A new capillary electrophoresis method to determine simultaneously eight of the most important anti-Parkinson's disease compounds has been developed. The generic names of the drugs studied are benactyzine (BA), trihexyphenidyl (TP), fenpiverin (FP), diphemin (DF), scopolamine (BL), adiphenine (TS), diethylaminoethylester 1-phenylcyclopentane-1-carboxylate (EKK), and diethylaminoethylester tetramethoxydiphenylacetate (EKO). An untreated fused-silica capillary tube (75 microns i.d., 57 cm total length, 49.5 cm length to the detector) was used with detection at 190 nm. The optimal separation conditions were 50 mM phosphate buffer (pH 2.7) with 7 mM-beta-cyclodextrin, electrokinetic injection for 15 sec at 5 kV, temperature 25 degrees C, and 15-20 kV separation voltage. Complete separation of all compounds was achieved in less than 16 min. The procedure was applied for the determination in urine and serum. The limits of detection (LOD, S/N = 3) for serum were 209 (FP), 234 (EKO), 168 (DF), 182 (BA), 168 (TP), 220 (BL), 174 (TS), and 163 (EKK) ppb. The method can be used for the therapeutic drug monitoring of these central active cholinolytics in clinical laboratories.
Risperidone and ziprasidone are commonly used as first line drugs for the treatment of psychotic disorders and overdose with these agents is increasingly being reported. Relatively few of these reports have involved co-ingestion of multiple psychotropic agents. We report a case of overdose with risperidone, ziprasidone, valproate, trihexyphenidyl and clonazepam in a 25 years female, who recovered uneventfully with supportive management. Notwithstanding the benign outcome in this instance, age, co-ingested drugs, active metabolites and medical co-morbidity are critical issues in overdose with atypical antipsychotics. As prescription of these drugs continues to increase in developing countries, systematic studies evaluating their clinical toxicity and management are necessary. The issues associated with overdose of multiple psychotropic agents and appropriate management policies are highlighted.
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The most effective treatment that addresses the cause of sialorrhea in children with cerebral palsy is training of sensory awareness and oral motor skills, performed by a speech therapist. Botulinum toxin injection and the use of anticholinergics have a transient effect and are adjuvant to speech therapy; they should be considered in cases of moderate to severe sialorrhea or respiratory complications. Atropine sulfate is inexpensive and appears to have good clinical response combined with good safety profile. The use of trihexyphenidyl for the treatment of sialorrhea can be considered in dyskinetic forms of cerebral palsy or in selected cases.
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To examine whether acute dystonia is induced by neuroleptic treatment, common marmosets were treated with haloperidol orally twice a week over 25 weeks until dystonic behavior was elicited. Movement disorders such as acute dystonia were observed 6 weeks after the initial treatment, and had appeared in all treated animals by 25 weeks. Once these movement disorders were induced, they consistently reappeared after further treatment with haloperidol, and once haloperidol dosing was discontinued, the episodes vanished. Then, various neuroleptic drugs (bromperidol, chlorpromazine, risperidone thioridazine, sulpiride, tiapride, and clozapine) or a nonneuroleptic drug (diazepam) were administered orally instead of haloperidol in the above animals. All the neuroleptic drugs except for clozapine elicited similar abnormal behavior, while diazepam failed to induce any dystonia. An anticholinergic drug, trihexyphenidyl, which is known to reduce acute dystonia in patients, was also given orally to the above haloperidol-sensitized animals, followed by further treatment with haloperidol 30 min later. This clearly suppressed the induction of dystonia by haloperidol. The similarity between these findings for haloperidol-pretreated common marmosets and clinical findings suggests that the present model is useful for predicting the potential of antipsychotics to induce acute dystonia in humans.
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Biperiden (BPR) and trihexyphenidyl (THP), the current antimuscarinic drugs of choice in the management of parkinsonism, have been shown to exert anticonvulsant effects induced by poisoning by the organophosphorus compound soman. The present study was undertaken to evaluate the effects of these drugs on performance of a simple light-intensity discrimination task in rats under a tandem schedule of fixed-ratio (FR) reward/ differential-reinforcement-of-low-rate (DRL) nonreward contingencies, for water reinforcement in 2-h experimental sessions. Both BPR (0.125-2.0 mg/kg, SC) and THP (0.25-8.0 mg/kg, SC) in general decreased overall reinforcement rates in a similar dose dependent and parallel manner, concurrent with increased overall nonreinforced responses in an inverted U-shaped dose-response relationship. Lower doses of BPR (0.125-0.5 mg/kg) and and THP (0.25-2.0 mg/kg) produced a moderate reduction in reinforcement (> or = 50% of baseline controls), which was correlated well with increases in nonreinforced responses emitted, whereas, higher doses of BPR (> 0.5 mg/kg) and TPH (> or = 2.0 mg/kg) markedly decreased reinforcements, which mainly resulted from the pausing of responding in the presence of stereotyped behavior. The behavioral disruption induced by BPR was much more rapid than that induced by THP. The ED50 values (0.6 mg/kg vs. 1.3 mg/kg, respectively) and parallel dose-effect curves suggest that these drugs have similar efficacy, and that BPR is about twice as potent as THP, a ranking that corresponds with their binding affinity at M-1 muscarinic acetylcholine receptors in rat cerebral cortex. Based on the similarity between the anticonvulsant doses of these drugs and the maximal doses that in this study did not disrupt operant responses (0.125 mg/kg vs. 0.25 mg/kg, respectively), it is suggested that both drugs may be useful in protection against seizures produced by the cholinesterase inhibitor soman. Overall, these results suggest that this multiple schedule operant contingency may have promise as a behavioral model to identify the therapeutic or toxic potentials of centrally acting antimuscarinic antiparkinsonian drugs based on their congnitive side effects.
