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Monitoring antipsychotic drugs in biological fluids, such as human serum and urine, is important for ensuring the safety and efficacy of psychiatric treatments. This process helps maintain therapeutic drug levels, minimize side effects, and optimize patient well-being. Chlorpromazine (CZ) is a widely prescribed antipsychotic drug used for conditions like schizophrenia, bipolar disorder, and acute psychosis. Almost all existing sensing techniques for CZ are either insensitive spectrophotometric methods or involve long and complex chromatographic procedures, limiting their routine use. In this work, we introduce a facile, green, and sensitive fluorimetric strategy with high reproducibility for detecting CZ in its pure form, tablet formulation, and spiked human plasma and urine without the need for derivatization reactions. The proposed method relies on the inhibition of the intramolecular photoinduced electron transfer (PET) effect by using 2.0 M acetic acid. This approach enables the linear detection of CZ from 3.0 to 600 ng/mL with remarkably low quantitation and detection limits of 1.51 and 0.49 ng/mL, respectively. Moreover, the developed method's greenness was evaluated., (© 2024 John Wiley & Sons Ltd.)

Monodisperse molecularly imprinted polymers (MIPs) for chlorpromazine (CPZ) and bromopromazine (BPZ), MIP CPZ and MIP BPZ , were prepared using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a crosslinker by multi-step swelling and polymerization. The retention and molecular-recognition properties of MIP CPZ and MIP BPZ were evaluated using a mixture of potassium phosphate buffer and acetonitrile or a mixture of water and acetonitrile including ammonium formate as a mobile phase in reversed-phase LC. On MIP BPZ , CPZ, BPZ and imipramine (IMP) gave the maximal retention factors at a mobile-phase pH 8, while the maximal imprinting factors were obtained at a mobile-phase pH 7. Each MIP recognized a template molecule the most, while CPZ metabolites, desmethyl CPZ (DM-CPZ), CPZ sulfoxide (CPZ-SO) and 7-hydroxy CPZ (7-OH-CPZ), were moderately recognized on MIP CPZ and MIP BPZ . Furthermore, both MIPs gave the similar retention and molecular-recognition for CPZ and its metabolites. For avoiding the template-leakage problems, MIP BPZ was used as the pretreatment column for the determination of CPZ and its metabolites in rat plasma in column-switching LC with UV detection. In addition to DM-CPZ and CPZ-SO, didesmethyl CPZ (DDM-CPZ) and CPZ N-oxide (CPZ-NO) were speculated as the metabolite in rat plasma after administration of CPZ using LC-ESI-TOF-MS, while 7-OH-CPZ was not detected. The column-switching LC method was validated and applied for the determination of CPZ and its metabolites, DM-CPZ, DDM-CPZ, CPZ-SO and CPZ-NO, in rat plasma after intravenous and oral administration of CPZ using IMP as an internal standard., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This manuscript describes a sensitive, selective, and online in-tube solid-phase microextraction coupled with an ultrahigh performance liquid chromatography-tandem mass spectrometry (in-tube SPME-UHPLC-MS/MS) method to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples from schizophrenic patients. Organic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolith was synthesized on the internal surface of a fused silica capillary (covalent bonds) for in-tube SPME. Analyte extraction and analysis was conducted by connecting the monolithic capillary to an UHPLC-MS/MS system. The monolith was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectrometry (FTIR). The developed method presented adequate linearity for all the target antipsychotics: R² was higher than 0.9975, lack-of-fit ranged from 0.115 to 0.955, precision had variation coefficients lower than 14.2%, and accuracy had relative standard error values ranging from -13.5% to 14.6%, with the exception of the lower limit of quantification (LLOQ). The LLOQ values in plasma samples were 10 ng mL -1 for all analytes. The developed method was successfully applied to determine antipsychotics and their metabolites in plasma samples from schizophrenic patients.

A new facile magnetic micro-solid-phase extraction coupled to gas chromatography and mass spectrometry detection was developed for the extraction and determination of selected antidepressant drugs in biological fluids using magnetite-MCM-41 as adsorbent. The synthesized sorbent was characterized by several spectroscopic techniques. The maximum extraction efficiency for extraction of 500 μg/L antidepressant drugs from aqueous solution was obtained with 15 mg of magnetite-MCM-41 at pH 12. The analyte was desorbed using 100 μL of acetonitrile prior to gas chromatography determination. This method was rapid in which the adsorption procedure was completed in 60 s. Under the optimized conditions using 15 mL of antidepressant drugs sample, the calibration curve showed good linearity in the range of 0.05-500 μg/L (r 2  = 0.996-0.999). Good limits of detection (0.008-0.010 μg/L) were obtained for the analytes with good relative standard deviations of <8.0% (n = 5) for the determination of 0.1, 5.0, and 500.0 μg/L of antidepressant drugs. This method was successfully applied to the determination of amitriptyline and chlorpromazine in plasma and urine samples. The recoveries of spiked plasma and urine samples were in the range of 86.1-115.4%. Results indicate that magnetite micro-solid-phase extraction with gas chromatography and mass spectrometry is a convenient, fast, and economical method for the extraction and determination of amitriptyline and chlorpromazine in biological samples., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Simple and rapid determinations of some psychotropic drugs in some pharmaceutical wastewater and human plasma samples were successfully accomplished via the tandem dispersive liquid-liquid microextraction combined with high performance liquid chromatography-ultraviolet detection (TDLLME-HPLC-UV). TDLLME of the three psychotropic drugs clozapine, chlorpromazine, and thioridazine was easily performed through two consecutive dispersive liquid-liquid microextractions. By performing this convenient method, proper sample preconcentrations and clean-ups were achieved in just about 7min. In order to achieve the best extraction efficiency, the effective parameters involved were optimized. The optimal experimental conditions consisted of 100μL of CCl 4 (as the extraction organic solvent), and the pH values of 13 and 2 for the donor and acceptor phases, respectively. Under these optimum experimental conditions, the proposed TDLLME-HPLC-UV technique provided a good linearity in the range of 5-3000ngmL -1 for the three psychotropic drugs with the correlation of determinations (R 2 s) higher than 0.996. The limits of quantification (LOQs) and limits of detection (LODs) obtained were 5.0ngmL -1 and 1.0-1.5ngmL -1 , respectively. Also the proper enrichment factors (EFs) of 96, 99, and 88 for clozapine, chlorpromazine, and thioridazine, respectively, and good extraction repeatabilities (relative standard deviations below 9.3%, n=5) were obtained., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased., Methods: To evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of "undetermined intent" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001., Conclusions: The removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.

