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PubMed2005

Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients.

INTRODUCTION: The objective of this study was to provide more clinical data of the potential neurotoxic metabolite haloperidol pyridinium (HP+) in psychiatric patients during long-term treatment with haloperidol and to investigate a possible relationship with extrapyramidal adverse effects. METHODS: Serum concentrations of HP+, reduced haloperidol pyridinium (RHP+), haloperidol (H), and reduced haloperidol (RH) were measured for 41 psychiatric patients of a nursing residence (27 females, 14 males, 34-79 years of age). Severity of tardive dyskinesia (TD) and parkinsonism were rated with the Tardive Dyskinesia Rating Scale (TDRS) and Extrapyramidal Symptom Rating Scale (EPS), respectively. In addition, several patient- and treatment-related variables were investigated, for example cumulative dose (Dcum) of haloperidol. RESULTS: Serum concentration were 0.69 microg/L (0-1.53) for HP+ and 0.41 microg/L (0-1.50) for RHP+ with ratios HP+/H of 0.072 (0.017-0.18) and RHP+/RH of 0.094 (0-0.36) at doses of 10.6 mg/day (3.6-30) [mean (range) in each case]. Multiple regression revealed decreased clearance of HP+ with age. One third of patients with more severe TD (TDRS > or = 10, n = 14) had an increased relative body burden of HP+ and H, as calculated by HP+/H * Dcum of haloperidol than patients with less severe or no TD (TDRS < 10, n = 27), i. e. 5.8 g (2.0-11.9) and 3.3 g (0-9.5), respectively [mean (range), p = 0.005, U test]. Patients with mild to severe parkinsonism (EPS > 0.3, n = 16) had a significantly higher aromatization ratio HP+/H than patients with no or minimal parkinsonism (EPS < or = 0.3, n = 25), i. e. 0.14 (0.04-0.36) and 0.06 (0-0.16), respectively [mean (range), p = 0.003, U test]. CONCLUSION: In psychiatric patients treated with haloperidol for the long-term, the severity of TD and parkinsonism is associated with an increased ratio HP+/H. This is explained by the neurotoxicity of HP+ according to the pyridinium hypothesis.

Adult↗
PubMedDate not supplied

Two fatalities involving haloperidol.

Two cases are presented in which haloperidol was identified in postmortem toxicological analysis. One case was a suicidal overdose of the drug; the blood concentrations of haloperidol and reduced haloperidol were 1.9 and 1.4 mg/L, respectively. Bile, liver, and urine concentrations were 3.4 mg/L, 44 mg/Kg and 6.6 mg/L for haloperidol and 1.6 mg/L, 43 mg/Kg, and 5.7 mg/L for reduced haloperidol, respectively. The second case was believed to be a natural cardiac death with a blood haloperidol concentration of 0.6 mg/L. The distribution of haloperidol and reduced haloperidol in this case was bile, 0.4 and 0.5 mg/L; kidney, 0.7 and 2.3 mg/Kg; liver, 5.0 and 13 mg/Kg; and urine, 0.4 and 2.3 mg/L.

Adult↗
PubMed1998

A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia.

We conducted a placebo-controlled, randomized, double-blind, 8-week trial of sertraline added to haloperidol treatment in patients with schizophrenia to evaluate changes in clinical measures and pharmacokinetic interactions with haloperidol. In addition to their haloperidol regimen, 36 inpatients with chronic schizophrenia were randomly assigned to receive capsulized sertraline (50 mg/day; N = 18) or identically capsulized placebo (N = 18) for 8 weeks. The results from the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) Scale, Simpson-Angus Extrapyramidal Effects (S-A) Scale, and plasma concentration levels of haloperidol and reduced haloperidol were examined at baseline and 2, 4, 6, and 8 weeks of treatment. No significant differences between the three PANSS factors (positive, negative, general psychopathology) scores, CGI Scale scores, or S-A Scale scores were recorded at any point during sertraline and placebo treatment. Neither plasma haloperidol or reduced haloperidol concentrations was changed significantly at any point during the sertraline and placebo treatments. In this study, the addition of sertraline 50 mg to the treatment regimen of inpatients did not differ significantly from the placebo effect on positive and negative symptoms and extrapyramidal side effects. The results further indicate that the pharmacokinetics of haloperidol are seemingly unaffected by sertraline.

Adult↗
PubMed1999

Acute mania: haloperidol dose and augmentation with lithium or lorazepam.

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.

Adult↗
PubMed1999

Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice.

