Haloperidol In Plasma Research Articles

Salt-assisted liquid–liquid microextraction for determination of haloperidol in human plasma by LC-MS/MS

Haloperidol is an antipsychotic used in the treatment of schizophrenia. Compared to other antipsychotics, it is widely used in developing countries due to its affordable price. Haloperidol has a narrow therapeutic range and variable pharmacokinetics; therefore, therapeutic drug monitoring (TDM) is recommended. For this reason, in this study, an easily applicable, fast, selective, accurate, reliable, and economical LC-MS/MS method was developed for the determination of haloperidol in human plasma for use in TDM and also method was validated according to European Medicines Agency (EMA) Bioanalytical method validation guidelines. In the developed method, analyte and internal standard were extracted from plasma by salt-assisted liquid-liquid microextraction (SALLME) technique and after that injected to the LC system. The limit of quantification of haloperidol was determined as 1 ng/ml. The calibration curve was validated between 1-15 ng/ml, with correlation coefficients >0.99. In addition, the developed method was used to determine drug concentration levels in the plasma of real patients.

Development of Sensitive and High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Method for Quantification of Haloperidol in Human Plasma with Phospholipid Removal Pretreatment.

Haloperidol, butyrophenone derivative, is a typical antipsychotic drug used in the treatment of schizophrenia, manic phase of bipolar disorder, and acute psychomotor agitations. According to the recent guidelines for therapeutic drug monitoring, it is strongly recommended to measure plasma level during the therapy with haloperidol. The objective of this study was to develop and validate a simple liquid chromatography-tandem mass spectrometry-based method to quantitate haloperidol in human plasma. After one-step extraction procedure using OSTROTM plate, gradient elution on Acquity UPLC BEH C18 (50 ×2.1mm, 1.7μm) column over 3.2 min was performed. The detection was conducted on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode in positive ionization mode with transitions at m/z 376.29 → 165.14 and m/z 380.28 → 169.17 for haloperidol and haloperidol-d4 (used as an internal standard), respectively. The method was fully validated to cover wide concentration range of 0.05-80 ng/mL in human plasma and meets the criteria for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability. The extraction recovery was nearly 100%, and no significant matrix effects were observed. Therefore, the method is applicable to routine therapeutic drug monitoring in patients' plasma.

Determination of Chlorpromazine, Haloperidol, Levomepromazine, Olanzapine, Risperidone, and Sulpiride in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS).

Background and Objective In this study, turbo-ion spray as an interface of tandem mass spectrometry (MS/MS) was performed for sensitive and accurate quantification of chlorpromazine, haloperidol, levomepromazine, olanzapine, risperidone, and sulpiride in plasma samples. Methods Separation was performed by gradient reversed phase high-performance liquid chromatography using a mobile phase containing ammonium formiate 2 mM, pH 2.7, and acetonitrile flowing through a Restek PFP Propyl C18 analytical column (50 mm×2.1 mm i.d.) with particle size of 5 µm, at a flow rate of 800 µL/min. Positive ion fragments were detected in multiple reaction monitoring (MRM) mode. Sample preparation was achieved by solid phase extraction (SPE) (Oasis HLB). Results Mean extraction recoveries ranged from 82.75% to 100.96%. The standard calibration curves showed an excellent linearity, covering subtherapeutic, therapeutic, and toxic ranges. Intraday and interday validation using quality control (QC) samples were performed. The inaccuracy and imprecision were below 12% at all concentration levels. The limits of detection (LOD) and quantification (LOQ) for all analytes were under therapeutic ranges for all tested analytes. Thus, the proposed method was sensitive enough for the detection and determination of subtherapeutic levels of these antipsychotics in plasma samples. No interference of endogenous or exogenous molecules was observed and no carryover effects were recorded. Conclusion According to the results, the proposed method is simple, specific, linear, accurate, and precise and can be applied for antipsychotic analysis in clinical routine. This method was applied for the determination of the tested antipsychotics in plasma samples taken from 71 individuals.