The purpose of this paper is to focus on the short-term effects of chlorpromazine on erythrocytes because it is reported that the drug, unstable in plasma but more stable in erythrocytes, interacts with erythrocyte membranes, membrane lipids, and hemoglobin. There is a rich literature about the side and therapeutic effects or complications due to chlorpromazine, but most of these studies explore the influence of long-term treatment. We think that evaluating the short-term effects of the drug may help to clarify the sequence of chlorpromazine molecular targets from which some long-term effects derive. Our results indicate that although the drug is primarily intercalated in the innermost side of the membrane, it does not influence band 3 anionic flux, lipid peroxidation, and protein carbonylation processes. On the other hand, it destabilizes and increases the autooxidation of haemoglobin, induces activation of caspase 3, and, markedly, influences the ATP and reduced glutathione levels, with subsequent exposure of phosphatidylserine at the erythrocyte surface. Overall our observations on the early stage of chlorpromazine influence on erythrocytes may contribute to better understanding of new and interesting characteristics of this compound improving knowledge of erythrocyte metabolism.

A 37-year-old man was admitted to our hospital with acute phenobarbital poisoning. On arrival, he was in deep coma with respiro-circulatory depressions. The serum concentration of the agent was elevated to 149.04 μg/mL which was consistent with a lethal concentration level. He underwent a gastric lavage, administration of activated charcoal, urinary alkalinazation and bowel irrigation. Respiro-circulatory status was recovered rapidly, while the serum concentration of phenobarbital did not decrease smoothly. Although the concentration of the agent decreased to 77.07 μg/mL that should be a comatose level, BIS values were gradually elevated, and then eventually the patient regained his consciousness. Because he was a chronic user of Vegetamin-A containing phenobarbital, the serum level might not have been correlated with symptoms. BIS values were highly reflective of the consciousness level, so it could be a useful indicator for predicting the consciousness levels of patients in deep coma with acute poisoning from hypnotic agents.

A new restricted access molecularly imprinted polymer coated with bovine serum albumin (RAMIP-BSA) was developed, characterized, and used for direct analysis of chlorpromazine in human plasma samples. The RAMIP-BSA was synthesized using chlorpromazine, methacrylic acid, and ethylene glycol dimethacrylate as template, functional monomer, and cross-linker, respectively. Glycerol dimethacrylate and hydroxy methyl methacrylate were used to promote a hydrophilic surface (high density of hydroxyl groups). Afterward, the polymer was coated with BSA using glutaraldehyde as cross-linker, resulting in a protein chemical shield around it. The material was able to eliminate ca. 99% of protein when a 44-mg mL(-1) BSA aqueous solution was passed through it. The RAMIP-BSA was packed in a column and used for direct analysis of chlorpromazine in human plasma samples in an online column switching high-performance liquid chromatography system. The analytical calibration curve was prepared in a pool of human plasma samples with chlorpromazine concentrations ranging from 30 to 350 μg L(-1). The correlation coefficient obtained was 0.995 and the limit of quantification was 30 μg L(-1). Intra-day and inter-day precision and accuracy presented variation coefficients and relative errors lower than 15% and within -15 and 15%, respectively. The sample throughput was 3 h(-1) (sample preparation and chromatographic analysis steps) and the same RAMIP-BSA column was efficiently used for about 90 cycles.

Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D₂ receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D₂ activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D₂ activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D₂ activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D₂ activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity.

Under the condition of 60 °C and 20 min at pH 6.12, chlorpromazine hydrochloride (CPZ) could react with fluorescein isothiocyanate (FITC) to produce FITC-CPZ, which increased the π-electron density (δ) of carbon atom in FITC conjugated system and the room temperature phosphorescence (RTP) intensity of FITC. Thus, a new solid substrate room temperature phosphorimetry (SSRTP) for the determination of residual CPZ was established. The regression equation of working curve was ΔI (p) = 4.254 + 7.906 m(CPZ) (ag spot(-1)) with the correlation coefficient (r) of 0.9990 in the range of 0.036-9.6 ag spot(-1) (corresponding concentration: 0.090-24 fg ml(-1), sample volume: 0.40 μl spot(-1)), and the detection limit (LD) was 0.018 ag spot(-1) (corresponding concentration: 4.5 × 10(-17) g ml(-1)). This method with wide linear range and high sensitivity was not only used to diagnose human disease based on the correlation between the residual quantity and lethal dose of CPZ in human serum, but also used to determine residual CPZ in biological samples with the results consisting with those obtained by gas chromatography (GC), showing good accuracy. The constituent of FITC-CPZ was analyzed by GC-MS (mass spectrometry) and the reaction mechanism of SSRTP for the determination of trace CPZ was also discussed.

