The role of phenothiazine derivatives in autophagy regulation: A systematic review.

In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Comparison of chloroquine-like molecules for lysosomal inhibition and measurement of autophagic flux in the brain.

Measurement of autophagic flux in vivo is critical to understand how autophagy can be used to combat disease. Neurodegenerative diseases have a special relationship with autophagy, which makes measurement of autophagy in the brain a significant research priority. Currently, measurement of autophagic flux is possible through use of transgenic constructs, or application of a lysosomal inhibitor such as chloroquine. Unfortunately, chloroquine is not useful for measuring autophagic flux in the brain and the use of transgenic animals necessitates cross-breeding of transgenic strains and maintenance of lines, which is costly. To find a drug that could block lysosomal function in the brain for the measurement of autophagic flux, we selected compounds from the literature that appeared to have similar properties to chloroquine and tested their ability to inhibit autophagic flux in cell culture and in mice. These chemicals included chloroquine, quinacrine, mefloquine, promazine and trifluoperazine. As expected, chloroquine blocked lysosomal degradation of the autophagic protein LC3B-II in cell culture. Quinacrine also inhibited autophagic flux in cell culture. Other compounds tested were not effective. When injected into mice, chloroquine caused accumulation of LC3B-II in heart tissue, and quinacrine was effective at blocking LC3B-II degradation in male, but not female skeletal muscle. None of the compounds tested were useful for measuring autophagic flux in the brain. During this study we also noted that the vehicle DMSO powerfully up-regulated LC3B-II abundance in tissues. This study shows that chloroquine and quinacrine can both be used to measure autophagic flux in cells, and in some peripheral tissues. However, measurement of flux in the brain using lysosomal inhibitors remains an unresolved research challenge.

Evaluation of medicine effects on the interaction of myoglobin and its aptamer or antibody using atomic force microscopy.

The effects of medicine on the biomolecular interaction have been given increasing attention in biochemistry and affinity-based analytics since the environment in vivo is complex especially for the patients. Herein, myoglobin, a biomarker of acute myocardial infarction, was used as a model, and the medicine effects on the interactions of myoglobin/aptamer and myoglobin/antibody were systematically investigated using atomic force microscopy (AFM) for the first time. The results showed that the average binding force and the binding probability of myoglobin/aptamer almost remained unchanged after myoglobin-modified gold substrate was incubated with promazine, amoxicillin, aspirin, and sodium penicillin, respectively. These parameters were changed for myoglobin/antibody after the myoglobin-modified gold substrate was treated with these medicines. For promazine and amoxicillin, they resulted in the change of binding force distribution of myoglobin/antibody (i.e., from unimodal distribution to bimodal distribution) and the increase of binding probability; for aspirin, it only resulted in the change of the binding force distribution, and for sodium penicillin, it resulted in the increase of the average binding force and the binding probability. These results may be attributed to the different interaction modes and binding sites between myoglobin/aptamer and myoglobin/antibody, the different structures between aptamer and antibody, and the effects of medicines on the conformations of myoglobin. These findings could enrich our understanding of medicine effects on the interactions of aptamer and antibody to their target proteins. Moreover, this work will lay a good foundation for better research and extensive applications of biomolecular interaction, especially in the design of biosensors in complex systems.

Are hERG channel blockers also phospholipidosis inducers?

Both pharmacophore models of the human ether-à-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/positively charged center, so it is interesting to investigate the overlap between the ligand chemical spaces of both targets. We have assayed over 4000 non-redundant drug-like compounds for both their hERG inhibitory activity and PLD inducing potential in a quantitative high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compounds identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compounds were positively charged. Among the 48 compounds that induced PLD without inhibiting hERG channel, 24 compounds (50.0%) carried steroidal structures. According to our results, hERG channel blockers and PLD inducers share a large chemical space. In addition, a positively charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.

A novel MWCNT-encapsulated (2-aminoethyl)piperazine-decorated zinc(II) phthalocyanine composite: development of an electrochemical sensor for detecting the antipsychotic drug promazine in environmental samples.

