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Toxicological Sciences : An Official... Apr 2017Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia,...
Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation of many pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses, microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins.
Topics: Antidepressive Agents; Antipsychotic Agents; Chlorpromazine; Gene Ontology; Gene Regulatory Networks; Genome-Wide Association Study; Microbial Sensitivity Tests; Protein Interaction Maps; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Toxicogenetics
PubMed: 28087837
DOI: 10.1093/toxsci/kfx007 -
Journal of the American Animal Hospital... 2016Emerging evidence from veterinary and medical clinical research shows that reducing preoperative fasting time may reduce the incidence of gastro-esophageal reflux (GER)... (Randomized Controlled Trial)
Randomized Controlled Trial
Emerging evidence from veterinary and medical clinical research shows that reducing preoperative fasting time may reduce the incidence of gastro-esophageal reflux (GER) intraoperatively. In order to evaluate the effect of two different preoperative fasting times on the incidence of GER during general anesthesia, 120 dogs were randomly assigned to two groups: administration of canned food 3 h before premedication (group C3, n = 60) and administration of canned food 10 h before premedication (group C10, n = 60). The animals were premedicated with propionyl-promazine. Anesthesia was induced with thiopental sodium and maintained with halothane. A pH electrode was introduced into the esophagus, and the esophageal pH was constantly monitored. Esophageal pH of less than 4 or greater than 7.5 was taken as an indication of GER. Three of the 60 dogs of group C3 and 12 of the 60 dogs of group C10 experienced a GER episode, the difference being statistically significant (P = .025). Feeding the dog 3 h before anesthesia at a half daily rate reduces significantly the incidence of GER during anesthesia, compared to the administration of the same amount and type of food 10 h before anesthesia. The administration of a half daily dose of an ordinary canine diet may be useful in clinical practice.
Topics: Anesthesia; Animal Feed; Animals; Dog Diseases; Dogs; Female; Gastroesophageal Reflux; Male; Meals; Preoperative Period; Time Factors
PubMed: 27685364
DOI: 10.5326/JAAHA-MS-6399 -
Chemosphere Nov 2016Toxic effects of the non-biodegradable drug chlorpromazine and its degradation products have been reported on microorganisms in aqueous media. Here, chlorpromazine...
Toxic effects of the non-biodegradable drug chlorpromazine and its degradation products have been reported on microorganisms in aqueous media. Here, chlorpromazine degradation assays in forced and non-forced conditions have been done to know its persistence and degradation products in river water. Sunlight irradiation promotes the complete degradation of chlorpromazine (2 μg L(-1)) in less than 4 h, but if the exposure to sunlight is limited chlorpromazine is detected during 4 weeks in river water. Sixteen degradation products in surface water are described for first time after solid-phase extraction and analysis by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry; their structures are proposed from the molecular formulae of the fragment-ions observed in high-resolution tandem mass spectra. Hydroxylation and oxidation products such as chlorpromazine sulfoxide, 2-hydroxypromazine and 2-hydroxypromazine sulfoxide were predominant degradation products in the early stages; some benzo[1,4]thiazin-6-ol derivatives resulting from the breakdown of the phenothiazine core were the major and relatively stable products after 20 weeks under non-forced conditions. A degradation pathway of chlorpromazine in water is outlined. Moreover, it is shown that chlorpromazine is very strongly adsorbed on sediment while the degradation products that kept the promazine core have a notable capacity of sorption, too; sorption coefficients are calculated. Finally, a prediction about the toxicity of the degradation products in aquatic ecosystems suggests that some of them have toxicities similar, or even higher, than chlorpromazine.
Topics: Absorption, Physicochemical; Biodegradation, Environmental; Biological Assay; Chlorpromazine; Chromatography, Liquid; Geologic Sediments; Rivers; Solid Phase Extraction; Tandem Mass Spectrometry; Water Pollutants, Chemical
PubMed: 27513549
DOI: 10.1016/j.chemosphere.2016.07.107 -
European Journal of Pharmaceutical... Oct 2016The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride,...
The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37°C. The pKa values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37°C and methanol/water at 25°C). The log S-pH profiles were measured at 24h incubation time in 0.15M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pKa values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S0) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25°C were 0.5, 1.1, and 2.7μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152kJ·mol(-1)). Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25°C. The effects persisted at 37°C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.
Topics: Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Micelles; Phenothiazines; Solubility; Spectrophotometry, Ultraviolet; Temperature
PubMed: 27449396
DOI: 10.1016/j.ejps.2016.07.013 -
European Journal of Pharmaceutics and... Aug 2016Tricyclic antidepressants (TCAs) are found to have an analgesic action for relieving cutaneous pain associated with neuropathies. The aim of this study was to assess...
