Phenothiazine Drugs Research Articles

Anti-apomorphine effects of phenothiazine drug metabolites.

The potencies in producing muscle relaxation, and in antagonizing apomorphine-induced climbing and hypothermia in mice, were examined for chlorpromazine, levomepromazine and their main metabolites, and for fluphenazine and 7-hydroxy fluphenazine. 3-Hydroxy chlorpromazine was more potent than chlorpromazine in antagonizing apomorphine-induced climbing, while levomepromazine and 3-hydroxy levomepromazine were equipotent in this test. The 3-hydroxy metabolites of chlorpromazine and levomepromazine were more potent than the parent compounds in antagonizing hypothermia, and had significantly weaker muscle relaxant effects than the parent compounds. The 7-hydroxy and N-monodesmethyl metabolites were generally less potent that the parent compounds in antagonizing apomorphine-induced effects. N-Monodesmethyl levomepromazine had a pronounced muscle relaxant effect, like levomepromazine itself. The sulphoxide metabolites of chlorpromazine and levomepromazine were inactive in all tests. Their potencies in these tests indicate that among the metabolites 7-hydroxy chlorpromazine, N-monodesmethyl chlorpromazine and 3-hydroxy levomepromazine, which have all been identified in plasma from patients, may contribute to the antipsychotic effects of the drugs, and furthermore that N-monodesmethyl levomepromazine may contribute to the sedative effects of levomepromazine.

Effect of Ophiobolin A on Stomatal Movement: Role of Calmodulin

Ophiobolin A enhanced stomatal opening of Commelina communis and partially abolished the inhibitory effect of calcium chloride. The same results were obtained by the phenothiazine drug, chloropromazine. The possibility of calmodulin involvement in stomatal response to both materials is discussed.

Trends in psychotropic drug prescribing in Australia.

In 1983-1984, 9.8 million prescriptions were written for the 12 most common psychotropic drugs that are available under the Pharmaceutical Benefits Scheme. Our analysis shows that, of these prescriptions, 59% (374 per 1000 persons) were for the four most commonly prescribed benzodiazepine agents; 34% (216 per 1000 persons) were for the five main antidepressant agents; and 7% (41 per 1000 persons) were for the three main phenothiazine agents. In the period from 1977-1978 to 1983-1984, prescription volumes were relatively stable for antidepressant and phenothiazine drugs. Fluctuations in the prescribing of individual benzodiazepine agents are discussed. Older patients and women of all ages receive the majority of the psychotropic drug prescriptions that are written by Australian general practitioners.

Positive secondary-ion mass spectra and thin-layer chromatography/mass spectrometry of phenothiazine drugs

The positive secondary-ion mass spectra of phenothiazine drugs contain abundant protonated molecules and structurally informative fragment ions that are characteristic of the N-substituent. Because the secondary-ion current is carried by a few characteristic ions, selected-ion monitoring is used with chromatographic separation for the determination of these drugs in mixtures. Drugs are extracted in situ from thin-layer chromatograms, and the secondary-ion mass spectra are obtained without destruction of the chromatograva. The spectra are dependent upon the solvent used and not the nature of the underlying chromatographic matrix. Spatially-resolved selected-ion monitoring of the protonated molecule provides the x-y spatial profiles of the sample in the chromatogram. Extended irradiation leads to a beam-induced tailing that alters the profile.

Determination of phenothiazine drugs by HPLC with electrochemical detection.

製剤中,あるいは血清中に共存する数種のフェノチアジン系薬物の同時定量を目的として,電気化学的検出HPLCの感度の向上と試料の前処理の簡易化を検討した.検出器の作用電極であるグラッシーカーボン電極にはあらかじめリン酸塩緩衝液中で陽極酸化前処理を施し,検出感度の向上を図った。分離カラムには陽イオン交換樹脂カラムを,移動相として0.2mol dm-3ホウ酸塩緩衝液-0.5mol dm-3硝酸ナトリウム-メタノール(65:35)を用いた.その結果,本法による検出限界は約30pg,定量範囲は100pg~10ngであった.フェノチアジン系薬物を含む処方剤を本法を用いて分析したところ,98%以上の回収率を得た.血清中薬物の定量時にはエキストレルートカラムを併用することにより,簡易に抽出・定量が可能であった.血清100μlにクロルプロマジン0.5ngを含む試料の場合,回収率90%以上,相対標準偏差は1.9%以下であった.