Flexible nano- and microliter injections on a single liquid chromatography–mass spectrometry system: Minimizing sample preparation and maximizing linear dynamic range

Lack of knowledge on the expected concentration range or insufficient linear dynamic range of the analytical method applied are common challenges for the analytical scientist. Samples that are above the upper limit of quantification are typically diluted and reanalyzed. The analysis of undiluted highly concentrated samples can cause contamination of the system, while the dilution step is time consuming and as the case for any sample preparation step, also potentially leads to precipitation, adsorption or degradation of the analytes.An injection set-up composed of 3 valves that allows the injection of two distinct volumes with a 200-fold difference (2μL and 10nL) on a single LC/MS system is introduced. As a proof of concept, the set-up was applied to the analysis of haloperidol in human plasma.By applying two different injection volumes, it was possible to double the linear dynamic range of a liquid chromatography – triple quadrupole mass spectrometry instrument. For the analysis of haloperidol in plasma, the linear dynamic range could be increased from 25–5,000ng/mL to 25–1,000,000ng/mL. Both 10nL and 2μL injection modes showed very similar accuracy and precision. Additionally, more than 1,000 direct injections of untreated plasma were successfully carried out using a nanoliter valve with no measurable effect on LC performance (retention time, peak width, column pressure and background signal).

Quantification of typical antipsychotics in human plasma by ultra-high performance liquid chromatography tandem mass spectrometry for therapeutic drug monitoring

A selective and sensitive method was developed for the simultaneous quantification of seven typical antipsychotic drugs (cis-chlorprothixene, flupentixol, haloperidol, levomepromazine, pipamperone, promazine and zuclopenthixol) in human plasma. Ultra-high performance liquid chromatography (UHPLC) was used for complete separation of the compounds in less than 4.5min on an Acquity UPLC BEH C18 column (2.1mm×50mm; 1.7μm), with a gradient elution of ammonium formate buffer pH 4.0 and acetonitrile at a flow rate of 400μl/min. Detection was performed on a tandem quadrupole mass spectrometer (MS/MS) equipped with an electrospray ionization interface. A simple protein precipitation procedure with acetonitrile was used for sample preparation. Thanks to the use of stable isotope-labeled internal standards for all analytes, internal standard-normalized matrix effects were in the range of 92–108%. The method was fully validated to cover large concentration ranges of 0.2–90ng/ml for haloperidol, 0.5–90ng/ml for flupentixol, 1–450ng/ml for levomepromazine, promazine and zuclopenthixol and 2–900ng/ml for cis-chlorprothixene and pipamperone. Trueness (89.1–114.8%), repeatability (1.8–9.9%), intermediate precision (1.9–16.3%) and accuracy profiles (<30%) were in accordance with the latest international recommendations. The method was successfully used in our laboratory for routine quantification of more than 500 patient plasma samples for therapeutic drug monitoring. To the best of our knowledge, this is the first UHPLC-MS/MS method for the quantification of the studied drugs with a sample preparation based on protein precipitation.

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

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

Determination of haloperidol in biological samples with the aid of ultrasound-assisted emulsification microextraction followed by HPLC-DAD

A rapid and simple quantitative method for preconcentration and determination of haloperidol in biological samples was developed using ultrasound-assisted emulsification microextraction, based on the solidification of floating organic droplet combined with HPLC-DAD. The effects of several factors were investigated. A total of 30 μL of 1-undecanol as an extraction solvent was injected slowly into a glass-centrifuge tube containing 4 mL alkaline sample solution that was located inside the ultrasonic water bath. The formed emulsion was centrifuged and the fine droplets of solvent were floated at the top of the test tube, then it was cooled in an ice bath and the solidified solvent was transferred into a conical vial, after melt, the analysis of the extract was carried out by HPLC. Under the optimal conditions, the extraction efficiencies were more than 90% and the preconcentration factors were obtained between 119-122. The LOQs were obtained between 4-8 μg/L and the calibration curves were linear within the range of 4-1000 μg/L. Finally this method was applied to the determination of haloperidol in plasma and urine samples in the range of μg/L and satisfactory results were achieved (RSDs <7%).

Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro

Objective. Plant antioxidants protect cells against oxidative stress. Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to assess whether there is a difference between a first-generation antipsychotic (FGA; haloperidol) and a second-generation antipsychotic (SGA; amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethysufonyl-2-methoxy-benzamide)) action on peroxidation of plasma lipids, and to establish the effects of polyphenol compounds (resveratrol (3,4′,5-trihydroxystilbene) and quercetin (3,5,7,3′,4′- pentahydroxyflavone)) and the antipsychotics action on this process in vitro. Methods. Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of polyphenols: resveratrol and quercetin. Results. The two-way analysis variance (ANOVA II test) showed that the differences in TBARS levels were depended on the type of tested drugs (P=8.35×10−6). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24 h incubation of plasma with haloperidol compared to the control samples (P<0.03, P<0.0002, respectively). Amisulpride, contrary to haloperidol (after 1 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples. Amisulpride induced significantly decrease of plasma TBARS level after 24 h (P=0.03). We showed that in the presence of polyphenols: resveratrol and quercetin, lipid peroxidation in plasma samples treated with tested drugs was significantly decreased. After incubation (24 h) of plasma with haloperidol in the presence of resveratrol or quercetin we observed a significantly decreased the level of TBARS (P=3.9×10−4, P=2.1×10−3, respectively). Conclusion. Considering the data presented in this study, we showed that haloperidol, contrary to amisulpride caused a distinct increase of lipid peroxidation. Polyphenols reduced significantly lipid peroxidation caused by haloperidol.

Simultaneous Analysis of Fluoxetine, Norfluoxetine, Citalopram, and Haloperidol in Plasma by LC–ESI-IT-MS

A reliable and simple method has been developed for simultaneous analysis of fluoxetine, its metabolite norfluoxetine, citalopram, and haloperidol with lamotrigine as internal standard. The method is based on solid-phase extraction on mixed-mode cation-exchange cartridges followed by LC separation on a C18 column at ambient temperature with a gradient prepared from acetonitrile and 5 mM ammonium acetate in 0.1% (v/v) aqueous formic acid. The flow rate was 0.5 mL min−1. Eluted compounds were ionized by the electrospray ionization ion source of an ion-trap mass spectrometer and were detected by selected ion monitoring. Co-extracted endogenous compounds from plasma were eluted in the first 5 min and discarded by valve-switching. The target drugs were eluted in the period 5.5–11 min. Calibration plots were linear in the ranges 5 (or 10)–400 ng mL−1 with correlation coefficients >0.999. Other statistical and validation results were within accepted ranges for clinical analysis.

Bioavailability and In-vivo Transdermal Delivery of Haloperidol

Background: Sustained blood level with effective therapeutic blood level inpsychotic patients in the range of usual therapeutic dose is favorable.Objectives: To investigate where this sustained and effective therapeutic blood level and improve in bioavailability could be achieved by usinghaloperidol/transdermal gel formulation.Materials and Methods: In-vivo transdermal delivery of haloperidol wasstudied in rabbits comparing transdermal gel formulation containing 1, 8-cineole as penetration enhancer and oral tablet. Concentrations of haloperidol in plasma were measured by reverse phase HPLC. The pharmacokinetic parameters generated from this study were evaluatedstatistically using one-way analysis of variance (ANOVA).Result: The results showed that transdermal gel formulation increased rate and extent of absorption and improve bioavailability of haloperidol. The plasma concentrations of haloperidol were declined in biexponential fashion where the area under the curves and absorption rate Cmax/AUC elimination rate constant Kel, Tmax, mean residence time (MRT), mean absorption time (MAT), and total clearance (CLtotal) were significantly different p < 0.05, but volume of distribution (Vd) did not differ significantly p >0.05.The absolute bioavailability from the oral tablet, and the transdermal formulation was 38% and 57% respectively and highly significant P < 0.01.Conclusion: This study suggest that it is possible to achieve significant sustained therapeutic blood levels for longer time and also suggest that further human investigations of the transdermal dosage are warranted.Key words: Haloperidol/Transdermal gel formulation, Oral tablet, Rabbits, Bioavailability,Pharmacokinetic.

Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro

Plant antioxidants protect cells against oxidative stress. Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to assess whether there is a difference between a first-generation antipsychotic (FGA; haloperidol) and a second-generation antipsychotic (SGA; amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethysufonyl-2-methoxy-benzamide)) action on peroxidation of plasma lipids, and to establish the effects of polyphenol compounds (resveratrol (3,4',5-trihydroxystilbene) and quercetin (3,5,7,3',4'- pentahydroxyflavone)) and the antipsychotics action on this process in vitro. Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of polyphenols: resveratrol and quercetin. The two-way analysis variance (ANOVA II test) showed that the differences in TBARS levels were depended on the type of tested drugs (P = 8.35 x 10(-6)). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24 h incubation of plasma with haloperidol compared to the control samples (P<0.03, P<0.0002, respectively). Amisulpride, contrary to haloperidol (after 1 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples. Amisulpride induced significantly decrease of plasma TBARS level after 24 h (P=0.03). We showed that in the presence of polyphenols: resveratrol and quercetin, lipid peroxidation in plasma samples treated with tested drugs was significantly decreased. After incubation (24 h) of plasma with haloperidol in the presence of resveratrol or quercetin we observed a significantly decreased the level of TBARS (P = 3.9 x 10(-4), P = 2.1 x 10(-3), respectively). Considering the data presented in this study, we showed that haloperidol, contrary to amisulpride caused a distinct increase of lipid peroxidation. Polyphenols reduced significantly lipid peroxidation caused by haloperidol.

Comparison of Time-of-Flight Mass Spectrometry to Triple Quadrupole Tandem Mass Spectrometry for Quantitative Bioanalysis: Application to Antipsychotics

Tandem mass spectrometry (MS/MS) is frequently used for the detection of small molecules in biological samples because of the high specificity and sensitivity associated with these instruments. Time-of-flight mass spectrometers (TOF-MS) are typically used qualitatively for accurate mass determination; however, recently they have gained more attention for quantitation. A selective and sensitive TOF-MS method was validated to determine risperidone, its active metabolite paliperidol, haloperidol, clozapine, and olanzapine in rat plasma using midazolam as an internal standard (IS). Comparisons were made between the use of LC-TOF and LC-MS/MS using a triple quadrupole for these compounds for specificity, linearity, precision, accuracy, matrix effects, and recovery. A focus of this study was the evaluation of recent instrumental and software improvements, which have been made to time-of-flight mass analyzers to increase the linearity and quantitative capabilities of these instruments.

Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine, risperidone, 9‐hydroxyrisperidone, clozapine, haloperidol and ziprasidone in rat plasma

A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method was developed and validated for simultaneous quantification of olanzapine, clozapine, ziprasidone, haloperidol, risperidone, and its active metabolite 9-hydroxyrisperidone, in rat plasma using midazolam as internal standard (IS). The analytes were extracted from rat plasma using a single step liquid-liquid extraction technique. The compounds were separated on a Waters Atlantis dC-18 (30 mm x 2.1 mm i.d., 3 microm) column using a mobile phase of acetonitrile/5 mM ammonium formate (pH 6.1 adjusted with formic acid) with gradient elution. All of the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. LLOQ was 0.1 ng/mL and correlation coefficient (R(2)) values for the linear range of 0.1-100 ng/mL were 0.997 or greater for all the analytes. The intra-day and inter-day precision and accuracy were better than 8.05%. The relative and absolute recovery was above 77% and matrix effects were low for all the analytes except for ziprasidone. This validated method has been successfully used to quantify the plasma concentration of the analytes after chronic treatment with antipsychotic drugs.