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k bipolar manic-depressive patient, developed while on lithium prophylaxis, akathisia at therapeutic serum lithium levels and subsequently bucco-linguo-masticatory dyskinesia. The authors propose that differential involvement of dopamine systems may account for the transition from akathisia to tardive dyskinesia. In the light of a brief review of literature, a prospective study of akathisia and tardive dyskinesia seems justified.
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The behavioral effects of a variety of advanced candidate anticonvulsants for organophosphate-induced seizures were evaluated under two rodent 'counting' models. Rats pressed the left of two levers a number of times (a 'run') before pressing the right lever. The targeted performance was a run of 12. The training contingency was a targeted percentile schedule, which provided food if the current run was closer to 12 than two-thirds of the most recent runs. Baseline performance was well controlled by the target, with mean run lengths slightly less than 12. Once this performance was acquired, half the subjects were switched to a procedure providing food following runs of different lengths with a probability yoked to previous percentile schedule performance. The two procedures generate comparable baseline performances, but behavioral disruptions generate reinforcement loss only under the yoked procedure. Atropine, scopolamine, azaprophen, aprophen, trihexyphenidyl, procyclidine, benactyzine, biperiden and diazepam were tested. All produced dose-related decreases in overall run length and response rate. Responding was disrupted more readily under the yoked procedure than under the percentile procedure. Only atropine affected responding at doses below those effective against soman-induced seizures. Of the present candidates, trihexyphenidyl, procyclidine, benactyzine and biperiden appear most promising for further development.
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The goal of medical therapy for primary dystonia is conservative. While botulinum toxin (BTX) therapy is a first choice for blepharospasm and cervical dystonia, medical therapy is selected as such for other types of dystonia. As oral medications, trihexyphenidyl and benzodiazepines are most frequently used. Muscle relaxants are also commonly used, but dopamine antagonists are not recommended because of the risk of inducing tardive dyskinesia. For childhood-onset generalized dystonia, levodopa should be considered to rule out levodopa-responsive dystonia. Mexiletine is reported to be effective not only for bleharospasm and cervical dystonia but for focal limb dystonia. To improve the therapeutic performance of BTX therapy for blepharospasm, it is recommended that corrugator supercilii and procerus muscles, as well as orbicularis oculi muscle, be added as target muscles. To improve the therapeutic performance of BTX therapy for cervical dystonia, it is recommended that this therapy be started as early as possible, especially within one year of illness, and that levator scapulae muscle be added as target if necessary. To improve usefulness of medical therapy for dystonia, its strategy must be standardized, and more useful therapies must be positively adopted. Algorithm for treatment of dystonia must also be established and generalized.
Anticholinergics, benzodiazepines and N-methyl-D-aspartate (NMDA) antagonists have been shown to modulate the expression of nerve agent-induced seizures. This study examined whether the anticonvulsant actions of these drugs varied depending on the duration of prior seizure activity. Rats implanted with electrodes to record electroencephalographic (EEG) activity were pretreated with the oxime HI-6 (125 mg/kg, IP) to prolong survival, and then challenged with a convulsant dose of the nerve agent soman (180 micrograms/kg, SC); treatment compounds (scopolamine, diazepam, MK-801, atropine, benactyzine, and trihexyphenidyl) were delivered IV at specific times after seizure onset. Both diazepam and MK-801 displayed a similar profile of activity: At both short or long times after seizure initiation the anticonvulsant efficacy of each drug remained the same. Diazepam, and especially MK-801, enhanced the lethal actions of soman by potentiating the respiratory depressant effects of the agent; scopolamine given prior to diazepam or MK-801 protected against the respiratory depression. Scopolamine and atropine showed a dose- and time-dependent effectiveness; the longer the seizure progressed the higher the dose of drug required to terminate the seizure, with eventual loss of anticonvulsant activity if the seizure had progressed for 40 min. In contrast, benactyzine and trihexyphenidyl showed a third profile of activity: There was a smaller increase in drug dosage required for anticonvulsant activity as seizure duration increased, and both drugs could terminate seizures that had progressed for 40 min. The early anticonvulsant action of anticholinergics is interpreted as a specific effect that blocks the primary cholinergic excitatory drive that initiates, and first maintains, nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory neurotransmitter systems (i.e., NMDA) that eventually maintain the seizure independent of the initial cholinergic drive. This is indicated by the eventual ineffectiveness of scopolamine and atropine as the duration of the seizure progresses. Diazepam and MK-801 appear to act to moderate nerve agent seizures by enhancing inhibitory activity (diazepam) or dampening the secondarily activated noncholinergic excitatory system (MK-801). Benactyzine and trihexyphenidyl represent compounds that possibly have both anticholinergic and NMDA antagonistic properties.