Crystal and molecular structure of the alimemazine cation radical

The crystal structure of the alimemazine (trimeprazine) cation radical, a phenothiazine drug molecule, has been determined from three-dimensional X-ray diffraction data and refined by least-squares methods. Cell constants were a 10.674 9(4), b 12.741 9(5), c 9.509 9(4)Å, α 110.863(3), β 103.433(3), γ 66.671(4)°, Z= 2. The molecule is planar, the angle between the best planes for the two benzene rings being 1.9(3)°, The C–S–C angle is 102.6(4)° and S–C bonds are 1.709(11) and 1.710(7)Å in length. The side-chain is protonated at the nitrogen atom and asymmetrically placed in relation to the tricyclic system.

Direct secondary-ion mass spectrometric analysis of mixtures separated by thin-layer chromatography and electrophoresis

Secondary-ion mass spectrometry (SIMS) is used to sputter ions directly from thin-layr chromatograms in which components in a mixture have been separated. Mixtures of phenothiazine drugs and small peptides have been separated an detected by the chromatography/SIMS method. Phosphonium salts have been separated by thin-layer chromatography and imaged in situ by mass spectrometer. Organometallic compounds such as the transition metral acetylacetonates have been simialry determined. Mixtures that have been separated by gel electrophoresis are transferred by using a standard blotting procedure to a nitrocellulose support, which is then examined by secondary-ion mass spectrometry. A mixture of organic dyes was separated by gel electrophoresis, and characterized by secondary-ion mass spectrometry. The use of the mass spectral information to deconvolute overlapping components on the chromatogram is discussed, and the ultimate spatial resolution for molecular mapping is estimated as about 1 μm.

ChemInform Abstract: Interactions Between Phenothiazine Drugs and Metal Ions. Part 2.

Chemischer InformationsdienstVolume 17, Issue 47 Physical Organic Chemistry ChemInform Abstract: Interactions Between Phenothiazine Drugs and Metal Ions. Part 2. N. J. MASON, N. J. MASONSearch for more papers by this authorW. J. GEARY, W. J. GEARYSearch for more papers by this authorL. A. NIXON, L. A. NIXONSearch for more papers by this authorI. W. NOWELL, I. W. NOWELLSearch for more papers by this author N. J. MASON, N. J. MASONSearch for more papers by this authorW. J. GEARY, W. J. GEARYSearch for more papers by this authorL. A. NIXON, L. A. NIXONSearch for more papers by this authorI. W. NOWELL, I. W. NOWELLSearch for more papers by this author First published: November 25, 1986 https://doi.org/10.1002/chin.198647052AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume17, Issue47November 25, 1986 RelatedInformation

Thin Layer Chromatographic Identification of Phenothiazine Derivative Drugs: Interlaboratory Study

A thin layer chromatographic method for the identification of phenothiazine derivative drugs was studied collaboratively by 8 laboratories. Twenty phenothiazine drugs were examined by each collaborator. The identification scheme depends on the color of the sprayed spots and the Rf values relative to the Rf of chlorpromazine (RCHL) in 4 solvent systems. In 98.13% of the cases, a correct identification could be made; the remaining drugs were reduced to a choice between pairs of phenothiazines. With respect to chlorpromazine, the data showed a significant decrease in variability of RCHL values compared with Rf values in the 4 solvent systems.

