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Pharmaceutics Jan 2022A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The...
A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.
PubMed: 35213988
DOI: 10.3390/pharmaceutics14020255 -
Contact Dermatitis Jun 2022
Topics: Dermatitis, Allergic Contact; Dermatitis, Photoallergic; Humans; Patch Tests; Promazine; Ultraviolet Rays
PubMed: 35195295
DOI: 10.1111/cod.14086 -
Addiction (Abingdon, England) Oct 2022There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of pharmacotherapies for AW.
METHODS
Six databases were searched for randomized clinical trials through November 2021. Trials were included after a blinded review by two independent reviewers. Outcomes included incident seizures, delirium tremens, AW severity scores, adverse events, dropouts, dropouts from adverse events, length of hospital stay, use of additional medications, total benzodiazepine requirements, and death. Effect sizes were pooled using frequentist random-effects network meta-analysis models to generate summary ORs and Cohen's d standardized mean differences (SMDs).
RESULTS
Across the 149 trials, there were 10 692 participants (76% male, median 43.5 years old). AW severity spanned mild (n = 32), moderate (n = 51), and severe (n = 66). Fixed-schedule chlormethiazole (OR, 0.16; 95% CI, 0.04-0.65), fixed-schedule diazepam (OR, 0.16; 95% CI, 0.04-0.59), fixed-schedule lorazepam (OR = 0.19; 95% CI, 0.08-0.45), fixed-schedule chlordiazepoxide (OR = 0.21; 95% CI, 0.08-0.53), and divalproex (OR = 0.22; 95% CI, 0.05-0.86) were superior to placebo at reducing incident AW seizures. However, only fixed-schedule diazepam (OR, 0.19; 95% CI, 0.05-0.76) reduced incident delirium tremens. Oxcarbazepine (d = -3.69; 95% CI, -6.21 to -1.17), carbamazepine (d = -2.76; 95% CI, -4.13 to -1.40), fixed-schedule oxazepam (d = -2.55; 95% CI, -4.26 to -0.83), and γ-hydroxybutyrate (d = -1.80; 95% CI, -3.35 to -0.26) improved endpoint Clinical Institute Withdrawal Assessment for Alcohol-Revised scores over placebo. Promazine and carbamazepine were the only agents significantly associated with greater dropouts because of adverse events. The quality of evidence was downgraded because of the substantial risk of bias, heterogeneity, inconsistency, and imprecision.
CONCLUSIONS
Although some pharmacotherapeutic modalities, particularly benzodiazepines, appear to be safe and efficacious for reducing some measures of alcohol withdrawal, methodological issues and a high risk of bias prevent a consistent estimate of their comparative performance.
Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Carbamazepine; Diazepam; Female; Humans; Male; Network Meta-Analysis; Seizures; Substance Withdrawal Syndrome
PubMed: 35194860
DOI: 10.1111/add.15853 -
Journal of Analytical Toxicology Aug 2022Promazine 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...
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.
Topics: Chromatography, Liquid; Female; Hair; Humans; Promazine; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 34518883
DOI: 10.1093/jat/bkab101 -
Journal of Biomolecular NMR Jul 2021We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild...
We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central β sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.
Topics: Amino Acid Substitution; Antipsychotic Agents; Humans; Models, Molecular; Mutation, Missense; Nuclear Magnetic Resonance, Biomolecular; Phenothiazines; Protein Binding; Protein Conformation, beta-Strand; Proto-Oncogene Proteins p21(ras)
PubMed: 34176062
DOI: 10.1007/s10858-021-00371-z -
Biochemical and Biophysical Research... Jan 2021Measurement of autophagic flux in vivo is critical to understand how autophagy can be used to combat disease. Neurodegenerative diseases have a special relationship... (Comparative Study)
Comparative Study
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.
Topics: Animals; Autophagy; Brain; Chloroquine; Drug Evaluation, Preclinical; Female; HeLa Cells; Humans; Lysosomes; Macrolides; Male; Mefloquine; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Promazine; Quinacrine; Trifluoperazine; Mice
PubMed: 33316543
DOI: 10.1016/j.bbrc.2020.12.008 -
Nordic Journal of Psychiatry May 2021This study examined the trend and role of antipsychotics as a method of self-poisoning suicide.
AIM
This study examined the trend and role of antipsychotics as a method of self-poisoning suicide.
MATERIALS AND METHODS
The basic data covered 483 poisoning suicides, occurring between the years 1988 and 2011, in Northern Finland, of which 178 (115 men, 63 women) were completed using antipsychotics.
RESULTS
During the 23-year follow-up period, second-generation antipsychotics (SGAs) overtook first-generation antipsychotics (FGAs) as a suicide method. Female victims, compared to males, had more commonly used quetiapine (17.5% vs. 6.1%, = .016), while suicides using promazine were more common in males compared to females (36.5% vs. 22.2%, = .049). People with unipolar depression had more frequently used SGAs (40.0%) or a combination of SGAs and FGAs (12.5%) than FGAs (19.2%) ( = .019) in their suicides.
CONCLUSION
The use of SGAs in suicides is becoming increasingly common, which calls for further studies.
Topics: Antipsychotic Agents; Female; Finland; Follow-Up Studies; Humans; Male; Suicide
PubMed: 33215967
DOI: 10.1080/08039488.2020.1847323 -
Frontiers in Microbiology 2020The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment...
The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well , most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5-2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant ( < 0.0001) activity against a strain compared with the vehicle, in an wound infection model. However, both and analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.
PubMed: 33101232
DOI: 10.3389/fmicb.2020.560798 -
Spectrochimica Acta. Part A, Molecular... Feb 2021Detection and qualification process related to impurities assume importance in pharmacological drug development programmes and the present article gives the structural...
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.
Topics: Adsorption; Fullerenes; Graphite; Promazine; Psychotropic Drugs; Quantum Theory; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Trifluoperazine
PubMed: 33039847
DOI: 10.1016/j.saa.2020.119012 -
Journal of Alzheimer's Disease : JAD 2020We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old...
We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.
Topics: Aged; Biperiden; Cerebral Cortex; Fluorodeoxyglucose F18; Frontotemporal Dementia; Humans; Male; Mental Status and Dementia Tests; Muscarinic Antagonists; Neuroimaging; Positron-Emission Tomography
PubMed: 32144991
DOI: 10.3233/JAD-191290