Interaction Of Haloperidol Research Articles

Interaction of haloperidol with human serum albumin and effect of metal ions on the binding

The interaction between human serum albumin (HSA) and haloperidol (HPD) was studied by fluorescence and absorption spectroscopy and molecular modeling under physiological conditions. Fluorescence spectroscopic data showed that the fluorescence quenching of HSA was a result of the formation of the HPD–HSA complex. Spectroscopic analysis of the emission quenching at different temperatures revealed that the quenching mechanism of human serum albumin by haloperidol shows a dynamic quenching. The binding constant (K) and the binding sites (n) between haloperidol and HSA were estimated to be 7.94 × 103 dm3 mol−1 and 1.12 at 298 K. The results of thermodynamic parameters, ΔH (− 89.56 kJ mol−1), ΔS (225.94 J mol−1 K−1) and ΔG (− 15.69 kJ mol−1), indicated that the binding process was spontaneous and the van der Waals interactions and hydrogen bonds were the main forces to stabilize the complex. The distance between the donor (HSA) and acceptor (HPD) molecules was obtained according to Forster energy transfer. The effects of metal ions (Ca2+, Mg2+, Cu2+, and Fe3+) on the binding constant of the haloperidol–HSA complex were also investigated. Finally, the binding of haloperidol to HSA was modeled using the molecular docking method. Molecular docking results were in agreement with the experimental conclusions of the thermodynamic parameters.

Spectroscopic Study on the Interaction of Haloperidol and 2,4-Dinitrophenylhydrazine and its Application for the Quantification in Drug Formulations

A simple and sensitive spectrophotometric procedure has been developed for the determination of haloperidol in bulk and its formulation/tablets. Method is based on the interaction of carbonyl group of haloperidol with 2,4-dinitrophenyl hydrazine [DNPH]. The condensation reaction produces a red coloured product which absorbs maximally at 456 nm. The effects of variables such as concentration of DNPH, KOH, HCl and the reaction time were investigated to optimize the procedure. Beer’s law was obeyed in the concentration range of 3.6–10.8 μg mL-1 with molar absorptivity of 2.84×104 L mol-1 cm-1. The results were validated statistically as per the ICH Guidelines. The proposed method has been applied to the determination of haloperidol in tablets with satisfactory results. The obtained results are compared statistically with those given by a reference method. The point and interval hypothesis results indicate that the proposed procedure is not biased.

Antidepressant and antipsychotic drugs differentially affect PON1 enzyme activity

Human serum paraoxonase (PON1, EC 3.1.8.1.) is a high-density lipid (HDL)-associated, calcium-dependent enzyme. In this study, the effects of Haloperidol, Fluoxetine hydrochloride, Diazepam and Acepromazine drugs used for the therapy of antidepressant and antipsychotic diseases, on paraoxonase enzyme activity was studied in in vitro inhibition studies on purified human serum PON1. PON1 enzyme was purified from human blood using two-step procedures, namely, ammonium sulfate precipitation and sepharose-4B-l-tyrosine-1-napthylamine hydrophobic interaction chromatography. The overall purification of human serum PON1 was obtained in a activity of 109.29 U/mL and this enzyme was purified 125-fold. The SDS–polyacrylamide gel electrophoresis of the enzyme indicates a single band with an apparent MW of 43 kDa. Inhibition studies indicated that haloperidol and fluoxetine hydrocloride were effective inhibitors on purified human serum PON1 activity with IC50 of 0.187 and 3.08 mM values, respectively. The kinetics of interaction of haloperidol and fluoxetine hydrocloride with the purified human serum PON1 indicated uncompetitive inhibiton pattern with Ki of 4.15 and 0.007 mM, respectively.

The Interaction of Haloperidol and Imipramine on Cost-benefit Decision Making in Rats

Organisms constantly assess the cost and benefit of the possible future outcomes of their behavior and use the information to guide the future behavior,a process called cost-benefit decision making.The current study used a T-maze delayed reward procedure to examine the effects of the non-selective dopamine receptor antagonist haloperidol and the norepinephrine/serotonin reuptake inhibitor imipramine on decision making(choice between a delayed high reward [HR] and an immediate low reward),and how delay on access to the HR alters the decision making.Six groups of rats(n=8 per group) were treated with saline,haloperidol,imipramine(3,8 or 10 mg/kg),or a combination of haloperidol(0.2mg/kg) and imipramine(8mg/kg).The experiment comprised three periods:initial training period during which animals had free access to the rewards located in both arms of the T-maze for each of the 10 daily trials;forced training period during which animals were allowed to have access to each of the two arms for the first two forced trials followed by 10 choice trials(access to both arms) with a delay imposed on the HR;and test period which was similar with the forced training period except that animals received drug treatment before the test session.Haloperidol decreased choice to HR when 15 or 30 s delay was applied to HR.In contrast,imipramine increased choice to HR.The decreased HR choice induced by haloperidol was reversed by imipramine.Increasing delay to HR decreased choice to HR.In conclusion,these data suggest that delay is an important factor for determining choice behavior,and that haloperidol and imipramine have opposing effects on decision making.

