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British Journal of Clinical Pharmacology Jun 1985Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and... (Clinical Trial)
Clinical Trial
Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and to determine the contributions from promethazine's major pharmacological actions. Twelve healthy subjects participated in a double-blind, within-subject comparison of promethazine and placebo each given acutely by mouth. Breathlessness was assessed with visual analogue scales during a progressive exercise test and was related to minute ventilation. Promethazine had no significant effect on breathlessness nor on the relationship between breathlessness and ventilation. The role of histamine-antagonism was investigated in a subgroup of the subjects by administration of mebhydrolin. No effect on breathlessness was detected. In contrast, the standard phenothiazine, chlorpromazine, caused a marked and statistically significant reduction in breathlessness without affecting ventilation and without causing detectable sedation. This unexpected finding merits further study in patients and is discussed with reference to the role of chlorpromazine as a constituent of Brompton's Mixture.
Topics: Adult; Carbolines; Chlorpromazine; Humans; Physical Exertion; Promethazine; Respiration
PubMed: 4027121
DOI: 10.1111/j.1365-2125.1985.tb02716.x -
Canadian Medical Association Journal Dec 1962The chief dangers reported with some common drugs are reviewed. Hazards of antibiotic therapy include: the increasing incidence of sensitization to penicillin with...
The chief dangers reported with some common drugs are reviewed. Hazards of antibiotic therapy include: the increasing incidence of sensitization to penicillin with occasional anaphylactic reactions; aplastic anemia with chloramphenicol, and the poor tolerance of infants for chloramphenicol; staphylococcal enterocolitis; unnecessary "prophylactic" use of antibiotics. Thiazide diuretics may precipitate potassium depletion, skin reactions, pancreatitis, blood dyscrasias, gout, diabetes mellitus and hepatic coma. Reserpine can increase gastric acidity, induce mental depression, and when used with digitalis lead to ventricular premature beats. Hydralazine may aggravate angina pectoris, cause tachycardia, and bring about a syndrome resembling disseminated lupus erythematosus. Guanethidine may result in loose stools, impotence, and postural hypotension. Hazards of phenothiazines include jaundice, parkinsonian states and tremors, convulsions, hypotension, and blood dyscrasias. The butanediols have numerous side effects including gastrointestinal, cutaneous and hypotensive reactions. Prolonged corticosteroid therapy introduces a new danger in surgical treatment. The progesterone-like drugs may induce masculinization of the female fetus.
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antihypertensive Agents; Antipsychotic Agents; Chloramphenicol; Chlorothiazide; Diuretics; Enterocolitis; Female; Gonadal Steroid Hormones; Guanethidine; Humans; Hydralazine; Hydrochlorothiazide; Male; Meprobamate; Penicillins; Phenothiazines; Reserpine; Sodium Chloride Symporter Inhibitors; Staphylococcal Infections; Steroids
PubMed: 13989937
DOI: No ID Found -
The Journal of Physical Chemistry. B Feb 2023In this study, we report a comprehensive time-resolved spectroscopic investigation of the excited-state deactivation mechanism in three push-pull isomers characterized...
In this study, we report a comprehensive time-resolved spectroscopic investigation of the excited-state deactivation mechanism in three push-pull isomers characterized by a phenothiazine electron donor, a benzothiazole electron acceptor, and a phenyl π-bridge where the connection is realized at the relative , , and positions. Spin-orbit charge-transfer-induced intersystem crossing takes place with high yield in these all-organic donor-acceptor compounds, leading also to efficient production of singlet oxygen. Our spectroscopic results give clear evidence of room-temperature phosphorescence not only in solid-state host-guest matrices but also in highly biocompatible aggregates of these isomers produced in water dispersions, as rarely reported in the literature. Moreover, aggregates of the isomers could be internalized by lung cancer and melanoma cells and display bright luminescence without any dark cytotoxic effect. On the other hand, the isomers showed significant cellular phototoxicity against the tumor cells due to light-induced reactive oxygen species generation. Our findings strongly suggest that nanoaggregates of the investigated isomers are promising candidates for imaging-guided photodynamic therapy.
Topics: Temperature; Isomerism; Luminescence; Phenothiazines
PubMed: 36735941
DOI: 10.1021/acs.jpcb.2c07717 -
Acta Poloniae Pharmaceutica 2001Two drugs in the form of coated tablets: Promazin (promazine hydrochloride) (1) and Thioridazin (thioridazine hydrochloride) (2), and tablets Clotrimazolum...
