19F NMR as a powerful technique for the assay of anti-psychotic drug haloperidol in human serum and pharmaceutical formulations

19F nuclear magnetic resonance was used as a suitable analytical tool for the identification and selective determination of haloperidol in human serum and pharmaceutical preparations. The method is based on the integration of appropriate signals of haloperidol and trifluoroacetic acid as an internal standard. The proposed method is a rapid and facile, while without any sample pretreatment, manipulation of large samples and lengthy instrument time. The regression equation for haloperidol in human serum showed a good linearity in the range of 60-600 microg ml(-1) with a detection limit of 1.4 microg ml(-1). The mean recovery results on human serum samples ranged from about 96-103%, with relative standard deviations <8%. The method was also applied successfully to the determination of haloperidol in real pharmaceutical samples, and compared with the results obtained by a reference method. The drug's degradation was studied by the proposed method in hydrochloric acid media and main products were identified.     

Neuroleptic monitoring: relation between antipsychotic efficiency and radioreceptor assay of serum haloperidol

Objective: We report preliminary results from use of a radioreceptor assay (RRA) to measure serum haloperidol levels and their relation to clinical response and adverse effects in 19 psychotic patients with positive symptoms treated with haloperidol. Methods: Blood samples were taken on Days 7, 14 and 21. Clinical evaluation was based on the PANSS, and UKU scales. The D2 antidopaminergic RRA was used to measure haloperidol serum levels. Results: Our results show a correlation between psychosis with positive symptoms assessed by positive scores in the PANSS and the serum drug level measured by RRA concentrations. The observed relationship made it possible to establish a therapeutic serum range of haloperidol equivalents 15–30 ng/ml⁻¹. This range contained no “non-responders”. Analysis of the correlation between each item on the positive subscale of the PANSS and the RRA concentration suggested that there was no specific symptom of psychosis closely related to RRA concentration during the first 15 days of treatment. In the third week, however, certain specific symptoms were closely connected to the RRA concentration. Conclusion: From these results, it can be concluded that antipsychotic activity can be related to blockade of serum D2 dopamine receptors. In future would be desirable to monitor neuroleptic treatment in this way. The study also showed that the antipsychotic treatment did not correct any specific component of the psychosis during the first stage of the treatment but that it did so at later times. Received: 19 May 1995/Accepted in revised form: 5 February 1996     

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response,side effects,serum haloperidol,and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.     

Stability of serum neuroleptic and prolactin concentrations during short- and long-term treatment of schizophrenic patients

The potential importance of neuroleptic activity measures in the management of schizophrenia warrants attention to the methods for assessing neuroleptic bioactivity and stability of neuroleptic bioactivity over time. We have carried out measurements of serum neuroleptic and prolactin concentrations in 18 schizophrenic patients treated with haloperidol or thioridazine for up to 1 year. Serum neuroleptic levels were measurd by a radioreceptor assay using porcine striatum. The lower limit of sensitivity of the assay was 0.6 ng haloperidol/ml, the intra- and interassay coefficients of variation 3 and 9%, respectively. A linear correlation was observed between haloperidol dose (5–30 mg/d) and serum neuroleptic activity (r=0.706, P<0.001) and a curvilinear relationship between thioridazine dose (50–600 mg/d) and serum neuroleptic activity in schizophrenic outpatients. There was a positive correlation between serum neuroleptic and prolactin concentrations for the patients taking haloperidol (r=0.620, P<0.001) or thioridazine (r=0.542, P<0.001). In patients taking a constant dose of haloperidol or thioridazine for up to 1 year serum neuroleptic activity remained stable, suggesting the absence of metabolic tolerance; the observation of a decrease of 38±16% (mean ± SD) in serum prolactin concentrations in patients treated with haloperidol but no prolactin decrease with thioridazine suggests that under certain neuroleptic treatment conditions a functional tolerance develops in the tuberoinfundibular dopamine system.     