Correlation of haloperidol levels between submandibular saliva and brain in the rat

The clinical usefulness of therapeutic drug monitoring (TDM) for haloperidol using blood samples has to be validated. Despite the potential advantage of TDM using saliva, there are few reports comparing drug levels in saliva and blood. Additionally, the relation between haloperidol levels in saliva and brain, the target organ of this drug, has not been reported. We compared haloperidol levels in rat submandibular saliva, plasma and brain. Haloperidol was administered through the femoral vein (0.25 mg/kg). Submandibular saliva was collected 30 min after drug administration. To stimulate secretion, the chorda (parasympathetic) and superior cervical ganglion (sympathetic) were electrically stimulated, and pilocarpine was administered. The concentration of haloperidol in saliva, plasma and brain homogenate was determined. Haloperidol levels in saliva elicited by any stimuli significantly correlated with levels in the brain and plasma. The correlation of haloperidol between saliva and brain was higher than that between plasma and brain. Immunohistochemistry showed that haloperidol was secreted from striated duct cells within the submandibular gland. These results suggested that haloperidol was specifically secreted from the striated duct system, and that salivary drug levels reflect the levels in the brain more precisely than plasma.

Validation of LC–MS electrospray ionisation method for quantitation of haloperidol in human plasma and its application to bioequivalence study

In the present investigation, a new sensitive LC/MS electrospray ionisation mass spectrometric method has been developed for the quantitation of haloperidol—an antipsychotic drug, in human plasma. The method was developed with the objective of accurately measuring the concentration of haloperidol in the plasma of human subjects enrolled in the bioequivalence study of haloperidol (5 mg) tablets of M/s. Cadila Health Care Ltd. India versus 5 mg haloperidol tablets of Geneva Pharma USA. The sample purification and pre-concentration was performed by liquid–liquid extraction (LLE) using duloxetine as internal standard. The chromatographic separation was achieved using an isocratic mobile phase containing 1.0 mM ammonium acetate pH 3.0 and acetonitrile (70:30, v/v) flowing through Xterra MS C18 100 mm × 2.1 mm, 3.5 μm analytical column, at a flow rate of 0.2 ml/min. The lower limit of quantitation (LLOQ) of 70.0 pg/ml was achieved using mass spectrometric detection in positive mode. The ion signals of m/ z 375.9 and 297.9 were measured for haloperidol and internal standard, respectively. An exhaustive pre-study method validation was performed in accordance with USFDA guidelines. The standard curves were linear in the concentration range of 70.0 pg/ml to 14.0 ng/ml with mean correlation coefficient of 0.998. The method was successfully applied to the bioequivalence study of haloperidol in healthy human male volunteers.

High-performance liquid chromatographic method with diode array detection to identify and quantify atypical antipsychotics and haloperidol in plasma after overdose

For toxicological purposes, an HPLC assay was developed for the simultaneous determination of haloperidol and atypical antipsychotics (risperidone, 9-hydroxyrisperidone, olanzapine, clozapine) in human plasma. After a double-step liquid–liquid extraction, compounds were separated on a C 8 column eluted with a gradient of acetonitrile and phosphate buffer 50 m M pH 3.8. A sequential ultraviolet detection was used (260, 280 and 240 nm). Calibration curves were linear in the range 10–1000 ng/ml. The limits of quantification were 5 ng/ml for all drugs. Average accuracy at four concentrations ranged from 93 to 109%. Both inter- and intra-day variation coefficients were lower than 11% for all drugs. This simple and rapid method (run time<15 min) is currently used for poison management.

