Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “HALOPERIDOL”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia.

BACKGROUND: The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol. METHODS: The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty-four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC. RESULTS: The mean +/- SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8+/-11.0, 30.1+/-10.6, and 31.2+/-21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1+/-2.9, 9.5+/-3.7, and 9.9+/-6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P < .05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P < .05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles. CONCLUSION: This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects.

Adult↗
PubMed1986

A clinical trial comparing intramuscular haloperidol decanoate and oral haloperidol in chronic schizophrenic patients: efficacy, safety, and dosage equivalence.

Thirty patients with chronic schizophrenia received oral haloperidol and haloperidol decanoate in a two-phase open study. In the first phase, patients were stabilized on haloperidol tablets for 2 weeks, then maintained on a constant daily dose for 2 more weeks. They were then switched to haloperidol decanoate for the second phase. Patients were first stabilized on a monthly dose of haloperidol decanoate and then received this dose for 5 consecutive months. Haloperidol decanoate, administered in monthly injections at 9.4 to 15 times the daily oral dose, was at least as efficacious as oral haloperidol in controlling the symptoms of schizophrenia. There were no serious adverse reactions to either drug. Blood samples were taken from 22 patients during both the oral and the decanoate phases and analyzed for steady state haloperidol concentrations. These determinations demonstrate that the release of haloperidol with the decanoate form is sustained throughout the 4-week dosing interval. Lower plasma drug concentrations were observed during decanoate treatment than during oral treatment. Despite these lower plasma concentrations, patients remained stable on both drug regimens. This finding suggests that haloperidol decanoate injected every 4 weeks can provide control of psychotic symptoms at least as effectively as daily oral haloperidol.

Administration, Oral↗
PubMed2000

Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia.

The effect of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady state plasma concentrations (Css) of haloperidol and reduced haloperidol was studied to clarify if these Css are dependent on the CYP1A2 activity. The subjects were 101 Japanese schizophrenic inpatients receiving oral haloperidol 12 mg/d. The Css of haloperidol and reduced haloperidol were measured in duplicate by high performance liquid chromatographic method, and were corrected to the mean body weight. A point mutation from guanine (wild-type) to adenine (mutated-type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction (PCR)-fragment length polymorphism method. Based on the present results, i.e., significant effects of CYP2D6 genotypes on the Css of haloperidol and reduced haloperidol, analyses were separately performed in two groups, i.e., patients with 0 mutated allele of the CYP2D6 (41 cases) and those with 1 or 2 mutated alleles (60 cases). Subjects in each CYP2D6 genotype group consisted of 4 subgroups according to smoking habit and the presence of the mutated allele of the CYP1A2. Neither the Css of haloperidol nor that of reduced haloperidol significantly differed among the 4 subgroups in either CYP2D6 genotype group. The present study thus suggests that the CYP1A2 activity does not play an important role in controlling the Css of haloperidol or reduced haloperidol.

Alleles↗
PubMed2003

Histamine H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma concentrations of haloperidol and reduced haloperidol.

