Relationship of the 1846G > A Polymorphism of the CYP2D6 Gene to the Equilibrium Concentration Levels of Haloperidol in Patients with Acute Alcoholic Hallucinosis.

Haloperidol is currently used in addictology for the treatment of acute psychotic disorders, including acute alcoholic hallucinosis. The use of haloperidol is often accompanied by the occurrence of adverse drug reactions (ADRs). There is evidence that CYP2D6 isoenzyme is involved in the biotransformation of haloperidol. Aim: The study aimed to evaluate the relationship of 1846G > A polymorphism of the CYP2D6 gene to the equilibrium concentration levels of haloperidol in patients with acute alcoholic hallucinosis. Material and Methods: The study was conducted on 100 male patients with acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile was evaluated using the PANSS (Positive and Negative Syndrome Scale) scale. The safety of therapy was assessed using the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Equilibrium plasma concentration levels of haloperidol were investigated using the high-performance liquid chromatography with mass spectrometry (HPLC with MS/MS). Results: No statistically significant results were obtained during the therapy efficacy assessment (dynamics of the PANSS score: GG genotype (-13.00 [-16.00; -16.00; -11.00]), GA genotype (-15.00 [-16.75; -13.00], p = 0.728). There was a statistically significant difference in safety assessment scores (dynamics of the UKU score: GG genotype (8.00 [7.00; 10.00]), GA genotype (15.00 [9.25; 18.00], p < 0.001); dynamics of the SAS score: GG genotype (11.00 [9.00; 14.00]), GA genotype (14.50 [12.00; 18.00], p < 0.001). The pharmacokinetic study results showed a statistically significant difference: GG (3.13 [2.32; 3.95]), GA (3.89 [2.92; 5.26], p = 0.010). Thus, a study conducted on a group of 100 patients with acute alcoholic hallucinosis demonstrated an association between the 1846G > A polymorphism of the CYP2D6 gene (rs3892097) and the safety profile of haloperidol therapy. We also revealed the presence of statistically significant difference in the equilibrium concentration levels of haloperidol in patients with the GG and AG genotypes. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients carrying the GG genotype. It is shown that 1846G > A polymorphism of the CYP2D6 gene (rs3892097) has a statistically significant effect on the equilibrium concentration levels of haloperidol.

Association of CYP2D6*4 Polymorphism with the Steady-State Concentration of Haloperidol in Patients with Alcohol-Induced Psychotic Disorders.

Background: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates. Purpose: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs). Material and methods: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction. Results: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

Conjugation to PEG as a Strategy to Limit the Uptake of Drugs by the Placenta: Potential Applications for Drug Administration in Pregnancy.

Here, we evaluated the feasibility of non-prodrug PEG-drug conjugates to decrease the accumulation of drugs within the placental tissues. The results showed that PEG was biocompatible with the human placenta with no alteration of the basal rate of proliferation or apoptosis in term placental explants. No significant changes in the released levels of lactate dehydrogenase and the human chorionic gonadotropin were observed after PEG treatment. The cellular uptake studies revealed that conjugating Cy5.5 and haloperidol to PEG significantly reduced (by up to ∼40-fold) their uptake by the placenta. These findings highlight the viability of novel non-prodrug polymer-drug conjugates to avoid the accumulation of drugs within the placenta.

Impact of study design and statistical model in pharmacogenetic studies with gene-treatment interaction.

Gene-treatment interactions, just like drug-drug interactions, can have dramatic effects on a patient response and therefore influence the clinician decision at the patient's bedside. Crossover designs, although they are known to decrease the number of subjects in drug-interaction studies, are seldom used in pharmacogenetic studies. We propose to evaluate, via realistic clinical trial simulations, to what extent crossover designs can help quantifying the gene-treatment interaction effect. We explored different scenarios of crossover and parallel design studies comparing two symptom-modifying treatments in a chronic and stable disease accounting for the impact of a one gene and one gene-treatment interaction. We varied the number of subjects, the between and within subject variabilities, the gene polymorphism frequency and the effect sizes of the treatment, gene, and gene-treatment interaction. Each simulated dataset was analyzed using three models: (i) estimating only the treatment effect, (ii) estimating the treatment and the gene effects, and (iii) estimating the treatment, the gene, and the gene-treatment interaction effects. We showed how ignoring the gene-treatment interaction results in the wrong treatment effect estimates. We also highlighted how crossover studies are more powerful to detect a treatment effect in the presence of a gene-treatment interaction and more often lead to correct treatment attribution.

Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study.

An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting "infective-pneumonia" and "pneumonia-aspiration" and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

Development of an Integrated Tissue Pretreatment Protocol for Enhanced MALDI MS Imaging of Drug Distribution in the Brain.

