Phenothiazine Group Research Articles

Phenothiazine-induced increase in thyroid autoantigens and costimulatory molecules on thyroid cells: a pathophysiological mechanism for drug-induced autoimmunity?

We have previously demonstrated (J Immunol 1995; 154:3593) that MHC class II antigens can be induced on thyroid epithelial cells (TEC) by alimemazine, a member of the phenothiazine group. Although this expression of MHC class II antigens on TEC confers the theoretical ability to behave as antigen-presenting cells (APC), the simultaneous expression of self antigens and co-receptor(s) must also occur for efficient presentation of self antigens. Therefore, we investigated whether alimemazine applied at pharmacologic doses would modify the expression of thyroid antigens, and simultaneously, the expression of intercellular adhesion molecule-1 (ICAM-1), B7, and LFA-1 co-receptors in human TEC in culture. Using polymerase chain reaction (PCR) amplification and Northern blot analysis, we showed that alimemazine induces increases in thyroglobulin (Tg) and thyroid-stimulating hormone receptor (TSH-R) cDNA, within the first 2 h following its addition. This phenomenon is followed 48 h later by an increase of Tg and TSH-R protein expression on the surface of TEC. Furthermore, increases in the expression of ICAM-1 and B7 co-receptors were concomitantly observed. These results suggest that alimemazine, a drug currently used in paediatrics, could play a role in the induction and perpetuation of thyroid autoimmune disorders by transforming TEC into functional APC.

Chlorpromazine interaction with glycerophospholipid liposomes studied by magic angle spinning solid state 13C-NMR and differential scanning calorimetry

Phosphatidylserine (PS) extracted from pig brain and synthetic dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylcholine (DMPC) were used to make DPPC/DMPC and DPPC/PS large unilamellar liposomes with a diameter of ∼1 μm. Chlorpromazine-HCl (CPZ), an amphipathic cationic psychotropic drug of the phenothiazine group, is known to partition into lipid bilayer membranes of liposomes with partition coefficients depending on the acyl chain length and to alter the bilayer structure in a manner depending on the phospholipid headgroups. The effects of adding CPZ to these membranes were studied by differential scanning calorimetry and proton cross polarization solid state magic angle spinning 13C-nuclear magnetic resonance spectroscopy (CP-MAS- 13C-NMR). CP-MAS- 13C-NMR spectra of the DPPC (60%)/DMPC (40%) and the DPPC (54%)/DMPC (36%)/CPZ (10%) liposomes, show that CPZ has low or no interaction with the phospholipids of this neutral and densely packed bilayer. Conversely, the DPPC (54%)/PS (36%)/CPZ (10%) bilayer at 25°C demonstrates interaction of CPZ with the phospholipid headgroups (PS). This CPZ interaction causes about 30% of the acyl chains to enter the gauche conformation with low or no CPZ interdigitation among the acyl chains at this temperature (25°C). The DPPC (54%)/PS (36%)/CPZ (10%) bilayer at a sample temperature of 37°C ( T C=31.2°C), shows CPZ interdigitation among the phospholipids as deduced from the finding that ∼30% of the phospholipid acyl chains carbon resonances shift low-field by 5–15 ppm.

Schizophrenia, psychotropic medication, and cataract

Objective To compare the distribution of cataract types between psychiatric patients diagnosed with schizophrenia and the general population not exposed to psychotropic medication, and to compare cataract prevalence between users and nonusers of various psychotropic medications in the general community. Design Case-control. Participants A total of 151 (93%) eligible patients from a community mental health service and 3271 (83%) eligible residents from the Melbourne Visual Impairment Project (VIP) were examined. Main outcome measures All patients 40 years of age and older from a community mental health service and residents of nine randomly selected areas of Melbourne were eligible. Best-corrected distance visual acuity was determined using a 4-m logarithm of the minimum angle of resolution (LogMAR) chart. The presence of cataract was determined by photographs or slit-lamp examination using direct and indirect retroillumination. Anterior, cortical, nuclear, and posterior subcapsular cataracts were measured. Participants from the Melbourne VIP were classified as to whether they had taken benzodiazepams, phenothiazines, thioxanthenes, butyrophenols, tricyclic antidepressants, or monoamine oxidase inhibitors for at least 12 months during their lifetime. Results The distribution of cataract type varied between persons with and without schizophrenia. Anterior subcapsular (ASC) cataract was significantly more prevalent (26%) in participants with schizophrenia from the community mental health service than Melbourne VIP participants (0.2%) not exposed to psychotropic medication (chi-square, 1 degree of freedom = 605.5, P = 0.001). This remained significant after controlling for age (odds ratios = 250, 95% confidence interval = 83.3, 1000). The distribution of the age-related cataract was similar across all groups of psychotropic medication users with the exception of the phenothiazine users. They had less of all types of the age-related cataracts, despite being slightly older than the control group (mean age, 60.0 vs. 58.4, t test = 0.85, P = 0.40). However, only cortical cataract in the phenothiazine group was statistically lower (chi-square, 1 degree of freedom = 3.96, P = 0.047). Conclusion This study has identified the need to investigate whether other newer agents, especially high-potency medications, cause ASC opacities if a certain threshold of exposure to psychotropic medications must be attained to develop cataract, or if schizophrenia itself is associated with cataract formation.

