVE: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenance treatment with olanzapine 20 mg/day, trihexyphenidyl 4 mg/day, and trazodone 50 mg/day, suffered from heat stroke in a heat wave and required intensive care. He recovered with the medical treatment provided. Discussion Several factors could have contributed to the impaired thermoregulation and the occurrence of heat stroke in this case: schizophrenia, the psychotropic regimen, and lack of preventive measures. Possible differential diagnoses of heat stroke in this case include infection, neuroleptic malignant syndrome, and serotonin syndrome. CONCLUSION: Heat stroke can occur during the maintenance treatment of olanzapine, trihexyphenidyl, and trazodone for schizophrenia. Clinicians should be proactive to reduce the risk of heat stroke in psychiatric patients.

Combination therapy for segmental craniocervical dystonia (Meige syndrome) with aripiprazole, trihexyphenidyl, and botulinum toxin: three cases reports.

Segmental craniocervical dystonia is characterized by blephalospasm and oromandibular dystonia and is also called Meige syndrome. The current treatment strategy including botulinum toxin (BTX) injections has not yet attained an acceptable level. We describe a long-term favorable response of a novel combination therapy with aripiprazole (ARP), trihexyphenidyl (THP), and BTX in three patients with segmental craniocervical dystonia. The symptoms of three patients responded promptly to the combination therapy with ARP 3-6 mg daily, THP 2-8 mg daily, and BTX. Although the patients were required to receive a BTX 50-100 IU injection every 3-6 months, their symptoms were kept in a satisfactory condition for up to 2 years without any adverse effects. ARP possesses the potential for dramatically improving dystonia. THP has the possibility to enhance the efficacy of ARP and prolong the effective period of BTX. It may be an important requisite to give all three agents together for a successful treatment. The combination therapy with ARP, THP, and BTX was well-tolerated and useful in controlling the symptoms of segmental craniocervical dystonia, however, the reason why this combination therapy succeeded is unknown. A further long-term follow-up is required to monitor the delayed neurological adverse effects.

Multidrug overdose-induced myoclonus complicated by rhabdomyolysis: possible role and mechanism of muscle toxicity of risperidone.

WHAT IS KNOWN AND OBJECTIVE: Atypical antipsychotics are considered safe for treating schizophrenia and are rarely reported to induce rhabdomyolysis. CASE SUMMARY: Here is a case of a woman with schizophrenia who developed rhabdomyolysis following overdose of risperidone, trihexyphenidyl and benzodiazepines. There was no recurrence of rhabdomyolysis when above medication was resumed with therapeutic dose. WHAT IS NEW AND CONCLUSION: Multidrug overdose are common but are rarely reported to induce rhabdomyolysis. Overdose risperidone may increase the risk of rhabdomyolysis and need to be kept in mind.

DYT16: the original cases.

OBJECTIVE: DYT16 is an autosomal recessive dystonia-parkinsonism due to putative mutations at PRKRA gene. The aim of this study was to describe clinical features providing video documentation of patients with DYT16 dystonia. METHODS: We examined and videotaped all homozygous carriers of the DYT16 gene. RESULTS: We identified two phenotypes, generalised dystonia and dystonia-parkinsonism non-responsive to levo-dopa, with three patients belonging to each of the groups. There was inter-individual and intra-family phenotypic heterogeneity. CONCLUSIONS: DYT16 is a rare autosomal recessive dystonia characterised by generalised dystonia or dystonia-parkinsonism. Patients are refractory to pharmacological therapy.

Trihexyphenidyl improves motor function in children with dystonic cerebral palsy: a retrospective analysis.

There are conflicting reports regarding the efficacy of trihexyphenidyl, an anticholinergic drug, for treatment of dystonia in cerebral palsy. The author hypothesized that trihexyphenidyl may be more effective in specific subgroups and performed a retrospective analysis of 31 children (8.2 ± 5.8 years) with dystonia following treatment with high-dose trihexyphenidyl (>0.5 mg/kg/day). Main outcome measure was extent of motor improvement calculated according to the body areas affected. Most (21/31) caregivers reported improvement in 1 or more areas, mainly arm, hand, and oromotor function. Improvement was greater in children without spasticity (P = .02) and in those with higher cognitive function (P = .02). While a third of caregivers (10/31) reported tone reduction, and half (15/31) noted overall functional improvement. Side effects were transient, with the exception of hyperopia (n = 1), and occurred less frequently in children with a history of prematurity (P = .02). In summary, trihexyphenidyl is effective particularly in absence of spasticity and in children with higher cognitive abilities.