The effects of histamine H1-receptor antagonists, promethazine and homochlorcyclizine, both of which are inhibitors of CYP2D6, on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol were studied in 23 schizophrenic inpatients receiving haloperidol, 12 to 36 mg/d, for 2 to 29 weeks. Promethazine, 150 mg/d, in 11 patients and homochlorcyclizine, 60 mg/d, in the others were coadministered for at least 1 week. Blood sampling was performed before and during coadministration of promethazine or homochlorcyclizine and 1 week after the discontinuation, together with clinical assessments by Brief Psychiatric Rating Scale (BPRS) and Udvalg for kliniske undersogelser (UKU) side effect rating scale. The Css (mean +/- SD) of haloperidol and reduced haloperidol during promethazine coadministration (27.6 +/- 24.9 and 8.6 +/- 13.2 ng/mL) were significantly higher than those before the coadministration (12.7 +/- 10.8 and 5.0 +/- 6.0 ng/mL; P < 0.01) or 1 week after the discontinuation (15.6 +/- 14.8 and 5.8 +/- 7.9 ng/mL; P < 0.05). The Css of haloperidol and reduced haloperidol during homochlorcyclizine coadministration (14.9 +/- 8.1 and 6.4 +/- 5.4 ng/mL) were also significantly higher than those before the coadministration (10.9 +/- 7.2 and 3.8 +/- 3.6 ng/mL; P < 0.01) or 1 week after the discontinuation (12.9 +/- 7.4 and 4.8 +/- 4.1 ng/mL; P < 0.05). No change in BPRS or UKU score was found throughout the study. Thus, the current study suggests that coadministration of clinical doses of promethazine and homochlorcyclizine increases the Css of haloperidol and reduced haloperidol via the inhibitory effects on the CYP2D6-catalyzed metabolism of haloperidol and reduced haloperidol.

Adult↗
PubMed1985

Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration.

Haloperidol, a butyrophenone neuroleptic, is metabolically reduced in man, but not in rat and not in many other experimental animals. Here we present data that describes reductive haloperidol metabolism in guinea pigs in vivo. When haloperidol was injected intraperitoneally to guinea pigs, it was converted to reduced haloperidol so quickly that 1 hr after the injection the concentration of haloperidol was only about one fifth of that of reduced haloperidol. Dopamine metabolism was enhanced in the striatum after the administration of reduced haloperidol, but this enhancement could mostly be explained by oxidation of a small amount of reduced haloperidol back to haloperidol. The molecular mechanisms of haloperidol reduction should be further studied using guinea pigs as a model for human haloperidol metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Effects of benztropine mesylate on haloperidol-induced prolactin secretion and serum haloperidol levels in rats.

The effects of benztropine mesylate on haloperidol-induced prolactin secretion and serum haloperidol levels were investigated in 240 rats. Animals were pretreated with benztropine mesylate or saline 20 min prior to receiving haloperidol or saline. Serum prolactin and haloperidol levels were analyzed at six time periods over 150 min. There was no significant difference in prolactin levels of control animals, i.e., saline pretreated/saline treated rats compared to benztropine mesylate pretreated/saline treated rats. Haloperidol caused a significant rise (p less than 0.0001) in serum prolactin compared with controls. The prolactin concentration for the 30-150-min sampling period was significantly higher when the rats received benztropine mesylate prior to haloperidol (p less than 0.05). There was a significant correlation (r = 0.57, p less than 0.001) between serum haloperidol levels and serum prolactin levels in haloperidol-treated animals pretreated with either saline or benztropine mesylate. Additionally, serum haloperidol levels were not significantly different in animals pretreated with benztropine mesylate compared with those pretreated with saline. Thus, the enhancement of prolactin levels by benztropine mesylate was independent of any effect of haloperidol metabolism. This study appears to indicate that in the rat, cholinergic mechanisms exert a weak inhibitory effect on prolactin secretion under conditions of dopamine blockade.

Animals↗
PubMed1990

Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients.

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15 +/- 0.32 l/h/kg and 0.76 +/- 54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.

Adult↗
PubMed1984

Reduced haloperidol in the post-mortem brains of haloperidol-treated patients.

We measured the concentrations of haloperidol and its reduced alcohol metabolite in human post-mortem tissues with high-performance/liquid chromatography using electrochemical detection. Both haloperidol and reduced haloperidol were detected and quantified in the occipital cortex of nine schizophrenic patients with a history of haloperidol treatment, but not in six samples from nontreated subjects. Reduced haloperidol concentrations were below the detection limit of the assay in several tissues of rats and mice even after 10 days of haloperidol treatment. The results suggest that reduced haloperidol is present in the brains of haloperidol-treated patients at slightly higher concentrations than haloperidol itself. Further studies are warranted to establish the possible biological importance of this haloperidol metabolite.

