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At least 19 recordsLinked to original sources
PubMed1977

Oxidation kinetics of phenothiazine and 10-methylphenothiazine in acidic medium.

The rate of phenothiazine degradation in an acidic oxygen-saturated medium was studied. 3H-Phenothiazine-3-one and phenothiazine 5-oxide are produced by parallel reactions, and 7-(10'-phenothiazinyl)-3H-phenothiazine-3-one is produced in a more complex manner. The overall phenothiazine degradation rate appears to be pH independent up to pH 7.0. The degradation kinetics of 10-methylphenothiazine were studied after isolation and identification of its degradation products, 10-methylphenothiazine 5-oxide and 3H-phenothiazine-3-one. The main degradation product is 10-methylphenothiazine 5-oxide; but at low pH values and high temperatures, more 3H-phenothiazine-3-one is formed. The degradation rate of 10-methylphenothiazine is pH independent up to pH 7.

Drug Stability↗
PubMed1975

High speed liquid-solid chromatography of phenothiazines using columns packed with spherosil porous silica beads.

Spherosil, a spherical porous silica, has been investigated for use in high speed liquid-solid chromatography and compared to Lichrosorb Si-60, using three phenothiazines as test solutes. Particle size distribution for four different size ranges with nominal mean diameters of 5, 10, 20 and 40 mu m is given. Distribution is very homogeneous. Columns from 15 to 100 cm in length and 1/4 or 1/8 in.o.d. have been prepared and efficiency measured by determination of HETP with the three phenothiazines: [methylamino-3-propyl]-10-chloro-3-phenothiazine [k' = 3]; [N-methyl-N-[dimethylamino-3-propyl]amino-3-propyl]-10-chloro-3-phenothiazine [k' = 6.5]; and [dimethylamino-3-propyl]-10-chloro-3-phenothiazine-N-oxide [k' = 15]. Influence of column length and incidence of bead diameter have been studied. 1/4 in.o.d. columns are easier to fill than 1/8 in.o.d. columns for Spherosil 5 mu m and have, therefore, a greater efficiency. HETP, H, varies according to flow rate as H = DVn with 0.4 less than n less than 0.6 and according to particle size ad H = A d beta p with 1.7 less than beta less than 1.8. The best figures for H are between 0.1 or 0.2 mm for a flow rate of 1800 ml hr-1 cm-2 [k' = 15]. The separation of a mixture of 6 phenothiazines with the mobile phase, anhydrous ethyl acetate 60 V, water saturated ethyl acetate 20 V, anhydrous methanol 20 V, 33% aqueous solution of ethylamine 0.25 V, is given. Its duration is 20 min. instead of 90 min. by thin-layer chromatography.

Adsorption↗
PubMed1978

Aromatic oxidation of some phenothiazines.

The previously reported N-oxidation products phenothiazine-N-OH, N-O. and -NOOH obtained upon chemical and metabolic oxidation of phenothiazine nuclei are now shown to be the C-oxidation products, 7-hydroxyphenothiazines, phenothiazin-3-ones and phenothiazin-7-ones which have the para-hydroquinoneimino and para-quinoneimino type systems. 2. The metabolism of various 2-substituted phenothiazines in vitro gave mainly ring-hydroxylated metabolites and sulphoxides. The phenolic metabolites were further oxidized to phenothiazones either as metabolites or as 'metabonates'. 3. After metabolism of chlorpromazine, nor1-chlorpromazine and nor2-chlorpromazine in vitro, phenothiazones ('pink compounds') were obtained as N-dealkylated products of the phenolic derivatives 7- or 3-hydroxy compounds. 4. The synthesis and physicochemical characteristics including t.l.c., u.v., g.l.c. and mass spectra of the oxidized phenothiazine nuclei and of 8-(N-methyl-anilino)-2-chlorophenothiazin-7-one are reported.

Animals↗
PubMedDate not supplied

Microsomal mixed-function amine oxidase. Oxidation products of piperazine-substituted phenothiazine drugs.

Oxidation products of fluphenazide, thioproperazine, and trifluoperazine obtained in reactions catalyzed by homogeneous preparations of the microsomal mixed-function amine oxidase have been isolated and identified. Approximately 0.5 g of metabolite of each piperazine-substituted phenothiazine drug was prepared in reactors containing, as catalyst, the purified oxidase covalently attached to glass beads. Nuclear magnetic resonance spectra of the isolated products indicated that with all three substrates the enzyme preferentially catalyzes N-oxidation of the piperazine nitrogen furthest from the phenothiazine nitrogen atom. The enzyme-catalyzed oxidation is quite specific and oxidation of the sulfur or nitrogen atoms in the phenothiazine ring could not be detected. Concentrations of piperazine-substituted phenothiazines required to half-saturate the amine oxidase were in the micromolar range and at pH 8.3 and 37 degrees C, all those tested were oxidized at approximately 2 mumol/min/mg of enzyme. Kinetic constants for the piperazine-substituted phenothiazines were very similar to those obtained with phenothiazines containing a dimethylaminopropyl sidechain.

Animals↗
PubMed1976

Anticonvulsant activity and selective inhibition of nicotinamide adenine dinucleotide-dependent oxidations by 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines.

