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PubMed1979

Phenothiazine analgesia--fact or fantasy?

Double-blind clinical trials involving the use of phenothiazines as analgesics or potentiators of analgesics (aspirin, meperidine, morphine sulfate) and adverse effects of phenothiazines are reviewed and evaluated. Promethazine, promazine and propiomazine were not found to possess analgesic or potentiating properties. One chlorpromazine study contained important design and reporting deficiencies which precluded a recommendation for use of chlorpromazine in the treatment of pain. Methotrimeprazine was determined by numerous authors to have analgesic properties; however, most of the studies also were deficient in design or data presented, or both. Adverse reactions to phenothiazines, including hypotension, sedation, drowsiness, extrapyramidal symptoms, tardive dyskinesia, cardiac toxicity and agranulocytosis, are often more common and severe than those attributed to narcotic analgesics. Because of the lack of data supportive of analgesic activity and the adverse reactions associated with phenothiazines, use of these agents in the management of pain should be discouraged. The prophylactic use of phenothiazine for narcotic analgesic-induced emesis also is, in most cases, a questionable practice.

Analgesics↗

PubMed1976

[Corneal and lens deposits due to treatment by phenothiazine type neuroleptics].

The authors have studied the corneal and lens lesions which appeared following a prolonged treatment by phenothiazines. They examined 186 patients: 147 took phenothiazines of which 35 of them presented anterior segment alterations. It seems that all phenothiazines can be held responsible for the apparition of these lesions. At this point the authors evaluated the global dose of the various phenothiazines which were administered. The threshold at which the association of these lesions seem to appear, seems to be situated around 300 gr. The total quantity of phenothiazines which are absorbed seems to be a good measure of the risk of ocular toxicity. In the case of one patient they observed that his visual keenness was lowered due to the importance of his corneal and lens lesions.

Antipsychotic Agents↗

PubMed2026

Antimicrobial photodynamic therapy mediated by phenothiazine photosensitizers against Candida albicans and Candida auris: a systematic review.

Fungal infections caused by Candida albicans and Candida auris represent an increasing clinical challenge, particularly due to biofilm formation and rising antifungal resistance. Antimicrobial photodynamic therapy (aPDT) has emerged as a potential alternative strategy, with phenothiazine-based photosensitizers being among the most extensively investigated compounds. This systematic review aimed to evaluate the application of phenothiazine-mediated aPDT in in vitro studies against C. albicans and C. auris. A comprehensive search was conducted in PubMed, Embase, and Scopus, including studies published within the last 10 years. Forty in vitro studies met the eligibility criteria and were synthesized descriptively due to substantial methodological heterogeneity. Overall, aPDT was associated with reductions in fungal viability, with generally greater effects reported in planktonic models compared with biofilms. Methylene blue was the most frequently investigated photosensitizer, applied across a broad range of concentrations and dosimetric parameters, resulting in variable antifungal responses. Other phenothiazine derivatives, including toluidine blue O, dimethyl methylene blue, new methylene blue, and S137, were also associated with antifungal activity under specific experimental conditions but remain comparatively underexplored. Studies involving C. auris were less frequent and suggested lower susceptibility compared with C. albicans, particularly in biofilm models. Given the substantial variability in experimental protocols, especially regarding photosensitizer concentration, light parameters, and biofilm maturation, the findings should be interpreted with caution and limit direct comparison across studies. These findings support the antifungal potential of phenothiazine-mediated aPDT while emphasizing the need for methodological standardization and expanded investigation of C. auris.

Photochemotherapy↗

PubMed1978

Thin layer chromatographic screening for methaqualone, phenothiazines, opiates and benzodiazepines.

A method is described which permits the simultaneous detection of methaqualone, phenothiazines, opiates and benzodiazepines in urine. Its diagnostic application is discussed. After cleavage of conjugates with hydrochloric acid, the substances are extracted and identified by thin-layer chromatography. In most cases analysis can be carried out using 2 solvent systems, phenothiazines, methaqualone and opiates being visualised using a three stage spray sequence. Since phenothiazines can interfere with the detection of methaqualone, a specific eluant is used to ensure reliable detection of the latter. Methaqualone can be positively identified by its characteristic metabolite pattern, whereas phenothiazines can only be detected as a group.

Analgesics, Opioid↗

PubMedDate not supplied

Metabolism of phenothiazine in the guinea pig.

The metabolism of phenothiazine was studied in the guinea pig. In the adult animal after 24 hr, about 7% of the administered dose was found in feces, with traces of the sulfoxide and phenothiazone. Small amounts of all these compounds also were found in urine, with leucophenothiazone sulfate (approximately 12%) and a metabolite identified as phenothiazine N-glucuronide (approximately 22%). This latter compound was also present in bile. Both phenothiazine and its sulfoxide were retained in body tissues for a long time, about 85% of the dose being excreted after 7 days. In neonatal animals, phenothiazine, with up to 12% of the sulfoxide together with traces of leucophenothiazone, phenothiazone, and thionol was excreted in urine.