Determination of haloperidol in biological samples using molecular imprinted polymer nanoparticles followed by HPLC-DAD detection

In this study an extraction procedure using molecular imprinted polymer nanoparticles for the determination of haloperidol in biological samples is proposed. The haloperidol imprinted polymer nanoparticles were synthesized successfully by precipitation polymerization in a flask containing haloperidol as a template, ethyleneglycoldimethacrylate as a crosslinking agent, methacrylic acid as a functional monomer, and 2,2′-azobisisobutyronitrile as an initiator. The leached and unleached polymer nanoparticles have been characterized by infrared spectroscopy and scanning electron microscopy. The effect of different variables such as the pH of solution, uptake and elution time, type, and the least amount of eluent for elution of haloperidol from polymer was evaluated. Extraction efficiencies more than 97% were obtained by elution of the polymer with 1.5 mL of methanol–acetic acid–trifluoroacetic acid 79.9:20:0.1. Under optimal conditions maximum adsorption capacity was obtained 153.84 mg g⁻¹. The detection limit of the proposed procedure was between 0.2 and 0.35 μg L⁻¹. Finally this method was applied to the determination of haloperidol in plasma and urine samples and satisfactory results were achieved (RSD < 6.9%).     

Development and validation of spectrofluorimetric method for determination of haloperidol in pharmaceutical dosage forms

A simple, sensitive, and accurate spectrofluorimetric method has been developed for the determination of haloperidol in pharmaceutical preparations. The present method is based on the formation of an ion‐pair complex between haloperidol and alizarin red S at pH 3.4 which is extractable with chloroform. The ion‐pair complex exhibits maximum fluorescence intensity at 564 nm with excitation at 466 nm. The reaction conditions were optimized to obtain maximum fluorescence intensity. The relation between the fluorescence intensity and concentration was found to be linear over the range 0.8–20 µg/mL with detection limit of 0.08 µg/mL. The method was successfully employed for quantitation of the active ingredient haloperidol in pharmaceutical preparations. Statistical comparison of the results with the reference method shows excellent agreement and indicates no significant difference between the methods compared in terms of accuracy and precision. Copyright © 2010 John Wiley & Sons, Ltd.     

Radioreceptor assay of haloperidol tissue levels in the rat

The levels of apparent haloperidol-like biological activity in serum and brain were estimated by a radioreceptor assay (RRA) involving competition for binding of [³H]-spiroperidol to a membrane preparation of calf caudate nucleus. The RRA was found to be capable of measuring haloperidol sensitively to 3 pmol/ml serum and 140 pmol/g brain. With the RRA technique, recovery of haloperidol from serum or brain was 90–100%. Excellent correlations were found among results obtained with the RRA, by a corroborative gas chromatography-mass spectrometry method, and by radioimmunoassay. Correlations between serum and brain levels in individual animals were quite close, and dose versus tissue level and time course versus tissue level relationships were demonstrated. Since the binding assay method is simple and evidently reliable, it provides a highly versatile addition to chemical assay methods. It is particularly well suited to experiments which attempt to correlate tissue drug levels with behavioral or clinical effects.     

Direct radioimmunoassay for haloperidol in human serum

A direct radioimmunoassay for the accurate determination of haloperidol in human serum has been developed. Based on recent information about the metabolism of haloperidol, a new haloperidol hapten, in which a (3-carboxypropionyl)methylamino group was attached as a bridge in the place of fluorine atom, was synthesized and coupled to bovine serum albumin through the bridge to provide a new immunogen. Guinea pigs were used for the immunization. Since the antisera obtained by the new immunogen still cross reacted greater than 10% with reduced haloperidol, the immunological tolerance to reduced haloperidol was induced by administration of a copolymer of D-glutamic acid and D-lysine linked with reduced haloperidol. This gave an antiserum in guinea pigs which was highly specific for unchanged haloperidol with negligible cross reactivity (less than or equal to 1.0%) to any haloperidol metabolites including the newly found ones. With the newly developed antiserum and [3H]haloperidol, serum haloperidol levels can be determined over the concentration range from 0.3 to 20 ng/mL, using 0.1 mL of human serum, without an extraction procedure.     

