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PubMed2002

Benperidol for schizophrenia.

BACKGROUND: Benperidol is a relatively old antipsychotic drug, marketed since 1966, used in Germany for 30 years, but also available in Belgium, Greece, Italy, the Netherlands and the UK. Benperidol is a butyrophenone antipsychotic, with the highest neuroleptic potency in terms of D2 receptor blockade. Those taking it are, therefore, reputed to be at high risk of extrapyramidal side effects, but benperidol's unusual profile may render it of value to subgroups of people with schizophrenia. OBJECTIVES: To examine the clinical effects and safety of benperidol for those with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's register (January 2001) which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile. We also searched the references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. SELECTION CRITERIA: Randomised controlled trials that compared benperidol with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by two reviewers and papers were ordered, re-inspected and quality assessed. We independently extracted data but excluded data if loss to follow up was greater than 50%. For homogeneous dichotomous data, we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat/harm (NNT/H), on an intention-to-treat basis. MAIN RESULTS: We identified only one unpublished poorly randomised controlled trial (N=40, duration 30 days, comparison perphenazine). Although benperidol was inferior to perphenazine (1 RCT, N=40, global state no better or worse RR 8.0 CI 2.1 to 30, NNH 1.4 CI 1 to 2) poor reporting suggests that an overestimate of effect is likely. It was not possible to report other outcomes. REVIEWER'S CONCLUSIONS: Currently, there are insufficient data from randomised trials to assess the clinical effects of benperidol. This interesting compound merits further research.

Antipsychotic Agents↗
PubMed1991

Determination of benperidol and its reduced metabolite in human plasma by high-performance liquid chromatography and electrochemical detection.

An isocratic high-performance liquid chromatographic method with electrochemical detection for the quantification of benperidol and its suggested reduced metabolite TVX Q 5402 in human plasma is described. The method included a two-step solid-phase extraction on reversed-phase and cation-exchange material, followed by separation on a cyanopropyl silica gel column (5 microns; 250 mm x 4.6 mm I.D.). The eluent was 0.15 M acetate buffer (pH 4.7) containing 25% acetonitrile (w/w). Spiperone served as internal standard. The inclusion of the cation-exchange step provided sample purity higher than those achieved with other methods. After extraction of 1 ml of plasma, concentrations as low as 0.5 ng/ml were detectable for both benperidol and the metabolite. In plasma samples collected from a schizophrenic patient treated with a single oral dose of 6 mg of benperidol, plasma levels of benperidol and of the metabolite could be measured from 20 min to at least 12 h after administration.

Benperidol↗
PubMed1994

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application.

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t1/2 beta values were 5.5 and 4.7 h, respectively, mean-g tmax data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g Cmax maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag, tmax, and Cmax. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite "reduced benperidol" were found to be very low.

Administration, Oral↗
PubMed1992

Specific binding of 3N-(2'-[18F]fluoroethyl)benperidol to primate cerebral dopaminergic D2 receptors demonstrated in vivo by PET.

3N-(2'-[18F]Fluoroethyl)benperidol ([18F]FEB) an 18F-labeled analogue of the D2 antagonist benperidol, was evaluated as a tracer for positron emission tomography (PET). PET imaging of a living baboon showed that the fluorinated ligand rapidly localized in vivo within D2 receptor-rich brain tissue, with selective retention lasting over 2 h after tracer injection. Pretreatment of the animal with unlabeled D2-specific antagonist eticlopride (4 mg/kg, i.v.) 1 h before [18F]FEB completely abolished the selective disposition of the radioligand, whereas the regional cerebral blood flow, blood volume and peripheral metabolism/protein binding of [18F]FEB were not changed. Tracer localization when the baboon was pretreated with unlabeled ketanserin (0.55 mg/kg, i.v.) or SCH 23390 (1.1 mg/kg, i.v.) was identical to that for the control case, indicating that the [18F]FEB did not bind to S2 of D1 receptors in vivo. [18F]FEB has advantages compared to previously used PET tracers, and may be an excellent radioligand for non-invasive study of D2 receptor binding.