Aging↗

PubMed1977

[Formation of an azoderivative of phenothiazine].

The reaction of phenothiazine-5-oxide in 2 N HCl with 2,4-dinitrophenylhydrazine gives rise to 3-azo-(2',4'-dinitrophenyl)phenothiazine and phenothiazine. The stoichiometric ratio is two molecules of phenothiazine-5-oxide to one molecule of 2,4-dinitrophenylhydrazine.

Azo Compounds↗

PubMed1978

Oxidative degradation of pharmaceutically important phenothiazines I: Isolation and identification of oxidation products of promethazine.

The thermal degradation of promethazine in water in the presence of oxygen was studied. After degradation, the products were isolated by TLC. Identification was carried out by comparison of the isolated compounds with reference compounds. Melting points, spectral data, and polarographic and chromatographic behavior were compared. The following products were identified: 10-methylphenothiazine, phenothiazine, 3H-phenothiazine-3-one, phenothiazine 5-oxide, promethazine 5-oxide, 7-hydroxy-3H-phenothiazine-3-one, acetaldehyde, formaldehyde, and dimethylamine.

Chemical Phenomena↗

PubMed1975

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

The antischizophrenic activity of phenothiazine drugs and their tendency to elicit extrapyramidal symptoms are thought to involve blockade of synaptic dopamine receptors in the brain. Space filling molecular models show how favorable Van der Waal's interactions between the side chain amino of phenothiazines and the 2-substituent on ring A can promote a conformation mimicking dopamine. These Van der Waal's attractive forces can expain (i) the greater potency of drugs with trifluoromethyl rather than chlorine as a 2-substituent; (ii) the enhanced activity of phenothiazines with piperazine instead of alkylamino side chains; (iii) the increased potency associated with hydroxyethylpiperazines as contrasted to piperazine side chains; (iv) the greater potency of cis rather than trans thioxanthenes; and (v) the crucial location of the ring A substituent at carbon no. 2. Potential energy calculations support the observations with molecular models and suggest an active conformation for the phenothiazines.

Antipsychotic Agents↗

PubMed1978

Schizophrenia following withdrawal from chronic phenothiazine administration: a case report.

The chronic administration of phenothiazines has come under increasing scrutiny recently, and the uncritical use of this form of treatment has been criticized. A case is presented illustrating the development of schizophrenia in a young adult following withdrawal from phenothiazines. As far as could be ascertained ther was no evidence of schizophrenia prior to withdrawal of phenothiazines. The possibility that withdrawal of phenothiazines may have aetiological significance in this case is discussed.

Adult↗

PubMed1978

Toxic psychosis induced by phenothiazine administration in patients with chronic renal failure.

Adverse reactions to phenothiazines have not been commonly recognized in patients with chronic renal failure. We wish to report a characteristic acute psychosis as a complication of phenothiazine use in such individuals. Four patients with chronic renal failure requiring hemodialysis were given doses of chlorpromazine ranging from 100--1000 mg over time intervals varying from 2--7 days. All developed extreme restlessness, auditory and visual hallucinations, and episodes of belligerent behavior. A fifth patient treated with promethazine developed a similar psychosis. Each became ill shortly after the initiation of phenothiazine therapy. All improved slowly after cessation of the drug. Hemodialysis in four patients did not appear to affect the course of the illness. The use of phenothiazines in patients with chronic renal failure is cautioned.

Aged↗

PubMed1976

Synthesis of some new phenothiazine derivatives of expected medicinal value.

2-Chloroacetyl phenothiazines were reacted with certain phenols and salts of some acids under different conditions to yield 2-substituted acetylphenothiazines. Another series of 10-substituted phenothiazines was synthesized by treatment of 10-chloroacetylphenothiazine with either the appropriate amines or salts of the respective acids. The optimum experimental conditions for the preparation of 2-chloroacetyl-10-acetyl-phenothiazine by Friedel-Crafts reaction were studied. Also N-chloroacetyl-o-aminophenol was synthesized in high yield by a simple method. The preliminary pharmacological screening showed that two of these compounds possess a low order of tranquillizing activity.

Animals↗

PubMed1975

Binding study of sulfonylureas and phenothiazines to bovine serum albumin using difference spectrophotometry.

2-(4'-Hydroxybenzeneazo)benzoic acid is a spectrophotometric probe which shows absorption spectrum changes upon binding to protein. Difference absorption spectra of this probe were used as an indirect measurement of the binding of selected sulfonylurea and phenothiazine drugs to bovine serum albumin. The results obtained using the spectrophotometric probe were similar to data obtained from other methods, especially fluorescent methods. Of the four sulfonylureas studied, tolbutamide showed the highest binding affinity, followed by glyburide, glipizide, and acetohexamide, in that order. The data collected for phenothiazine drugs indicated that chlorpromazine has the highest affinity, followed in order by trifluoperazine, perphenazine, fluphenazine, and promazine. Correlation of these results with chemical composition indicated that the interaction of phenothiazine drugs with bovine serum albumin was of a hydrophobic nature.