In the present study a method to quantify chlorpromazine in human plasma using cyclobenzaprine as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by a liquid-liquid extraction with diethyl ether/dichloromethane (70/30, v/v) and analyzed by an ultra performance liquid chromatography (UPLC) coupled to an electrospray tandem triple quadrupole mass spectrometer in positive mode (UPLC-ES(+)-MS/MS). Chromatography was performed isocratically on an Aquity UPLC BEH C18 1.7 μm (50 mm × 2.1 mm i.d.) operating at 40°C. The mobile phase was a mixture of 65% water+1% formic acid and 35% of acetonitrile at a flow-rate of 0.5 mL/min. The lowest concentration quantified was 0.5 ng/mL and a linear calibration curve over the range 0.5-200 ng/mL was obtained, showing intra-assay precisions from 2.4 to 5.8%, and inter-assay precisions from 3.6 to 9.9%. The intra-assay accuracies ranged from 96.9 to 102.5%, while the inter-assay accuracies ranged from 94.1 to 100.3%. This analytical method was applied in a relative bioavailability study in order to compare a test chlorpromazine 100 mg simple dose formulation versus a reference in 57 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a fourteen days washout period. Plasma samples were obtained over a 144-h interval. Since the 90% CI for both C(max), AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration and ANVISA, it was concluded that chlorpromazine 100 mg/dose was bioequivalent to the reference formulation, according to both the rate and extent of absorption., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To develop a method to measure trihexyphenidyl, chlorpromazine and clozapine in human blood with GC-MS., Methods: The specimens were alkalized (pH > 10) and extracted with V (benzene):V(ethyl acetate) = 1:1, and qualitatively analyzed using GC-MS-Full Scan with internal standard SKF525A. The specimens were alkalized (pH > 10) and extracted with V(benzene):V(ethyl acetate) = 1:1, and quantitatively analyzed using GC-MS-SIM with internal standard diazepam-d5., Results: The lowest detection limits of trihexyphenidyl, chlorpromazine and clozapine were 0.3, 0.3 and 0.7 ng/mL (S/N > or = 3) respectively. The calibration curve in 20-10 000 ng/mL showed a good linear distribution. The recovery rate was 79.9% to 85.5%. The RSDs of intraday and interday were less than 5.1%., Conclusion: The established method was simple, sensitive and accurate for simultaneous determination of trihexyphenidyl, chlorpromazine and clozapine in human blood, and can be applied in forensic toxicological cases.

A sensitive and reproducible stir bar sorptive extraction and HPLC-UV detection method was used for the therapeutic drug monitoring of chlorpromazine and trifluoperazine in human serum. The separation was achieved using a C(18) column. The mobile phase consisted of methanol/sodium acetate buffer (pH 4.1; 0.1 M) (95:5, v/v) including 0.5% triethylamine. This miniaturized method can result in faster analysis, lower solvent consumption and less workload per sample while maintaining or even improving sensitivity. In the second part, stir bar sorptive extraction/HPLC-UV method was optimized by a chemometrics approach. An experimental design was therefore used to evaluate the statistically influential and/or interacting factors, among those described in the literature, and to find the best extraction and desorption conditions. Optimal sample volume of 1 mL, extraction time of 24 min at 31°C with pH 8.1 were obtained in a screening 2(5) half fractional factorial design followed by a Box-Behnken design. For the desorption conditions, a Box-Behnken design showed that the best conditions were 150 μL mobile phase for 20 min at 50°C. The optimized method was repeatable (CV<10%, linear (LOQ-500 ng/mL)), with the LOQs equal to 0.7 and 1.5 ng/mL for chlorpromazine and trifluoperazine, respectively., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report an autopsy case of a man who died 2 days after taking an overdose of vegetamin. The autopsy findings were as follows: the epidermis on the axillary fossa and the inguinal skin had become macerated. Skeletal muscle was discolored. Concentrations of urea nitrogen, creatinine and urine myoglobin were 1.95 g/day, 0.66 g/day and 1100 ng/mL, respectively. Immunohistochemically, myoglobin was strongly stained at the Bowman's capsule, and tubular lumen and epithelium. 8-OH-dG was strongly stained in renal tubular epithelium in which cell nuclei were strongly stained. ORP-150 was observed in intraglomerular cells and renal tubular epithelium. The concentrations of phenobarbital, promethazine and chlorpromazine ranged from therapeutic to toxic levels, from toxic to lethal levels and toxic level, respectively. His cause of death was considered to be vegetamin-induced rhabdomyolysis. In genetic analysis of this subject, there were two heterozygous silent mutations in the three hot-spot regions in the RYR1 gene. In the CPT II gene, the subject was found to be heterozygous for an amino acid substitution in exon 4, (1203)G>A causing a (368)Val>Ile amino acid substitution. There was no mutation in the VLCAD gene or CYP2C19 gene. The subject was heterozygous for CYP2D6*1 and CYP2D6*2., (2009 Elsevier Ltd and Faculty of Forensic and Legal Medicine. Published by Elsevier Ltd. All rights reserved.)

Learning potential and memory capacity are factors that strongly predict the level of rehabilitation and the long-term functional outcome in patients with schizophrenia. Unfortunately, however, the effects of antipsychotic drugs (i.e. the primary treatments for schizophrenia) on these components of cognition are unclear, particularly when they are administered chronically (i.e. a standard clinical practice). In this rodent study we evaluated the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the first generation antipsychotic chlorpromazine (10.0 mg/kg/day), or the second generation antipsychotic olanzapine (10.0 mg/kg/day) on the repeated acquisition of a water maze task (i.e. a method of assessing spatial learning potential in a repeated testing format). We assessed locomotor function (in an open field) and employed a radial arm maze (RAM) task to assess antipsychotic effects (5.0 and 10.0 mg/kg/day doses) on spatial working memory during the treatment period between 15 days and 2 months. Finally, we conducted experiments using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to evaluate the therapeutic relevance of our method of drug delivery (oral administration in drinking water). In the water maze experiments, both antipsychotics were associated with impairments in acquisition in the earlier test sessions that could eventually be overcome with repeated testing while olanzapine also impaired retention in probe trials. Both antipsychotics were also associated with impairments in delayed non-match-to-position trials in the RAM and some impairments of motor function (especially in the case of olanzapine) as indicated by slightly reduced swim speeds in the water maze and decreased activity in some components of the open field assessment. Finally, LC-MS/MS studies indicated that the method of antipsychotic administration generated clinically relevant plasma levels in the rat. These animal data indicate that chronic oral treatment with chlorpromazine or olanzapine can impair the performance of tasks designed to assess specific components of cognition that are affected in schizophrenia.

