Plasma levels and half lives of thioridazine and some of its metabolites

Summary Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of thioridazine plus metabolites ranged from 43–74%. The mean early disappearance half-life of thioridazine was 5 hours, and its mean late disapperance half-life was 26 hours.     

Determination of some psychotropic phenothiazine drugs by charge-transfer complexation reaction with chloranilic acid

A spectrophotometric method is described for the determination of four commonly used psychotropic phenothiazine drugs. The method is based on the measurement of the intensely coloured charge-transfer complex formed by the interaction of these drugs as n-electron donors with chloranilic acid as the pi-acceptor. The coloured species measured exhibits maximum absorption at 535 nm. The molar-combining ratio and optimum assay conditions are reported. Beer's law is obeyed over the range, 25-250 microg ml(-1) with apparent molar absorptivity in the range, 0.93 x 10(3)-1.45 x 10(3) l mol(-1) cm(-1). The limits of detection and quantification are reported. The proposed method was applied to the determination of these psychotropics in pharmaceutical formulations and the results demonstrated that the method is equally accurate, precise and reproducible as the official methods. The validity of method was established by recovery studies via standard-addition technique with satisfactory results.     

Solubility and pKa determination of six structurally related phenothiazines

Solubilities of six structurally related phenothiazines, namely chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride at constant pH were measured in the temperature range from 290 K to 350 K in three important drugs solvents: water, ethanol and 1-octanol using the dynamic method and UV-vis method. Dissociation constants and corresponding pK(a) values of drugs were obtained with Bates-Schwarzenbach method at temperature 298.15K in the buffer solutions. Our experimental pK(a) values for chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride are 9.15, 10.01, 9.37, 8.89, 8.97, and 9.03, respectively. The basic thermal properties of pure drugs i.e. melting and solid-solid phase transition as well as glass-transition temperatures, the enthalpy of melting and phase transitions and the molar heat capacity at glass transition (at constant pressure) were measured with differential scanning microcalorimetry (DSC) technique. Molar volumes were calculated with Barton group contribution method. The experimental solubility data were correlated by means of three commonly known G(E) equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here have revealed simple eutectic mixtures. The root-mean-square deviations of temperature were used for the precision of the correlation. The activity coefficients of drugs at saturated solutions in each correlated binary mixture were calculated from the experimental data. These new data will help in all prediction-methods and their precision.     

Cytotoxic effects of neuroleptic drugs

Agranulocytosis and the release of transaminase enzymes from liver cells are known consequences of neuroleptic drug use. These effects are most common with low potency neuroleptic drugs. It has been hypothesized that these effects are due to the direct toxic action of these drugs on blood and liver cells.The purpose of this study is to compare the cytotoxic effects of eight neuroleptic drugs in five different biological test systems. In all of the test systems, thioridazine, chlorpromazine, trifluoperazine, fluphenazine and thiothixene (group one drugs) were the most toxic drugs and molindone was the least toxic. Thioridazine was between 25 and 84 times more toxic than molindone. Loxapine was significantly more toxic than molindone, but less toxic than the group one drugs. Haloperidol was intermediate in toxicity between the group one drugs and loxapine. We conclude that the difference in cytotoxicity of the neuroleptic drugs observed in these experiments accounts in part for the increase in agranulocytosis and hepatotoxicity with thioridazine and chlorpromazine and for the lower incidence of these side effects with less toxic drugs.The possibility that tardive dyskinesia may be due to the cytotoxic effects of neuroleptic drugs is discussed and an experiment to test this hypothesis is suggested.     

钙调素拮抗剂对非酶体系中羟自由基水平影响的研究

研究了钙调素拮抗剂(Calmodulin Antagonist,简写CaM A)与抗坏血酸体系产生的羟自由基(~.OH)的相互作用。结果显示,小檗胺(E_0)及其衍生物(E_5、E_6)、蝙蝠葛碱(D_1)及氯丙嗪(CPZ)在高浓度时均有清除~.OH的作用;除E_0和CPZ外,其它药物在低浓度均可促进~.OH的生成。研究表明,研究钙调素(CaM)与自由基的相互关系时,在合理的浓度范围内使用CaM A作为研究手段是可行的。     

No evidence for neoantigens in human plasma after photochemical virus inactivation

Summary Photodynamic virus inactivation of human fresh plasma mediated by visible light in the presence of the phenothiazine dyes methylene blue or toluidine blue was investigated to determine whether it influences functional, structural, and immunological properties of plasma proteins. The activities of the coagulation factors I, VIII, IX, X, and XI were affected to a certain degree, while those of most other plasma proteins were not. The elution profiles obtained by ion exchange chromatography of untreated and photodynamically treated plasma were almost identical. Using a number of antisera against human plasma and single plasma proteins, different immunochemical techniques revealed identical patterns for untreated and treated plasma. Thus, there was no indication that the photodynamic virus inactivation procedure applied considerably influences the properties of plasma proteins.     