Light-Induced Charge Separation across Ru(II)-Modified Nanocrystalline TiO2 Interfaces with Phenothiazine Donors

Long-lived interfacial charge-separated pairs, [TiO2(e-), D+], have been created by visible light excitation of Ru(II) polypyridyl compounds anchored to TiO2 particles in the presence of phenothiazine donors, D. The kinetic aspects of the formation and recombination have been kinetically resolved for analogous colloidal TiO2 solutions and films. Charge-separated pair lifetimes are shortened in colloidal films due to their high local concentrations. Less than 1% incident photon-to-current efficiency is observed when PTZ (phenothiazine) derivatives are employed as donors in regenerative solar cells. Light excitation of Ru(4,4‘-(CO2H)2-2,2‘-bipyridine)2(4-CH3,4‘-CH2-PTZ-2,2‘-bipyridine)]2+, anchored to TiO2, results in rapid intramolecular electron transfer from PTZ to the ruthenium metal center which efficiently translates the hole away from the chromophoric unit to the pendant PTZ group. The net result is the formation of a remarkably long-lived charge-separated pair, TiO2(e-)|−RuII−PTZ+, that lives for ∼ ...

Photoionization of phenothiazinyl- and (carbazolylalkyl)trimethylammonium bromides in frozen AOT reversed micellar solutions studied by electron spin echo modulation and electron spin resonance

Electron spin echo (ESE) modulation and electron spin resonance of photoionized N-({omega}-phenothiazin-10-alkyl)-N,N,N-trimethylammonium bromide (PC{sub n}TAB) and N-({omega}-(3,6-didodecyl)carbazol-9-ylalkyl)-N,N,N-trimethylammonium bromide (CzC{sub n}TAB) (where alkyl = C{sub 4}H{sub 9}, C{sub 12}H{sub 25}, and C{sub 4}H{sub 9}, C{sub 8}H{sub 17}, C{sub 12}H{sub 25}) have been studied as a function of the size of the water pool of sodium bis(2-ethyl-1-hexyl)sulfosuccinate (AOT) reverse micellar solutions in D{sub 2}O and isooctane. Deuterium modulation effects measured by ESE spectroscopy from the photogenerate carbazole or phenothiazine cation radical show that the heterocyclic moiety experiences strong water interactions and is located near the AOT-water interface of the reverse micelle and that the alkyl chain is bent. Thus, both the location of the phenothiazine or carbazole group near the micellar interface and the degree of water disorder near the interface affect optimization of the photo efficiency for charge separation.

Synergy between a non-neuroleptic thioxanthene stereo-isomer and penicillin in vivo.

Some neuroleptic drugs of the phenothiazine and thioxanthene groups have an antimicrobial effect in vitro. This is also true for neuroleptically inactive stereo-isomeric analogs of the thioxanthenes e.g. trans(E)-clopenthixol (t-CPT). In a murine pneumococcus peritonitis model t-CPT demonstrated a slight, but non-significant antibacterial effect in doses of 0.3-0.9 mg per mouse, while higher doses seemed to enhance the bacterial virulence. If combined with subtherapeutic doses of penicillin, a significantly higher survival rate was obtained compared with either drug given alone. In vitro studies demonstrated a similar synergistic effect. These results indicate that at least one non-neuroleptic thioxanthene stereo-isomer has an antibiotic potential also in vivo. The mechanism of action is not known.