Animals↗
PubMed1995

Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.

[18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.

Animals↗
PubMed1985

Syntheses and specific activity determinations of no-carrier-added (NCA) F-18-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone.

A general method for the syntheses of no-carrier-added (NCA) 18F-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone is described. These 18F-labeled neuroleptic drugs are synthesized by a multistep synthesis in an overall radiochemical yield of 10-20% at end of bombardment (EOB) in a synthesis time of 90 min from EOB. The sequence involves the synthesis of NCA p-[18F]fluorobenzonitrile from NCA [18F]-fluoride and p-nitrobenzonitrile using the rapidly converted to gamma-chloro-p-[18F]fluorobutyrophenone which is alkylated with appropriate amines to give NCA 18F-labeled benperidol, haloperidol, spiroperidol, and pipamperone. The final product is purified by preparative high performance liquid chromatography (HPLC). The 18F solution used in the synthesis as determined by ion chromatography contains 15.3 +/- 9.0 nmol of stable fluoride. The specific activities of the resulting butyrophenone neuroleptics were determined to be 3 Ci/mumol (at EOB) (range 1-6 Ci/mumol) as determined by radioreceptor assay and HPLC assay.

Antipsychotic Agents↗
PubMed1992

Production of fluorine-18 labeled (3-N-methyl)benperidol for PET investigation of cerebral dopaminergic receptor binding.

The multi-millicurie synthesis of the D-2 receptor ligand [18F](3-N-methyl)benperidol (NMB; 1-[3-(4'- [18F]fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1- benzimidazolinyl)piperidine) is described. [18F]NMB was produced via a 3-step reaction sequence with an overall radiochemical yield of 5-10% and a specific activity greater than 3000 Ci/mmol within 100 min. In vitro binding assays indicated that NMB has high affinity for D-2 receptors in primate brain (K1 = 3.6 nM), with a receptor specificity exceeding that of spiperone. The technique described here permits the routine production of 10-20 mCi of this promising radiopharmaceutical for PET study of D-2 receptor binding in vivo.

Animals↗
PubMed1984

Determination of benperidol in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the quantitative determination of benperidol in human plasma using haloperidol as internal standard is described. The method involves liquid-liquid extraction, separation of the substances on a reversed-phase column C18 followed by ultraviolet detection at 254 nm. The mobile phase consists of 32% acetonitrile in 0.05 M potassium dihydrogen phosphate buffer (pH 2.8). The detection limit is 0.5-1.0 ng/ml using 2- or 4-ml plasma samples.

Benperidol↗
PubMed1997

Voltammetric determination of droperidol and benperidol.

In this study two butyrophenones, droperidol and benperidol were voltammetrically investigated using platinum and specially activated glass carbon electrodes. The behaviours of the substance were investigated in various electrolyte solutions having different pH values and by different scan rates. As a result of the studies it was shown that the quantitative determinations of the substances from their pharmaceutical preparations could be made rapidly and simply without any separation from the excipients.

Antipsychotic Agents↗
PubMed1997

Radiation dosimetry of [18F] (N-methyl)benperidol as determined by whole-body PET imaging of primates.

Radiation absorbed doses due to IV administration of [18F](N-methyl) benperidol ([18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladder, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET studies of D2 receptor binding.

Animals↗
PubMed1994

Plasma levels of benperidol, prolactin, and homovanillic acid after intravenous versus two different kinds of oral application of the neuroleptic in schizophrenic patients.