The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique has attracted intense interest in the visualization of drug distribution in tissues. Its capability to spatially resolve individual molecules makes it a unique tool in drug development and research. However, low drug content and severe ion suppression in tissues hinder its broader application to resolve drug tissue distribution, especially small molecule drugs with a molecular weight below 500 Da. In this work, an integrated tissue pretreatment protocol was developed to enhance the detection of central nervous system drugs in the mouse brain using MALDI MSI. To evaluate the protocol, brain sections from mice dosed intraperitoneally with donepezil, tacrine, clozapine, haloperidol, and aripiprazole were used. The tissue sections were pretreated serially by washing with ammonium acetate solution, incubation with trifluoroacetic acid vapor, and n-hexane washing before MALDI MSI. Compared with the untreated sample, the signal intensities for the test drugs increased by 4.7- to 31.5-fold after pretreatment. Besides the enhancement of signal intensity, fine optimization of pretreatment time and washing solvents preserved the spatial distribution of target drug molecules. The utility of the developed protocol also provided tissue-specific distribution for five drugs which were well resolved when imaged by MALDI MS.

Anticholinergic Load and Nutritional Status in Older Individuals.

OBJECTIVES: The association between anticholinergic load-based Anticholinergic Risk Scale scores and nutritional status is unclear in Japanese patients. The aim of this study was to establish whether anticholinergic load affects the nutritional status of geriatric patients in convalescent stages. DESIGN: Retrospective longitudinal cohort study. SETTING: Convalescent rehabilitation wards. PARTICIPANTS: Of the 1490 patients aged ≥65 years who were discharged from convalescent rehabilitation wards between July 2010 and October 2018, 908 patients met the eligibility criteria. They were categorized according to the presence or absence of increased anticholinergic load from admission to discharge. MEASUREMENTS: Demographic data, laboratory data, the Functional Independence Measure were analyzed between the groups. The primary outcome was Geriatric Nutritional Risk Index (GNRI) at discharge. Multiple linear regression analysis was performed to analyze the relationship between anticholinergic load and GNRI at discharge. RESULTS: Multiple linear regression analysis after adjusting for confounding factors revealed that anticholinergic load was independently and negatively correlated with GNRI at discharge. Particularly, the use of chlorpromazine, hydroxyzine, haloperidol, metoclopramide, risperidone, etc. increased significantly from admission to discharge. CONCLUSION: Increased anticholinergic load during hospitalization may be a predictor of nutritional status in geriatric patients.

Real-life persistence of long-acting injectable antipsychotics in schizophrenic patients: A retrospective observational study in France
.

OBJECTIVE: Antipsychotics exhibit different profiles of efficacy and safety in patients with schizophrenia. It has recently been reported that the risk of rehospitalization was the lowest with paliperidone palmitate (PP), a long-acting injectable (LAI), when compared with other LAIs (of zuclopenthixol, perphenazine, and olanzapine). We aimed to investigate whether treating patients with PP was also associated with improved real-life treatment persistence. MATERIALS AND METHODS: We conducted a retrospective observational study of the LAI antipsychotics (LAIAs) dispensed in French retail pharmacies. Treatment persistence was defined as the non-discontinuation of LAIAs for ≥ 5 months after LAIA initiation (and was also analyzed by Kaplan-Meier persistence curves). RESULTS: A total of 4,492 patients were included in the study. The persistence rate was significantly greater for LAI-PP (64.5%) than for either LAI haloperidol decanoate (HD) or LAI risperidone microspheres (R) (46.4% and 35.4%, respectively). Multivariate Cox analyses illustrated that LAIA initiation with HD or R significantly increased the risk of discontinuation when compared with PP. CONCLUSION: PP demonstrated a significantly higher persistence rate than HD or R. Moreover, LAIA initiation with HD or R significantly increased the risk of treatment discontinuation relative to PP. Further comparative studies are required to comprehensively determine whether PP has a better efficacy and/or safety profile than other LAIs.

Enhancement of Transdermal Delivery of Haloperidol via Spanlastic Dispersions: Entrapment Efficiency vs. Particle Size.

Haloperidol (Hal) is a well-known typical antipsychotic. Hepatic first pass metabolism leads to its limited oral bioavailability. This study aimed at enhancing transdermal delivery of Hal via spanlastic formulae. Hal-loaded spanlastics of Span®60 and an edge activator (EA) were successfully prepared by ethanol injection method according to a 31.41 full factorial design. In this design, independent variables were X1, EA type, and X2, Span®60 to EA ratio. Y1, percentage entrapment efficiency (EE%); Y2, particle size (PS); Y3, deformability index (DI); and Y4, percentage drug released after 4h (Q4h), were chosen as dependent variables. The Fourier-transform infrared spectral analysis showed no considerable chemical interaction between Hal and the used excipients. Both factors affected significantly all the responses except DI. Desirability of each prepared formula was calculated based on maximizing EE% and Q4h and minimizing PS. Formula F6, with X1, Tween®80, and X2, 8:2, had the highest desirability value followed by F7, with X1, Tween®80, and X2, 6:4, and both were chosen as selected formulae (SF) for further investigation. F6 (having more entrapped Hal), F7 (of smaller PS), and Hal solution in propylene glycol were subjected to ex vivo permeation test through newborn rat skin. Both formulae showed marked enhancement in drug permeation compared with drug solution. The significantly higher Q36h and J36h of F7 from F6 may indicate that the smaller particle size aided more than higher entrapment in achieving a higher permeation for Hal of 3.5±0.2µg/cm2.h. These results are promising for further investigation of this formula.