Adult↗
PubMed2001

Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol.

AIMS: We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol. METHODS: The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. RESULTS: Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated Ki values (0.24 microM and 0.09 microM, respectively) that were substantially lower than that of haloperidol (0.89 microM). The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(+)-enantiomer, with estimated Ki values of 0.11 microM and 1.1 microM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 microM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 microM. CONCLUSIONS: The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.

Binding, Competitive↗
PubMed2000

Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment.

In an open clinical trial, serum concentrations of haloperidol pyridinium (C(HP+)) and reduced haloperidol pyridinium (C(RHP+)), as well as haloperidol (CH) and reduced haloperidol (C(RH)), were measured in 57 schizophrenic and schizoaffective inpatients during 6 weeks of short-term treatment. Psychopathology was monitored with the Brief Psychiatric Rating Scale (BPRS), and extrapyramidal adverse effects were assessed with the Extrapyramidal Symptom Rating Scale (EPS). Significantly linear relationships were found between haloperidol dose (D) and pyridinium metabolite serum concentrations, as well as between C(H) and the pyridinium metabolite serum concentrations. C(HP+) (range, 0.2-4.9 ng/mL) and C(RHP+) (range, 0.03-6.23 ng/mL) were low compared with C(H) and C(RH), being as mean values approximately 7% and 14% of C(H) and C(RH), respectively. Additionally, the values of C(RHP+) and the slope of the correlation of C(H) with the C(RHP+)/C(HP+) ratio were considerably lower than in a previous report of long-term treatment with haloperidol. This is explained by the shorter time of treatment of the present study. Carbamazepine comedication was found to not influence relative pyridinium metabolite serum concentrations C(HP+)/D and C(RHP+)/D. However, the aromatization ratios of haloperidol (C(HP+)/C(H)) and reduced haloperidol (C(RHP+)/C(RH)) were increased by concomitant carbamazepine. As the main result, no relationships between the pyridinium metabolite serum concentrations and clinical variables (BPRS change, EPS, dose of biperiden) were detected. For instance, the aromatization ratios C(HP+)/C(H) and C(RHP+)/C(RH) did not predict clinical improvement or extrapyramidal adverse effects. Therefore, no confirmation of the "pyridinium hypothesis," which suggests haloperidol pyridinium metabolites to be the origin of adverse effects and decreased therapeutic effect, can be derived from this study. However, the authors emphasize that pyridinium metabolites cannot be excluded as the origin of decreased therapeutic effect in long-term treatment and of adverse effects not investigated in the present study, such as tardive dyskinesia. Finally, it is concluded that the serum concentration of the parent drug remains the main variable of interest in the therapeutic drug monitoring of haloperidol during short-term treatment.

Adult↗
PubMed1992

Regional distribution and kinetics of haloperidol binding in human brain: a PET study with [18F]haloperidol.

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.

Adult↗
PubMed1989

Haloperidol and reduced haloperidol plasma levels in Chinese vs. non-Chinese psychiatric patients.

Haloperidol and reduced haloperidol plasma concentrations were measured in age-matched Chinese and non-Chinese patients (n = 32). Steady-state plasma concentrations were obtained 10-12 hours after the bedtime dose. Haloperidol and reduced haloperidol concentrations were measured by liquid chromatography and radioimmunoassay. Haloperidol plasma concentrations did not significantly differ between the populations, but reduced haloperidol levels were 3 times greater in non-Chinese patients than in Chinese patients. The incidence of extrapyramidal side effects was higher in Chinese patients (18 vs. 10), while non-Chinese patients with extrapyramidal symptoms had higher reduced haloperidol plasma levels. Logistic regression analysis revealed that ethnicity and reduced haloperidol/haloperidol ratios were important variables in predicting extrapyramidal symptoms. These results suggest that the metabolism and disposition of haloperidol and reduced haloperidol could differ among ethnic populations.