Complete resolution of clozapine-induced sialorrhea with low dose trihexyphenidyl.

Clozapine-induced sialorrhea (CIS) is a frequently occurring debilitating adverse effect. Although various treatment options exist, none has been proved to be distinctly superior to others. We report a case of CIS that responded to low dose of trihexyphenidyl (2 mg/day).

Multicenter clinical study on the treatment of children's tic disorder with Qufeng Zhidong Recipe.

OBJECTIVE: To assess the effect and adverse reaction of Qufeng Zhidong Recipe (QZR) in treating children's tic disorder (TD). METHODS: With multicenter randomized parallel open-controlled method adopted, the patients enrolled were assigned to two groups, 41 cases in the Chinese medicine (CM) group and 40 in the Western medicine (WM) group. They were treated by QZR and haloperidol plus trihexyphenidyl respectively for 12 weeks as one course. In total, two courses of treatment were given. The curative effect and adverse reactions were evaluated by scoring with Yale Global Tic Severity Scale (YGTSS), Traditional Chinese Medicine Syndrome Scale (TCMSS), and Treatment Emergent Symptom Scale (TESS), as well as results of laboratory examinations. RESULTS: After one course of treatment, the markedly effective rate in the CM and the WM group was 14.6% and 17.5%, respectively, and the total effective rate 43.9% and 47.5%, respectively, which showed insignificant difference between groups (P>0.05). However, after two courses of treatment, markedly effective rate in them was 73.2% and 7.5%, and the total effective rate was 100.0% and 57.5%, both showing significant differences between groups (P<0.05). Besides, the adverse reactions occurred in the CM group was less than that in the WM group obviously. CONCLUSION: QZR has definite curative effect with no apparent adverse reaction in treating TD, and it can obviously improve the symptoms and signs and upgrade the quality of life and learning capacities in such patients.

Study of bipathic effect of haloperidol.

Parallel treatment with haloperidol and ultralow-dose haloperidol significantly increased the psychotropic neuroleptic effect of traditional doses of the drug under conditions of preliminary of simultaneous administration, which attests to a bipathic effect of this preparation. Combination of ultralow and therapeutic doses of haloperidol significantly reduced its cataleptogenic side effect.

Interactions between neurons in the frontal cortex and hippocampus in cats trained to select reinforcements of different value in conditions of cholinergic deficiency.

An operant food-related conditioned reflex was developed in six cats by the "active choice" protocol: short-latency pedal presses were followed by presentation of low-quality reinforcement (bread-meat mix), while long-latency pedal presses were followed by presentation of high-quality reinforcement (meat). Animals differed in terms of their food-procuring strategies, displaying "self-control," "ambivalence," or "impulsivity." Multineuron activity was recorded from the frontal cortex and hippocampus (field CA3). Cross-correlation analysis of interneuronal interactions within (local networks) and between (distributed networks) study structures showed that the numbers of interneuronal interactions in both local and distributed networks were maximal in animals with "self-control." On the background of systemic administration of the muscarinic cholinoreceptor blockers scopolamine and trihexyphenidyl, the numbers of interneuronal interactions decreased, while "common source" influences increased. This correlated with impairment of the reproduction of the selected strategy, primarily affecting the animals' self-controlled behavior. These results show that the "self-control" strategy is determined by the organization of local and distributed networks in the frontal cortex and hippocampus.

Sustained improvement of motor function in hemiparkinsonian rats chronically treated with low doses of caffeine or trihexyphenidyl.

The effects of chronic oral treatment with low doses of caffeine (1-3 mg/kg) and trihexyphenidyl (0.1-0.2 mg/kg) were tested on hemiparkinsonian rats, which received the following treatments in a counterbalanced order: vehicle, caffeine, trihexyphenidyl, and caffeine plus trihexyphenidyl. Three preclinical models were used: the stepping test, the cylinder test, and the staircase test. Compared to pre-lesion values, the forepaw contralateral to the dopamine-denervated side showed impaired stepping, fewer wall contacts in the cylinder test, and fewer pellets retrieved in the staircase test. In the stepping test both doses of caffeine produced a complete recovery of motor function (100%), whereas the effect of trihexyphenidyl was less intense (77-80%). In this same test the maximal effect of drugs did not develop tolerance during 2-3 weeks, and was completely reversible after drug cessation. In the cylinder test only the wall contacts performed simultaneously with both forepaws were significantly increased by caffeine (3 mg/kg) and trihexyphenidyl (0.2 mg/kg), and this effect was also reversible. In the staircase test none of the treatments improved food pellet retrieval with the contralateral forepaw. Altogether, these results show that chronic treatment with caffeine, at doses similar to daily human consumption, produces a sustained improvement in the use of the contralateral forelimb in unilaterally 6-hydroxydopamine denervated rats, without the development of tolerance. Although the combined administration of caffeine plus trihexyphenidyl showed no synergism in these models, the results suggest that low doses of caffeine (1-3 mg/kg/day) could be of therapeutic value for the reversal of motor symptoms in parkinsonian patients.