The relationship of haloperidol concentrations to therapeutic response

Data from pharmacokinetics studies that examined the relationship of haloperidol serum concentrations and therapeutic response in schizophrenic patients were reexamined utilizing the method of logistic regression analysis. A linear rather than a curvilinear relationship was obvious between serum haloperidol concentration and therapeutic response according to both the regression analysis and inspection of the distribution of the data. It was concluded that a serum haloperidol concentration in the range of 9 to 15 ng/ml was associated with a 30% decrease in the total Brief Psychiatric Rating Scale (BPRS) score. Haloperidol concentrations above these appear unlikely in the majority of patients to produce any additional reduction of symptoms. The BPRS psychosis factor finding suggested an analogous finding for serum haloperidol concentrations between 12 and 17 ng/ml. The analyses suggest that the probability of response to haloperidol seems to reach a point of diminishing return at concentrations of approximately 9 to 17 ng/ml. Serum concentrations above this limit do not appear to either decrease or increase the probability of response.     

Pharmacokinetics of haloperidol in psychotic patients

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5–5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79±0.03. The blood clearance was then calculated to be 550±133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9±2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60±0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3±1.1 h and a longer absorption half-life (1.9±1.4 h) was found in the patients compared with healthy volunteers.     

Neurometabolic and behavioural effects of haloperidol in relation to drug levels in serum and brain

Summary A method has been developed for the quantitative determination of haloperidol in brain and other tissues. Such determinations have been made after acute and chronic administration of haloperidol to Sprague-Dawley rats. Different regions of the brain including the striatum, the limbic forebrain and the cerebellum have been analyzed separately. The haloperidol effects on Dopa formation have been studied in the same tissue samples. The stimulation of prolactin secretion via blockade of hypothalamic dopaminergic mechanisms and behavioural effects of the drug have been evaluated in parallel experiments.The elimination of haloperidol from brain tissue is a multiphasic process. The fourth phase of elimination is the slowest with a half life of 4 days. No strict correlation was found between serum and brain concentrations of haloperidol. Both after acute and chronic administration there exists apparently a saturating dose above which the brain concentration of the drug increases very little. The dose seems to coincide with that beyond which little increase in Dopa formation is observed. A pharmacokinetic analysis suggests an element of saturable binding or transfer of haloperidol to brain tissue. This mechanism is not preferentially localized to areas of brain rich in dopaminergic synapses. A good correlation was found between the haloperidol concentration in the brain on the one hand and its effects on behaviour, on serum prolactin values and on Dopa formation on the other.     

Simultaneous Spectrophotometric Estimation of Haloperidol and Trihexyphenidyl in Tablets

The combination of haloperidol and trihexyphenidyl is a dosage form to be used as antidyskinetic agent. Literature revealed that there is no single method for the simultaneous estimation of these drugs in tablet dosage form, which prompted us to develop a simple, rapid, accurate, economical and sensitive spectrophotometric method. The simultaneous estimation method is based on the principle of additivity of absorbance, for the determination of haloperidol and trihexyphenidyl in tablet formulation. The absorption maxima of the drugs were found to be at 245.0 nm and 206.0 nm respectively for haloperidol and trihexyphenidyl in methanol and 0.1N HCl (90:10). The obeyance of Beer Lambert’s law was observed in the concentration range of 2.5-12.5 µg/ml for haloperidol and 1.0-5.0 µg/ml for trihexyphenidyl. The accuracy and reproducibility of the proposed method was statistically validated by recovery studies.     

Change in haloperidol level due to carbamazepine--a complicating factor in combined medication for schizophrenia

Serum haloperidol levels were measured in patients who received haloperidol alone and, subsequently, haloperidol in combination with carbamazepine or lithium carbonate. Haloperidol levels and the level- dose ratios dropped about 50% in patients receiving carbamazepine. They remained the same in most patients receiving lithium carbonate. One patient receiving added carbamazepine experienced worsening of symptoms; this was associated with a drop in serum haloperidol level. Two other patients receiving added carbamazepine showed significant symptom reduction, although they also sustained drops in serum haloperidol levels. It is not clear whether these two individuals benefited from a primary antipsychotic effect of carbamazepine or from reduction of "toxic" haloperidol levels. Serum levels of antipsychotic medication should be monitored carefully when these medications are prescribed in combination with carbamazepine.     

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8–18 ng/ml or 25–35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Week 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r=–0.43,P<0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol+reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (<25% improvement in BPRS from baseline and week 2 BPRS <55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.From the Mental Health Research Center — Major Psychoses, funded in part by NIMH Grant #5 P50 MH43271     

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.     