CSF concentrations and clinical effects following intravenous dixyrazine premedication

Single concurrent plasma and lumbar spinal fluid samples were collected from twenty-two patients given IV dixyrazine 0.15 mg/kg, 10–106 min earlier in an open study.Dixyrazine penetrated rapidly into the spinal fluid; the CSF/P ratio was 0.3 by 10 min after drug administration and persisted at that level during the study period. The uncontrolled sedative and anxiolytic effects assessed by the patients were slight, and were correlated with the CSF drug concentrations only during the first 30 min after medication.     

Phenothiazines reduce ischemic damage to the central nervous system

We found substantial alterations in reactions catalyzed by calcium/phospholipid-dependent and calcium/calmodulin-dependent protein kinases during CNS ischemia which suggested that phenothiazines, drugs capable of inhibiting these reactions, might reduce neurologic damage. To test this hypothesis, we used chlorpromazine and trifluoperazine. Both drugs reduced neurologic function deficits relative to controls in a rabbit multiple cerebral embolism model and a rabbit spinal cord ischemia model. Chlorpromazine was effective despite reduction of blood pressure, and trifluoperazine did not alter blood pressure. These findings suggest that phenothiazines may be useful for preserving neurologic function when administered shortly after the onset of CNS ischemia.     

Intracystic papilloma in the breast of a male given long-term phenothiazine therapy: A case report

We experienced a very rare case of intracystic papilloma in a 57-year-old man who came to our hospital complaining of a left subareolar mass and nipple discharge. The patient had a history of chronic schizophrenia, necessitating long-term treatment with phenothiazines. His serum prolactin levels were elevated. Mammography demonstrated a well defined mass with microcalcifications. Ultrasonography revealed a cyst with an intracystic component. The inner lesion of the mass enhanced on contrast-enhanced computed tomography. The carcinoembryonic antigen concentration of the cyst fluid was 400 ng/mL and no malignant cells were found by aspiration biopsy cytology. Excisional biopsy was performed under local anesthesia. Pathological examination revealed the intracystic component to be intracystic papilloma. There are ten reports of male intracystic papilloma including ours. We report the second case of a patient given long-term phenothiazine therapy, which is known to increase serum prolactin levels.     

Effects of cyamemazine on hERG, INa, ICa, Ito, Isus and IK1 channel currents, and on the QTc interval in guinea pigs

The antipsychotic and anxiolytic phenothiazine, cyamemazine, was investigated for its effects on the hERG (human ether-à-go-go related gene) channel expressed in HEK 293 cells and on native INa, ICa, Ito, Isus, or IK1 of human atrial myocytes. Moreover, cyamemazine and terfenadine were compared for their effects on the QT interval in anesthetized guinea pigs. Cyamemazine reduced hERG current amplitude with an IC50 value of 470 nM. Cyamemazine 1 microM failed to significantly affect INa, Ito, Isus, or IK1 amplitudes and slightly decreased ICa (18%). For comparison, haloperidol (30 nM) and olanzapine (300 nM) reduced hERG current amplitude by 44.2+/-3.9% and 49.7+/-4.2%, respectively. The cardiac safety ratio of cyamemazine, calculated from the IC50/receptor affinity ratios, is 81 and 313 against dopamine D2 receptors and 5-HT2A receptors, respectively. In guinea pigs, QT and QTcBazett were not significantly modified by intravenous cyamemazine when compared to the effects produced by the vehicle. Conversely, terfenadine (5 mg/kg iv) increased significantly QTcBazett (+58 ms), QTcFrediricia (+83 ms) and QTcVan de Water (+78 ms). In conclusion, cyamemazine concentrations required to inhibit hERG current exceed substantially those necessary to achieve therapeutic activity in humans. Moreover, cyamemazine, in contrast to terfenadine, does not delay cardiac repolarization in the anesthetized guinea pig. These non-clinical findings confirm the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use.