In the present work, hollow fiber liquid phase microextraction (HF-LPME) in conjunction with reversed-phase HPLC/UV was developed for extraction and determination of trace amounts of chlorpromazine in biological fluids. The drug was extracted from an 11 ml aqueous sample (source phase; SP) into an organic phase impregnated in the pores of the hollow fiber (membrane phase; MP) followed by the back-extraction into a second aqueous solution (receiving phase; RP) located in the lumen of the hollow fiber. The effects of several factors such as the nature of organic solvent, compositions of SP and RP solutions, extraction time, ionic strength and stirring rate on the extraction efficiency of the drug were examined and optimized. Under the optimal conditions, enrichment factor of 250, dynamic linear range of 1-500 microgl(-1), and limit of detection of 0.5 microgl(-1) were obtained for the drug. The percent relative intra-day and inter-day standard deviation (R.S.D.%) based on three replicate determinations were 6.7 and 10.3%, respectively. The method was applied to drug level monitoring in the biological fluids and satisfactory results were obtained.

A simple, sensitive and robust liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for quantification of chlorpromazine in rat plasma and brain tissue. Chlorpromazine was extracted from rat plasma and brain homogenate using liquid-liquid extraction. 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/20 mM ammonium formate (pH 4.25 adjusted with formic acid) with gradient elution. Chlorpromazine was 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. The LLOQ was 0.2 ng/ml for plasma and 0.833 ng/g for brain tissue. The method was linear over the concentration range from 0.2 to 200.0 ng/ml for plasma and from 0.833 to 833.3 ng/g for brain tissue. The correlation coefficient (R(2)) values were more than 0.998 for both plasma and brain homogenate. The precision and accuracy for intra-day and inter-day were better than 7.54%. The relative and absolute recovery was above 84.9% and matrix effects were lower than 5.6%. This validated method has been successfully used to quantify the rat plasma and brain tissue concentration of chlorpromazine after chronic treatment.

The interaction of chlorpromazine and promethazine in vivo has been investigated. The drugs were administered to the rabbit orally as a single dose (100 mg of each drug) as well as simultaneously with an interval of 15 min. The presence of multiple peaks at the separate administration of promethazine and chlorpromazine on the one hand, and increase of number of peaks, symbathic character of kinetic curves of mentioned drugs and its prolonged appearance in the systemic circulation of the blood by simultaneous administration on the other hand, may be explained by the intensive presystem metabolism and surface-activity ability of these drugs, and by the periodic 'lassitude' of liver for their capture and elimination (either presystem or systemic). The micelle formation from these drugs in the gastro-intestinal tract and formation of the mixed micelles on simultaneous administration were also taken into consideration. Chlorpromazine is more strongly captured by the liver at its first pass through it than promethazine, from comparison of pharmacokinetics of these drugs administered separately. Therefore, chlorpromazine on simultaneous administration occupies the sites of the liver which were covered by promethazine at single dose, thereby substituting promethazine and promoting its transferral into the systemic blood circulation. This results in a large increase in promethazine content in blood, additional peaks appear and the presence of promethazine in the blood is prolonged. The influence of chlorpromazine on the kinetics of promethazine is especially obvious when chlorpromazine enters the organism first and more easily occupies those sites in the liver which participate in the capture and elimination of both drugs. Concerning influence of promethazine on the kinetics of chlorpromazine, promethazine reinforces in some way the ability of liver to capture chlorpromazine, thereby intensifying the presystem metabolism of chlorpromazine and inhibiting its own metabolism. The analogous effect was observed in the study of the influence of promethazine on the kinetics of carbamazepine., (Copyright 2004 John Wiley & Sons, Ltd.)

A 21-year-old female inpatient who was enrolled in a population pharmacokinetic study of chlorpromazine was given an oral chlorpromazine dose of 100 mg three times daily, and plasma concentrations of chlorpromazine were measured weekly. This dose was well tolerated during the first week of therapy. In the second week the patient took a combined oral contraceptive; this was followed by severe dyskinesias and tremor. Plasma chlorpromazine levels were found to be about sixfold higher than those in the first week, although the dose of chlorpromazine had not changed. This observation suggests that the oral contraceptive increased the plasma concentration of chlorpromazine.

Chlorpromazine (CPZ), a widely used tranquilizer, is known to induce stomatocytic shape changes in human erythrocytes. However, the effect of CPZ on membrane mechanical properties of erythrocyte membranes has not been documented. In the present study we show that CPZ induces a dose-dependent increase in mechanical stability of erythrocyte ghost membrane. Furthermore, we document that spectrin specifically binds to CPZ intercalated into inside-out vesicles depleted of all peripheral proteins. These findings imply that CPZ-induced mechanical stabilization of the erythrocyte ghost membranes may be mediated by direct binding of spectrin to the bilayer. Membrane active drugs that partition into lipid bilayer can thus induce cytoskeletal protein interactions with the membrane and modulate membrane material properties.

A new method to measure two different drugs simultaneously by time-resolved fluoroimmunoassay (TR-FIA) has been developed. In the TR-FIA reported here, psychopharmaceuticals [chlorpromazine (CPZ) and desipramine (DSP)] and methamphetamine (MA) contained in serum are assayed by a combined use of a new europium (Eu) chelate and a samarium (Sm) chelate, as labels. The drug concentrations were determined by the competition between a labeled antigen with Eu(3+) or biotin and a sample antigen. A microtiter plate coated with a mixture of rabbit IgGs (anti-MA and anti-CPZ or anti-MA and anti-DSP) was used. In the assay of MA and CPZ, Eu(3+) labeled MA-bovine serum albumin conjugate (MA-BSA) and biotinylated CPZ-BSA were added to the well with their non-labeled standard solutions or samples. MA was assayed by measuring the fluorescence intensity of Eu(3+) at 615 nm. After incubation of the Sm(3+) labeled streptavidin, CPZ was assayed by measuring the fluorescence of Sm(3+) at 643 nm. In the assay of MA and DSP, Eu(3+) labeled DSP-BSA and biotinylated MA-BSA were used. In our dual-assay, the minimum detection limits of these drugs were 1ng/ml for MA, 10 ng/ml for CZP and 10 ng/ml for DSP. Since the simultaneous detection of different drugs by TR-FIA is time and sample saving, the method can be employed in rapid and sensitive screening tests.