Two drugs in the form of coated tablets: Promazin (promazine hydrochloride) (1) and Thioridazin (thioridazine hydrochloride) (2), and tablets Clotrimazolum (clotrimazole) (3) were assayed gravimetrically and spectrophotometrically in the same process using complexes with ammonium molybdate. Stoichiometry of these complexes was established by elemental analysis and analysis of the incineration residue (MoO3). The complexes were subsequently characterized using their IR and UV spectra and melting points. The active substances of the complexes were also determined spectrophotometrically. Using this method Beers Law was found to hold for the concentration ranges of 5-40 microg/ml (complex of 1), 5-60 (microg/ml (complex of 2) and 2-10 microg/ml (complex of 3). The method was validated in terms of precision, linearity, detection limit and quantification limit. The two methods of drug determination, used in a single analytical process verify each other.
Topics: Anti-Bacterial Agents; Enzyme Inhibitors; Imidazoles; Macrolides; Phenothiazines; Spectrophotometry, Ultraviolet; Tablets; Tablets, Enteric-Coated
PubMed: 12197611
DOI: No ID Found -
Daru : Journal of Faculty of Pharmacy,... Sep 2018Fluphenazine and prochlorperazine as phenothiazine-class antipsychotic drugs are widely used to treat schizophrenia, however their use is associated with significant...
PURPOSE
Fluphenazine and prochlorperazine as phenothiazine-class antipsychotic drugs are widely used to treat schizophrenia, however their use is associated with significant side effects such as extrapyramidal symptoms, as well as ocular and skin disorders. Our goal was to determine the effect of fluphenazine and prochlorperazine on cell viability and melanogenesis in lightly pigmented normal human melanocytes.
METHODS
The viability of melanocytes was evaluated by the WST-1 colorimetric assay, while melanin content and tyrosinase activity were tested spectrophotometrically.
RESULTS
It has been shown that both phenothiazines induce the concentration-dependent loss in cell viability. The EC values were calculated to be 6.13 and 0.63 μM for fluphenazine and prochlorperazine, respectively. Fluphenazine in the concentration of 5.0 μM and prochlorperazine in concentrations of 0.5 and 0.75 μM decreased melanin content and tyrosinase activity. The observed inhibition of melanogenesis may be explained by the decrease of enzyme activity.
CONCLUSIONS
The demonstrated changes in melanization process in lightly pigmented cells exposed to fluphenazine and prochlorperazine in vitro suggest a significant role of melanin and melanocytes in the mechanisms of undesirable side effects of these drugs in vivo. Graphical abstract Fluphenazine and prochlorperazine significantly inhibits melanogenesis in lightly pigmented melanocytes HEMn-LP.
Topics: Cell Survival; Cells, Cultured; Fluphenazine; Humans; Melanins; Melanocytes; Monophenol Monooxygenase; Prochlorperazine
PubMed: 30159761
DOI: 10.1007/s40199-018-0206-4 -
Pharmacological Reports : PR 2012The metabolism of phenothiazine neuroleptics (promazine, perazine) in a primary culture of human hepatocytes after pretreatment of cells with those neuroleptics was...
BACKGROUND
The metabolism of phenothiazine neuroleptics (promazine, perazine) in a primary culture of human hepatocytes after pretreatment of cells with those neuroleptics was studied.
METHODS
The hepatocytes were pretreated with 25 μM promazine or perazine for 96 h. Then, the cells were incubated for 2, 4, 6, 8 and 24 h in the presence of neuroleptics. At the indicated time points, concentrations of phenothiazines and their metabolites (5-sulfoxides and N-desmethyl derivatives) were measured in the culture medium using HPLC with UV detection.
RESULTS
Pretreatment of the primary culture of human hepatocytes with promazine or perazine resulted in accumulation of their metabolites in the culture medium. Such an effect was not observed in the case of control cultures (not pretreated with neuroleptics).
CONCLUSION
The obtained results suggest that the tested phenothiazines may stimulate their own metabolism by inducing CYP1A2, CYP3A4 and CYP2C19 isoforms.