A nanocomposite of (2-aminoethyl)piperazine ligand substituted with zinc(II) tetra carboxylic acid phthalocyanine (ZnTEPZCAPC) and MWCNTs was constructed and employed to develop an electrochemical sensor with outstanding sensitivity and a low detection limit. The macrocyclic complex ZnTEPZCAPC was first synthesized and then employed for the electrochemical determination of the antipsychotic drug promazine (PMZ). The as-prepared ZnTEPZCAPC and MWCNT nanocomposite was characterized using different techniques, such as Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), UV-visible spectroscopy (UV-Vis), field emission scanning electron microscopy (FE-SEM), and thermogravimetric analysis (TGA). Further, the prepared ZnTEPZCAPC@MWCNT nanocomposites were modified on a glassy carbon electrode (GCE) surface, and the electrochemical activity was investigated using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and chronoamperometry (CA) tests in pH 7.0 phosphate buffer solution (PBS) in the potential window of 0.0-1 V. The ZnTEPZCAPC@MWCNTs displayed a superior electrochemical performance because of their high electrochemical active surface area (0.453 cm2), good conductivity, and a synergetic effect. The developed electrochemical sensor exhibited a broad linear range of 0.05-635 µM and the lowest detection limit of 0.0125 nM, as well as excellent sensitivity, repeatability, and reproducibility. Finally, the fabricated sensor was successively used for the real-time detection of PMZ in environmental and biological samples and displayed feasible recoveries.

Competitive adsorptive removal of promazine and promethazine from wastewater using olive tree pruning biochar: operational parameters, kinetics, and equilibrium investigations.

This research aims to remove two phenothiazines, promazine (PRO) and promethazine (PMT), from their individual and binary mixtures using olive tree pruning biochar (BC-OTPR). The impact of individual and combinatory effects of operational variables was evaluated for the first time using central composite design (CCD). Simultaneous removal of both drugs was maximized utilizing the composite desirability function. At low concentrations, the uptake of PRO and PMT from their individual solutions was achieved with high efficiency of 98.64%, 47.20 mg/g and 95.87%, 38.16 mg/g, respectively. No major differences in the removal capacity were observed for the binary mixtures. Characterization of BC-OTPR confirmed successful adsorption and showed that the OTPR surface was predominantly mesoporous. Equilibrium investigations revealed that the Langmuir isotherm model best describes the sorption of PRO/PMT from their individual solutions with maximum adsorption capacities of 640.7 and 346.95 mg/g, respectively. The sorption of PRO/PMT conforms to the pseudo-second-order kinetic model. Regeneration of the adsorbent surface was successfully done with desorption efficiencies of 94.06% and 98.54% for PRO and PMT, respectively, for six cycles.

Use of potentiometric sensors to study (bio)molecular interactions.

Potentiometric sensors were used to study molecular interactions in liquid environments with sensorgram methodology. This is demonstrated with a lipophilic rubber-based and a collagen-based hydrogel sensor coating. The investigated molecules were promazine and tartaric acid, respectively. The sensors were placed in a hydrodynamic wall-jet system for the recording of sensorgrams. Millivolt sensor responses were first converted to a signal, expressing the concentration of adsorbed organic ions. Using a linearization method, a pseudo-first order-kinetic model of adsorption was shown to fit the experimental results perfectly. K(assoc), k(on), and k(off) values were calculated. The technique can be used over 4 decades of concentration, and it is very sensitive to low-MW compounds as well as to multiply charged large biomolecules. This study is the first to demonstrate the application of potentiometric sensors as an alternative and complement to surface plasmon resonance methods.

Antiviral activity and synthesis of quaternized promazine derivatives against HSV-1.

N-(4-chlorobenzyl)triflupromazinium chloride, a known antitubercular agent, has been found to also be active against HSV-1. A preliminary structure-activity relation has been explored to determine which groups are crucial to viral inhibition. Antiviral assessments such as GFP reduction, plaque reduction, treatment timing and wash-out studies have also been probed to determine a mode of action for QPD-1. Based on this preliminary data, it appears that QPD-1 is a reversible inhibitor, suspected to inhibit early stages of viral replication of HSV-1 at 50 µM, equipotent to acyclovir.

Promazine Detection in Human Hair: Presentation of an LC-MS-MS Method and Pattern of Drug Discontinuation.