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An electromyographic method was used to study the effect of combination therapy with L-dopa and trihexyphenidyl on tremor in thirty patients suffering from extrapyramidal motor system disease. In this method tremor activity was measured and documented so that the course of the disease could be followed objectively. L-dopa alone was slightly more effective against tremor than was trihexyphenidyl alone. The combination of the two drugs was more effective than either drug used alone, and its side-effects were mild and definitely fewer than had been reported with L-dopa combined with a decarboxylase inhibitor. Good control of tremor with L-dopa and trihexyphenidyl was obtained clinically and verified electromyographically.
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We present an interim report of an ongoing, single-blind study of the effectiveness and safety of bromocriptine mesylate (Parlodel) in 15 patients, 14 of whom had severe idiopathic Parkinson's disease (Stages 4 and 5 on the Hoehn and Yahr Scale). The patients had never received levodopa, amantadine, or bromocriptine. Gradually increasing doses of bromocriptine were assessed: Initial daily dosage was 1.25 mg, with weekly increments of 1.25 mg/day until either the clinical response was satisfactory or a maximum of 15 mg/day was reached. The patients were on no other antiparkinsonian agents, except trihexyphenidyl HCl (Artane). Response to treatment was scored on the Columbia Scale. The patients discussed in this report had been in the study for varying times, ranging from 1 month to 3 years. Only one patient who entered this study dropped out because his response to bromocriptine was unsatisfactory; he had taken the drug for 2 weeks. No serious adverse reactions were noted with the gradually increasing dosage regimen. Response on the whole was very satisfactory; patients improved by at least two stages on the Hoehn and Yahr Scale. Improvement began within 48 h of onset of treatment with 1.25 mg daily. The preliminary results of this study indicate that low-dose bromocriptine as a first-line drug in severe Parkinson's disease is definitely warranted.
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The PD models were established by intraperitoneal injection of MPTP (30 mg/kg). 30 C57BL/6J mice were randomly divided into six groups: control group, PD model group, QXT high dosage group, QXT middle dosage group, QXT low dosage group and trihexyphenidyl hydrochloride group. After 7 days of treatment, the behavior pattern of mice were observed, and striatum were seperated to detect the content of TNF-alpha by ELISA.
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The nature of the antagonism by anticholinergic compounds of nicotine-induced convulsion in mice has not been defined clearly. Although, because they do not compete effectively for agonist binding to brain tissue in-vitro, these compounds are thought to be non-competitive antagonists in the brain, pharmacological evidence is lacking. This study describes the anti-nicotinic properties of the clinically used anticholinergic antiparkinson drugs, benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl. Nicotine-induced convulsion and arecoline-induced tremor in mice were effectively prevented by these drugs. The concentrations of benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl affording 50% prevention of nicotine-induced convulsion (ED50 values) were 7.4, 4.6, 7.8, 4.9, 3.1 and 3.3 mg kg(-1), respectively. The classical muscarinic receptor antagonist atropine had potent anti-muscarinic effects but very weak anti-nicotinic activity. The classical nicotinic receptor antagonist mecamylamine had potent anti-nicotinic activity but no anti-muscarinic effects. The pattern of shift of the dose-response curve for nicotine-induced convulsion in mice was determined in the presence of increasing concentrations of the anticholinergic antiparkinson drugs. These drugs were found to increase the ED50 (0.49 mg kg(-1)) of nicotine-induced convulsion in a dose-related manner. The maximum effect of nicotine and the slope of nicotine dose-response curve were not significantly influenced by either low or high doses of benztropine, procyclidine or trihexylphenidyl, which suggests competitive action. Biperiden, caramiphen and ethopropazine, at low doses which significantly increased the ED50 of nicotine, did not affect the maximum effect of nicotine or the slope of the nicotine dose-response curve; at higher doses, however, they reduced the maximum effect and the slope, which suggests that these drugs have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice. The experiments demonstrate that the anticholinergic antiparkinson drugs and mecamylamine effectively antagonize nicotine-induced convulsion, but atropine does not; some of these drugs have competitive properties whereas others seem to have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice.
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Three clinical cases of essential blepharospasm are discussed. On the basis of both therapeutical results and a review of the literature, pathogenetic hypothesis concerning such pathology are reexamined.
Among the 188,284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4-93). The maximal number of cases occurred between 40-49 and 50-59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin.