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PubMed1981

Effect of haloperidol withdrawal on motor activity and circadian rhythm of rats.

The influence of haloperidol withdrawal on motor activity and circadian rhythm was observed in rats. Haloperidol was administered with the food at a concentration of 0.005%. Motor activity was recorded for 2 days on normal food, for 4 days on food with haloperidol addition and for another 5 days on normal food again in two groups of four rats each. Withdrawal of haloperidol raised the peak values during both phases impressively. The highest activity was observed on the day of haloperidol withdrawal but subsided again on the fifth day. The circadian rhythm remained unchanged.

Animals↗
PubMed1981

Effects of haloperidol and pimozide on classical conditioning of the rabbit nictitating membrane response.

Classical conditioning of the nictitating membrane response of the rabbit was accomplished by presenting tone and light conditioned stimuli for 800 msec before delivery of the unconditioned stimulus, consisting of a 100-msec electric shock to the skin over the paraorbital region of the head. Both haloperidol (250 microgram/kg i.v.) and an equimolar dose of pimozide (308 microgram/kg i.v.) significantly retarded the rate of acquisition of conditioned responses (CRs). Control experiments conducted with separate groups of rabbits indicated that the retardant effect of haloperidol on CR acquisition was not due to an effect on sensitization, pseudoconditioning, base-line responding or the unconditioned nictitating membrane reflex. In previously trained animals, haloperidol produced a significant (12.0 ob) elevation in the intensity threshold of a tone conditioned stimulus for elicitation of CRs. In a separate group of animals, and before any conditioning, haloperidol significantly blocked the amplitude and duration of a tone-induced facilitation of the nictitating membrane reflex. It was concluded that haloperidol blocks both the conditioned and unconditioned excitatory properties of a tone and this accounts for its ability to retard the rate of CR acquisition.

Animals↗
PubMedDate not supplied

[Standard and high doses of haloperidol. Clinical, pharmacokinetic and pharmacodynamic aspects].

The investigation was designed to study plasma drug concentration and prolactin response determined by two different doses of haloperidol, a standard one and four-fold higher the other, and to explore the relationships between clinical effects and pharmacokinetic and physiological variables in psychotic patients. 24 psychotic patients received haloperidol during 40 consecutive days. During the first 10 days they received 0,25 mg/kg b.w. During the next 20 days they were given 1 mg/kg b.w. Finally they received 0,25 mg/kg b.w. during the last ten days. The patients were clinically assessed and plasma haloperidol and prolactin concentrations were determined on days 0, 5, 10, 20, 30 and 40. In the range of dose studied, the use of higher than conventional doses of haloperidol results in an increased concentration in the cellular site of action and in a more complete blockade of central dopamine receptors. Prolactin response was positive correlated with serum haloperidol concentration. Clinical remission was not direct correlated, neither with serum neuroleptic concentration nor with prolactin level. Those patients who reached higher levels of plasmatic neuroleptic and prolactin concentrations were more susceptible to develop severe extrapyramidal side-effects. Pharmacokinetic and pharmacodynamic monitoring of neuroleptic treatment could be useful to identify these patients.

Adolescent↗
PubMed1980

Enhanced sensitivity to pentobarbital in haloperidol or pimozide treated mice and rats.

The influence of intraperitoneal administration of two neuroleptic drugs, haloperidol and pimozide (2.5 and 5.0 mg/kg) on pentobarbital induced narcosis, hypothermia and lethality were investigated in mice and rats. Haloperidol and pimozide administered 10 min prior to pentobarbital sodium (60 mg/kg) injection in rats increased significantly the onset time and duration of sleep. Both neuroleptic drugs also enhanced the intensity of hypothermic response to pentobarbital (50 mg/kg). Similar enhancement of narcosis and hypothermia to pentobarbital (75 mg/kg) was observed in haloperidol and pimozide pretreated mice. Pimozide pretreatment decreased the LD50 value of pentobarbital in mice. Brain and plasma levels of pentobarbital in haloperidol and pimozide treated rats on awakening were lower than in the corresponding saline treated rats. Brain and plasma levels determined at identical time interval in saline and neuroleptic treated rats showed similar results. These data indicate that disposition of pentobarbital cannot explain its enhanced pharmacological effects in haloperidol or pimozide treated animals but the brain sensitivity to pentobarbital is altered. These studies suggest an interaction between pentobarbital and neuroleptic drugs which may have clinical relevance.

Animals↗
PubMedDate not supplied

[Evaluation of clinical usefulness of decaldol (haloperidol decanoate) produced by WZF Polfa in Warsaw in long-term treatment of schizophrenia].

In the study the usefulness was assessed of haloperidol depot preparation in 50 mg ampoules produced by Warsaw Pharmaceutical Works POLFA in the treatment of schizophrenia. The study group comprised 30 patients, 12 females and 18 males, aged 18-70 years. Before haloperidol administration all other drugs were withdrawn. Haloperidol depot was injected intramuscularly after 7-10 days of oral administration of haloperidol. The injections were done at 3-week intervals during 26 weeks. The mean interval between the injections was 17.8 days, and the mean dose was 77.0 mg. The effectiveness of the drug was assessed using Overall scale (BPRS) measuring the intensity of 18 psychotic symptoms in the following weeks of the trial: 0, 1, 2, 3, 4, 7, 10, 13, 17, 20, 23 and 26. The depot haloperidol preparation (Decaldol) was studied assessing its effects on productive and defect symptoms and depression. The strongest effect was exerted on productive symptoms, less pronounced effect was on psychotic defects, and lowest on depression symptoms. Improvement of the psychosis was noted in 20 cases, deterioration in 8 and no change was observed in two patients. The present trial period was not completed by 19 patients, 6 due to psychotic deterioration, 5 patients had intense extrapyramidal adverse effects and in 2 cases worsening of mental condition was associated with adverse effects. In this subgroup of 19 patients 9 were improved, 8 were worse, and 2 had no change in relation to initial status. In the remaining 11 cases who completed the study only full of considerable improvement was found.

Adolescent↗
PubMed1994

A double-blind controlled study of intramuscular zuclopenthixol acetate and liquid oral haloperidol in the treatment of schizophrenic patients with acute exacerbation.

We carried out a 9-day double-blind clinical trial comparing intramuscular zuclopenthixol acetate with liquid oral haloperidol in the treatment of 40 newly admitted schizophrenic patients with acute exacerbation. A parallel-group design was used with stratification by sex. Zuclopenthixol acetate (50 to 150 mg) was given intramuscularly every 3 days, whereas liquid haloperidol (10 to 30 mg daily) was given orally three times a day, with supplementary doses of each medication given under double-blind conditions when needed for agitation. No other sedative drugs, including benzodiazepines, were administered. The mean daily dose was 18.9 mg for haloperidol as compared with a mean dose per 3 days of 117.6 mg for zuclopenthixol. The two treatments were found to be equally efficacious on the Brief Psychiatric Rating Scale and Clinical Global Impression Scale. Both drugs induced similar extrapyramidal side effects. However, more tremors were associated with zuclopenthixol as was a tendency for tardive dyskinesia to be unmasked at the end of the injection interval. Sedation was higher with zuclopenthixol acetate than with haloperidol. Serum creatinine phosphokinase levels were not significantly increased after zuclopenthixol injections. The results of this trial suggest that zuclopenthixol acetate given intramuscularly every second to third day offers an alternative to conventional liquid oral haloperidol in the management of acute schizophrenia.

Acute Disease↗
PubMed1993

Comparative study of 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9, 10-hexahydrocycloocta[b]pyridine (AD-5423) and haloperidol for their pharmacological activities related to antipsychotic efficacy and/or adverse side-effects.

Pharmacological effects of the novel antipsychotic, 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9,10-hexahydrocycl oocta [b]pyridine (AD-5423), were compared with those of haloperidol in rats. AD-5423 suppressed hyperactivity induced by microinjecting dopamine into the nucleus accumbens (0.3-3 mg/kg p.o.), and also antagonized both apomorphine- and methamphetamine-induced decreases in firing rate of neurons in the medial prefrontal cortex (1 mg/kg i.v.), indicating antidopaminergic effects of the compound in the possible brain areas involved in pathophysiology of schizophrenia. During repeated treatment with AD-5423 (0.5 and 1 mg/kg/day p.o.), the antiavoidance effect (predictive of antipsychotic efficacy) persisted at least for 14 days, whereas tolerance developed as rapidly as within 10 days to the antagonistic effect on apomorphine-induced gnawing (predictive of acute extrapyramidal side-effects). In these tests, AD-5423 was quite similar to haloperidol in potencies and time-course patterns of the effects. However, different results were obtained between the effects of AD-5423 and haloperidol in possible animal models of tardive dyskinesia and malignant syndrome. In rats treated for 21 days with haloperidol (3 mg/kg, once a day p.o.) and (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine [(+)SCH23390] (0.05 mg/kg, twice a day s.c.), but not with AD-5423 (10 mg/kg, once a day p.o.), 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF38393) induced a greater number of vacuous oral movements than in nontreated rats. Unlike haloperidol (3 mg/kg p.o.), AD-5423 (10 mg/kg p.o.) did not cause hyperthermia in combined treatment with veratrine (into the preoptic anterior hypothalamus).(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania.

BACKGROUND: Uncontrolled evidence suggests that divalproex administered via the oral loading strategy of 20 mg/kg/day may produce clinically significant antimanic response within 3 days of treatment in some patients. We conducted a prospective study to compare the antimanic response of divalproex oral loading with that of haloperidol in the initial treatment of acute psychotic mania. METHOD: After a < or = 1-day screening period, 36 consecutive hospitalized patients with bipolar disorder, manic or mixed phase and with psychotic features, were randomly assigned to receive either divalproex 20 mg/kg/day or haloperidol 0.2 mg/kg/day for 6 full days, without other psychotropic agents except lorazepam up to 4 mg/day for management of agitation. Serum valproate concentrations were measured after 1 day of treatment. Response was measured daily by a blind rater using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms. RESULTS: Divalproex oral loading and haloperidol were equally effective in acutely reducing manic and psychotic symptoms. The greatest rate of improvement for both drug regimens occurred over the first 3 full days of treatment. Side effects were infrequent and minor for both treatments, except for extrapyramidal side effects which were significantly more common with haloperidol. CONCLUSION: Divalproex oral loading may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side effects in the initial treatment of acute psychotic mania in a subset of bipolar patients.

Acute Disease↗
PubMed1996

Causes of haloperidol discontinuation in patients with Tourette's disorder: management and alternatives.

BACKGROUND: Neuroleptics are considered the mainstay of treatment in Tourette's disorder, and haloperidol is deemed the treatment of choice by many. Factors such as treatment efficacy and the side effects that appear in response to neuroleptic administration have been implicated in affecting medication compliance. However, a detailed evaluation of these factors has yet to be undertaken in Tourette's disorder. METHOD: Of 51 consecutive referrals to a Tourette's disorder clinic, 48 met DSM-III-R criteria for Tourette's disorder. Of these 48, 28 had previously received neuroleptics. In this set of 28 patients, 24 (16 male, 8 female) had initially received treatment with haloperidol, and they made up the present sample; their ages ranged from 10.4 to 47.9 years (mean = 27.1), and age at onset ranged from 2 to 16 years. Each patient completed an evaluation consisting of a Tourette Syndrome Questionnaire and a clinical interview with the patient and involoved family members. Charts were also reviewed to gather information concerning side effects and other factors that led to haloperidol discontinuation and/or noncompliance. RESULTS: Duration of treatment ranged from 3 days to 14 years (mean = 3.6 years). In this sample, 12.5% (3/24) of the subjects continued medication without interruption (mean +/- SD = 8.4 +/- 5.1 years of medication). Of the 21 patients who discontinued haloperidol, 66.7% (14/21) did so because they experienced intolerable side effects, 9.5% (2/21) because of the fear of experiencing certain side effects, and 14.3% (3/21) because of a combination of these factors. The principal side effects that led to discontinuation included dysphoric reactions, akathisia, nervousness, sedation, dystonic reactions, and cognitive dulling/feeling drugged. CONCLUSION: Careful monitoring of side effects and efficacy is essential to continued compliance with haloperidol. In addition, psychoeducation about potential consequences of medication administration may help promote compliance in those patients who develop fears of possible adverse reactions.

Adolescent↗
PubMed1995

Haloperidol-induced cell death--mechanism and protection with vitamin E in vitro.

Haloperidol, a dopamine receptor antagonist and sigma-receptor-active neuroleptic drug, is cytotoxic to primary hippocampal neurones, C6 glioma cells and NCB20 cells. A 24 h challenge of these cells with haloperidol resulted in reduced cell viability and ultimately cell lysis. The most dramatic changes in cellular morphology were the retraction of cellular extensions, development of membrane blebs, and finally cell detachment from the culture dish. DNA isolated from haloperidol-treated cells was randomly degraded, indicating a necrotic rather than an apoptotic pathway of cell death. Vitamin E (alpha-tocopherol), a lipophilic free radical scavenger, prevented haloperidol-induced DNA fragmentation and ultimately cell death. These findings suggest that haloperidol induces necrotic cell death in which free radicals play a major role.

Animals↗
PubMed1996

Effect of d-limonene, alpha-pinene and cineole on in vitro transdermal human skin penetration of chlorpromazine and haloperidol.

The aim of this research is to carry out a comparative study of the ability to cross human skin of two neuroleptic drugs: chlorpromazine (CAS 50-53-3) and haloperidol (CAS 52-86-8), in the absence and in the presence of three terpenes (cineole, d-limonene and alpha-pinene) with the purpose of considering the possibility of improving their transdermal penetration profile. Franz diffusion cells were used, in conjunction with human skin as permeation membrane. The permeation parameters calculated were permeability constant (Kp), flux (J) and lag time (Tl) in the presence and in the absence of enhancers. None of the three enhancers assayed improved the penetration profile of chlorpromazine, and d-limonene even reduced the transdermal permeability (enhancement index, EI = 0.67) since its coefficient of relative activity was reduced, (Xr = 0.73). Cineole and d-limonene increased the permeation profile of haloperidol, giving EI values of 1.95 and 4.21, respectively, and leading to a fourfold increase in the flux value for both enhancers. alpha-Pinene did not modify the permeation profile of haloperidol. None of the three terpenes assayed had a significant effect on the lag time of chlorpromazine or haloperidol. In these experimental conditions the concentration values predicted at steady state of chlorpromazine formulated without enhancers are within the therapeutic range. In contrast, therapeutic levels of haloperidol cannot be predicted in the absence of enhancers such as d-limonene or cineole.

Antipsychotic Agents↗
PubMed1997

Effect of haloperidol dose on iodine-123-IBZM brain SPECT imaging in schizophrenic patients.

UNLABELLED: Studies have suggested that antipsychotic drug therapy with haloperidol in schizophrenic patients requires an optimal dose that blocks the brain dopamine D2 receptors. We evaluated the effect of different doses of haloperidol on D2 receptor occupancy in schizophrenia. METHODS: Three normal subjects and three patients with acute schizophrenia had serial brain SPECT imaging studies (every 5 min) for 3 hr following the injection of [123I]IBZM. The patients had IBZM studies off medication and at different doses (1-10 mg) of haloperidol. RESULTS: The basal ganglia (BG) were well visualized in normals and in schizophrenics off medication. After haloperidol therapy, SPECT images showed qualitatively diminished activity in the basal ganglia. ROIs were drawn over the basal ganglia and cerebellum (CE). The results were expressed as BG/CE ratios. At 2 hr postinjection of IBZM, the mean BG/CE ratio in normals was 1.75 +/- 0.025. In schizophrenics, the BG/CE ratio off medication was 1.54 +/- 0.12. The BC/CE ratio showed an inverse relationship to haloperidol dose; 1.46 at 1 mg, 1.25 at 4 mg and 1.05 at 10 mg, respectively. CONCLUSION: These results demonstrate that IBZM brain SPECT imaging studies are potentially useful to relate the antipsychotic drug D2 receptor occupancy with the administered dose in schizophrenic patients and may ultimately help optimize antipsychotic treatment.

Adult↗
PubMed1997

A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia.

The authors compared the efficacy and side effects of trazodone and haloperidol for treating agitated behaviors associated with dementia. Twenty-eight elderly patients with dementia and agitated behaviors were randomly assigned to double-blind treatment with either trazodone (50-250 mg/day) or haloperidol (1-5 mg/day) for 9 weeks. There was no significant difference in improvement between the medication groups. Adverse effects, however, were more common in the group treated with haloperidol. Improvement in individual areas suggested that repetitive, verbally aggressive, and oppositional behaviors responded preferentially to trazodone, whereas symptoms of excessive motor activity and unwarranted accusations responded preferentially to haloperidol. These results indicate that moderate doses of trazodone and haloperidol are equally effective for treatment of overall agitated behaviors in patients with dementia, but specific symptoms may respond preferentially to a particular agent.

Aged↗
PubMed1997

Haloperidol-induced catalepsy: a model for screening antidepressants effective in treatment of depression with Parkinson's disease.

Incidence of severe depression is very common in Parkinson's disease (PD). Use of antidepressants in such cases is known to improve or worsen the existing PD. However, prediction of the effect of antidepressant on symptoms of PD is limited due to lack of suitable animal model. The present study examines the possibility of using haloperidol-induced catalepsy model in rats for this purpose. Antidepressants showed distinct effect on haloperidol-induced catalepsy, although most of them reduced forced-swimming induced immobility. In general, antidepressants with greater noradrenergic reuptake inhibition (desipramine, imipramine, amitriptyline, nortriptyline, protriptyline and maprotiline) reduced, whereas those with serotonergic reuptake inhibition (fluoxetine and clomipramine) increased haloperidol-induced catalepsy. Mianserin, an atypical antidepressant, and alprazolam, a benzodiazepine receptor analogue had no effect on haloperidol-induced catalepsy. The results suggest that haloperidol-induced catalepsy model in rats needs to be incorporated in the screening procedure when evaluating the utility of antidepressant drugs for the treatment of depression associated with PD.

Animals↗
PubMed1998

[Involvement of cytochromeP4503A4 in the metabolism of haloperidol and bromperidol].

To clarify the involvement of cytochromeP450 (CYP) 3A4 in the metabolism of haloperidol and bromperidol in humans, the effects of itraconazole, a potent inhibitor of CYP3A4, on steady-state plasma concentrations of both drugs and their reduced metabolites were investigated using 21 schizophrenic patients. Patients treated with haloperidol 12 or 24 mg/day (n = 13) or bromperidol 12 or 24 mg/day (n = 8) for at least 2 weeks were then given itraconazole 200 mg/day for 7 days. Blood samplings were performed before administration, 1 week during itraconazole coadministration and 1 week after its discontinuation together with clinical assessments. Plasma concentrations of haloperidol and bromperidol and their reduced metabolites were significantly higher during itraconazole treatment (P < 0.01). Deterioration in the neurological side effects of haloperidol was observed during itraconazole coadministration. Thus, this study suggests that itraconazole inhibits the metabolism of haloperidol and bromperidol, and that CYP3A4 is involved in the metabolism of both drugs.

Adult↗
PubMedDate not supplied

Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.

Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different.

Adult↗
PubMed1998

An NR2B point mutation affecting haloperidol and CP101,606 sensitivity of single recombinant N-methyl-D-aspartate receptors.

Haloperidol and ifenprodil are N-methyl-D-aspartate (NMDA) receptor (NR) antagonists with preference for the NR1/NR2B subunit combination. Previous investigations utilizing 125I-MK801 binding assays with recombinant receptors distinguished certain structural determinants on the NR2B subunit for these two drugs, with glutamate 201 being critical for haloperidol sensitivity and arginine 337 being important for ifenprodil block. Other studies, however, suggested that these two sites pharmacologically overlap. In an attempt to resolve these discrepancies, we have characterized the actions of haloperidol and CP101,606, an ifenprodil analog, on the single-channel properties of NR1/NR2B(E201R) receptors transiently expressed in Chinese hamster ovary cells, because receptors formed by NR1/NR2B(R337K) appear to be nonfunctional. Haloperidol (10 microM) inhibited wild-type NR1/NR2B channels by decreasing the frequency of channel opening, whereas CP101,606 (0.5 microM) antagonized NR1/NR2B channel activity by decreasing both the open dwell time and the frequency of channel opening. The inhibitory actions of both drugs were virtually absent in the mutant NR1/NR2B(E201R) receptors. These results suggest that glutamate 201 is critical for both haloperidol and CP101,606 inhibition, thus demonstrating common features in the action of these two antagonists.

Animals↗
PubMed1998

[Effects of serotonergic drugs on the up-regulation of dopamine D2 receptors induced by haloperidol in rat striatum].

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with atypical antipsychotic drugs clozapine (10 mg/kg) and ORG 5222 (0.25 mg/kg). Chronic treatment with MK 212, a serotonin (5-HT)2A/2C receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptor, while that with (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg), had no influence on the dopamine D2 receptor up-regulation. Co-administration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg), attenuated the dopamine D2 receptor up-regulation. Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined with use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile that 5-HT2A receptors were highly occupied compared with dopamine D2 receptors was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.

8-Hydroxy-2-(di-n-propylamino)tetralin↗