Ethacizin: A new efficacious Soviet antiarrhythmic drug of the phenothiazine group

Ethacizin, a new Soviet antiarrhythmic agent of the phenothiazine group, was tested on 82 patients with ventricular rhythm disturbances. Antiarrhythmic effects of the drug were assessed by means of ambulatory ECG monitoring. The investigation protocol included acute drug testing with 50 mg, 100 mg, and 150 mg, and short-term maintenance therapy with 150 to 300 mg/24 hours of ethacizin (mean 183 ± 46 mg/24 hours) for 3 to 14 days (mean 7 ± 3 days). Ethacizin reduced the total number of ventricular premature beats (VPBs) from 17,263 24 hours (on placebo) to 3458 24 hours ( p < 0.001) and suppressed couplets and ventricular tachycardia (VT) runs by 90% in 94% and 96% of patients, respectively. Maximum blood plasma concentration of ethacizin was observed in 110 to 120 minutes and accounted for 300 to 447 ng/ml (mean 354 ± 77 ng/ml), with a minimum therapeutic drug plasma concentration ranging from 29 to 101 ng/ml (mean 73 ± 27 ng/ml). There was a significant increase in PQ and QRS intervals with ethacizin. Ethacizin was well tolerated. Thus ethacizin had high antiarrhythmic efficacy in patients with VPBs and no significant side effects.

Effects of calcium antagonists on KCl-evoked calcium uptake by rat cortical synaptosomes

1. 1. A series of calicum antagonists were used to study their blocking effect on high potassium-induced calcium uptake into rat cortical synaptosomes; these antagonists were classified into five groups: (1) dihydropyridine group (i.e. nifedipine and nitrendipine), (2) benzothiazepine group (i.e. diltiazem), (3) phenylalkylamine group (i.e. verapamil and D600), (4) phenothiazine group (i.e. trifluoperazine) and (5) diphenylpiperazine group (i.e. flunarizine and cinnarizine). 2. 2. Voltage-dependent 45Ca 2+-uptake into this fraction was measured after 20 see KCl-induced depolarization. The ID 30 values of the above-mentioned antagonists affecting 45Ca 2+-uptake were calculated to be nitrendipine (80 μM), nifedipine (100 μM), verapamil (50 μM), D600 (15 μM), diltiazem (70 μM), trifluoperazine (7 μM), cinnarizine (1.2 μM) and flunarizine (0.7 μM). 3. 3. Our results reveal that in rat brain synaptosomal fractions, calcium influx via the voltage-gated calcium channel appears to be more sensitive to diphenylpiperazine and phenothiazine groups; whereas, phenylalkylamine, benzothiazepine and dihydropyridine groups were relatively insensitive. 4. 4. This contrasts with the well known data obtained from vascular smooth muscle, in which the dihydropyridine group is the most sensitive of all the groups studied. 5. 5. Our results suggest that calcium channels in neuronal tissue are most likely different from those in non-neuronal tissue.

向精神薬服用中患者の血清脂質およびアポリポ蛋白濃度

Concentrations of lipids and apolipoproteins in male schizophrenics treated with major tranquilizers were measured. The patients were separated into three groups according to the drugs used i. e., phenothiazine alone (n=17), butyrophenone alone (n=13) and combination of phenothiazine and butyrophenone (n=13). Concentrations of HDL cholesterol and apo A-I of three major tranquilizer groups were significantly low compared to normal controls. Apo A-II levels of phenothiazine and butyrophenone groups were significantly low compared to normal controls. Concentrations triglycerides, apo C-II and C-III of phenothiazine and combination of phenothiazine and butyrophenone groups were significantly higher than those of butyrophenone group.

A study of inhibition of cholera toxin-induced intestinal hypersecretion by neuroleptics.

Various types of neuroleptics and other agents were examined for inhibitory effect in cholera toxin-induced hypersecretion in ligated loops of mice jejunum. Several agents belonging to the phenothiazine group or thioxanthene group were inhibitory. Only three other neuroleptics, loxapin, haloperidol and penfluridol, inhibited the hypersecretion. Among the miscellaneous agents the calcium antagonist nifedipine was inhibitory. The potencies of the neuroleptics did not correlate with the dopamine antagonistic potencies. The results indicate that the site of antisecretory action of the drugs is to be found outside the central nervous system.

Clastogenic effect of the psychotropic drug thioridazine on human chromosomes in vivo.