The effects of repeated ingestion of grapefruit juice, an inhibitor of cytochrome P4503A4 (CYP3A4), on the steady-state plasma concentrations of haloperidol and reduced haloperidol were examined. Twelve schizophrenic inpatients receiving haloperidol 12 mg/day, ingested grapefruit juice 600 ml/day for 7 days. Blood samples were collected before and during grapefruit juice coadministration and 1 week after its discontinuation together with an assessment of clinical status. Plasma drug concentrations were measured using high-performance liquid chromatography. Clinical status for each patient was assessed by the Brief Psychiatric Rating Scale (BPRS) and the UKU side-effect rating scale (UKU). Plasma concentrations of haloperidol and reduced haloperidol during grapefruit juice coadministration (9.0 +/- 3.0 and 2.6 +/- 1.4 ng/ml, respectively) were not significantly different from those before grapefruit juice coadministration (9.1 +/- 2.8 and 2.6 +/- 1.5 ng/ml) or those 1 week after its discontinuation (8.8 +/- 2.7 and 2.6 +/- 1.3 ng/ml). There was no change in the scores of BPRS or UKU during the study period. The present results shows that grapefruit juice does not affect the plasma concentrations of haloperidol and reduced haloperidol or clinical status in patients receiving haloperidol.

Adult↗
PubMed2000

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance.

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.

Animals↗
PubMed2003

Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients.

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.

Adult↗
PubMed1995

Characterization of inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current in rat phaeochromocytoma cells.

1. Inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current was characterized in rat phaeochromocytoma PC12 cells by use of whole-cell voltage-clamp techniques. 2. Haloperidol or chlorpromazine (1 and 10 microM) inhibited a K+ current activated by a test potential of +20 mV applied from a holding potential of -60 mV. The K+ current inhibition did not exhibit voltage-dependence when test potentials were changed between -10 and +40 mV or when holding potentials were changed between -120 and -60 mV. 3. Effects of compounds that are related to haloperidol and chlorpromazine in their pharmacological actions were examined. Fluspirilene (1 and 10 microM), an antipsychotic drug, inhibited the K+ current, but pimozide (1 and 10 microM), another antipsychotic drug did not significantly inhibit the K+ current. Sulpiride (1 or 10 microM), an antagonist of dopamine D2 receptors, did not affect the K+ current whereas (+)-SCH-23390 (10 microM), an antagonist of dopamine D1 receptors, reduced the K+ current. As for calmodulin antagonists, W-7 (100 microM), but not calmidazolium (1 microM), reduced the K+ current. 4. The inhibition by haloperidol or chlorpromazine of the K+ current was abolished when GTP in intracellular solution was replaced with GDP beta S. Similarly, the inhibition by pimozide, fluspirilene, (+)-SCH-23390 or W-7 was abolished or attenuated in the presence of intracellular GDP beta S. The inhibition by haloperidol or chlorpromazine was not prevented when cells were pretreated with pertussis toxin or when K-252a, an inhibitor of a variety of protein kinases, was included in the intracellular solution. 5. Haloperidol and chlorpromazine reduced a Ba2+ current permeating through Ca2+ channels. Inhibition by haloperidol or chlorpromazine of the Ba2+ current was not affected by GDP beta S included in the intracellular solution. 6. It is concluded that haloperidol and chlorpromazine inhibit voltage-gated K+ channels in PC12 cells by a mechanism involving GTP-binding proteins. The inhibition may not be related to their activity as antagonists of dopamine D2 receptors or calmodulin antagonists.

Animals↗
PubMed1990

A double-blind multicentre study comparing remoxipride, two and three times daily, with haloperidol in schizophrenia.

A double-blind multicentre study comparing the efficacy and safety of remoxipride in relation to haloperidol was conducted in 160 inpatients with schizophrenic illness diagnosed according to DSM-III. The study period was 4 weeks. The mean daily dose of remoxipride (whether given twice or three times daily) during the last week of treatment was 395 mg; the corresponding dose of haloperidol was 17 mg per day. No significant difference in therapeutic efficacy was found; Brief Psychiatric Rating Scale (BPRS) median total scores dropped from 41 to 20 (remoxipride twice daily, n = 51), 43 to 20 (remoxipride three times daily, n = 44) 40 to 19 (haloperidol three times daily, n = 48) at last valid rating. According to Clinical Global Impression (CGI) 68% in the remoxipride twice daily, 58% in the three times daily and 60% in the haloperidol group were very much or much improved. Treatment-emergent extrapyramidal checklist symptoms (hypokinesia, rigidity and tremor) were statistically significantly more frequent and more severe during haloperidol than during remoxipride treatment despite a statistically significantly higher concurrent use of anticholinergic drugs in the haloperidol group. Haloperidol treated patients reported more tiredness and drowsiness than remoxipride treated patients. Also, haloperidol treated patients had a significantly higher frequency of extrapyramidal symptoms on 8 out of 10 items of the Simpson and Angus scale.