Promazine is one of the oldest phenothiazine derivatives that have been proposed for the treatment of various psychiatric disorders. The drug is available as tablets, as syrups and in injectable forms. Despite its prescription to millions of subjects, its detection in human hair has seldom been reported. The aim of the present work is to develop a specific method to identify promazine in human hair by liquid chromatography-tandem mass spectrometry and to apply it to a patient who was self-medicating. The method involves overnight incubation of 20 mg of cut hair in 1 mL of pH 9.5 borate buffer in the presence of amitriptyline-d3 at 40°C. The chromatographic separation was performed using a reverse phase column HSS C18 with a gradient elution for 15 min. Linearity was verified from 0.5 to 500 pg/mg (r2 = 0.9996), after spiking blank hair with the corresponding amounts of promazine. The limit of detection was estimated at 0.1 pg/mg. The precision was lower than 20%. Promazine was detected in the hair of a psychotic subject at 228-270 pg/mg in a 3 × 1 cm segment. Given this was a patient who was self-medicating, her physician requested an immediate drug discontinuation. In a fresh hair specimen collected 3 months later, the proximal segment (0-1 cm) tested positive at 0.9 pg/mg, clearly indicating that the time to obtain a negative result after promazine discontinuation is about 3-4 months.

Exanthema medicamentosum as a side effect of promazine.

Dermatological side effects of psychopharmacological drugs are fortunately not so often. They are mostly presented in the group of mood stabilizers and antiepileptic drugs, particularly the carbamazepine and lamotrigine, and can be manifested through the Stevens Johnson syndrome, Toxic Epidermal Necrolysis (TEN)/Lyell's syndrome with about 30% lethality. According to the literature the group of phenothiazines is the category of drugs with rare appearances of skin reactions. Promazine, aliphatic phenothiazines antipsychotic, including less frequent side effects in the leaflet states increased skin sensitivity to sun, skin rash-associated with contact dermatitis, allergic reactions, cholestatic icterus. The only reported dermatological side effect of promazine is its metabolites deposition in the cornea. Analyzing the e-data basis we have not found references connecting the Exanthema medicamentosum as a side effect of promazine. A forty-two years old female patient was admitted to the Dermatological Clinic because of suspected exanthema, undoubtedly caused by promazine as a medication for Sy. Borderline.

Promazine in the treatment of delusional parasitosis.

Delusional parasitosis (DP) is an uncommon and complex to treat form of delusional disorder, somatic type. The syndrome may occur in association with a number of psychotic disorders, such as schizophrenia, organic mental disorder, or even in dementia with behavioral and psychological symptoms. Evidence of efficacy of treatment options is weak and there is little known about the specific use of typical and atypical antipsychotics. We report on a case of primary DP in a 75-year-old Caucasian woman with a 3-year-long history of dermatological consultations due to unspecified complains who responded to the typical antipsychotic promazine. This case is unique in pharmacological respect as it presents the first reported DP treatment with promazine. It also raises the issue of efficacy and safety of low-potency typical antipsychotics in the elderly population.

DFT computational study towards investigating psychotropic drugs, promazine and trifluoperazine adsorption on graphene, fullerene and carbon cyclic ring nanoclusters.

Detection and qualification process related to impurities assume importance in pharmacological drug development programmes and the present article gives the structural and spectral characterisation of phenothiazine derivatives, promazine (PME) and trifluoperazine (TPE) and their self-assembly with graphene/fullerene/carbon ring (CG/CF/CR) systems theoretically. The investigation of adsorption behaviour of these compounds can provide valuable information about its reactivity, electronic and structural properties. Three-dimensional electrostatic potential diagrams were mapped. The frontier orbital energies and energy band gaps of the molecules were computed. Delocalization of charge density between the bonding or lone pair and antibonding orbitals is calculated by NBO analysis. Docking was executed to investigate binding areas of chemical compounds. Bioactivity scores show that the pharmacokinetic and pharmacological properties of the ligands are appropriate leading to be considered potential drug agents. The obtained theoretical wavenumber results of the present study were fully compatible with the experimental results.

Influence of phenothiazine molecules on the interactions between positively charged poly-l-lysine and negatively charged DPPC/DPPG membranes.

Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular mechanism of the biological actions of these molecules is not yet understood in detail. The role of the interactions between phenothiazines and proteins or lipid membranes has been much discussed. Herein, fourier-transform infrared (FTIR) spectroscopic studies were used to investigate the effect of three phenothiazines: fluphenazine (FPh); chlorpromazine (ChP); and propionylpromazine (PP) on the structures of a positively charged poly-l-lysine (PLL) peptide, a negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membrane, and on the mutual interactions between electrostatically associated PLL molecules and DPPC/DPPG membranes. Phenothiazine-induced alterations in the secondary structure of PLL, the conformational state (trans/gauche) of the hydrocarbon lipid chains, and the hydration of the DPPC/DPPG membrane interface were studied on the basis of amide I' vibrations, antisymmetric and symmetric stretching vibrations of the CH2 groups of the lipid hydrocarbon chains (νsCH2), and stretching vibrations of the lipid C=O groups (νC = O), respectively. It was shown that in the presence of negatively charged DPPC/DPPG membranes, the phenothiazines were able to modify the secondary structure of charged PLL molecules. Additionally, the effect of PLL on the structure of DPPC/DPPG membranes was also altered by the presence of the phenothiazine molecules.

