Analysis of tricyclic antidepressants using electrogenerated chemiluminescence

A novel method has been investigated for the selective and sensitive determination of a range of tricyclic antidepressants including amitriptyline, doxepin, nortriptyline, promazine, chlorpromazine, imipramine, clomipramine, desipramine, protriptyline and trimipramine using electrogenerated chemiluminescence (ECL). The ECL mechanism is based on the reaction between tris(2,2'-bipyridyl)ruthenium(II) [Ru(bpy)3(2+)] and the tertiary amino groups on the antidepressants. After selecting the best operating parameters calibration curves were obtained over three orders of magnitude for amitriptyline, doxepin, nortriptyline, promazine and chlorpromazine. Linear calibrations were used to obtain limits of detection in the range 0.09-0.24 microgram ml-1 with relative standard deviations below 4% for five replicate samples. Rapid depression in the signal was observed with repeat analysis of imipramine, clomipramine, protriptyline, desipramine and trimipramine due to electrode fouling by the oxidation product of the reaction. Use of a lower concentration of the compound was found to alleviate the problem. Finally the concentration of doxepin was determined in a pharmaceutical preparation.     

SPECIES DIFFERENCES IN RESPONSE TO PHOTOHEMOLYTIC AGENTS

Species differences in red blood cell susceptibility to the photohemolytic agents chlorpromazine, menadione and tetracycline were examined in mouse, rat, dog, and human blood. Menadione and tetracycline (25 microM) hemolyzed mouse but not dog, rat, or human red blood cells (RBC) when irradiated with UV light but not in the dark. Chlorpromazine (25 microM) produced a photohemolytic response in all four species with mouse and rat RBC lysing fastest followed by human then dog cells. Investigations into the nature of these species differences suggested that the size of mouse RBC may contribute to its high sensitivity to photohemolytic agents. An investigation of the effect of UV light on key antioxidant enzymes revealed species differences in enzyme inactivation. These data suggest that mouse RBC may be particularly vulnerable to phototoxic agents, especially those compounds which produce active oxygen species and, therefore, may prove more useful than human RBC as a model for predicting phototoxic potential of some chemical entities.     

Determination of seven selected antipsychotic drugs in human plasma using microextraction in packed sorbent and gas chromatography–tandem mass spectrometry

A method using microextraction by packed sorbent (MEPS) and gas chromatography–tandem mass spectrometry (GC-MS/MS) is described for the determination of seven antipsychotic drugs in human plasma. The studied compounds were chlorpromazine (CPZ), haloperidol (HAL), cyamemazine, quetiapine, clozapine, olanzapine (OLZ), and levomepromazine; promazine, protriptyline, and deuterated CPZ were used as internal standards. The validation parameters included selectivity, linearity and limits of detection and quantitation, intra- and interday precision and trueness, recovery, and stability and were studied according to internationally accepted guidelines. The method was found to be linear between the lower limit of quantitation and 1000 ng/mL, except for OLZ and HAL (200 ng/mL), with determination coefficients higher than 0.99 for all analytes, and extraction efficiencies ranged from 62 to 92 %. Intra- and interday precision ranged from 0.24 to 10.67 %, while trueness was within a ±15 % interval from the nominal concentration for all analytes at all studied levels. MEPS has shown to be a rapid procedure for the determination of the selected antipsychotic drugs in human plasma, allowing reducing the handling time and the costs of analysis. Furthermore, GC-MS/MS has demonstrated to be a powerful tool for the simultaneous quantitation of the studied compounds, enabling obtaining adequate selectivity and sensitivity using a sample volume of as low as 0.25 mL.     

Subtractive differential pulse voltammetry following adsorptive accumulation of organic compounds

Subtractive differential pulse voltammetry following adsorptive preconcentration of organic compounds at solid electrodes is described. Different preconcentration periods are used, and the difference between the oxidation (stripping) currents is recorded. Background currents which are independent of the preconcentration period cancel out. Combining the enhanced peak current, due to the preconcentration step, with the background current correction of the subtractive mode, gives improved sensitivity and/or allows the use of shorter preconcentration periods. Chlorpromazine and dopamine have been used as test systems. A detection limit of around 1 x 10(-9)M has been obtained for chlorpromazine with a 10-min preconcentration period. Applicability to clinical samples is illustrated by the determination of chlorpromazine in whole blood and urine.     