Nicotine–antipsychotic drug interactions and attentional performance in female rats

Schizophrenia is marked by pronounced cognitive impairments in addition to the hallmark psychotic symptoms like hallucinations. Antipsychotic drugs can effectively reduce these hallucinations; however, the drugs have not resolved the cognitive impairment. Interestingly, nicotine, a drug commonly self-administered by people with schizophrenia, has been shown to significantly improve cognitive function of people with schizophrenia. The current study was conducted to determine the effect of typical (haloperidol) and atypical (clozapine and risperidone) antipsychotic drug treatment on sustained attention in rats performing a visual signal detection task. In addition, the interaction of haloperidol with chronic nicotine administration was assessed. Female Sprague–Dawley rats were injected subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg), risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol (0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the study, the interaction of acute haloperidol (0, 0.005, 0.01 and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4 weeks via osmotic minipump) was characterized. Clozapine, risperidone and haloperidol all caused dose-related impairments in percent hit performance. There was a significant linear dose-related impairment in percent hit caused by risperidone. All the doses of clozapine caused a significant impairment in percent hit at the higher luminance intensities in the visual signal detection task. The 0.01 and 0.02 mg/kg haloperidol doses caused significant decreases in percent hit. The 0.04 mg/kg haloperidol dose impaired performance of the task to the point that reliable choice accuracy measurements could not be made. Chronic nicotine infusion significantly diminished the impairing effects of haloperidol on performance during weeks 1–2. In summary, both typical and atypical antipsychotic drugs significantly impaired sustained attention in rats. Haloperidol was more detrimental than clozapine and risperidone. Chronic nicotine diminished the adverse effects of haloperidol on performance. This study establishes a paradigm to reliably determine the attentional impairment caused by antipsychotic drugs.

Pharmacokinetics of haloperidol: an update.

Haloperidol is commonly used in the therapy of patients with acute and chronic schizophrenia. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine diphosphoglucose glucuronosyltransferase. The greatest proportion of the intrinsic hepatic clearance of haloperidol is by glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for the metabolism of haloperidol in humans. The intrinsic clearances of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude, suggesting that the same enzyme system is responsible for the 3 reactions. Large variation in the catalytic activity was observed in the CYP-mediated reactions, whereas there appeared to be only small variations in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and an inhibitor, as well as a stimulator, of CYP2D6. Reduced haloperidol is also a substrate of CYP3A4 and inhibitor of CYP2D6. Pharmacokinetic interactions occur between haloperidol and various drugs given concomitantly, for example, carbamazepine, phenytoin, phenobarbital, fluoxetine, fluvoxamine, nefazodone, venlafaxine, buspirone, alprazolam, rifampicin (rifampin), quinidine and carteolol. Overall, drug interaction studies have suggested that CYP3A4 is involved in the biotransformation of haloperidol in humans. Interactions of haloperidol with most drugs lead to only small changes in plasma haloperidol concentrations, suggesting that the interactions have little clinical significance. On the other hand, the coadministration of carbamazepine, phenytoin, phenobarbital, rifampicin or quinidine affects the pharmacokinetics of haloperidol to an extent that alterations in clinical consequences would be expected. In vivo pharmacogenetic studies have indicated that the metabolism and disposition of haloperidol may be regulated by genetically determined polymorphic CYP2D6 activity. However, these findings appear to contradict those from studies in vitro with human liver microsomes and from studies of drug interactions in vivo. Interethnic and pharmacogenetic differences in haloperidol metabolism may explain these observations.

Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol.

1. Human cytochrome P450 (CYP) isoenzymes expressed in a human cell line were used to elucidate their involvement in the metabolism of haloperidol (HAL). 2. It was found that CYP3A4 catalyzes the metabolism of HAL to HAL 1,2,3,6-tetrahydropyridine (HTP). HTP is further metabolized to HAL pyridinium (HP+) by both CYP3A4 and CYP2D6. 3. CYP3A4 and CYP2D6 are also responsible for the N-dealkylation of HAL. The N-dealkylation of reduced HAL (RH) was observed, which is catalyzed by CYP3A4. In addition, CYP3A4 also catalyzes the oxidation of RH back to HAL. 4. These results are discussed in terms of the metabolic interactions of HAL with other drugs and how this knowledge may be used to reduce the movement disorders induced by HAL.

Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the F1 at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001-0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Interaction of haloperidol and area postrema lesions in the disruption of amphetamine-induced conditioned taste aversion learning in rats

Two experiments were run to determine the mechanisms underlying the acquisition of an amphetamine-induced conditioned taste aversion. In the first experiment, it was shown that pretreatment with haloperidol (0.1–0.5 mg/kg, IP) attenuated, but did not prevent, taste aversion learning produced by amphetamine (3 mg/kg, IP). In the second experiment, combining area postrema lesions with haloperidol (0.5 mg/kg) pretreatment completely blocked the acquisition of an amphetamine-induced taste aversion. The results are interpreted as indicating that amphetamine-induced taste aversion learning has both a central component, which is mediated by dopaminergic receptors, and a nondopaminergic peripheral component, which is mediated by the area postrema.

Interaction of haloperidol and risperidone (R 64 766) with amphetamine‐induced motility changes in rats

AbstractThe interaction of the new antipsychotic risperidone (RIS) and haloperidol (HAL) with amphetamine (AMP) was studied in rats using an activity meter which measured horizontal, vertical, and stationary components of motility. All three components increased markedly and progressively after AMP doses between 0.63 and 5.00 mg/kg (hyperactivity dose range). At still higher doses of 10.0 to 80.0 mg/kg, stationary movements (reflecting stereotypy) further increased, whereas horizontal activity was much reduced and vertical activity virtually abolished. Both HAL and RIS were potent AMP antagonists. Doses on the order of 0.02 to 0.04 mg/kg significantly reduced hyperactivity and reversed stereotypy to a motility pattern equivalent to that of a lower AMP dose. Both compounds were able to restore normal motility at any dose level of AMP stimulation. At the lowest dose of AMP (0.63 mg/kg), the required normalization doses were comparable for HAL (0.022–0.046 mg/kg) and RIS (0.034–0.16 mg/kg). In order to normalize motility induced by higher AMP doses up to 5.00 mg/kg, however, a relatively small dose increment of HAL (to 0.045–0.071 mg/kg), but a large dose increment of RIS (to 0.50–0.96 mg/kg) was required. In other words, the dose‐normalization curves of RIS and HAL diverged at low doses of AMP (0.63–5.0 mg/kg). At higher doses of AMP (10–80 mg/kg), however, this difference disappeared, and the slopes of the dose‐normalization curves became comparable for the two antagonists. It is suggested from these experiments that RIS and HAL are equipotent in controlling a low level of dopaminergic overactivity by partially occupying dopamine‐D2 receptors. Higher levels of functional dopamine antagonism up to saturation of the D2 receptors require a much higher dose of RIS than of HAL. Therefore, the risk of dopaminergic overblockade (and induction of EPS) is considered to be much smaller with RIS than with HAL.

Interactions of haloperidol with discriminative responding controlled by 10 mg/kg of cocaine in rats

AbstractNine rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two‐lever food‐reinforced drug discrimination procedure. Saline and 0.31–10 mg/kg doses of cocaine were tested for generalization after pretreatment with either vehicle or 0.04 and 0.16 mg/kg of haloperidol. The 0.04 and 0.16 mg/kg doses of haloperidol produced a 2.3 and 5.0‐fold shift to the right, respectively, of the cocaine generalization gradient. Extrapolation of the generalization data suggests that about 3 mg/kg of haloperidol is required to antagonize completely the discriminative effects of the 10 mg/kg training dose of cocaine. Cocaine (0.63 mg/kg) reversed the rate‐depressant effects of 0.04 mg/kg of haloperidol, but even 10 mg/kg only partially attenuated the behavioral depression produced by 0.16 mg/kg of haloperidol. Also, up to 10 mg/kg doses of cocaine exerted no reliable effect on the alternative lever responding produced by 0.04 or 0.16 mg/kg of haloperidol. The data suggest that 2.3–5.0‐fold shift of the cocaine gradient, but not a complete blockade of the discriminative effects of the 10 mg/kg training dose of cocaine, can be achieved with doses of haloperidol at which the drug presumably interacts in a specific manner with dopamine receptors in the brain.

Interaction of haloperidol and ?-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain

The interaction of (+)-amphetamine with haloperidol and gamma-butyrolactone on synthesis of monoamines in rat brain regions was investigated using an in vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of the in vivo release of dopamine (DA) into the extraneuronal space. (+)-Amphetamine at doses of 1--3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied. 3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited by gamma-butyrolactone. Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment with gamma-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted the gamma-butyrolactone-induced increase in dopa formation especially in the DA-rich areas. The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.