Several Several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl)phenothiazines were synthetized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate and alpha-ketoglutarate selectively, whereas NAD-independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 20-60% protection observed against pentylenetetrazol-induced convulsions in mice. The ability of substituted thiosemicarbazidophenothiazines to inhibit cellular respiratory activity was reduced considerably by cyclization to the corresponding substituted thiazolidinophenothiazines. On the other hand, cyclization generally resulted in increased anticonvulsant activity. Thus, the anticonvulsant activity possessed by these substituted phenothiazines bore no relationship with their ability to inhibit selectively the NAD-dependent oxidations. Selective inhibition of NAD-dependent oxidation of pyruvate and alpha-ketoglutarate in isolated rat brain mitochondria by some 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines was concentration dependent and competitive in nature.

Animals↗
PubMed1978

Calorimetric, 13C NMR, and 31P NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes.

1. The dipalmitoyl phosphatidylcholine/water system was employed to study the interaction of phenothiazines with model membranes. In particular the effects of the drugs upon the lipid phase transition were examined using differential scanning calorimetry and NMR spectroscopy. The studied phenothiazines have peripheral (diethazine) or central (chlorpromazine) properties. 2. Both drugs were observed to lower the phase transition temperature of dipalmitoyl phosphatidylcholine. The molar activity of chlorpromazine is somewhat higher than of diethazine. At low concentrations the drugs affect the dipalmitoyl phosphatidylcholine pretransition endotherm. 3. In the 13C NMR spectra of the drug-containing samples the signal of the trimethylammonium group of dipalmitoyl phosphatidylcholine is broadened, whereas a narrowing of the signal of the fatty-acid chain methylene groups is observed. Further, addition of the phenothiazines causes higher values of the effective chemical shift anisotropy of the 31P in the phosphate group, in comparison to the pure dipalmitoyl phosphatidylcholine sample. 4. The results obtained by three different techniques indicate a higher fluidity in the fatty-acid chain region and a mobility reduction of the polar headgroup of the dipalmitoyl phosphatidylcholine molecules in the presence of the phenothiazines. These phenomena can be well accounted for by a model for the incorporation of the phenothiazines in the dipalmitoyl phosphatidyl-choline bilayer, in which the dialkylaminoalkyl chains are located near the polar headgroups and the ring system does not penetrate far beyond the glycerol backbone into the hydrocarbon phase.

Calorimetry, Differential Scanning↗
PubMed1978

Melanocyte-stimulating hormone--mimetic action of the phenothiazines.

We have compared the melanophore-stimulating action of four phenothiazines, trifluoperazine, perphenazine, chlorpromazine, and prochlorperazine, with alpha-MSH on the skin of the lizard Anolis carolinensis, using a new rate method of bioassay. The dose-response curves for the phenothiazines were parallel to that of alpha-MSH, and when given together alpha-MSH and chlorpromazine were additive. The phenothiazines may therefore stimulate melanosome dispersion in the lizard skin by the same mechanism as alpha-MSH; a MSH-mimetic action of phenothiazines may similarly explain their pigmentary action in man. The pigmentary potency of the phenothiazines corresponded with their therapeutic potency in man; this is in keeping with a neuro-regulatory role for MSH peptides and suggests a possible therapeutic use for them.

Animals↗
PubMed1978

The determination of sulphoxide in degraded phenothiazine formulations by difference spectrophotometry.

A method is described for the assay of phenothiazine sulphoxides which may be formed in phenothiazine formulations during storage under unfavourable conditions. The assay is based upon the measurement of difference absorbance of the sulphoxide solution in 0.2 M hydrochloric acid relative to an equimolar solution reduced with zinc dust. A solvent extraction procedure avoids interference from colouring agents and coloured photolytic breakdown products of the phenothiazines. The assay is specific in the presence of intact drug, sulphone and co-formulated drugs for the formulations examined and is sensitive to 0.5% of the total phenothiazine present as sulphoxide. Many aqueous formulations stored in partially filled containers have been shown to contain up to 31.5% of the total phenothiazine as sulphoxide.

Drug Stability↗
PubMed1977

The possible role of dopamine in phenothiazine-induced hypothermia in rats: an application to DA hypothesis of schizophrenia.

Hypothermic effects of d-Amphetamine, chlorpromazine, a variety of other phenothiazines, ET495 and haloperidol in rats at 4 degrees C were measured separately and in combination. All the drugs produced some hypothermia. Among the phenothiazines, degree of hypothermia induced was found to be correlated with relative effectiveness of the drug as an antipsychotic agent. Hypothermic effects of each of the phenothiazines in combination with d-Amphetadrugs as an antipsychotic agent. Hypothermic effects of each of the phenothiazines in combination with d-Amphetamine was greater than for either drug alone. Hypothermic effects of the combination CPZ with Amphetamine was potentiated by haloperidol but blocked by ET495. The evidence supports a model of neuronal feedback loops either within the central DA mesolimbic pathway or between the mesolimbic and nigrostriatal DA systems. The establishment of interdependency between antipsychotic and hypothermic effects of phenothiazines offers promise not only to a greater understanding of the mechanisms underlying these effects, but the possibility of an objective test for screening new materials for antipsychotic effectiveness.

Animals↗
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↗