The interaction of carbamazepine and chlorpromazine in rabbits has been studied. The drugs were administrated as single oral doses (200 mg of each drug). The sequence of administration of the drugs was varied. It has been established that by simultaneous administration these drugs decrease absorption of each other in plasma. This may be explained by competition of the drugs to transfer from the gastrointestinal tract into plasma, as well as by the formation of complexes, more or less stable and more or less bound to gastrointestinal tissues. Carbamazepine intensifies the biotransformation of chlorpromazine, which may be caused by the ability of carbamazepine to induce microsomal liver enzymes. Chlorpromazine suppresses the biotransformation of carbamazepine, however. This may be caused by intensive capture of chlorpromazine by liver tissues and by its intensive biotransformation, which in turn is conditioned by its surface-active nature and by the increase of its metabolism with carbamazepine. Therefore the biotransformation of chlorpromazine is increased and metabolism of carbamazepine is reduced. The sequence of administration of the drugs affects their pharmacokinetics significantly., (Copyright 1999 John Wiley & Sons, Ltd.)

Chlorpromazine (CPZ) is widely used in South African hospitals. The purpose of this study was to determine whether any physiological parameter (side-effect) could be correlated with plasma concentrations of CPZ or its metabolites. In the absence of a blood level, such a correlation could serve as a qualitative indicator of the amount of chlorpromazine in the body. Such a marker can assist the psychiatrist with therapeutic decisions regarding poor compliance and the lack of response with the drug. Fifteen schizophrenic patients were included in this study and regression analysis was used to determine any correlation between CPZ, 7-hydroxychlorpromazine, Chlorpromazine-N-oxide, Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine sulfoxide, Nor2 chlorpromazine sulfoxide and blood pressure, pulse rate, sedation and finger tremor. No correlation was seen between blood pressure or pulse rate and plasma concentrations of CPZ or the metabolites. A good correlation was seen between sedation, 7- hydroxychlorpromazine (P=0.035) and chlorpromazine sulfoxide (P=0.016). The results suggest that as the levels of chlorpromazine sulfoxide increase, the probability of sedation increases, while increasing levels of 7-hydroxychlorpromazine have the opposite effect. A good correlation was also seen between finger tremor and chlorpromazine levels (P=0.035). These results suggest that there is a 50% probability that the patient would experience finger tremor when the plasma concentration of chlorpromazine is 46 ng/ml. This study demonstrated the potential for the use of sedation and finger tremor as qualitative indicators of the plasma concentration of CPZ and two metabolites. Further studies with larger patient numbers are warranted.

Background: Very little is known about the pharmacokinetics of neuroleptic drugs in breast-feeding mothers and their infants or about possible adverse effects in the infants., Method: Twelve mothers who breast-fed their infants were prescribed haloperidol, chlorpromazine or trifluoperazine. Two methods, enzyme immunoassay (EIA) and high performance liquid chromatography (HPLC) were used to assay these drugs in samples from mothers, but infants' samples were assayed only by the more sensitive EIA. Repeated clinical and developmental assessments of the breast-fed infants were carried out up to 30 months of age. The control subjects were 18 bottle-fed infants whose mothers were also prescribed neuroleptic or mood-stabilizing drugs., Results: The total concentrations of neuroleptic drugs and their principal metabolites in maternal plasma were correlated with concentrations in fore-milk. Infants were ingesting up to 3% of the maternal daily dose per kg body weight and small amounts of the drugs were detected in infants' plasma and urine. Concentrations of haloperidol in the adult range were found in plasma from 2 of 5 infants assayed by EIA but there was no evidence of any acute or delayed adverse effects. Three other breast-fed infants whose mothers were prescribed both haloperidol and chlorpromazine showed a decline in their developmental scores from the first to the second assessment at 12-18 months., Conclusion: More extensive longitudinal studies are needed but, in the meantime, there appears to be grounds for caution if breast-feeding mothers are prescribed doses of single or two neuroleptic drugs at the upper end of their recommended ranges.

A high-performance liquid chromatographic method has been developed and tested for simultaneous extraction, elution and determination of doxorubicin and prochlorperazine content in human plasma samples. The procedure consists of extraction through a conditioned C18 solid-phase extraction cartridge, elution from a Spherisorb C8 reversed-phase column by an isocratic mobile phase (60% acetonitrile, 15% methanol and 25% buffer) followed by detection with electrochemical and fluorescence detectors. Recovery of doxorubicin and prochlorperazine from pooled human plasma samples (n=3) containing 100 ng/ml of the two drugs was 77.8+/-3.5% and 89.1+/-6.0%, respectively. The lower limits of quantitation for doxorubicin and prochlorperazine in plasma samples were 6.25 ng/ml and 10 ng/ml, respectively. A linear calibration curve was obtained for up to 2 microg/ml of doxorubicin and prochlorperazine. This combination method may be of particular value in clinical studies where phenothiazines such as prochlorperazine are used to enhance retention of doxorubicin in drug resistant tumor cells.

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production.

A reversed-phase HPLC method for determination of phenothiazines and tricyclin antidepressants in whole blood was described. In this paper, a model 1090 HPLC with DAD and a zorbax ODS column was used. The mobile phase was methanol: water: tritely amine (75:24.7:0.3) with pH 7.5. Cyproheptadine was used as internal standard in this method. Blood samples were extracted with the solid-phase extraction method and the liquid-liquid method. This method is suitable in forensic toxicology analysis for basic drugs.

