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Journal of Pharmaceutical and... Aug 2024The misuse of pharmaceuticals has significantly increased in recent decades, becoming a major public health concern. The risks associated with medication misuse are...
Milligram scale enantioresolution of promethazine and its main metabolites, determination of their absolute configuration and assessment of enantioselective effects on human SY-SY5Y cells.
The misuse of pharmaceuticals has significantly increased in recent decades, becoming a major public health concern. The risks associated with medication misuse are particularly high in cases of overdose, especially when the active substances are chiral, as enantioselectivity plays an important role in toxicity. Promethazine (PMZ) is a chiral antihistamine marketed as a racemate and it is misused in "Purple Drank", a recreational drug beverage, that combines codeine and/or PMZ, with soda or alcohol leading to serious health consequences and fatalities in consumers around the world, particularly among teenagers. Information regarding the enantioselectivity in the toxicity of (R,S)-PMZ and its main metabolites, namely promethazine sulfoxide (PMZSO) and desmonomethyl promethazine (DMPMZ), is unknown. This work reported, for the first time, the enantioseparation, in milligram scale, of (R,S)-PMZ, (R,S)-DMPMZ, (R,S)- PMZSO and the determination of their absolute configurations by electronic circular dichroism (ECD). The enantioseparation of all the six enantiomers was accomplished in a homemade semi-preparative column with amylose tris-3,5-dimethylphenylcarbamate (AD) coated with aminopropyl Nucleosil silica. The enantiomeric purity was evaluated using the analytical Lux® 3 µm i-Amylose-3 column, yielding enantiomeric purity values ranging between 94.4% and 99.7%. The elution order of all the enantiomers was accomplished combining the ECD results with an optical rotation detector. The elution order of the enantiomers was influenced only by the chiral selector, rather than the mobile phase. The cytotoxicity of the racemates and the isolated enantiomers towards differentiated SH-SY5Y cells was evaluated. (R,S)-DMPMZ exhibited a significantly higher cytotoxicity than (R,S)-PMZ, suggesting the metabolic bioactivation of (R,S)-PMZ. Conversely, no significant cytotoxicity was found for (R,S)-PMZSO, underscoring a metabolic detoxification pathway. Remarkably, enantioselectivity was observed for the cytotoxicity of PMZ; (R)-PMZ was significantly more cytotoxic than (S)-PMZ. The results underscore the importance to isolate the enantiomers in their enantiomerically form and their correct identification for toxicity enantioselectivity studies, which are vital to understand the drug's behaviour and safety, especially in case of overdoses.
Topics: Promethazine; Stereoisomerism; Humans; Cell Line, Tumor; Circular Dichroism; Cell Survival; Chromatography, High Pressure Liquid
PubMed: 38643704
DOI: 10.1016/j.jpba.2024.116152 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jul 2010
Topics: Contraindications; Humans; Infant; Infant, Newborn; Promethazine
PubMed: 21055102
DOI: No ID Found -
Deutsche Medizinische Wochenschrift... Jul 1976An allergic agranulocytosis developed after promethazine administration to a 34-year-old man with a compulsion neurosis. Promethazine-specific leucocyte antibodies were...
An allergic agranulocytosis developed after promethazine administration to a 34-year-old man with a compulsion neurosis. Promethazine-specific leucocyte antibodies were demonstrated in the antiglobulin consumption test. Four similar cases, reported in the literature, are discussed in relation to this personal case. The findings are contrasted to the majority of cases of toxic "phenothiazine agranulocytosis".
Topics: Adult; Agranulocytosis; Autoantibodies; Drug Hypersensitivity; Humans; Leukocytes; Male; Promethazine
PubMed: 1278057
DOI: 10.1055/s-0028-1104227 -
Acta Microbiologica Hungarica 1993The antibiotic resistance of 6 Staphylococcus aureus strains was eliminated with a frequency from 1.2 to 10% in the presence of subinhibitory concentrations of...
The antibiotic resistance of 6 Staphylococcus aureus strains was eliminated with a frequency from 1.2 to 10% in the presence of subinhibitory concentrations of promethazine. The pigment production of the cells was also eliminated by the promethazine to an extent of 0 to 5%. The cell size was increased and the protein A production was markedly decreased in S. aureus cells cultured in the presence of promethazine. Complex formation between protein A and promethazine was detected by differential spectrophotometry. The biological activity of staphylococcus protein A was abolished by promethazine in the passive haemagglutination of rabbit antiserum treated sheep red blood cells. Evidence has been found that plasmid-encoded functions of S. aureus cells can be altered in the presence of promethazine, and the chromosomally controlled synthesis of protein A, one of the weakest virulence factor of S. aureus is also lowered by promethazine.
