Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C.

Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We screened the Prestwick Chemical Library, a library of approved drugs, for inhibitors of coxsackievirus B3, identified pirlindole as a potent novel inhibitor, and confirmed the inhibitory action of dibucaine, zuclopenthixol, fluoxetine, and formoterol. Upon testing of viruses of several EV species, we found that dibucaine and pirlindole inhibited EV-B and EV-D and that dibucaine also inhibited EV-A, but none of them inhibited EV-C or rhinoviruses (RVs). In contrast, formoterol inhibited all enteroviruses and rhinoviruses tested. All compounds acted through the inhibition of genome replication. Mutations in the coding sequence of the coxsackievirus B3 (CV-B3) 2C protein conferred resistance to dibucaine, pirlindole, and zuclopenthixol but not formoterol, suggesting that 2C is the target for this set of compounds. Importantly, dibucaine bound to CV-B3 protein 2C in vitro, whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.

THE EFFECT OF A SLOW-RELEASE FORMULATION OF ZUCLOPENTHIXOL ACETATE (ACUNIL®) ON CAPTIVE BLUE WILDEBEEST (CONNOCHAETES TAURINUS) BEHAVIOR AND PHYSIOLOGICAL RESPONSE.

The study investigated the effect of a slow-release formulation of zuclopenthixol acetate (Acunil®) on blue wildebeest ( Connochaetes taurinus ) in captivity. Two groups of trials were conducted using either Acunil or a placebo (control). Animals (Acunil: n = 17; placebo: n = 12) were observed for a 12-hr period before the administration of Acunil or the placebo (pretreatment). After 24 hr, animals were administered Acunil (1.5 mg/kg) or a placebo (1.0-3.0 ml of sterile water) and observed again for 12 hr (posttreatment). During both treatments, animals were stimulated every 2 hr for 1 min by a person entering the enclosure (referred to as periods of stimulation). Behavioral observations and continuous heart rate, respiration rate, and motion measurements were taken throughout. Animals treated with Acunil spent more time lying with their heads folded back, eating and standing with their heads down, and less time being vigilant and exploring while walking around. Animals treated with the placebo also spent less time being vigilant and more time lying with heads up. Animals treated with Acunil groomed less while standing and performed less head shaking; no such changes were observed in the control group. Neither Acunil nor the placebo had any effect (P > 0.05) on heart rate. However, overall mean respiration rate was lowered (P = 0.02) when animals were treated with Acunil (pretreatment: 14.5 ± 0.82 breaths/min; posttreatment: 12.5 ± 0.83 breaths/min). Acunil also caused a lowered (P < 0.05) respiration rate during periods when animals were stimulated (pretreatment: 16.2 ± 0.87 breaths/min; posttreatment: 13.7 ± 0.87 breaths/min) and when animals were trotting and being vigilant. No such changes were observed with the placebo. Both placebo- and Acunil-treated animals spent more time being stationary during periods of stimulation. However, Acunil-treated animals also spent less time moving fast when they were stimulated.

Therapeutic drug monitoring of zuclopenthixol in a double-blind placebo-controlled discontinuation study in adults with intellectual disabilities and aggressive behaviour.

The trial was a double-blind, placebo-controlled comparison with a discontinuation design. 49 mentally retarded patients with aggressive behaviour were treated with zuclopenthixol at a dose of 2-20 mg/d. At each visit the clinical effect was evaluated. Correlations between dose, serum concentration, and efficacy measures were calculated. The mean dose was 10.0 mg/day (±5.17); the mean serum concentration 4.19 ng/mL (±3.16). Associations of dosage, serum concentration and clinical efficiency did not result in coherent patterns. Correlations with clinical efficiency measures appeared to be contradictory for dosage and serum concentrations, respectively. As no consistent associations between dosage, serum concentration, and clinical efficiency measures were found, different hypotheses explaining the results are discussed.

Anaesthesia with medetomidine, midazolam and ketamine in six gorillas after premedication with oral zuclopenthixol dihydrochloride.