Acute Disease↗
PubMed1990

A double-blind comparative multicentre study of remoxipride and haloperidol in schizophrenia.

In a double-blind multicentre study of parallel group design the efficacy and safety of remoxipride and haloperidol were compared in a total of 96 patients with acute episodes of schizophrenic or schizophreniform disorder according to DSM-III. There were 48 patients in each treatment group; 27 men and 21 women in the remoxipride group, 33 men and 15 women in the haloperidol group. The median duration of illness was 7 years in both groups. The mean daily dose was 437 mg for remoxipride and 10.6 mg for haloperidol during the last week of treatment. No statistically significant differences in total BPRS scores were found between remoxipride and haloperidol. The median total BPRS scores at the start of active treatment were 26 in the remoxipride and 27 in the haloperidol group; these were reduced to 16 and 12.5, respectively, at the last rating. According to Clinical Global Impression (CGI), 43% of patients in the remoxipride group and 68% of those in the haloperidol group improved much or very much during treatment. This difference was not statistically significant. Treatment-emergent extrapyramidal side effects such as akathisia, tremor, and rigidity occurred significantly more frequently in the haloperidol group; this group also made more frequent use of anticholinergic drugs. Neither of the trial drugs seriously affected laboratory or cardiovascular variables. It is concluded that remoxipride has an antipsychotic effect in a dose range of 150-600 mg per day comparable to that of haloperidol in doses up to 20 mg per day but with fewer extrapyramidal side effects.

Acute Disease↗
PubMed2003

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.

Administration, Oral↗
PubMed1997

Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette's disorder.

OBJECTIVE: The authors evaluated the relative efficacy and safety of pimozide and haloperidol in the treatment of Gilles de la Tourette's syndrome in children and adolescents. METHOD: A double-blind, 24-week, placebo-controlled double crossover study of equivalent dose formulations of haloperidol and pimozide was conducted with 22 subjects, aged 7-16 years, with Tourette's disorder who were randomly assigned to first one active drug treatment and then the other. Biweekly assessment and flexible dose titration mimicked clinical practice. The primary outcome variable was total score on the Tourette Syndrome Global Scale. Final outcome was determined after 6 weeks of each treatment (placebo, pimozide, haloperidol), with a 2-week placebo baseline period and intervening 2-week placebo washout periods between treatments. RESULTS: Pimozide proved significantly different from placebo in affecting the primary outcome variable, whereas haloperidol failed to have a significant effect. Haloperidol exhibited a threefold higher frequency of serious side effects and significantly greater extrapyramidal symptoms relative to pimozide. Haloperidol-associated treatment-limiting adverse events were experienced by 41% of the patients. The therapeutic doses of pimozide and haloperidol were equivalent (mean = 3.4 mg/day, SD = 1.6, and mean = 3.5 mg/day, SD = 2.2, respectively). CONCLUSIONS: At equivalent doses, pimozide is superior to haloperidol for controlling symptoms of Tourette's disorder in children and adolescents.

Adolescent↗
PubMed2002

Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety.

OBJECTIVE: The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania. METHOD: This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures. RESULTS: The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively. CONCLUSIONS: Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated.

Acute Disease↗
PubMed1979

A comparative study of haloperidol and diazepam in the treatment of anxiety.

In a single-blind study in general practice, 60 patients with anxiety neuroses were randomly allocated to receive either 0.5 mg haloperidol twice daily or 2 mg diazepam 3-times daily for 6 weeks. Eighteen patients (6 on haloperidol and 12 on diazepam) were excluded from the analysis of efficacy. On the Hamilton Rating Scale both haloperidol and diazepam reduced the anxiety and depression scores. The investigator's assessment of 14 anxiety symptoms and signs indicated that haloperidol produced significantly (p=0.05) greater symptomatic improvement than diazepam after 4 and 6 weeks of treatment, and the patients' overall response was also significantly (p less than 0.005) greater with haloperidol. After 6 weeks, 93% of patients felt 'better' or 'much better' on haloperidol, compared with 83% on diazepam. A few, minor side-effects were reported, slightly fewer on haloperidol than on diazepam. In the parameters tested in this study, haloperidol has been shown to be more effective than diazepam in the treatment of anxiety neuroses and appears to provide significantly better overall symptomatic relief and to be more acceptable to patients than diazepam.

Adult↗
PubMed1995

Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group.