Increased cerebral blood flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles.

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed Arterial Spin Labelling (ASL) rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor (D2R) antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and with brain post-mortem microarray mRNA expression data for the DRD2 gene from the Allen Human Brain Atlas (ABA). For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range = 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all pcorrected<0.05). In addition, the spatial coupling between ΔCBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.

The sigma 1 receptor (σ1R) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of σ1R are poorly understood, and molecular interactions of selective ligands with σ1R have not been elucidated. The recent crystallographic determination of σ1R as a homo-trimer provides the foundation for mechanistic elucidation at the molecular level. Here we report novel bioluminescence resonance energy transfer (BRET) assays that enable analyses of ligand-induced multimerization of σ1R and its interaction with BiP. Haloperidol, PD144418, and 4-PPBP enhanced σ1R homomer BRET signals in a dose dependent manner, suggesting their significant effects in stabilizing σ1R multimerization, whereas (+)-pentazocine and several other ligands do not. In non-denaturing gels, (+)-pentazocine significantly decreased whereas haloperidol increased the fraction of σ1R multimers, consistent with the results from the homomer BRET assay. Further, BRET assays examining heteromeric σ1R-BiP interaction revealed that (+)-pentazocine and haloperidol induced opposite trends of signals. From molecular modeling and simulations of σ1R in complex with the tested ligands, we identified initial clues that may lead to the differed responses of σ1R upon binding of structurally diverse ligands. By combining multiple in vitro pharmacological and in silico molecular biophysical methods, we propose a novel integrative approach to analyze σ1R-ligand binding and its impact on interaction of σ1R with client proteins.

Investigation of the synergistic effects of haloperidol combined with Calculus Bovis Sativus in treating MK-801-induced schizophrenia in rats.

Clinical studies that focused on treating schizophrenia showed that Calculus Bovis Sativus (CBS), a substitute of Calculus Bovis, when used in combination with haloperidol could significantly lower the dosage of haloperidol compared with treatment with haloperidol alone, whereas efficacy was maintained. The aim of this study was to investigate the synergetic anti-schizophrenia effects in rats using CBS in combination with haloperidol. An open field test was conducted to verify the pharmacodynamic effects of a combination treatment of CBS and haloperidol on MK-801-induced schizophrenic rats. Rat plasma concentrations of intragastric haloperidol and intravenous haloperidol were determined after oral administration of a single dose or 1-week of pretreatment with CBS (50 mg/kg). The pharmacodynamic data showed a significant decrease in locomotor activity and an increase in the percentage of the central distance when haloperidol was concomitantly administered with CBS compared with haloperidol administration alone. The AUC0-∞ and Cmax of haloperidol in the orally coadministered groups were significantly higher compared with the oral treatment with haloperidol alone. In conclusion, oral coadministration of CBS with haloperidol resulted in a synergistic effect in rats. The enhanced oral bioavailability of haloperidol when combined with CBS might be attributed to the interaction between them.

In silico repurposing of antipsychotic drugs for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. RESULT: A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule. CONCLUSION: The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration.

BACKGROUND: Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. METHODS: The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-ß-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-ß-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS. RESULTS: Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037]. CONCLUSIONS: The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Population pharmacokinetics of haloperidol in terminally ill adult patients.

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Development of a new HPLC method for in vitro and in vivo studies of haloperidol in solid lipid nanoparticles

ABSTRACT A simple and sensitive HPLC method was developed and validated for the quantification of haloperidol in solid lipid nanoparticles (SLNs). The developed method was used for detection of shelf life of haloperidol in SLNs. Calibration curve of haloperidol was also constructed in rat plasma using loratidine as internal standard. In vivo studies were performed on rats and concentration of haloperidol in brain and blood was measured for the determination of various pharmacokinetic and hence brain targeting parameters. Chromatogram separation was achieved using C18 column as stationary phase. The mobile phase consisted of 100 mM/L potassium dihydrogen phosphate-acetonitrile-TEA (10:90:0.1, v/v/v) and the pH was adjusted with o-phosphoric acid to 3.5. Flow rate of mobile phase was 2 mL/minute and eluents were monitored at 230 nm using UV/VIS detector. The method was validated for linearity, precision, accuracy, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). Linearity for haloperidol was in the range of 1-16 µg/mL. The value of LOD and LOQ was found to be 0.045 and 0.135 μg/mL respectively. The shelf life of SLNs formulation was found to be 2.31 years at 4 oC. Various parameters like drug targeting index (DTI), drug targeting efficiency (DTE) and nose-to-brain direct transport (DTP) were determined for HP-SLNs & HP-Sol administered intranasally to evaluate the extent of nose-to-brain delivery. The value of DTI, DTE and DTP for HP-SLNs was found to be 23.62, 2362.43 % and 95.77% while for HP-Sol, values were 11.28, 1128.61 % and 91.14 % respectively.

Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution.

Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy.

The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.