Gas chromatography-mass spectrometry (GC-MS), which combines the separation power of GC with the power of MS for the identification of unknown compounds, possesses high potential in systematic toxicological analysis (STA). Different factors, however, do not allow this potential to be fully exploited. Between them, the low selectivity of the mass spectrometer operating in continuous scan plays a critical role, in many cases precluding the possibility of selecting mass spectra in the total ion chromatogram (TIC) sufficiently clean for a positive identification by library search, even when using reverse search algorithms. Moreover, the large amount of information contained in GC-MS data file that results from the analysis of a biological extract makes the efforts of manual search almost useless and requires the availability of reliable methods for the automated detection and identification of peaks in a TIC. In this paper, a simple procedure that improves the performance of a bench-top GC-MS system in the purification of mass spectra of coeluting compounds and that can be easily combined with the automated processing of a GC-MS data file is described. It is based on the subtraction of the intensities of successive pairs of scans in the TIC, on the detection of positive and negative peaks in the transformed chromatograms, and on the search of the corresponding background-subtracted electron ionization mass spectra against reference libraries. In order to evaluate the proposed procedure, GC-MS data files obtained for the analysis of extracts of blank whole blood spiked with more than 100 drugs, poisons, and their metabolites at a concentration of 0.5 mg/L were used. Compared with the search of the raw TICs, the proposed procedure increased the number of identified substances and, in many cases, obtained higher match quality values for identification.

The relationship between chlorpromazine, six of its metabolites and therapeutic response in chronic schizophrenic patients was investigated in this study. Logistic regression revealed no correlation between therapeutic response and four metabolites viz. Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine-N-oxide and Nor2 chlorpromazine sulfoxide. A good correlation was seen between CPZ (P = 0.036), 7-hydroxychlorpromazine (P = 0.004), chlorpromazine sulfoxide (P = 0.002) and therapeutic response. Good therapeutic response was correlated to high levels of chlorpromazine and its 7-hydroxy metabolite while high levels of the sulfoxide metabolite appeared to have a negative effect on therapeutic response. Poor responders who had high levels of chlorpromazine also had high levels of the sulfoxide metabolite. This suggests that the difference in response may lie in the difference in the metabolism of the drug.

A single oral dose of 90 mg kg-1 chlorimipramine or chlorpromazine, corresponding to 54.5 or 55.9 mumol, respectively, was given to male Sprague-Dawley rats and concentrations of parent drugs and their N-desmethyl metabolites measured by gas chromatography in plasma and major organs (brain, liver, lung, kidney, heart, spleen and peritoneal fat). In the case of chlorimipramine, N-desmethyl metabolite levels were consistently higher than those of the parent drug for the entire observation period of 24 h in all tissues except fat, while lower N-desmethyl metabolite/parent compound ratios were observed for chlorpromazine. N-Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination-rate limited, while those of chlorpromazine were formation-rate limited. In all analysed organs, the maximu detectable drug+metabolite concentrations accounted for only 2.3 and 4.6% of the initial dose of chlorimipramine and chlorpromazine. Chlorpromazine treatment gave rise to an area under the total amount-time curve (AUC0-24) for parent drug+metabolites, 3.9-fold that for chlorimipraine. Closer scrutiny discloses a conversion ratio of parent compound to N-desmethyl metabolite of 1.1 for chlorpromazine and of 2.2 for chlorimipramine, indicating the greater efficiency of chlorimipramine metabolism in all compartments. The expected high conversion index found in the liver (2.3) reaches its maximum of 5.4 in the lung. Fractional data analysis of chlorimipramine and chlorpromazine distribution patterns revealed greater organ transfer for the N-desmethyl metabolites than for the more stably-located parent compounds. The N-desmethyl metabolites of chlorimipramine apparently moved from liver to lung, kidney and spleen, whereas N-desmethylchlopromazine moved preferentially to the brain and lung tissue. This single dose study of chlorimipramine and chlorpromazine kinetics, highlights the two distinct dispositional processes at work in the rat in all likelihood, attributable to different absorption patterns, to a slower metabolism and, thus, to the longer persistence of chlorpromazine.

A LC method was developed for the concurrent assay of R(+) and S(-) promethazine from human urine and serum. The method involves the use of solid-phase extraction for sample clean-up. Chromatographic resolution of the enantiomers was performed under isocratic conditions using a mobile phase of hexane-1,2-dichlorethane-absolute ethanol-trifluoroacetic acid (400:150:100:1, v/v/v/v) at a flow rate of 1 ml min-1 on a brush-type column KK-CARNU. The enantiomers were detected by fluorescence using an excitation wavelength of 250 nm and a 280 nm emission cutoff filter. Chlorpromazine was used as the internal standard for urine analysis. Standard addition was used for promethazine analysis from serum. Drug to internal standard ratios were linear from 0.25 to 10 micrograms ml-1 in urine. Serum levels were linear from 2 to 10 ng ml-1.

The time courses of the total concentration of chlorpromazine (CPZ) and its S-oxide (CPZSO) in serum after i.v. administration of CPZ are described by a two compartment model and a simple metabolism model, respectively. The time course of the free CPZ concentration in serum is predicted by the correlation between the ratio of CPZSO/CPZ and the free fraction of CPZ in serum which was established in the previous study. The time course of CPZ concentration in cerebrospinal fluid (CSF) is described by a basic physiological model in which the CSF compartment is connected with the serum compartment (free drug) by the apparent diffusion clearance. Equilibrium dialysis of the striatum homogenate was carried out to clarify the CPZ disposition in the striatum. Since the binding curves of CPZ in the striatum on the Langmuir plot and the Scatchard plot were a sigmoidal and an upward curve, the time course of the drug's concentration was analyzed on a simple kinetic model designed in conformity with a blood-flow limited model. The time course was described by a simple kinetic model for up to 8 h after CPZ administration. These pharmacokinetic models for CSF and the striatum will be used to analyze the relationship between the pharmacokinetics and pharmacodynamics of CPZ.