Thioridazine (Mellaril), a psychotropic drug belonging to the phenothiazine group of drugs, was evaluated for its in vivo clastogenic effect on human chromosomes in lymphocyte cultures. Lymphocyte cultures were set up with peripheral blood samples of psychiatric patients (diagnosis: schizophrenia, mania, manic depressive psychosis, acute psychotic episode) who were on therapeutic doses of thioridazine for over 4 weeks. Two sets of controls were used: (1) newly diagnosed psychiatric cases (same type as above) who were not yet under therapy and (2) healthy individuals from the general population. The chromosomal aberration frequency was found to be significantly increased in the patients exposed to this drug as compared to the two sets of controls. The results point to a clastogenic and mutagenic potential of thioridazine and warrent a more careful consideration of its use in medicine.

Growth Hormone, Prolactin, and Growth Responses in Hyperkinetic Males Treated with D-Amphetamine

Growth patterns in previously unmedicated hyperactive boys were assessed monthly for 1 year or more while they received treatment with d-amphetamine (N = 13) or phenothiazines (N = 8). The d-amphetamine group, who sustained their behavior improvement throughout the study, underwent sleep and endocrine studies before and after 6 months on drug therapy. By 1 year, the phenothiazine group had achieved a 7-point increase in weight percentile and a 4-percentile gain in height, but the d-amphetamine group had lost 16 percentile points in weight and 10 percentile points in height. Height and weight velocities had fallen significantly (p < 0.001, p < 0.005) for the entire d-amphetamine group by 1 year, and remained low in a subgroup of 8 followed for an additional 9 months. While there were no d-amphetamine effects on growth hormone secretion or on sleep paramenters, mean-sleep-related prolactin concentrations during treatment fell significantly (p < 0.015). The inhibition of height velocity was significantly correlated with the prolactin suppression (Pearson r = 0.57, p < 0.05) for the d-amphetamine group.

Cardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazine

The phenothiazine derivatives, particularly chlorpromazine and thioridazine, are known to produce significant electrocardiographic abnormalities. Until now, documented life-threatening arrhythmias have not been reported following large doses of mesoridazine, the besylate salt of a metabolite of thioridazine and a relatively recent addition to the phenothiazine group. We describe such a case in which alterations in both impulse conduction (first-degree atrioventricular block, prolonged QRS duration, and right axis deviation) and impulse formation (supraventricular and ventricular tachycardia) were noted following a suicidal ingestion of mesoridazine. The electrophysiologic mechanisms underlying phenothiazine-induced arrhythmogenesis are reviewed.

An alternative mechanism of action for neuroleptic and antidepressant drugs

It has earlier been proposed by the author that the aetiology of schizophrenic symptomatology may be due to the presence of abnormally connected interhemispheric fibres which link specialised functions in the brains of schizophrenics that are not connected in normal subjects, and that the neuroleptic drugs may produce their action through a local anaesthetic-like effect in suppression of conduction in these fibres. This line of thought has been extended here to consider the possible mechanism of action of the neuroleptic drugs in more detail, as well as that of the tricyclic antidepressant drugs which are derivatives of the phenothiazine group. Pharmacological similarities with the local anaesthetics both structurally and functionally have been considered, as well as the effects that these drug groups may have in common with the lithium salts. It has been suggested that these drugs all produce their primary effect on cell membranes, though not necessarily at the synapse, that the time course of their clinical effect may correlate with their incorporation into various cell membranes within the CNS, and that they may thus bring about a fundamental alteration in cell membrane microstructure. The possible role of electroconvulsive therapy has also been considered. The corollary of this argument is that the affective disorders may be genetically determined diseases of cell membrane microstructure.

Photochemical inactivation of deoxyribonucleic and ribonucleic acid viruses by chlorpromazine.

Chlorpromazine, a widely used tranquilizing drug of the phenothiazine group, was found to be a very potent photochemical inactivator of both deoxyribonucleic acid and ribonucleic acid viruses in the presence of long-wave ultraviolet light (320 to 380 nm). Neither the light alone nor chlorpromazine alone caused any appreciable inactivation. The known chlorpromazine photoreactions with nucleic acids are somewhat similar to those of psoralen (furocoumarin) derivatives. As in the case of the psoralens, chlorpromazine is capable of photoinactivating viruses totally within a few minutes under near-physiological or other gentle conditions. The antiviral effects of the chlorpromazine photoreaction could make it valuable for the development of inactivated viral vaccines as well as for use in the photochemotherapy of viral dermatoses.