Monoclonal antibodies against a 60 kDa phenothiazine-binding protein from Trypanosoma brucei can discriminate between different trypanosome species

The dominant structure of the cytoskeleton of the Trypanosomatidae consists of a tight array of singlet pellicular microtubules, which surround the entire cell body. These microtubules are in close and stable contact with the cellular membrane. These contacts can be selectively disrupted by the action of phenothiazine drugs, which are potent trypanocides in vitro. Phenothiazine-affinity chromatography of detergent solubilized proteins from Trypanosoma brucei has resulted in the isolation of a protein of an apparent molecular weight of 60 000. Polyclonal antibodies raised against this protein (p60) have been used to investigate the presence of similar proteins in other protozoa. No such crossreacting proteins have been observed outside the family Trypanosomatidae. Within this family, a strong crossreactivity was observed with Crithidia fasciculata, while only a marginal reaction was seen with two species of Leishmania and, quite unexpectedly, also with the stereorarian trypanosomes T. cruzi and T. rangeli. Different monoclonal antibodies against p60 are able to clearly distinguish different subgenera of salivarian trypanosomes, and most notably to differentiate between various isolates of T. congolense. Therefore, these antibodies may prove valuable for diagnostic and epidemiological applications.

Determination of chlorpromazine and thioridazine by differential pulse voltammetry in acetonitrile medium

This work describes optimal conditions for the determination of chlorpromazine and thioridazine by DPV, with a detection limit of 4.0 × 10 −7 M (0.16 μg/ml). The well-defined peaks indicate that direct measurement in a medium of 0.03 M perchloric acid in acetonitrile is possible and the use of DPV is advantageous when small amounts are to be determined. The sample procedure for pharmaceutical tablets is simple and fast. The method is useful for control of the quality and purity of phenothiazine drugs. The possibility of using numerical analysis to resolve composite signals of the compounds studied has also been demonstrated.

The restless legs syndrome.

The first description of the restless legs syndrome (RLS) is attributed to Thomas Willis in the 'London Practice of Physick' of 1685 (Ekbom, 1960). Here he wrote 'wherefore to some, when being a bed they betake themselves to sleep, presently in the arms and leggs, leapings and contractions of their tendons, and so great a restlessness and tossings of their members ensue, that the diseased are no more able to sleep than if they were in a place of the greatest torture'. In 1861 Whittmaack used the term anxietas tibiarum to describe nocturnal discomfort of the legs, which he considered was a common symptom of hysteria (Ekbom, 1945). The same phenomenon was called 'impatience musculaire' in the French literature (Ekbom, 1944; Bonduelle, 1952) and the leg jitters by Allison (1943). Ekbom's earliest descriptions of the RLS distinguished a common form which he called 'asthenia crurum paraesthetica' from a painful variant 'asthenia crurum dolorosa' (Ekbom, 1946). He identified the first of these in 34 cases. Paraesthesia with deep calf and shin discomfort started only when the legs were at rest and necessitated that they were moved to provide relief. He postulated that pregnancy was an aetiological factor and in some patients he diagnosed prostatitis, testosterone deficiency and the burning feet syndrome due to malnutrition. Ask-Upmark noted the disorder as a late effect of gastrectomy (Ask-Upmark & Meurling, 1955) and on the basis of anecdotal evidence of postural dependence of symptoms, suggested the cause was vascular congestion ofthe spinal cord (AskUpmark, 1959). Some authors doubted the existence ofa distinct syndrome; Purdon-Martin (1946) believed the symptoms were due to acroparaesthesia and Masland (1947) that they were a manifestation of myokymia. By 1960 Ekbom had studied 175 people whom he had identified with restlessness of the legs. He found that 5% of normal psychiatrically stable individuals were disturbed by restless sensations, but also believed it was symptomatic of anaemia, certain infectious diseases, diabetes, cold exposure or those taking phenothiazine drugs (Ekbom, 1945, 1950, 1960). A diabetic patient whose symptoms vanished on the side of a recent leg amputation was presented as evidence for a peripheral origin (Ekbom, 1961) and Bornstein (1961) speculated about abnormal connections with the reticular system. In recent years neuroleptic-induced akathisia has been compared with idiopathic RLS. Akathisia was originally described in its uncommon idiopathic form by Haskovec (1901) and later in relation to Parkinson syndromes (Sicard, 1923) and drugs such as promethazine (Sigwald et al., 1947) and the phenothiazines (Steck, 1954). It is characterized by a state of mental and motor restlessness which is accompanied by an irresistible compulsion to physically move about. Restlessness of the legs is common and similar to that occurring in idiopathic RLS, but inner restlessness of the mind and body is peculiar to akathisia. Confusion between these two conditions explains why promethazine and prochlorperazine have been considered both cause and ineffective remedy of RLS.