Adult↗
PubMed1988

An ultrasensitive method for the measurement of haloperidol and reduced haloperidol in plasma by high-performance liquid chromatography with coulometric detection.

A new analytical method has been developed for the simultaneous quantitation of haloperidol and reduced haloperidol in plasma. The method is based on high performance liquid chromatography (HPLC) with coulometric detection. The extraction and sample clean up procedures are simple and rapid to execute, yet yield chromatograms virtually free of interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. The detection limits for haloperidol and reduced haloperidol are 20 pg/ml plasma, and the limits of quantitation are 50 pg/ml for both drug and metabolite. Standard curves were linear down to 50 pg/ml with coefficients of variation of less than 7.0% at the limits of quantitation. The method was applied to the study of the plasma levels of haloperidol and reduced haloperidol in two healthy subjects. It was possible to monitor the plasma levels of haloperidol for at least 96 h (4 days) after the administration of a 5-mg oral dose of haloperidol. It was also possible to monitor reduced haloperidol levels over 96 h in one subject, although the metabolite was not detectable in the plasma of the other at any stage.

Chromatography, High Pressure Liquid↗
PubMed1984

Possible interference by the reduced haloperidol metabolite with the radioimmunoassay and radioreceptor assay of blood haloperidol.

Serum or plasma samples from haloperidol-treated patients were analyzed by high performance liquid chromatography (HPLC) with electrochemical detection, radioimmunoassay (RIA), and radioreceptor assay (RRA). The HPLC assay allows simultaneous quantitation of the reduced alcohol metabolite of haloperidol. The HPLC and RIA haloperidol results correlated fairly well (r = 0.63), while the HPLC reduced haloperidol and the RIA haloperidol had a weak correlation (r = 0.28). The RRA haloperidol results had a fair correlation with those of the HPLC (r = 0.55), but their correlation with the HPLC reduced haloperidol was almost as good (r = 0.52). The RIA tended to give lower and the RRA higher apparent haloperidol concentrations than the HPLC assay. The results indicate that the reduced haloperidol does not interfere with the RIA procedure used in this study, but it may partially account for higher concentrations obtained with the RRA.

Chromatography, High Pressure Liquid↗
PubMed1995

Intra- and interethnic variability in reduced haloperidol to haloperidol ratios.

Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.

Adult↗
PubMed1998

Mirtazapine enhances the effect of haloperidol on apomorphine-induced climbing behaviour in mice and attenuates haloperidol-induced catalepsy in rats.

Activation of 5-HT1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT1A receptor stimulating properties as well as antagonist properties at alpha2-adrenoceptors and 5-HT2 receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2-22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/kg) was attenuated by mirtazapine (2.2-22 mg/kg). The strongest effect was seen at 90 min after haloperidol treatment. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window.

Animals↗
PubMed1989

Repeated haloperidol administration changes basal release of striatal dopamine and subsequent response to haloperidol challenge.

The effects of acute or repeated administration of haloperidol on release of dopamine (DA) and homovanillic acid (HVA) from striata of awake rats were studied using a microdialysis probe. A single injection of haloperidol (1 mg/kg, i.p.) produced a time-dependent increase in DA and HVA in the perfusate. Comparative studies in rats anesthetized with 300 mg/kg of chloral hydrate given i.p. found that anesthesia decreased the basal release of DA, but not HVA, and significantly blocked haloperidol-induced increases in DA, while haloperidol-induced increases in HVA were not affected. Studies done in awake rats found that 21 repeated daily injections of haloperidol increased the basal release of DA, but not HVA. Subsequent challenge with haloperidol indicated a significant decrease in responsiveness to haloperidol-induced release of DA, but not HVA, in chronically dosed rats. These data suggest that repeated exposure to haloperidol causes a compensatory increase in extracellular DA release. That these compensatory changes may be associated with the increased therapeutic efficacy or extrapyramidal side effects of neuroleptics following repeated dosing warrants further study.

Animals↗