Plasma levels of prolactin (PRL) and the butyrophenone neuroleptic benperidol (BPD) were closely followed 0 to 48 h after acute application of 6 mg BPD as intravenous injection, orally as liquid, and orally as tablets in 12 schizophrenic patients using a partially randomized cross over design. Drug concentrations showed application specific pharmacokinetic behavior with complete elimination within 48 h. All three applications led to a biphasic PRL response with pronounced initial plasma PRL peaks returning to baseline levels within 48 h. The results suggest that after acute neuroleptic challenge BPD plasma levels as low as 2-3 ng/ml can be sufficient for complete depletion of pituitary PRL stores. This initial peak was followed by a PRL plateau about twice above pretreatment values indicating doubling of the PRL synthesis and secretion independent of supraeffective actual BPD concentrations. The PRL plateau persisted as long as BPD concentrations were above those levels which triggered the initial PRL response. As compared with the time of maximum concentrations (tmax) for BPD, the PRL tmax was later after i.v. injection, equal after liquid application, and earlier after tablet administration leading to pronounced application specific differences in shape, direction, and position of resulting hysteresis curves. Plasma levels of homovanillic acid (HVA) were not affected by BPD treatment. The PRL and HVA levels registered after acute doses of BPD indicated that the hormone responses were most likely the result of acute depletion of PRL stores and subsequent stimulation of hormone synthesis whereas it seemed unlikely that dopaminergic activities were relevant.

Administration, Oral↗
PubMed1997

In vivo kinetics of [18F](N-methyl)benperidol: a novel PET tracer for assessment of dopaminergic D2-like receptor binding.

A novel D2-like receptor-binding radioligand, [18F](N-methyl)benperidol ([18F]NMB), was evaluated via positron emission tomographic (PET) imaging studies of baboons. [18F]NMB rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and striatum-to-cerebellum ratios as high as 35 were achieved after 3 hours. Pretreatment of an animal with unlabeled receptor-specific antagonists before injection of [18F]NMB confirmed that the radioligand bound specifically to central D2-like receptors in vivo, and not to S2- or D1-like receptors. Unlabeled eticlopride displaced striatal [18F]NMB in vivo, showing that D2-like binding is reversible. Receptor-binding by the radioligand was resistant to competitive displacement by synaptic dopamine, as illustrated by the lack of effect of intravenous d-amphetamine on the in vivo localization of [18F]NMB. Studies involving sequential intravenous administration of [18F]NMB, d-amphetamine, and eticlopride show that the radioligand does not undergo agonist-mediated internalization with subsequent trapping. The feasibility of applying a three-compartment non-steady state model for quantification of [18F]NMB receptor binding was demonstrated. These in vivo characteristics give [18F]NMB distinct advantages over the PET radiopharmaceuticals currently used for clinical investigation of D2-like receptor binding.

Animals↗
PubMed1987

Electrochemical detection of benperidol in serum for drug monitoring in humans.

A high-pressure liquid chromatographic (HPLC) method for the serum assay of benperidol is described. One ml of serum is required for a single estimation. The method involves a simple and rapid extraction step (BondElut columns), HPLC separation (C8 10-mu column), and electrochemical detection (+0.65 V). Haloperidol is used as internal standard. On the basis of this procedure, recovery (93-97%) and reproducibility (intra-assay and inter-assay coefficients of variation less than 9%) are satisfactory. The detection limit is 0.2 ng/ml of serum. After therapeutic doses, trough serum levels ranged from 3.8 to 12 ng/ml in five patients.

Benperidol↗
PubMed2001

Imaging of striatal dopamine D(2) receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: a validation study with (18)F-(N-methyl)benperidol.