Tricyclic antidepressants (TCAs) are found to have an analgesic action for relieving cutaneous pain associated with neuropathies. The aim of this study was to assess cutaneous absorption and analgesia of topically applied TCAs. Percutaneous delivery was investigated using nude mouse and pig skin models at both infinite and saturated doses. We evaluated the cutaneous analgesia in nude mice using the pinprick scores. Among five antidepressants tested in the in vitro experiment, mesoridazine, promazine and doxepin showed a superior total absorption percentage. The drug with the lowest total absorption percentage was found to be fluphenazine (<7%) either at an infinite dose or at saturated solubility. The follicular pathway was important for mesoridazine and promazine delivery. Mesoridazine showed stronger skin analgesia than the other TCAs although the in vivo skin absorption of mesoridazine (0.34nmol/mg) was less than that of promazine (0.80nmol/mg) and doxepin (0.74nmol/mg). Mesoridazine had a prolonged duration of pain relief (165min) compared to promazine (83min) and doxepin (17min). The skin irritation test demonstrated an evident barrier function deterioration and cutaneous erythema by promazine and doxepin treatment, whereas mesoridazine caused no obvious adverse effect by topical application for up to 7days.
Topics: Administration, Topical; Analgesia; Animals; Antidepressive Agents, Tricyclic; Female; Mesoridazine; Mice; Mice, Nude; Skin Absorption
PubMed: 27260201
DOI: 10.1016/j.ejpb.2016.05.025 -
Addictive Behaviors Sep 2016A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with...
A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with psychosis, agitation, and insomnia at the emergency department of a university hospital. She had been abusive and physically aggressive frequently without specific reasons and was involved in criminal legal cases. She was hospitalized twice. During her first hospital stay she experienced a brief episode of detachment from her environment, similar to episodes reportedly suffered at home. Psychosis had developed following heavy polysubstance abuse. Her mother provided sachets containing benzylglycinamide, a substance with no known psychotropic effects, which were also present in the patient's urine. She was occasionally positive for cannabinoids. She used to buy various novel psychoactive substances (NPSs) from the internet and used experimentally various substances freely made available to her by drug suppliers/dealers. She was unable to explain clearly why she was taking any of the identified NPS. She stated she was taking benzylglycinamide to calm her when smoking synthetic cannabinoids. While it appears that benzylglycinamide is not likely to constitute a novel drug of abuse, her polysubstance use exemplifies trends in NPS use patterns among the youths in the Western world and should alert mental health workers as to the possible dangers of such behavior and its reflection on social behavior and psychopathology.
Topics: Adult; Anti-Anxiety Agents; Anti-Retroviral Agents; Antipsychotic Agents; Female; Glycine; HIV Infections; Humans; Illicit Drugs; Italy; Lorazepam; Paliperidone Palmitate; Promazine; Psychoses, Substance-Induced; Substance-Related Disorders; Young Adult
PubMed: 27088514
DOI: 10.1016/j.addbeh.2016.03.032 -
Journal of Chromatography. A May 2016The mixed-mode (C18/strong cation exchange-SCX) solid-phase microextraction (SPME) fiber has recently been shown to have increased sensitivity for ionic compounds...
The mixed-mode (C18/strong cation exchange-SCX) solid-phase microextraction (SPME) fiber has recently been shown to have increased sensitivity for ionic compounds compared to more conventional sampler coatings such as polyacrylate and polydimethylsiloxane (PDMS). However, data for structurally diverse compounds to this (prototype) sampler coating are too limited to define its structural limitations. We determined C18/SCX fiber partitioning coefficients of nineteen cationic structures without hydrogen bonding capacity besides the charged group, stretching over a wide hydrophobicity range (including amphetamine, amitriptyline, promazine, chlorpromazine, triflupromazine, difenzoquat), and eight basic pharmaceutical and illicit drugs (pKa>8.86) with additional hydrogen bonding moieties (MDMA, atenolol, alprenolol, metoprolol, morphine, nicotine, tramadol, verapamil). In addition, sorption data for three neutral benzodiazepines (diazepam, temazepam, and oxazepam) and the anionic NSAID diclofenac were collected to determine the efficiency to sample non-basic drugs. All tested compounds showed nonlinear isotherms above 1mmol/L coating, and linear isotherms below 1mmol/L. The affinity for C18/SCX-SPME for tested organic cations without Hbond capacities increased with longer alkyl chains, ranging from logarithmic fiber-water distribution coefficients (log Dfw) of 1.8 (benzylamine) to 5.8 (triflupromazine). Amines smaller than benzylamine may thus have limited detection levels, while cationic surfactants with alkyl chain lengths >12 carbon atoms may sorb too strong to the C18/SCX sampler which hampers calibration of the fiber-water relationship in the linear range. The log Dfw for these simple cation structures closely correlates with the octanol-water partition coefficient of the neutral form (Kow,N), and decreases with increased branching and presence of multiple aromatic rings. Oxygen moieties in organic cations decreased the affinity for C18/SCX-SPME. Log Dfw values of neutral benzodiazepines were an order of magnitude higher than their log Kow,N. Results for anionic diclofenac species (logKow,N 4.5, pKa 4.0, log Dfw 2.9) indicate that the C18-SCX fiber might also be useful for sampling of organic anions. This data supports our theory that C18-based coatings are able to sorb ionized compounds through adsorption and demonstrates the applicability of C18-based SPME in the measurement of freely dissolved concentrations of a wide range of ionizable compounds.