The serum protein binding curve of chlorpromazine (CPZ) on the Scatchard plot in vitro was a two-phase downward curve. However, after i.v. administration of CPZ the curve was altered to an upward curve. To clarify the reasons for these in vivo changes, the influence of chlorpromazine S-oxide (CPZSO), chlorpromazine N-oxide (CPZNO), desmethylchlorpromazine (nor1-CPZ), chlorpromazine sulfone (sul-CPZ) and 7-hydroxychlorpromazine (7-OH-CPZ) on CPZ protein binding were studied in vitro. The results indicated that the characteristics of the CPZ protein binding are altered by the combination of CPZSO or CPZNO or by either of them. Since it was very difficult to explain the relationship between serum total and free concentrations of CPZ in vivo using mass-balance equations like Hill's equation or a competitive inhibition equation on the multiple binding sites for drug, the correlation between the ratio ot total concentration of CPZ metabolites and CPZ (CPZSO/CPZ or CPZNO/CPZ) and the free fraction of CPZ was examined using the in vitro and in vivo data. The correlation between the ratio of CPZSO/CPZ and the free fraction of CPZ was good in both the in vivo and the in vitro studies. There was no statistically significant difference between the population regression coefficient of the two studies. The values of the slope and the intercept became almost the same as those obtained using the in vivo studies when combined with CPZNO.(ABSTRACT TRUNCATED AT 250 WORDS)

Forward and backward masking of contour by light was investigated with stimulus onset asynchronies from 20 to 180 ms in a group of 22 schizophrenic patients and 22 matched normal controls. Individuals with schizophrenia were selected using American Psychiatric Association (1987) criteria and were also assessed using the Andreasen scales for the presence of positive and negative symptoms (N.C. Andreasen, 1981, 1983). The Andreasen scales were used to divide schizophrenic patients into 2 subgroups (positive and negative symptoms). Positive-symptom schizophrenic patients showed no differences in their target duration thresholds or in their backward masking functions. Negative-symptom schizophrenic patients showed significantly longer target duration thresholds and experienced significantly more backward masking. There was no difference between schizophrenic patients and controls in forward masking.

Interaction of Chlorpromazine with tricyclic antidepressants was investigated in twenty schizophrenic patients after their concurrent administration. A significant increase in serum chlorpromazine concentration was observed when administered in combination with both amitriptyline and imipramine with chlorpromazine. If combined therapy is indicated, the dose of chlorpromazine should be reduced or the time of administration of other two drugs should be adjusted to maintain therapeutic levels of chlorpromazine.

Plasma concentrations of chlorpromazine (CPZ) and six metabolites were measured in 12 chronic schizophrenic patients on a fixed dose of CPZ. All six metabolites were measured in significant concentrations, ranging from 12 to 57% of the parent drug concentration. They are listed in order of decreasing mean concentration as follows: chlorpromazine-N-oxide > chlorpromazine sulfoxide > 7-OH chlorpromazine > Nor2 chlorpromazine sulfoxide > Nor2 chlorpromazine > Nor1 chlorpromazine. CPZ concentrations showed significant correlation with the 7-OH chlorpromazine metabolite concentration. Since these metabolites have been associated with in vitro activity and occur in significant concentrations, it is recommended that all six metabolites be measured in studies correlating drug levels with pharmacodynamic effects.

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.

A single oral dose of 0.7 mg kg-1 chlorimipramine (n = 18) and chlorpromazine (n = 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC0-24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 +/- 87 and 124 +/- 14 ng mL-1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43.8 ng mL-1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.

In a double-blind, placebo-controlled, crossover study, the blood levels and pharmacodynamic properties of single oral doses of 15 and 30 mg d-fenfluramine (d-FEN) and 30 mg l-fenfluramine (l-FEN) were investigated as compared with 50 mg chlorpromazine (CPZ) and 20 mg d-amphetamine (AMPH) utilizing pharmaco-electroencephalogram (EEG) mapping as well as prolactin and safety assessments. Eighteen healthy young volunteers randomly (Latin square) received at weekly intervals the different treatments. Blood sampling to determine AMPH, FEN and its main metabolite norFEN, as well as plasma prolactic levels, EEG recordings and evaluation of hemodynamics and spontaneous side effects were carried out at 0, 2, 4, 6 and 8 h after drug administration. Before and 24 h after drug intake morning subjective sleep quality was also assessed. Blood level investigations after d-FEN demonstrated dose-dependent blood concentrations peaking after 2-4 h and slowly declining thereafter. NorFEN, the main metabolite, exhibited a steady increase in plasma concentrations up to the 8th h. After l-FEN a similar time course was obtained but the concentrations of the parent compound were higher and those of the metabolite lower in comparison with the d-isomer, suggesting stereoselective kinetics. d-FEN induced significant and dose-dependent pharmaco-EEG changes characterized by a decrease in total power and combined delta/theta activity and by an increase in beta activity and an acceleration of the centroid of the total activity with no changes in alpha power, which were quite different from those of the reference drugs. l-FEN produced only minimal changes (of the same type as d-FEN). 50 mg CPZ and 20 mg d-AMPH produced significant changes as compared to placebo but with quite opposite patterns, the former exhibiting the typical sedative-neuroleptic profile and the latter that typical of psychostimulants. Dose/treatment- and time-efficacy calculations based on all variables showed in the V-EEG that only 30 mg d-FEN and 50 mg CPZ were different from placebo (with peak effects in the 8th and 4th h, respectively), while in the resting condition (R-EEG) all drugs/dosages but 30 mg l-FEN differed from placebo (with the peak effect occurring in the 4th-6th h after d-FEN and l-FEN, in the 2nd h after CPZ and in the 4th-6th h after AMPH). Plasma prolactin levels were only modified by CPZ (maximal increase in the 2nd h).(ABSTRACT TRUNCATED AT 400 WORDS)

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of chlorpromazine in serum and human breast milk. Chlorpromazine in serum and human breast milk was extracted by a rapid and simple procedure based on C18 bonded-phase extraction, and a reversed-phase HPLC separation technique was developed. Chlorpromazine and levomepromazine as the internal standard were detected by ultraviolet absorbance at 254 nm. Determination was possible for chlorpromazine in the concentration range 10-300 ng/ml. The recoveries of chlorpromazine added to serum and human breast milk were 80.1-87.6 and 80.3-84.4%, respectively, with coefficients of variation of less than 10.2 and 7.8%. The method is applicable to drug level monitoring in the serum and human breast milk of patients treated with chlorpromazine.