OBJECTIVE: To evaluate the effects of medetomidine, midazolam and ketamine (MMK) in captive gorillas after premedication with oral zuclopenthixol. STUDY DESIGN: Case series. ANIMALS: Six gorillas, two males and four females, aged 9-52 years and weighing 63-155 kg. METHODS: The gorillas were given zuclopenthixol dihydrochloride 0.2 ± 0.05 mg kg(-1) per os twice daily for 3 days for premedication. On the day of anaesthesia the dose of zuclopenthixol was increased to 0.27 mg kg(-1) and given once early in the morning. Anaesthesia was induced with medetomidine 0.04 ± 0.004 mg kg(-1) , midazolam 0.048 ± 0.003 mg kg(-1) and ketamine 4.9 ± 0.4 mg kg(-1) intramuscularly (IM). Upon recumbency, the trachea was intubated and anaesthesia was maintained on 1-2% isoflurane in oxygen. Physiological parameters were monitored every 10 minutes and arterial blood gas analysis was performed once 30-50 minutes after initial darting. At the end of the procedure, 42-115 minutes after initial darting, immobilisation was antagonized with atipamezole 0.21 ± 0.03 mg kg(-1) and sarmazenil 5 ± 0.4 µg kg(-1) IM. RESULTS: Recumbency was reached within 10 minutes in five out of six animals. One animal required two additional darts before intubation was feasible. Heart rate ranged from 60 to 85 beats minute(-1) , respiratory rate from 17 to 46 breaths minute(-1) and temperature from 36.9 to 38.3 °C. No spontaneous recoveries were observed and anaesthetic level was stable. Blood gas analyses revealed mild respiratory acidosis, and mean PaO(2) was 24.87 ± 17.16 kPa (187 ± 129 mmHg) with all values being above 13.4 kPa (101 mmHg). Recovery was smooth and gorillas were sitting within 25 minutes. CONCLUSION AND CLINICAL RELEVANCE: The drug combination proved to be effective in anaesthetizing captive gorillas of various ages and both sexes, with minimal cardio-respiratory changes.

Allosteric Inhibition of HER2 by Moesin-Mimicking Compounds Targets HER2-Positive Cancers and Brain Metastases.

Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2+ cancer. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the Ezrin/Radixin/Moesin (ERM) family. Under physiologic conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of Moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2-ERM interaction allowed for screening of about 1,500 approved drugs. From this screen, we found Zuclopenthixol, an antipsychotic drug that behaved as a Moesin-mimicking compound, because it directly binds the juxtamembrane region of HER2 and specifically inhibits HER2 activation in HER2+ cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2+ breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2+ brain tumor progression. Collectively, these data reveal a novel class of allosteric HER2 inhibitors, increasing the number of approaches to consider for intervention on HER2+ breast cancers and brain metastases. SIGNIFICANCE: This study demonstrates the functional role of Moesin in maintaining HER2 in a catalytically repressed state and provides novel therapeutic approaches targeting HER2+ breast cancers and brain metastasis using Moesin-mimicking compounds.

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug.

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

QEEG alpha 1 changes after a single dose of high-potency neuroleptics as a predictor of short-term response to treatment in schizophrenic patients.

Baseline quantitative electroencephalographic (QEEG) characteristics and their changes after a single test dose of either haloperidol or clopenthixol were investigated in a group of 29 schizophrenics as possible predictors of short-term response to those drugs. On baseline QEEG assessment, responders (R) to subsequent treatment showed fewer slow and more fast activities than nonresponders (NR). A large overlap between R and NR with respect to these measures was observed, however, revealing their practical inadequacy to predict short-term response in individual patients. On the contrary, changes in alpha 1, observed 6 hr after the administration of a single test dose of either haloperidol or clopenthixol, discriminated to a very large extent between R and NR, correctly identifying 17 out of 18 R and 8 out of 10 NR. The QEEG test dose procedure might be used in the selection of the most appropriate antipsychotic drug for individual schizophrenic patients.

Effects of antipsychotics on prepulse inhibition of the startle response in drug-naïve schizophrenic patients.

BACKGROUND: Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. METHODS: First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. RESULTS: The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. CONCLUSIONS: The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.

Can neuroleptics influence the function of the brain hemispheres asymmetrically?