Topics: Adsorption; Alkanesulfonic Acids; Anions; Cations; Hydrophobic and Hydrophilic Interactions; Illicit Drugs; Ion Exchange Resins; Pharmaceutical Preparations; Silanes; Solid Phase Microextraction; Water
PubMed: 27083257
DOI: 10.1016/j.chroma.2016.04.017 -
European Journal of Pharmaceutical... Feb 2016The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for...
The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for simulation of phase I metabolism of drugs was studied by comparing the reaction products of buspirone, promazine, testosterone and 7-ethoxycoumarin with phase I metabolites of the same compounds produced in vitro by human liver microsomes (HLM). Reaction products were analysed by UHPLC-MS. TiO2 photocatalysis simulated the in vitro phase I metabolism in HLM more comprehensively than did EC-Fenton or EC. Even though TiO2 photocatalysis, EC-Fenton and EC do not allow comprehensive prediction of phase I metabolism, all three methods produce several important metabolites without the need for demanding purification steps to remove the biological matrix. Importantly, TiO2 photocatalysis produces aliphatic and aromatic hydroxylation products where direct EC fails. Furthermore, TiO2 photocatalysis is an extremely rapid, simple and inexpensive way to generate oxidation products in a clean matrix and the reaction can be simply initiated and quenched by switching the UV lamp on/off.
Topics: Buspirone; Catalysis; Coumarins; Dealkylation; Electrochemistry; Humans; Hydrogenation; Hydroxylation; Iron; Microsomes, Liver; Oxidation-Reduction; Promazine; Testosterone; Titanium; Ultraviolet Rays
PubMed: 26690045
DOI: 10.1016/j.ejps.2015.12.012 -
Analytical Sciences : the International... 2015Novel, sensitive and rapid electrochemical methods for the determination of phenothiazine and azaphenothiazine derivatives were developed. A boron-doped diamond (BDD)...
Novel, sensitive and rapid electrochemical methods for the determination of phenothiazine and azaphenothiazine derivatives were developed. A boron-doped diamond (BDD) electrode was used for electrochemical oxidation of levomepromazine, promazine and prothipendyl. The electrooxidation of these substances demonstrated reversible peaks of oxidation at the potential range 0.55 - 0.75 V vs. SCE. Examining the influence of scan rate allowed is to demonstrate that the currents registered typical of the diffusion-controlled process. Determinations of the studied analytes were carried out by means of a square wave voltammetry (SWV) method and a differential pulse voltammetry (DPV) method. Linear ranges of determination with the use of the BDD electrode and the SWV method were obtained in the ranges: from 4 × 10(-7) to 1.38 × 10(-4) mol L(-1) for levomepromazine, from 4 × 10(-7) to 1.17 × 10(-5) mol L(-1) for promazine and from 4.95 × 10(-7) to 4.54 × 10(-5) mol L(-1) for prothipendyl. The influence of interferences on the voltammetric signal of the studied analytes was also checked. The proposed procedures were used for quantitative determination of the studied compounds in pharmaceutical preparations. The measurements showed high accuracy. The recovery values obtained ranged from 98.52 to 99.57%. The developed procedures were compared with pharmacopoeial reference methods.
Topics: Boron; Diamond; Electrochemistry; Electrodes; Hydrogen-Ion Concentration; Limit of Detection; Pharmaceutical Preparations; Phenothiazines; Reproducibility of Results; Time Factors
PubMed: 26460359
DOI: 10.2116/analsci.31.961 -
European Journal of Pharmaceutical... Jan 2016Multiple drug resistance requires a flexible approach to find medicines able to overcome it. One method could be the exposure of existing medicines to ultraviolet laser...
Multiple drug resistance requires a flexible approach to find medicines able to overcome it. One method could be the exposure of existing medicines to ultraviolet laser beams to generate photoproducts that are efficient against bacteria and/or malignant tumors. This can be done in droplets or bulk volumes. In the present work are reported results about the interaction of 266nm and 355nm pulsed laser radiation with microdroplets and bulk containing solutions of 10mg/ml Chlorpromazine Hydrochloride (CPZ) in ultrapure water. The irradiation effects on CPZ solution at larger time intervals (more than 30min) are similar in terms of generated photoproducts if the two ultraviolet wavelengths are utilized. The understanding of the CPZ parent compound transformation may be better evidenced, as shown in this paper, if studies at shorter than 30minute exposure times are made coupled with properly chosen volumes to irradiate. We show that at exposure to a 355nm laser beam faster molecular modifications of CPZ in ultrapure water solution are produced than at irradiation with 266nm, for both microdroplet and bulk volume samples. These effects are evidenced by thin layer chromatography technique and laser induced fluorescence measurements.
Topics: Antipsychotic Agents; Chlorpromazine; Chromatography, Thin Layer; Fluorescence; Lasers; Ultraviolet Rays
PubMed: 26432595
DOI: 10.1016/j.ejps.2015.09.017