Chemiluminescence determination of promazine in human serum and drug formulations using Ru(phen)3(2+)-Ce(IV) system and a chemometrical optimization approach.

A new chemiluminescence (CL) method using flow injection has been described for the rapid and sensitive determination of promazine hydrochloride (PMH). The method is based on the CL reaction of PMH with tris(1,10 phenanthroline)ruthenium(II), [Ru(phen)3(2+)] and Ce(IV) in sulfuric acid medium. Effects of chemical variables were investigated employing central composite design and response surface methodology. Under the optimum conditions, the CL intensity was proportional to the concentration of the drug in solution over the ranges 0.020-0.32 and 0.32-32 microg/mL. The limit of detection (signal-to-noise ratio = 3) was 0.012 microg/mL. The method was applied successfully to the determination of PMH in drug formulations and human serum (recovery percentages between 96.7 and 105.0%). The relative standard deviation for 11 replicate determinations of 1.5 microg/mL of PMH was 1.7%. The minimum sampling rate was 100 samples per hour.

Acute intoxication by triazolam and promazine: a case report.

A fatality due to ingestion of triazolam and promazine is reported. Triazolam is a benzodiazepine widely prescribed as a hypnotic drug for the treatment of sleep disorders. Promazine is a neuroleptic drug. There is no previous evidence in the literature of death due to an overdose related to the contemporaneous intake of these two drugs. In this report the authors present the case of a 76-year-old woman who was found deceased at home with no evidence of trauma or asphyxia; near the body several empty pharmaceutical boxes containing triazolam and promazine were noticed. Toxicological analyses were performed and drug levels measured by means of gas chromatography coupled with mass spectrometry. The triazolam concentration in each specimen was as follows: blood 1100ng/ml; gastric content 1300ng/ml; the promazine concentration in blood and in gastric content was 3450ng/ml and 5800ng/ ml respectively. Based on the autopsy findings, patient history and toxicological results, the cause of death was determined to be acute intoxication due to the effect of triazolam and promazine and the manner of suicide.

Validation of derivative spectrophotometry method for determination of active ingredients from neuroleptics in pharmaceutical preparations.

First (DI) and second (D2) order derivative spectrophotometric method with an application of base line to peak technique was used for determination of active pharmaceutical ingredients (API) at two wavelengths: fluphenazine (D1 at lambda = 251 nm and lambda = 265 nm, D2 at lambda = 246 nm and lambda = 269 nm), pernazine (D1 at lambda = 246 nm and lambda = 258 nm, D2 at lambda = 254 nm and lambda = 262 nm), haloperidol (DI at = 235 nm and lambda = 253 nm, D2 at lambda = 230 nm and lambda = 246 nm), and promazine (D1 at lambda = 246 nm and lambda = 251 nm, D2 at lambda = 255 nm and lambda = 262 nm). Linear dependence of derivative values on analyte concentration is maintained in a range 3.12 microg x mL(-1) - 44.80 microg x mL(-1). Detection and determination limits are in the range 0.51 - 3.23 microg x mL(-1) and 1.27 microg x mL(-1) - 9.80 microg x mL(-1), respectively. Determination results of drug constituents are very accurate. Recovery percentage is in a range 95.50% - 103.60%.

[Drug-induced agranulocytosis--case reports and literature review]. / Agranulocytozy polekowe--opis przypadków i przeglad pismiennictwa.

Drug-induced agranulocytosis is believed to be an extremely rare adverse drug reaction. It can be caused by various drugs, but it is mostly described in patients taking antithyroid drugs, antipsychotics and antibiotics. Four cases of patients treated for drug-induced agranulocytosis from January 2006 to March 2007 were described. In two cases agranulocytosis appeared in the course of therapy with methimazole. In one patient agranulocytosis was caused by perazine and by promazine or olanzapine in the last one. In all of the cases the leading symptom was fever, three of our patients had changes of mouth mucosa. All patients were treated with betalactam antibiotics. Granulocyte colony-stimulating factor (G-CSF) was not used in anyone. The recovery of white blood cell count and granulocyte count in all of the patients was detected in the first ten days of hospitalization.