Animals↗

PubMed1977

Effects of adenine nucleotides on oxidation of phenothiazine tranquilizers.

The effects of adenosine diphosphate and triphosphate on the periodic acid oxidation of the phenothiazine tranquilizing drugs were studied. The principal effect was a marked reduction in the rate of formation and decay of the drug free radical. The oxidation rates of the nucleotide free drugs seemed to be most strongly influenced by the inductive effects of substituents at the 2-position of the phenothiazine nucleus. However, the oxidation rates of the drugs in the presence of nucleotide were most strongly influenced by the substituents at the 10-position. Variations of the structure of substituents at the 10-position have only a modest effect on the electronic state of the phenothiazine nucleus. Therefore, the marked effect of structural variation in the 10-substituents in the presence of nucleotide on the periodate oxidation rate most likely is an expression of steric effects related to an interaction between drug and nucleotide.

Adenine Nucleotides↗

PubMed1977

Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score.

In a prospective cohort study of 50,282 gravidas and their offspring, over-all rates of congenital malformations were similar in 1,309 children of women exposed to phenothiazine drugs during the first four lunar months of pregnancy and in 48,973 children of women who were not exposed. There was a suspicion of association between phenothiazine exposure and cardiovascular malformations. In a cohort reduced to 41,337 mother-child pairs for technical reasons, perinatal mortality rates and mean birth weight were similar according to phenothiazine exposure or nonexposure, as were intelligence quotient scores measured at four years of age in 28,358 of the children. Control of potential confounding factors with a variety of multivariate techniques did not materially alter the findings.

Abnormalities, Drug-Induced↗

PubMed1975

The liquid chromatographic properties of phenothiazines.

The high-pressure liquid chromatographic behaviour of different groups of phenothiazines (drug substances) has been investigated on 10-mu m silica gel particles. Variation of the ammonia concentration between 0.5 and 1.5% in an isopropanol-diisopropyl ether (15:85) mixture permits the adjustment of the solvent system to fit the different basicities of the various groups of interest. While the capacity factors (k') for pairs of compounds in two homologous oxidation series vary considerably owing to differences in basicity, there is reasonably good agreement between the relative retention (alphs) values. This fact can be utilized in order to identify phenothiazine homologues of series that have not previously been studied. Elutropic diagrams in connection with alpha values can be used to predict the chromatographic behaviour of new groups of phenothiazines.

Chromatography↗

PubMed1979

Phenothiazine-induced ventricular tachycardia following acute overdose.

The chronic use of phenothiazine is known to result in ventricular arrhythmias in certain patients. The occurrence of cardiac abnormalities following acute phenothiazine overdose is less well documented. Phenothiazine-induced ventricular tachycardia, when it occurs in the overdose situation, may be refractory to conventional antiarrhythmic drugs. We present a case in which the usual therapy was unsuccessful. Only after a transvenous pacemaker was inserted was the patient's condition reversed.

Adult↗

PubMed1979

Effect of structure on phenothiazine cation radical reactions in aqueous buffers.

The reactions of the cation radicals of 11 phenothiazine tranquilizers were examined in mildly acidic aqueous buffers. Of the 11, those having an aminopropyl side chain in the 10 position reacted to form 0.5 mol of sulfoxide and 0.5 mol of parent drug per mole of initial radical. Cation radicals with different side chains react to form additional products, which remain to be identified but probably result from hydroxylation of the phenothiazine ring. The decay kinetics of three of the cation radicals undergoing reactions with known stoichiometry, namely, chloropromazine, promazine, and triflupromazine, were studied in detail, and it was concluded that they all react via the same mechanism. The mechanism involves attack of the cation radical by a nucleophile, and radicals with electron-withdrawing groups in the 2 position react more quickly. Since the cation radicals with faster reaction rates with nucleophiles are more pharmacologically active, it is hypothesized that the cation radical-nucleophile interaction may be responsible for binding of phenothiazines to receptor proteins.

Antipsychotic Agents↗

PubMed1977

Quantitative correlations between albumin binding constants and chromatographic Rm values of phenothiazine derivatives.

The binding constants of 15 phenothiazine derivatives to bovine serum albumin were obtained by a circular dichroic probe technique; The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as RMw. The binding constants were of the same order of magnitude as the literature values, and the RMw values correlated well with log P octanol values from the literature. Correlations of log K with RMw were found to be more satisfactory when corrections for the state of ionization of the phenothiazines were made, the nonprotonated species accounting for the bulk of the binding. A better correlation was obtained when contributions from both species were taken into account. Similar correlations were attempted between RMw values and enzyme inhibitory activities of these phenothiazines taken from the literature.

Binding Sites↗