BACKGROUND: This study was performed in order to evaluate the short-term efficacy and safety of fixed risperidone doses compared to haloperidol. METHOD: In a multi-national, parallel-group, double-blind study, patients with chronic schizophrenia (DSM-III-R) were randomly assigned to risperidone 1, 4, 8, 12 or 16 mg or haloperidol 10 mg daily for 8 weeks. Efficacy was assessed by the Positive and Negative Syndrome Scale for schizophrenia (PANSS) and clinical global impression (CGI), and safety primarily by the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: One thousand three hundred and sixty-two patients were evaluated. The optimum risperidone doses were 4 mg and 8 mg, with response rates of 63.4% (56.8%; 69.7%) and 65.8% (59.2%; 71.9%) respectively. Response rate in haloperidol-treated patients was 58.7% (52.0%; 65.3%); the 95% confidence intervals (CI) of the differences between risperidone 4 mg or 8 mg and haloperidol were (- 4.3%; 13.7%) and (- 1.9%; 16.0%) respectively. There were no significant differences in CGI scores at endpoint between risperidone 4 mg, 8 mg, 12 mg and 16 mg and haloperidol (3.0, 3.0, 3.2, 3.1 and 3.1 respectively); the 95% CI of the differences between risperidone 4 mg or 8 mg and haloperidol were ( - 0.4; 0.1) and ( - 0.3; 0.2) respectively. Mean shifts to the maximum total ESRS scores versus baseline (mean (confidence interval)) were significantly greater in haloperidol-treated patients (5.1 (4.0; 6.2)) than in the risperidone 1, 4, 8 and 12 mg groups (1.1 (0.3; 1.9); 1.8 (0.9; 2.7); 2.7 (1.8; 3.6) and 3.2 (2.3; 4.1) respectively (P < 0.05)). CONCLUSION: Risperidone is an effective antipsychotic for the treatment of chronic schizophrenia; doses of 4 and 8 mg seem to be optimal and have a lower incidence of side-effects than haloperidol.

Adult↗
PubMed1999

[Functional characterization of a sigma receptor and its gene expression by haloperidol].

Sigma (sigma) receptors are expressed in the brain as well as endocrine and immune systems. Several antipsychotic drugs such as haloperidol and pentazocine can bind to the sigma receptor, which is believed to play important roles in the pathogenesis of schizophrenia by as yet unknown mechanisms. Two subtypes of sigma receptors (sigma 1 and sigma 2) have been identified, and the sigma 1 receptor was cloned. The chronic administration of haloperidol to guinea pigs produced a marked inhibition of the binding to sigma 1 receptor, but did not change sigma 2-receptor binding. Scatchard analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. The treatment with haloperidol also did not affect sigma 1-receptor mRNA detected by the RNase protection assay. The treatment of rats with haloperidol inhibited sigma 1-receptor binding to a much lesser extent than that to guinea pigs. These finding suggest that haloperidol or its metabolite, reduced haloperidol, which is produced in greater quantity in humans and guinea pigs than in rats and mice, might influence protein translation or modification of sigma 1-receptor without changing the transcriptional activity. The mechanisms through which sigma receptors could be differently regulated in vivo by chronic treatment with haloperidol may contribute to the therapeutic efficacy of haloperidol.

Animals↗
PubMed2002

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.

OBJECTIVE: To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. DESIGN: Retrospective population pharmacokinetic study. PARTICIPANTS: 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. METHODS: Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. RESULTS: The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.

Adolescent↗
PubMed1985

Preparation and characterization of antisera and monoclonal antibodies to haloperidol.

For the first time a library, of monoclonal antibodies (MoAbs) to the butyrophenone haloperidol (D-2 antagonist) has been prepared. Synthesis of a haloperidol derivative suitable for chemical coupling to a protein carrier via oxobutyric acid produced an immunogen which was used to develop two polyclonal antisera and twelve MoAbs specific for the hapten. Our library of MoAbs can be grouped into three classes; 1) high affinity and specificity for free 3H-haloperidol, 2) moderate affinity with significant cross-reactivity to other butyrophenone ligands, and 3) a group which binds poorly to free 3H-haloperidol but instead recognizes the ligand only when it is coupled to carrier protein. Clone (189(2)-6) was found to have the highest equilibrium binding affinity (Kd = 4 nM) and is far more specific than the currently available antisera to haloperidol. This MoAb has significantly lower affinity for all of the common metabolites of haloperidol. This capability makes 189(2)-6 a candidate for further development with regard to use in clinical radioimmuno-assays of therapeutic drug levels. In addition, one of the anti-haloperidol Moabs (190(2)-6) binds more tightly to spiperone than to haloperidol and displays a qualitative correlation in the rank order of neuroleptic binding affinity for a limited series of analogs when compared to membrane bound D-2 receptor binding.

Animals↗