A long-term intracarotid tube was implanted in 32 rats. Intracarotid injection of 4 different neuroleptics (haloperidol, cis- and trans-flupenthixol, clopenthixol and reserpine) elicited a typical posture with abduction of the limbs on one side and and adduction on the other. Only the neuroleptically-active cis-isomers of flupenthixol and clopenthixol provoked this dystonic reaction. The posture spontaneously vanished after 24 hr and could be antagonized with the anticholinergic biperiden. Sham injections of Ringer's solution and isotonic glucose proved to be behaviourally inert. These results indicate an asymmetric distribution of the drugs in this experimental procedure. Their implications concerning drug-induced and spontaneous dystonias as well as psythopathology are discussed.

The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.

1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism.

Effect of trans(E)-clopenthixol on Plasmodium berghei in vivo.

Previous in vitro studies have shown suppression of the growth of Plasmodium falciparum by the neuroleptic agents chlorpromazine and zuclopenthixol (formerly known as cis(Z)-clopenthixol) as well as by the neuroleptic inactive steroisomer trans(E)-clopenthixol. These compounds are chemically related to riboflavin and may act as inhibitors of riboflavin metabolism. As trans(E)-clopenthixol has been found active against chloroquine-resistant strains of P. falciparum in vitro and has been approved for human use, though inactive as a neuroleptic, this drug was selected for the present in vivo study. The dosage of trans(E)-clopenthixol was optimized through a pharmacokinetic study, and the suppression of the growth of Plasmodium berghei in vivo was tested in mice, with chloroquine acting as the positive and saline as the negative control. Trans(E)-clopenthixol did not inhibit the growth of P. berghei, whereas chloroquine almost eradicated the infection. The use of in vitro screening for anti-malarial activity in drugs approved for human use for other indications is discussed in the light of the results. It is concluded that the selection of drugs for further studies in vivo cannot solely be based on positive results in vitro.

Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions.

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.

Effect of some psychotropic drugs and a barbiturate on mycoplasmas.

The inhibitory effect of selected membrane stabilisers on Mycoplasma pneumoniae, M. hominis and Ureaplasma urealyticum was investigated in vitro. The phenothiazine chlorpromazine (CPZ) and the barbiturate thiopental (Leopental(R)) as well as the stereo-isomeric thioxanthene derivatives; cis(Z)-clopenthixol (Zu-clopenthixol(R))/ trans (E)-clopenthixol and cis (Z)-chlorprothixen (Truxal(R))/trans(E)-chlorprothixen, all have antimycoplasmal effect in the range 3.9-312 mg/l, measured as growth inhibition. It was also demonstrated that the enzymatic functions of the different mycoplasma strains, such as breakdown of glucose, arginine and urea, were abolished by concentrations of CPZ that were sufficiently low to allow multiplication of the organisms. A similar effect was obtained with Leopental(R) although the mycoplasmas were generally only half as sensitive to this drug. Also M. gallisepticum and Acholeplasma laidlawii were inhibited by CPZ and Thiopental. The four thioxanthenes were all inhibitory to mycoplasmal growth and the effect was independent of their stereo-isomeric configuration. The clopenthixol stereoisomers, but not the chlorprothixene isomers, inhibited colour change at concentrations lower than those which inhibited growth. While enzyme activity may continue for some time in vitro when classic antibiotics have inhibited mycoplasmal growth, the reverse effect was observed with phenothiazines and thioxanthenes. The membrane stabilisers may be useful tools in the investigation of microbiological activity on the mycoplasma membrane. From these drugs, new 'antibiotics' might be developed with another action than that of the known antimycoplasmal drugs.

Effect of a dopamine D-1 agonist in rats treated chronically with zuclopenthixol.