Topics: Drug Resistance, Microbial; Hemagglutination; Promethazine; Staphylococcal Protein A; Staphylococcus aureus; Virulence
PubMed: 8184673
DOI: No ID Found -
Biopharmaceutics & Drug Disposition 1986Data from a five-way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Data from a five-way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were administered as a single oral dose. The five objectives of the study were to investigate bioequivalency, to estimate dose proportionality at two dose levels, to establish validity of a reference production solution for future bioequivalency studies, to estimate intersubject variation, and to compare bioavailability/tablet dissolution data. Blood samples were collected at given intervals over a 24-hour period and analysed for promethazine using an HPLC technique. Pharmacokinetic parameters were calculated using standard procedures and a two-way analysis of variance (ANOVAR) was used to assess whether the differences were statistically significant. The AUC0----infinity data from the ANOVAR analysis showed that the 50 mg innovator and generic products and the 50 mg solution were not significantly different. However, the innovator product had a significantly lower Cmax and longer tmax than the solution. The generic product did not differ significantly from the solution. Promethazine was found to exhibit linear dose proportionality in the range and product studied. Intersubject variation was high for all parameters (23 to 63 per cent) and the in vivo and in vitro data showed a positive relationship.
Topics: Adolescent; Adult; Humans; Kinetics; Male; Promethazine; Tablets; Therapeutic Equivalency
PubMed: 3730528
DOI: 10.1002/bdd.2510070309 -
Stroke 1982The metabolic effects of intraperitoneal administration of promethazine on normoxic, hypoxemic and hypoxemic-oligemic rat brain were assessed by measurement of the...
The metabolic effects of intraperitoneal administration of promethazine on normoxic, hypoxemic and hypoxemic-oligemic rat brain were assessed by measurement of the cerebral contents of energy phosphates, and selected glycolytic-citric acid cycle intermediates. In normoxic brain promethazine (25-100 mg/kg-1) was associated with unaltered adenylates, increased glucose and aspartate and decreased pyruvate, lactate and malate; a pattern which was compatible with cerebral metabolic depression. Hypoxemic animals receiving either saline or promethazine (25 mg/kg-1) showed equivalent decreases in ATP and increases in lactate which indicated that promethazine had no significant effect on the metabolism of the acutely hypoxic brain. In animals exposed to hypoxemia plus right carotid artery occlusion (oligemia) the promethazine treated group (25 mg/kg-1) showed significantly lower ATP and higher AMP contents which suggested an adverse effect on the metabolism of the acutely hypoxic-oligemic brain. It is concluded that promethazine does not beneficially alter the energy metabolism of the acutely hypoxic or hypoxic-oligemic brain.
Topics: Adenine Nucleotides; Animals; Brain; Cell Membrane; Energy Metabolism; Hypoxia, Brain; Male; Models, Biological; Oxygen Consumption; Promethazine; Rats; Rats, Inbred Strains
PubMed: 7101346
DOI: 10.1161/01.str.13.4.464 -
American Journal of Health-system... Sep 1999
Topics: Chromatography, High Pressure Liquid; Dihydroergotamine; Drug Combinations; Drug Incompatibility; Drug Stability; Promethazine
PubMed: 10511233
DOI: 10.1093/ajhp/56.18.1835 -
Canadian Medical Association Journal Dec 1959
Topics: Disease; Ephedrine; Humans; Hypersensitivity; Immune System Diseases; Promethazine; Respiration Disorders; Respiratory Hypersensitivity; Respiratory System; Respiratory Tract Diseases
PubMed: 13795911
DOI: No ID Found -
American Journal of Hospital Pharmacy Jun 1988
Topics: Chemistry, Pharmaceutical; Drug Incompatibility; Morphinans; Nalbuphine; Promethazine
PubMed: 3414694
DOI: No ID Found -
Free Radical Biology & Medicine 1996Promethazine sulfoxide was obtained with a quantitative yield in a horse radish peroxidase-catalyzed reaction of promethazine and hydrogen peroxide and was also prepared...
Promethazine sulfoxide was obtained with a quantitative yield in a horse radish peroxidase-catalyzed reaction of promethazine and hydrogen peroxide and was also prepared by direct chemical synthesis. The enzymatic sulfoxidation of promethazine was studied in vitro as a function of pH, promethazine, and hydrogen peroxide concentration. Promethazine sulfoxide inhibits with an apparent K(i) of 59.7 microM at pH 5.5 the enzymatic reaction, followed spectrophotometrically, polarographically, potentiometrically, and luminometrically. The reaction was also inhibited by ascorbic acid (K(i) 26.8 microM) and glutathione (K(i) 41.8 microM). The spectrophotometric techniques employed, together with ESR spectrometry, allowed the identification of at least three radical species formed in the course of the reaction. Promethazine sulfoxide is devoid of the antioxidant effect exhibited by promethazine on rat brain synaptosomes. The sulfoxide also lacks photosensitizing action, while retaining the neuroleptic effect of the parent compound.
Topics: Animals; Antioxidants; Ascorbic Acid; Barbiturates; Brain; Electron Spin Resonance Spectroscopy; Free Radicals; Horseradish Peroxidase; Hydrogen Peroxide; Kinetics; Lipid Peroxidation; Luminescent Measurements; Male; Oxygen Consumption; Phenothiazines; Promethazine; Rats; Rats, Wistar; Sleep; Synaptosomes
PubMed: 8728028
DOI: 10.1016/0891-5849(95)02213-9