[Interrelations between neurons of the frontal cortex and hippocampus under cholinergic deficit in choice behavior of cats].

Appetitive instrumental conditioned reflexes on light (CS+) were formed in six cats by the method of "active choice" of quality of reinforcement; bread-meat mixture was given after short-delay conditioned bar-press responses, and the delayed responses were rewarded by meat. The animals differed in choice behavior strategy: "self-control", "ambivalent", "impulsive". The multiunit activity in the frontal cortex and hippocampus (CA3) was recorded. Cross-correlation analysis was used for estimation of correlation of activities in neuronal pairs in the frontal cortex and hippocampus (distributed frontal-hippocampal networks) and pairs within the same structure (frontal and hippocampal local neuronal networks). It was shown that the number of cross-correlations between the discharges of neurons both in the local and distributed networks was significantly higher in "self-control" cats. Under conditions of systemic administration of antagonists of muscarinic central cholinoreceptors (trihexyphenidyl and scopolamine), the bar-press conditioning impaired, the number of direct interneuronal connections decreased, and the number of externally synchronized correlations ("common input") significantly increased. The results suggest that the local and distributed neural networks of the frontal cortex and hippocampus are involved in the system of brain structures that determine the behavioral strategy of "self control".

Trihexyphenidyl (Artane): a Brazilian study of its abuse.

In Brazil, the medicinal misuse of trihexyphenidyl (Artane) has been observed among several segments of society. The present study was conducted in the city of São Paulo during 2002 to characterize this abuse. A sample of 21 users and 16 ex-users was interviewed using qualitative methodology; the subjects were single, unemployed, male polydrug users, who used trihexyphenidyl in order to attain states of mental alterations, mainly hallucinations and deliriums. Trihexyphenidyl is consumed in association with alcohol, other licit drugs (benzodiazepines), or illicit drugs, impairing cognitive functions such as memory, attention, and learning, intervening with some activities of users' daily life.

Assessment of the therapeutic and anticonvulsive efficacy of a drug combination consisting of trihexyphenidyle and HI-6 in soman-poisoned rats.

1. The influence of two anticholinergic drugs (atropine, trihexyphenidyle) on the effectiveness of antidotal treatment to eliminate soman-induced lethal effects and convulsions was studied in rats. 2. The oxime HI-6 when combined with centrally acting anticholinergic drug trihexyphenidyle seems to be more efficacious in the elimination of acute toxic effects of soman than its combination with atropine. 3. The findings support the hypothesis that the choice of the anticholinergic drug is important for the effectiveness of antidotal mixture in the case of antidotal treatment of soman-induced acute poisoning.

Trihexifenidilo: droga con dificultades en su prescripción, mal usada y poco conocida / Trihexyphenidyl: a drug with difficulties in its prescription, poorly used and little known

Se realizó una amplia revisión de lo descrito en la literatura sobre el trihexifenidilo, droga anticolinérgica empleada básicamente en enfermedades psiquiátricas y neurológicas, con el fin de contribuir desde el punto de vista educativo a la información del personal de salud sobre las potencialidades farmacológicas de este medicamento en cuanto a su consumo. Se valoró el binomio riesgo-beneficio, se particularizó en los detalles de sus indicaciones, dosificaciones y posibles alternativas de sustitución del fármaco, así como implicaciones de su consumo de riesgo y su poder adictivo. Se hacen recomendaciones para ejecutar buenas prácticas en medicina y la valoración de sus aspectos médico-legales. Finalmente, se hacen referencias de la función del personal de la salud como divulgador de la temática y su responsabilidad en la consecución de estilos de vida saludables y mayor calidad de vida de nuestra población(AU)