‘High throughput’ solid-phase extraction technology and turbo ionspray LC-MS-MS applied to the determination of haloperidol in human plasma

A quantitative method for the analysis of haloperidol in human plasma is described. Sample clean-up was performed by means of solid-phase extraction using 3M Empore™ extraction disk plates in the 96-well format, automated with a Canberra Packard pipetting robot. Separation was performed by reversed phase high performance liquid chromatography with turbo ionspray tandem mass spectrometric detection by monitoring the decay of protonated haloperidol of m/ z 376 to its fragment at m/ z 165, versus the decay of protonated haloperidol-D4 at m/ z 380 to its fragment at m/ z 169. The validated concentration range was from 0.100 to 50.0 ng ml −1, with an inaccuracy and overall imprecision below 10% at all concentration levels. Validation results on linearity, specificity, precision, accuracy and stability are shown and are found to be adequate. The average sample preparation time for a batch of 96 samples is approximately 50 min. The chromatographic run time is 3 min. A sample throughput of at least 240 samples per day can be achieved.

Blood levels of reduced halopertool versus clinical efficacy and extrapyramidal side effects of haloperidol

1. 1. The studies of relationships between blood levels of reduced haloperidolHL (RH) and clinical efficacy in haloperidol (HL) -treated patients have yielded variable results. On the other hand, the contribution of RH upon HL' s extrapyranidal side effects (EPS) had been suggested in animal nodeIs as well as in preliminary clinical studies with united subjects. 2. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) ( n = 37) were Measured by high perfornance liquid chromatography. 3. 3. The Bean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL|RH], and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 ± 1.71 (S.D.J ng/ml vs. 1.38 ± 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.

全自動ＥＬＩＳＡシステムによるゾニサミドおよびハロペリドールの血しょう中濃度測定

A fully automated enzyme immunoassay system, Omni (BIO-TEK Co.) (ELISA system), using Markit-M Excegran and Markit-M Haloperidol (Dainippon Pharmaceutical Co.) was evaluated to determine the concentrations of zonisamide (ZNS) and haloperidol (HP) in human plasma. At first, the within-run (ZNS: n=8, HP: n=10) and the between-run (4 days) precisions of ZNS and HP were examined.The coefficient of the variations in both the within-run and the between-run precisions of HP were below 5.0 and 7.0%, respectively. In contrast, the some values of ZNS were below 6.5 and 8.4%, respectively. A good correlation was observed between this ELISA system and HPLC (r=0.917), which was used to determine the plasma ZNS concentration. In the case of HP, a good correlation was seen between this ELISA system and the manual ELISA method (r=0.978).This method was thus used to monitor the serum levels in patients receiving ZNS or HP therapy. The relationship was observed between the daily dose (mg/kg) and the plasma concentration of the trough level for ZNS and HP, respectively (r=0.750 p<0.001, r=0.669 p<0.001). However, the ratio of the plasma concentration of ZNS and the daily dose increased significantly with aging.

Determination of haloperidol and its reduced metabolite in human plasma by liquid chromatography-mass spectrometry with electrospray ionization.

A sensitive and accurate liquid chromatographic-electrospray mass spectrometric (LC-ES-MS) method for the determination of haloperidol (H) and reduced haloperidol (RH) in human plasma is presented, using chlorohaloperidol as the internal standard. A 2-ml volume of plasma was subjected to basic (NaOH) extraction, acid (HCl) back-extraction, acid wash and basic (NaOH) re-extraction. The extraction solvent was hexane-isoamyl alcohol (99:1, v/v) for the whole procedure. A Nucleosil C18 column (150 x 1 mm) was used for high-performance liquid chromatography, together with 2 mM HCOONH4-acetonitrile (55:45, v/v; pH 3.0) as the mobile phase. For each drug, four characteristic ions were monitored. Linearity was assessed in the ranges 0.1-50 and 0.25-50 ng/ml for H and RH, respectively. Recoveries were 58 and 70% and detection limits were 0.075 and 0.100 ng/ml for H and RH, respectively. Correlation coefficients were better than 0.999 for both compounds. R.S.D.s for repeatability and reproducibility at 0.25 ng/ml were 11.1 and 8.5% for H and 9.4 and 11.2% for RH, respectively. One of the main advantages of (LC-ES-MS) over other detection systems is the increase in selectivity obtained by monitoring three ions of confirmation for each of the drugs.