Colorimetric Determination of Certain Phenothiazine Drugs by Using Morpholine and Iodine-Potassium Iodide Reagents

A colorimetric method was developed for the quantitative estimation of 11 phenothiazine drugs. The method is based on the interaction of unsulfoxidized drug with morpholine and iodine-potassium iodide reagents. The interaction for all studied phenothiazine drugs yields a blue product with 2 absorption maxima: one in the range of 620-640 nm with lower molar absorptivity and the other in the range of 662-690 nm with higher molar absorptivity. The color was stable for at least 10 h. The reproducibility and recovery of the method were excellent. The method was applied successfully to the analysis of various commercially available phenothiazines in different dosage forms. The results were comparable to those obtained by official procedures. The suitability of the method for detection and estimation of promethazine excreted in urine has been suggested by preliminary experiments. Reaction products have been isolated and identified.

Phenothiazine drugs and metabolites: Molecular conformation and dopaminergic, alpha adrenergic and muscarinic cholinergic receptor binding

The solid state molecular structures of methoxypromazine and N-monodesmethyl chlorpromazine sulphoxide were determined by X-ray crystallography, as an extension of previous studies on the molecular structures of chlorpromazine sulphoxide and methotrimeprazine sulphoxide. The binding affinities of phenothiazine drugs and metabolites with known crystal structures to dopaminergic, alpha adrenergic and muscarinic cholinergic receptors in rat brain were examined using radio-ligand binding techniques. Comparison of their solid state molecular structures and potencies in neurotransmitter receptor binding reveals that these compounds exist in two different conformations: One, associated with low biological activity, has an angle between the planes of the two aryl rings in the range of 155–160°, and a torsion angle of −80 to −84° around the N(10)-C bond of the side-chain, calculated from the substituted benzene ring. In the other conformation, which is found in the biologically active derivatives, the angle between the planes of the two aryl rings is in the range of 134–145°, and the torsion angle around the N(10)-C bond of the side-chain is in the range of 64–69° or 129–144°. The “active” and “inactive” conformations thus have the side-chain on opposite sides of the ring system.

Interaction of phenothiazines with nitroso-R salt and extractive spectrophotometric determination of phenothiazine drugs

A selective and sensitive method is based on the interaction of phenothiazines with nitroso-R salt to form 1:1 complexes which are extracted into chloroform and measured spectrophotometrically.

Calmodulin-Calcium- abhängige Fluoreszenz mechanisch zerstörter Stärkegranula mach Fluphenazinapplikation

Summary Application of fluphenazine (50,μMol), a phenothiazine drug, leads to a detectable fluorescence in partly destroyed starch granules of potatoes in a calcium and calmodulin dependent manner after uv-irradiation. For comparison a calcium or calmodulin pretreatment alone of the granules did'nt show a fluorescence response. The binding of the fluorescence probe fluphenazine is a valuable indicator for the interaction of certain enzymes (e.g. the starch synthezising system) and the calciumcalmodulin-complex. First results have shown that starch granules themselves contain calmodulin.