Treatment of tardive dyskinesia

Neuroleptic drugs cause many forms of extra-pyramidal syndromes. One of these, tardive dyskinesia,1 occurs only after the patient has been taking the drug for some time (‘tardive’ refers to the late onset). The movements are involuntary and repetitive usually involving the face and tongue, but they may also affect the limbs and trunk. Tongue protrusion, licking and smacking of the lips, sucking and chewing movements, grimacing, grunting, blinking and furrowing of the forehead have all been described and attributed to long-continued medication with neuroleptic drugs of the phenothiazine, butyrophenone and thioxanthene groups. The patient can inhibit the movements, but anxiety makes them worse. Many of these symptoms were noticed in schizophrenic patients before neuroleptic drugs were introduced2 and they can occur in otherwise normal untreated elderly people. Nevertheless it is generally accepted that in most cases tardive dyskinesia is an unwanted effect of neuroleptic medication. Despite suggestions to the contrary, the abnormal movements are not necessarily associated with high dosage of neuroleptic drugs or with pre-existing brain damage.3 4 Tardive dyskinesia has been reported in 3–6% of a mixed population of psychiatric patients5 and over half of a group of chronic schizophrenics on long-term treatment.4 The more careful the neurological examination, the greater the apparent incidence.

Ab initioLCAO‐MO‐SCF calculation of the electrostatic molecular potential of chlorpromazine and promazine

AbstractThe electrostatic potential V(r) arising from the ab initio LCAO‐MO‐SCF wave functions of chlorpromazine (CPZ) and promazine (PZ) has been calculated and discussed. In this approximation, the most probable sites of attack and reaction paths of electrophilic reagents are pointed out and compared. The analysis of V(r) shows that the phenothiazine group has strong nucleophilic properties which are influenced by the phenothiazine substituent and that the electrostatic reactivity of CPZ and PZ is decidedly different near the phenothiazine substituent and similar near the side chain N atom. The dependence of V(r) on the accuracy of the wave function has also been discussed by comparing some ab initio results on pyrrole, pyrazole, and imidazole obtained with a large basis set with an ab initio minimum basis set and with CNDO calculations.

Mutagenesis by photoactivation of chlorpromazine, a tranquilizer of the phenothiazine group.

The tranquilizer chlorpromazine, in combination with visible light or near-u.v. radiation, can cause base-pair substitution mutations and frameshift mutations in Salmonella typhimurium. The mutagenic damage is subject to repair by the bacterial excision~repair system.

The work of a psychosurgical unit.

Summary The widespread use of standard leucotomy terminated in the early 1950's with the advent of the phenothiazine group of drugs. But since then, psychosurgical techniques have been considerably refined and the indications for the newer operations are becoming increasingly precise. Knight's (1969) stereotactic tractotomy is probably the most frequently performed contemporary operation for the relief of some psychiatric illnesses, and the number of patients now referred for this treatment have justified the organization of a specific unit for the purpose. The value of such a special unit, involving close co-operation between neurosurgeon and psychiatrist is emphasized. It provides a supportive environment for patients who are sharing a highly specialized treatment, and offers opportunities for studying outcome after operation with resulting improvement in selection. It also facilitates research possibilities in general. The clinical work of the Geoffrey Knight Psychosurgical Unit, probably in its way unique, is described and questions often encountered from doctors and from patients are considered. The importance of rehabilitation after operation is stressed and some aspects of the longer term post-operative psychiatric care involved are dealt with.

Determination of Phenothiazine Compounds in Biologic Specimens by UV Spectrophotometry

A UV spectrophotometric technique for specific determination of drugs that have the phenothiazine group as part of their molecular structure was developed. The method utilizes the oxidation capability of the cobalt (III) ion. The phenothiazines and their sulfoxide metabolites are oxidized to a product that is stable in a hexane-tertiary butanol mixture. No other group of alkaline-extractable compounds gives a UV-absorbing product by the conditions of the proposed method. The procedure is sensitive, and the spectra of the products are highly specific for the phenothiazine drugs. Analysis is linear over the concentration range of 0.5–50.0 mcg./ml. The distribution pattern of certain phenothiazine drugs in the rat is presented.