The Effect of Haloperidol on Ventricular Fibrillation Threshold in Pigs

Abstract: Ventricular fibrillation has been observed in association with the administration of haloperidol. This study was designed to determine the effect of intravenous haloperidol on ventricular fibrillation threshold (VFT). VFT's were determined prior to and 15 min. following an intravenous infusion of haloperidol (50 mg administered over 10 min.) in five pigs anaesthetized with α-chloralose. VFT's were determined using a single stimulus method. Mean arterial pressure (MAP), heart rate (HR), and electrocardiogram (ECG) were monitored continuously. Mean VFT (mA) at baseline and following haloperidol infusion was 50.2 + 4.6 and 65.1 + 12.8, respectively (P < 0.05). Mean MAP (mmHg) at baseline and following haloperidol infusion was 127 + 32 and 107 + 23, respectively (P < 0.05). Haloperidol infusion did not significantly influence mean HR, QRS duration or corrected QT interval. Intravenous haloperidol increases VFT and decreases MAP in pigs. In this model, haloperidol may offer protection against ventricular fibrillation. Further study is required to determine the clinical significance of the antifibrillatory effect of haloperidol.     

国产利培酮对男性精神分裂症患者催乳素影响的临床研究

目的探讨国产利培酮（索乐）对精神分裂症男性患者血清催乳素（PRL）水平影响。方法将60例符合中国精神疾病障碍分类第3版（CCMD-3）精神分裂症诊断标准的男性患者随机分为利培酮（索乐）组（30例）和氟哌啶醇组（30例）,采用酶联免疫法测定两组治疗前后的PRL水平;采用PANSS量表评定两组临床疗效。结果①两组治疗8周末的PANSS量表评分均显著低于治疗前（P〈0．01）;②治疗前利培酮（索乐）组与氟哌啶醇组的PRL水平差异无统计学意义;治疗后利培酮（索乐）组与氟哌啶醇组的PRL水平均比治疗前升高,但两组间无显著性差异（P〉0．05）。结论国产利培酮（索乐）和氟哌啶醇均能升高患者的PRL水平,但两者差异无显著性。     

Behavioural and biochemical effects of haloperidol during the oestrous cycle of the rat

The effects of two doses (1 and 2 mg/kg, i.p.) of haloperidol (HAL) on catalepsy, on concentrations of DA and DOPAC in frontal cortex, nucleus accumbens and striatum and on serum levels of oestradiol were investigated in intact female rats during the 4-day oestrous cycle. Catalepsy induced by haloperidol did not vary much during phases of the cycle. The turnover of DA in the cortex induced by haloperidol was significantly greater on proestrus and smaller on oestrus. The effect of haloperidol on the turnover of DA in the nucleus accumbens and in striatum was marginally affected by the oestrous cycle being greatest on oestrus. The levels of serum oestradiol were higher on proestrus and lower on oestrus. No significant differences were detected between diestrus and metestrus. After haloperidol there was a dramatic increase in serum oestradiol on oestrus, a slight increase on metestrus and diestrus and a decrease on proestrus. However, serum levels of oestradiol were not significantly different between phases of the cycle in rats treated with haloperidol. The results indicate that the oestrous cycle has a detectable influence on DAergic mechanisms in the frontal cortex and possibly in the tuberoinfudibular system, brought about by treatment with haloperidol.     

Age-related alteration of haloperidol-serum protein binding

Serum haloperidol levels were determined in 59 patients, 50-88-years-old, with psychosis, receiving long-term treatment with haloperidol. Although the total (bound and free form) haloperidol level in serum showed a linear correlation with daily dose, there was a larger variation in the relationship between free form and the daily dose compared with total because of inter-individual variation in the serum protein binding of haloperidol. The free fraction of haloperidol in serum increased with age. There was no difference in the ratio of total haloperidol level per daily dose between the adult and elderly groups, whereas the ratio of free haloperidol level per daily dose was significantly higher in the elderly than in the adult group. In the elderly, therefore, the therapeutic window of haloperidol should be assessed using free form level rather than total level, which is influenced by serum protein binding of the drug.