Interactions between phenothiazine drugs and metal ions. Part 2. Crystal and molecular structure of protonated trichloro[2-chloro-10-(3′-dimethylaminopropyl)phenothiazine-S]palladium(II), [Pd(cpzH)Cl3]; hydrogen-1 and carbon-13 nuclear magnetic resonance data for the chlorpromazine complexes [M(cpzH)Cl3](M = Pd or Pt)

The structure of the chlorpromazine complex [Pd(cpzH)Cl3] has been elucidated by single-crystal X-ray crystallography. Crystals are monoclinic, space group C2/c, Z= 8, in a unit cell with lattice parameters a= 29.757(9), b= 9.487(4), c= 16.184(6)Å, β= 116.5(1)°. The structure has been solved using heavy-atom methods and refined by least squares to R= 0.056 (R′= 0.060) for 1 277 independent reflections collected by counter methods. Chlorpromazine is sulphur-bonded to a PdCl3 unit, the counter ion being a protonated nitrogen on the drug substituent. The side chain adopts an unusual conformation apparently to facilitate both intra- and inter-molecular hydrogen bonding. The n.m.r. data show that this conformation is maintained in the aprotic solvent NN-dimethylformamide.

Irreversible binding with biological macromolecules and effects in bacterial mutagenicity tests of the radical cation of promethazine and photoactivated promethazine. Comparison with chlorpromazine

The irreversible binding of the radical cation of promethazine (PMZ±) to DNA and protein in vitro and bacterial macromolecules in situ has been studied. Binding experiments were performed with synthesized [ 35S] promethazine. The results are compared to those with the chlorpromazine radical cation (CPZ±). Secondary reaction products which result from fission of the alkylamino side chain are involved in the macromolecular binding of PMZ±. Compared to CPZ± the covalent DNA binding of PMZ± is significantly less. A larger amount of PMZ± binds to single-stranded DNA than to double-stranded DNA. The extent of binding to proteins and RNA is of the same order as that of CPZ±. Bacterial mutagenicity tests show that the low genotoxicity of PMZ± is related to the low DNA binding. The bacterial cytotoxicity is possibly related to the covalent protein binding. Similar results have been obtained with photoactivated promethazine (PMZ) and chlorpromazine (CPZ). The role of radical cations in the photosensitization and metabolic activation of phenothiazine drugs is discussed.

Automated determination of phenothiazine drugs by spectrophotometry with palladium(II) chloride.

多種類のフェノチアジン系医薬品の製剤を連続流れ分析装置により一斉に定量することを目的として,塩化パラジウムを用いる吸光光度法の測定条件の統一化及び前処理の簡易化を検討した.その結果,試料を0.625M硫酸-ジメチルホルムアミド(DMF)混液(2:3)に溶かし,連続流れ分析装置により0.625M硫酸-DMF混液(4:1)で希釈し,塩化パラジウム溶液を加えて490nmの吸光度を測定する方法を確立した.本法の正確さは塩化物の多い製剤を除いて99～100%,繰り返し精度は0.1～0.3%である.又,手操作の2～3倍に相当する30検体/日の処理能力がある.フェノチアジン系化合物とパラジウム(II)の錯体組成は連続変化法により1:1と推定された.錯体による490nm付近の吸収はフェノチアジン環の2位及び10位の置換基により影響される.

Adsorptive/extractive stripping voltammetry of phenothiazine compounds at carbon paste electrodes

An investigation of the extractive/adsorptive accumulation behavior of various phenothiazine drugs at carbon paste electrodes is presented. These compounds exhibit different degrees of accumulation, depending on the side-chains of the molecule. The voltammetric experiments are accompanied by analogous solvent extraction studies. The extraction/adsorption process serves as an effective preconcentration step which improves the subsequent voltammetric measurement with respect to the sensitivity and selectivity. After 10 min preconcentration, a detection limit near 1.5 × 10 −9 M perphenazine is obtained. By making the measurement in an exchange (blank) solution, the accumulated phenothiazines can be measured in the presence of macro solution constituents with similar redox properties. Applicability to selective measurements in serum is illustrated.