Topics: Aged; Antipsychotic Agents; Biotransformation; Cells, Cultured; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Dealkylation; Enzyme Induction; Female; Hepatocytes; Humans; Isoenzymes; Perazine; Primary Cell Culture; Promazine; Spectrophotometry, Ultraviolet; Sulfoxides; Time Factors
PubMed: 23406770
DOI: 10.1016/s1734-1140(12)70957-x -
International Journal of Molecular... May 2021The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new...
The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride () and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds and with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of , two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of , sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents.
Topics: Amines; DNA; Dimerization; Intercalating Agents; Magnetic Resonance Spectroscopy; Methylene Blue; Models, Molecular; Molecular Conformation; Molecular Structure; Spectrometry, Fluorescence; Structure-Activity Relationship
PubMed: 34072560
DOI: 10.3390/ijms22115847 -
Biochimica Et Biophysica Acta Jul 2014Methicillin-resistant Staphylococcus aureus (MRSA) is currently one of the principal multiple drug resistant bacterial pathogens causing serious infections, many of...
Methicillin-resistant Staphylococcus aureus (MRSA) is currently one of the principal multiple drug resistant bacterial pathogens causing serious infections, many of which are life-threatening. Consequently, new therapeutic targets are required to combat such infections. In the current work, we explore the type 2 Nicotinamide adenine dinucleotide reduced form (NADH) dehydrogenases (NDH-2s) as possible drug targets and look at the effects of phenothiazines, known to inhibit NDH-2 from Mycobacterium tuberculosis. NDH-2s are monotopic membrane proteins that catalyze the transfer of electrons from NADH via flavin adenine dinucleotide (FAD) to the quinone pool. They are required for maintaining the NADH/Nicotinamide adenine dinucleotide (NAD(+)) redox balance and contribute indirectly to the generation of proton motive force. NDH-2s are not present in mammals, but are the only form of respiratory NADH dehydrogenase in several pathogens, including S. aureus. In this work, the two putative ndh genes present in the S. aureus genome were identified, cloned and expressed, and the proteins were purified and characterized. Phenothiazines were shown to inhibit both of the S. aureus NDH-2s with half maximal inhibitory concentration (IC50) values as low as 8μM. However, evaluating the effects of phenothiazines on whole cells of S. aureus was complicated by the fact that they are also acting as uncouplers of oxidative phosphorylation. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Inhibitory Concentration 50; NADH Dehydrogenase; Phenothiazines; Quinone Reductases; Staphylococcus aureus
PubMed: 24709059
DOI: 10.1016/j.bbabio.2014.03.017 -
PloS One 2021The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are...
The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial activity against C. difficile. The purpose of this present study was to investigate the potential of a novel phenothiazine derivative, JBC 1847, as an oral antimicrobial for treatment of intestinal pathogens and CDIs. The minimal inhibition concentration and the minimum bactericidal concentration of JBC 1847 against C. difficile ATCC 43255 were determined 4 μg/mL and high tolerance after oral administration in mice was observed (up to 100 mg/kg bodyweight). Pharmacokinetic modeling was conducted in silico using GastroPlusTM, predicting low (< 10%) systemic uptake after oral exposure and corresponding low Cmax in plasma. Impact on the intestinal bacterial composition after four days of treatment was determined by 16s rRNA MiSeq sequencing and revealed only minor impact on the microbiota in non-clinically affected mice, and there was no difference between colony-forming unit (CFU)/gram fecal material between JBC 1847 and placebo treated mice. The cytotoxicity of the compound was assessed in Caco-2 cell-line assays, in which indication of toxicity was not observed in concentrations up to seven times the minimal bactericidal concentration. In conclusion, the novel phenothiazine derivative demonstrated high antimicrobial activity against C. difficile, had low predicted gastrointestinal absorption, low intestinal (in vitro) cytotoxicity, and only induced minor changes of the healthy microbiota, altogether supporting that JBC 1847 could represent a novel antimicrobial candidate. The clinical importance hereof calls for future experimental studies in CDI models.
Topics: Administration, Oral; Animals; Caco-2 Cells; Clostridioides difficile; Clostridium Infections; Feces; Gastrointestinal Microbiome; Humans; Mice; Phenothiazines; RNA, Ribosomal, 16S
PubMed: 34597343
DOI: 10.1371/journal.pone.0258207 -
Journal of Enzyme Inhibition and... Dec 201910-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives,...
10-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced H and C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and , -diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of , , , and genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Phenothiazines; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 31307242
DOI: 10.1080/14756366.2019.1639695