Fluorimetric determinations by ion-pair extraction : Part V. Studies on ion-pair extraction with the fluorescent anion 9,10-dimethoxyanthracene-2-sulphonate

The fluorescent anion 9,10-dimethoxyanthracene-2-sulphonate has been studied in ion-pair extractions. Its ability to extract amines and quaternary ammonium compounds was investigated by fluorimetric determination of extraction and dissociation constants with methylene chloride as organic phase for two amines (amitriptyline and protriptyline) and two quaternary ammonium ions (tetrabutyl-and tetrapropylammonium). The optical properties of the anion and its ion pairs were characterized by quantum yield of fluorescence and a fluorescence sensitivity index. The determination of two of the ion pairs was studied, both after extraction to an organic phase and after a subsequent back-extraction of the anion component to an aqueous phase. Recoveries and standard deviations are given.     

HYDROPHOBICITY-DEPENDENT FLUORESCENCE PROPERTIES AND INTRACELLULAR FLUOROSPECTROSCOPIC BEHAVIOR OF PHOTOTOXIC DRUGS

Fluorospectroscopic behavior of chlorpromazine, mequitazine, afloqualone and piroxicam, which are known to induce skin photosensitivity, was examined in both homogeneous solutions and human buccal mucosal cells. Each drug showed large Stokes' shifts and their fluorescence intensities increased in hydrophobic solvents. These results indicated that the drugs tested can be used as hydrophobic fluorescence probes. Fluorescence microscopic observations of buccal mucosal cells treated with these drugs showed that all the drugs, especially chlorpromazine and mequitazine, were distributed in intracellular membranous regions.     

Individual and Simultaneous Stopped-Flow Fluorimetric Determination of Perphenazine and Chlorpromazine

Abstract

The stopped-flow technique is used to develop fluorimetric determinative methods for two phenothiazine drugs: perphenazine and chlorpromazine. The methods are based on the oxidation of these compounds to their corresponding fluorescent sulfoxides. Owing to the intrinsic characteristics of this technique, which allow rapid and thorough mixing of reactants, the oxidation is affected by dissolved oxygen itself, which therefore makes an oxidizing reagent unnecessary. Two methods are proposed for each phenothiazine, one based on initial rate and another on maximum fluorescence intensity measurements. Their linear ranges are 0.1–40 μg mL^?1 and their precision (%RSD) between 0.9 and 2.8%. These methods have been satisfactorily applied to the determination of both phenothiazines in several pharmaceutical preparations. On the basis of the additivity of the initial rate and maximum fluorescence intensity of perphenazine and chlorpromazine, the proportional equations principle is applied to the simultaneous determination of these compounds. Perphenazine/chlorpromazine mixtures in ratios between 1:8 and 8:1 are successfully resolved.     

PHOTOSENSITIZATION BY DRUGS IN SURFACTANT SOLUTIONS

Abstract— Chlorpromazine, promazine, anthracene and furosemide were tested as photosensitizers using 365 nm UV light in micellar solutions of cationic, anionic and nonionic surfactants. In all cases, micelles enhanced the ability of these compounds to photosensitize the oxidation of 2,5-dimethylfuran and the free radical polymerization of acrylamide. pH variation showed that the base form of chlorpromazine and the acid form of furosemide are the principal photosensitizing forms of these compounds. Rate differences between cationic and anionic surfactant media indicate the cation radical to be the major photochemical species formed from chlorpromazine and promazine in micellar media. Photodechlorination of chlorpromazine accounted for a significantly higher reactivity of chlorpromazine over promazine. Anthracene was found to be a very active photosensitizer by the singlet oxygen mechanism but also yielded a small concentration of cation radicals in micellar solution. In its neutral form, furosemide reacted strongly in both photooxidation and photopolymerization systems.
The implications of this study to drug-induced photosensitivity are that (i) free radical reactions may play a major role, and (ii) these sensitizers are more reactive in a hydrophobic environment, suggesting that the cellular membrane or the hydrophobic surfaces of proteins or DNA are more important sites of action in photosensitivity.     