Dehalogenaton and N-demethylation of chlorpromazine (CPZ) were studied in twelve psychotic inpatients orally treated for four weeks with a daily CPZ dose of 6.4 +/- 1.1 (S.E.) mg/kg body weight (1.5-14.1, range). Weekly drug and metabolite plasma concentrations were measured by a gas liquid chromatography-nitrogen/phosphorus detector method (GLC/NPD). Plasma concentrations of the parent compound CPZ, of the dehalogenated metabolite promazine (PZ) and of the N-dealkylated metabolites N-monodemethylated chlorpromazine (CPZ-nor1) and N-didemethylated chlorpromazine (CPZ-nor2) had already reached a steady state by the end of the first week of treatment. During the entire treatment period the major plasma component was found to be PZ. Patients (N = 6) on a low dose regimen (3.7 +/- 0.2 mg/kg body weight) showed significantly lower mean plasma concentrations of CPZ and nor metabolites than patients (N = 6) on a higher dose regimen (8.6 +/- 0.7 mg/kg body weight). PZ mean plasma concentrations, however, were not significantly different in the two groups of patients, indicating that the yield of the CPZ dechlorination pathway, as opposed to that of the N-demethylation pathway, was already maximal at the CPZ concentrations attained under the low dose regimen. Male patients (N = 5) exhibited significantly higher mean PZ plasma concentrations over the 4 week period of the study than female patients (N = 7).

A simple and sensitive method is described for quantitative analysis of chlorpromazine in blood, serum, urine and tissue homogenate. The chlorpromazine cation radical produced by adding perchloric acid and 2,3-dichloro-5,6-dicyano-p-benzoquinone to the sample can be detected by the ESR method at room temperature. The sensitivity limit is 10 ng, that is, 20 microliters of the solution containing 0.5 microgram chlorpromazine/ml. The time needed for the measurement is within 10 min. The chlorpromazine radical thus produced is very stable; for example, 95% of the radical was observed after 24 h. The advantage of this method is discussed by comparing with the ordinary spectrophotometry which requires the purification of the sample.

The concentrations of chlorpromazine (CPZ) and six of its metabolites in patient plasma samples that had been stored for 24 h at -20 degrees C, for 1 week at -20 degrees C, and for 4 weeks at -70 degrees C were compared. The concentrations of CPZ and six of its metabolites in human plasma spiked with known concentrations and stored at -70 degrees C for either 3 or 12 months were also compared. No significant difference was seen in the concentrations after storage under nitrogen and analysis by a high-performance liquid chromatography technique.

There is enormous variation in plasma levels of most neuroleptics in patients on the same dose. Much of the past research on the relation between plasma levels of antipsychotic drugs and clinical change, however, has been difficult to interpret. It does appear that decreased bioavailability, at least in public institutions, is rarely the cause of treatment failure. Aberrantly low plasma levels are more likely due to surreptitious noncompliance or drug interactions with enzyme inducers such as carbamazepine. Therapeutic plasma level ranges, in which good antipsychotic effect occurs without undue side effects, have been tentatively identified for perphenazine, haloperidol, fluphenazine, and chlorpromazine. The extent to which aberrantly high plasma levels are associated with inferior antipsychotic response is unclear. Antipsychotic plasma levels may be most useful when the distinction between side effects and worsening psychosis is unclear. The utility of high neuroleptic plasma levels in the treatment-resistant patient is unclear.

A combination of ultrafiltration with either equilibrium dialysis or frontal gel chromatography has been used to evaluate the effects of thermodynamic nonideality in mixtures of bovine serum albumin and charged ligands. Studies with methyl orange, chlorpromazine and chromate as ligand all demonstrated inadequacy of the Donnan effect for description of the difference between the concentrations of free ligand in a mixture and the protein-free phase with which it is in dialysis equilibrium. On the basis of a quantitative relationship derived for the situation in which Donnan and thermodynamic nonideality effects both operate, values of the second virial coefficient for albumin and ligand have been determined. For albumin and either methyl orange or chlorpromazine the magnitude of this second virial coefficient has been rationalized on the statistical-mechanical basis of excluded volume. For the albumin-chromate system, however, the thermodynamic nonideality was manifested as a negative deviation from Raoult's Law, in keeping with the classical behaviour of electrolyte ions. From the viewpoint of the characterization of ligand binding a unique feature of the ultrafiltration/gel chromatography and ultrafiltration/equilibrium dialysis methods is their ability to define not only the binding function but also the activity coefficient of ligand for a given acceptor-ligand mixture. Consequently, irrespective of whether the ligand is charged or uncharged, the intrinsic binding constant that is determined is the thermodynamic parameter instead of the apparent value that is obtained from methods based on assumed thermodynamic ideality.

Factors which influence the plasma drug concentrations in whole blood have been investigated in-vitro using human blood containing radio-labelled phenytoin or chlorpromazine. Phenytoin (3.55 micrograms mL-1, 0.01 mM) or chlorpromazine (2.74 micrograms mL-1, 0.01 mM) was mixed with normal or modified blood and the plasma drug level was measured. Plasma phenytoin and chlorpromazine levels decreased with decrease in the protein concentration of plasma, but were not influenced by addition of gamma-globulin to the blood specimen. Plasma phenytoin levels increased with an increase in haematocrit from 20 to 45%, whereas the chlorpromazine level remained constant. The partition coefficients of phenytoin and chlorpromazine between blood cells and plasma were almost the same at various haematocrit values. By cooling the blood containing each drug to 4 degrees C, plasma phenytoin and chlorpromazine levels were higher compared with those at 37 degrees C. Similar temperature effects on the drug levels in plasma were obtained when the washed erythrocytes were resuspended in albumin medium, but not when resuspended in saline.