We have previously demonstrated long-lasting increases in vacuous chewing movements (VCM) and tongue protrusions in rats treated discontinuously (DISC), but not continuously (CONT), with neuroleptics. To test whether this increase in mouth movements could be a result of exaggerated activity at the D-1 site, 34 rats were divided into three groups receiving the neuroleptic zuclopenthixol (ZU) DISC or CONT for 15 weeks, or no treatment. After withdrawal DISC treated animals showed an increase in oral activity compared to CONT treated. Two weeks after termination of medication the animals were tested with the D-1 agonist SK&F 38393. The increases in VCM after SK&F 38393 did not differ among the groups, but in contrast to control (CTRL) rats, treated rats showed a significant increase in tongue protrusions. There were no significant differences in the densities of D-1 and D-2 receptors in the striatum between the groups. The increase in tongue protrusions after SK&F 38393 in neuroleptic treated animals implies behavioural D-1 receptor supersensitivity. No significant differences in the rise in tongue protrusions and VCM after SK&F 38393 were seen between DISC and CONT treated animals. Our results thus do not indicate that increased D-1 receptor responsiveness is significant for the rise in spontaneous oral activity found after neuroleptic withdrawal.

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions.

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.

The role of stereoselectivity of chemosensitizers in the reversal of multidrug resistance of mouse lymphoma cells.

The effect of three different stereoisomer pairs of CNS (central nervous system) active compounds was studied on the activity of human mdr1 p-glycoprotein. The methotrimeprazine, clopenthixol and butaclamol isomers had an antiproliferative effect (ID50) on the mdr1 expressing cells at 0.250 microgram/ml, while the parental cells were less sensitive having ID50 at 0.37-0.69 microgram/ml. Enantiomers of methotrimeprazine and clopenthixol had similar effectivity on the drug efflux of mdr cells. However, (-)butaclamol was found to inhibit mdr efflux-pump activity much more than the CNS active (+) isomer. Based on these results, tricyclic compounds does not seem to have stereoselectivity in methotrimeprazine and clopenthixol on the mdr reversal effect. In general, both active and inactive members of stereoisomers had a similar effect on the drug accumulation of the mdr cells. Therefore, hypothetically the CNS inactive member of stereoisomer pairs can be used as a resistance modifier without any risk in patients suffering from drug resistant cancer.

Effects of butaclamol, clopenthixol, mepromazine and cannabinol stereoisomers on apoptosis induction.

The efflux pump of multidrug resistant mdr cells have different sensitivities to some stereoisomeric forms of CNS-active compounds. The ABC transporters of mdr cells were more sensitive to (-)butaclamol than to its stereoisomeric counterpart (8), which may function to alter the membrane structure. We suppose that the drug-accessible membrane structure possesses an important role in the induction (or prevention) of apoptosis. Therefore the apoptosis-inducing effect of three stereoisomeric pairs was studied on mouse lymphoma cells. In these experiments levo- and dextromepromazine had similiar effects. The cis- and trans-clopenthixol were less effective in apoptosis induction than the 12H-benzo(a)-phenothiazine used as a positive control. The effect of stereoisomeric pairs on induced apoptosis was studied when the cells were exposed to the stereoisomers for 60 minutes before subjection apoptosis induction by benzo(a)phenothiazine, a well-known apoptosis inducer. Then the pretreated cells were exposed to 12H-benzo(a)-phenothiazine for 60 minutes. The samples were washed and incubated for 24 hours. The cells were stained with annexin-V-FITC and propidium iodine and investigated by flow cytometry. The mdr cells with increased membrane integrity may result in the preferential killing of multidrug resistant cancer cells in the presence of some stereoisomers.

Central D2 receptor occupancy and effects of zuclopenthixol acetate in humans.

Repeated positron emission tomography (PET) measurements of D2 receptor occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 receptor occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 receptor occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 receptor occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 receptor occupancy calls for careful assessment of acute extrapyramidal symptoms.

Effects of low-dose risperidone and low-dose zuclopenthixol on cognitive functions in first-episode drug-naive schizophrenic patients.

BACKGROUND: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogeneous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal. OBJECTIVE: The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogeneous group of drug-naive first-episode schizophrenic patients in a longitudinal setting. METHODS: First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N=25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naive, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time. RESULTS: The patients showed considerable cognitive deficits when drug-naive. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls. CONCLUSION: The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naive schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.

Zuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.

Although disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated. The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes. In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats. Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) before retrieval testing increased step-through latency during the test session. The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties. This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (AChE) activity, both of which are known to be important in control of cognitive function. Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) neither affected dopamine (DA) level nor AChE activity in rat cortex and hippocampus. On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level. These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory. Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.