盐酸氯丙嗪与Fe(Ⅲ)的显色反应及测定

研究了在盐酸介质中,三价铁离子能将盐酸氯丙嗪氧化成一种红色的物质,且氧化的程度与盐酸氯丙嗪的量呈正比关系,据此建立了测定盐酸氯丙嗪的分光光度分析方法。实验中最大吸收波长为530nm,摩尔吸光系数为5.13×103 L/(mol·cm),盐酸氯丙嗪的量在5~250μg/10mL范围内与吸光度A有良好的线性关系,方法用于盐酸氯丙嗪药物的测定,其相对标准偏差为0.11%~0.19%,加标回收率为95.0%~97.0%。     

Comparative chemical ionization mass spectra of tricyclic antidepressant amines and related compounds

Positive-ion methane chemical ionization (CI) mass spectra were obtained for seven underivatized tricyclic amines: amitriptyline, nortriptyline, protriptyline, imipramine, desipramine, cyclobenzaprine and cyproheptadine. Some discrepancies in previously reported spectra were noted. Spectra of protriptyline, cyclobenzaprine and cyproheptadine are reported for the first time. Comparisons are made among the CI spectra and with electron ionization spectra, and relative abundances of major CI ions among the seven compounds are rationalized in terms of substituent and geometric effects. In most cases low-mass iminium ions from anion abstraction were more abundant than [MH]⁺. Hydride abstraction and adduct formation with reagent-gas ions were important. The three heterocyclic amines gave abundant [M]⁺˙ by electron transfer. Protonation at the nitrogen atom on the side chain followed by amine elimination gave tricyclic aromatic fragment ions.     

邻二氮菲分光光度法测定盐酸氯丙嗪

在HAc-NaAc缓冲介质中,盐酸氯丙嗪(CPZ)能定量使Fe(Ⅲ)还原为Fe(Ⅱ),还原生成的Fe(Ⅱ)与邻二氮菲反应生成稳定的红色络合物,并且在一定范围内,CPZ的浓度和生成的红色络合物的吸光度呈良好的线性关系。据此,提出邻二氮菲-Fe(Ⅲ)体系测定盐酸氯丙嗪的新方法。在优化的实验条件下,盐酸氯丙嗪的质量浓度在0.040～15.00 mg/L范围内与吸光度呈现良好的线性关系,线性相关系数R=0.9995,摩尔吸光系数ε=2.8×104 L.mol-1.cm-1,检出限为0.020 mg/L。11次重复测定的相对标准偏差小于2.9%。该方法用于药物中盐酸氯丙嗪的测定,结果满意。     

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

We describe two water‐soluble ruthenium complexes, [ 1 ]Cl₂ and [ 2 ]Cl₂, that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm⁻²) of red light in an oxygen‐independent manner. Using a specific NAMPT activity assay, up to an 18‐fold increase in inhibition potency was measured upon red‐light activation of [ 2 ]Cl₂, while [ 1 ]Cl₂ was thermally unstable. For the first time, the dark and red‐light‐induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O₂). In skin (A431) and lung (A549) cancer cells, a 3‐ to 4‐fold increase in cytotoxicity was found upon red‐light irradiation for [ 2 ]Cl₂, whether the cells were cultured and irradiated with 1 % or 21 % O₂. These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient.     

氯丙嗪分子印迹敏感膜传感器的制备与应用

以氯丙嗪为模板分子,邻氨基酚为功能单体,在金电极表面电聚合制备具有特异性识别孔穴的氯丙嗪分子印迹敏感膜(MIP)。 采用循环伏安法(CV)、差分脉冲伏安法(DPV)等研究了印迹膜的性能、结构和分子印迹效应,并与其结构相似的化合物奋乃静和异丙嗪的选择性响应进行了比较,发现传感器对氯丙嗪具有良好的选择性。 氯丙嗪浓度在6.0×10-7～9.0×10-5 mol/L范围内与峰电流呈线性关系,线性方程为:I(μA)=61.25lg c(μmol/L)+23.47(r=0.9975),根据DL=3δb/s计算检出限为2.0×10-7 mol/L,该传感器具有良好的重复性、再生性和高灵敏度。     

Ion-selective electrodes for basic drugs

Coated-wire ion-selective electrodes based on dinonylnaphthalene sulfonic acid (DNNS) are prepared for methadone, methylamphetamine, cocaine and protriptyline in protonated form. In each set, nearly-Nernstian responses are obtained while detection limits range from 10^-5.5M for cocaine and methylamphetamine electrodes, to 10^-6.0M for methadone, and 10^-6.5 M for protriptyline electrodes. Selectivity is found to decrease in the order methadone, protriptyline, cocaine and methylamphetamine; these results are consistent with systematic selectivity studies reported earlier for electrodes in this family.     

SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS–VIII. A SPIN-TRAPPING STUDY OF LIGHT INDUCED FREE RADICALS FROM CHLORPROMAZINE and PROMAZINE

Abstract— The clinically important phenothiazine drugs, particularly chlorpromazine, often elicit phototoxic and photoallergic reactions. We have used the spin traps 2-methyl-2-nitrosopropane (MNP) and 5,5-dimethyl-pyrroline-N-oxide (DMPO) to define the radical photolysis pathways of chlorpromazine and promazine. In the absence of oxygen the dechlorination product of chlorpromazine is trapped by MNP. The reactivity of the dechlorination product is similar to that of the phenyl radical as shown by its ability to extract hydrogen atoms from donors. Our results suggest that the dechlorination product is sufficiently reactive to account for the observation that chlorpromazine is more phototoxic than its parent promazine. In the presence of oxygen both chlorpromazine and promazine form a superoxide-dismutase-insensitive oxygen-centered intermediate which, when trapped by DMPO, rapidly decays to DMPO-OOH and subsequently to DMPO-OH. In addition, chlorpromazine readily undergoes photoelectron ejection only when it is excited into the second excited singlet state (Δ < 280 nra). This previously unknown wavelength dependence of photoionization should be considered in establishing the mechanism of chlorpromazine photosensitization.     

南中国海海藻刺状鱼栖苔的化学成分(Ⅲ)

采自南中国海刺状鱼栖苔的乙醇提取物经多种柱层析分离并鉴定出四种化合物,分别为:(24S) 5 烯 3β 谷甾醇、对羟基苯甲酸、黄酮类化合物槲皮素及类黄酮化合物(-) 表儿茶精.其结构通过各种波谱技术如IR,GC MS、FABMS、1HNMR、13CNMR(DEPT)、1H 1HCOSY和HMBC等加以证实.这些化合物均是首次从刺状鱼栖苔中检测到.其中槲皮素和(-) 表儿茶精是首次从红藻中检测到     

Interaction of surface-active drugs in rabbits

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.     

Glassy carbon electrodes coated with cellulose acetate for adsorptive stripping voltammetry

The utility of glassy carbon electrodes coated with cellulose acetate for adsorptive stripping voltammetry of oxidizable organic compounds is evaluated. This surface modification alleviates the co-adsorption problem commonly encountered at conventional electrodes. Interferences from electro-inactive surfactants and, in certain situations, from adsorbable electroactive substances, are minimized. Quantitation of the drugs, chlorpromazine and trimipramine, is not affected by the presence of up to 120 mg 1^?1 albumin or gelatin. The chlorpromazine response is not affected by the bilirubin or perphenazine peaks which overlap at uncoated electrodes. The adsorptive stripping response at the coated electrode is evaluated with respect to hydrolysis time, preconcentration time, concentration dependence, reproducibility, and other variables. The detection limit for chlorpromazine is 1.3 × 10^?8 M (5-min preconcentration). Applicability to assays of urine and serum samples is illustrated.     

Spectrophotometric Determination of Chlorpromazine and Levomepromazine Hydrochlorides In Injectables and Drops By Reaction With Ferric Ion

Abstract

The principal aim of this research was the standardization of a spectrophotometric method using the reaction with ferric ion for quantitative determination of these substances in pharmaceutical preparations. By reaction with ferric ion chlorpromazine gave a pink compound with maximum absorption at 525 nm. the violet product obtained by the reaction with ferric ion and levomepromazine had a maximum at 565 nm. Beer's law was obeyed in a wide range of concentrations for both compounds. the method was applied to simulated and commercially available samples. the efficiency of the method was confirmed by recovery tests.     

Synthesis of possible metabolites of chlorpromazine. II. 3-, 8- and 9-hydroxychlorpromazine

The title compounds have been prepared as analytical standards for the identification of chlorpromazine metabolites in biological materials. Unequivocal structural proof of key compounds was accomplished by using at least two unrelated syntheses for each one. Resistance of some phenothiazines to preparation via classic Smiles rearrangement is discussed. More examples are offered of halogen-induced Smiles rearrangement. A rare example of phenothiazine polymorphism is presented.