UNLABELLED: Several groups have developed high-resolution PET systems and shown the feasibility of in vivo studies on small laboratory animals. In this investigation, one of these systems was validated for the performance of receptor imaging studies. For this, the radiotracer concentrations obtained in the same animals with PET and with autoradiography were quantified, and the correspondence between both methods was assessed by means of correlation analysis. METHODS: Striatal radioactivity was measured in 10 Sprague-Dawley rats after injection of 60 +/- 10 MBq of the dopamine D(2) receptor ligand (18)F-(N-methyl)benperidol in 6 time frames of 6 min each. On completion of the scans, animals were killed, and their brains were removed and sectioned using a cryostat microtome. Coronal slices were subjected to storage phosphor autoradiography with BaFBr:Eu(2+)-coated imaging plates. Striatal radioactivity was quantified in both modalities using region-of-interest analysis and activity standards. RESULTS: After partial-volume correction, the median of striatal radioactivity concentration measured with PET was 0.40 MBq/cm(3) (25th percentile, 0.32; 75th percentile, 0.44). Radioactivity concentrations determined by means of storage phosphor autoradiography amounted to 0.42 MBq/cm(3) (25th percentile, 0.24; 75th percentile, 0.51). Correlation of striatal radioactivity values yielded a Pearson correlation coefficient of 0.818 (P = 0.002). Radioactivity accumulation in Harder's glands led to an overestimation of striatal activity concentrations by approximately 5%. The median of striatal radioactivity concentration after spillover correction decreased slightly to 0.38 MBq/cm(3) (25th percentile, 0.30; 75th percentile, 0.43). Correlation of striatal radioactivity values after spillover correction yielded a Pearson correlation coefficient of 0.824 (P = 0.002). CONCLUSION: The results show a significant positive correlation between radioactivity values obtained with PET and storage phosphor autoradiography used as the gold standard. Because we applied a selective dopamine D(2) receptor radioligand and because radioactivity concentrations could be reliably quantified in the target region, we may infer that in vivo receptor binding studies will be possible in small laboratory animals.

Animals↗
PubMed2003

In vivo measurement of D2 receptor density and affinity for 18F-(3-N-methyl)benperidol in the rat striatum with a PET system for small laboratory animals.

UNLABELLED: A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D(2) receptor radioligand (18)F-(3-N-methyl)benperidol ((18)FMB) in rat striatum by determining receptor density (B(max)) and affinity (K(d)) in vivo. For validation, K(d) and B(max) additionally were determined in vitro using storage phosphor autoradiography. METHODS: Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of (18)FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of (18)FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis. RESULTS: PET yielded a K(d) of 6.2 nmol/L and a B(max) of 16 fmol/mg for the striatal D(2) receptor. In vitro, K(d) and B(max) amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of (18)FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively. CONCLUSION: K(d) values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B(max) values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B(max) and K(d) may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.

Animals↗
PubMed1990

In vivo labeling of the dopamine D2 receptor with N-11C-methyl-benperidol.

A new dopamine D2 receptor radiotracer, N-11C-methyl-benperidol (11C-NMB), was prepared and its in vivo biologic behavior in mice and a baboon was studied. Carbon-11-NMB was determined to bind to specific sites characterized as dopamine D2 receptors. The binding was saturable, reversible, and stereospecific. Kinetic studies in the dopamine D2 receptor-rich striatum showed that 11C-NMB was retained five times longer than in receptor-devoid regions, resulting in a high maximum striatal-to-cerebellar ratio of 11:1 at 60 min after injection. From frontal cortex and cortex, on the other hand, the tracer washed out as rapidly as it did from cerebellum, resulting in tissue-to-cerebellar ratios close to one in these regions at any time after injection. Blocking studies confirmed the specificity and selectivity of the 11C-NMB binding to the dopamine D2 receptor. A PET study with 11C-NMB of the baboon brain revealed highly selective labeling of dopamine D2 receptor sites which was blocked by preinjection of raclopride.

Animals↗
PubMed1988

Pharmacokinetics of benperidol in volunteers after oral administration.

Benperidol in a 4 mg single dose was administered orally to five healthy male volunteers. The drug was rapidly absorbed (tmax = 2.27 +/- 0.57 h) and largely distributed, the volume of distribution being 5.19 +/- 1.99 l.kg-1. Elimination half-life was 7.65 +/- 2.14 h. Urinary excretion represented only a minimal fraction of ingested dose (0.1 +/- 0.007%). Variability of the area under the curve makes a first-pass metabolism a reasonable possibility. Acute dystonias appeared in two subjects.

Administration, Oral↗