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Frontiers in Medicine 2019is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In the transport of polyamines is essential because this organism is unable...
is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In the transport of polyamines is essential because this organism is unable to synthesize these compounds . Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in . Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine, and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a high trypanocidal activity against amastigotes (IC values of 3.8, 1.9, and 2.9 μM, respectively) and trypomastigotes (IC values of 3.4, 2.7, and 1.3 μM, respectively) while in epimastigotes the IC were significantly higher (34.7, 41.4, and 39.7 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.
PubMed: 31781568
DOI: 10.3389/fmed.2019.00256 -
Psychiatria Danubina 2022To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and...
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.
Topics: Antipsychotic Agents; Benzodiazepines; Flurazepam; Humans; Hypnotics and Sedatives; Male; Methotrimeprazine; Nitrazepam; Promazine; Quetiapine Fumarate; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Zolpidem
PubMed: 35772134
DOI: 10.24869/psyd.2022.245 -
JMIR Medical Informatics Dec 2022Data analysis is used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on a hypothesis-driven...
Identifying Patterns of Clinical Interest in Clinicians' Treatment Preferences: Hypothesis-free Data Science Approach to Prioritizing Prescribing Outliers for Clinical Review.
BACKGROUND
Data analysis is used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on a hypothesis-driven approach.
OBJECTIVE
This study aimed to develop a hypothesis-free approach to identify unusual prescribing behavior in primary care data. We aimed to apply this methodology to a national data set in a cross-sectional study to identify chemicals with significant variation in use across Clinical Commissioning Groups (CCGs) for further clinical review, thereby demonstrating proof of concept for prioritization approaches.
METHODS
Here we report a new data-driven approach to identify unusual prescribing behaviour in primary care data. This approach first applies a set of filtering steps to identify chemicals with prescribing rate distributions likely to contain outliers, then applies two ranking approaches to identify the most extreme outliers amongst those candidates. This methodology has been applied to three months of national prescribing data (June-August 2017).
RESULTS
Our methodology provides rankings for all chemicals by administrative region. We provide illustrative results for 2 antipsychotic drugs of particular clinical interest: promazine hydrochloride and pericyazine, which rank highly by outlier metrics. Specifically, our method identifies that, while promazine hydrochloride and pericyazine are barely used by most clinicians (with national prescribing rates of 11.1 and 6.2 per 1000 antipsychotic prescriptions, respectively), they make up a substantial proportion of antipsychotic prescribing in 2 small geographic regions in England during the study period (with maximum regional prescribing rates of 298.7 and 241.1 per 1000 antipsychotic prescriptions, respectively).
CONCLUSIONS
Our hypothesis-free approach is able to identify candidates for audit and review in clinical practice. To illustrate this, we provide 2 examples of 2 very unusual antipsychotics used disproportionately in 2 small geographic areas of England.
PubMed: 36538350
DOI: 10.2196/41200 -
ACS Omega May 2022Four aliphatic phenothiazine cations (promazinium, promethazinium, chlorpromazinium, and triflupromazinium) were each paired with docusate anions and three different...
Four aliphatic phenothiazine cations (promazinium, promethazinium, chlorpromazinium, and triflupromazinium) were each paired with docusate anions and three different NSAID anions (ibuprofen, salicylate, and naproxen) to form fifteen glassy materials and one solid. The compounds were prepared the metathesis reaction between the corresponding phenothiazine hydrochloride salts and sodium docusate or sodium NSAID salts and were obtained as liquid co-crystals with various degrees of ionization. The self-diffusion coefficients of several derivatives in 0.06 M DMSO- solutions were determined using DOSY NMR spectroscopy. The influence of the size, shape of the compounds, and intermolecular forces has been investigated by using the four promazine and the four ibuprofen co-crystals. The ion pairs (or aggregates) were found to be maintained in six out of the seven compounds examined. All fifteen glassy compounds showed reversible glass transitions in the -25 to 10 °C range with the docusate derivatives exhibiting the highest thermal stability ( values being at least 40 °C higher than those of the corresponding phenothiazine hydrochlorides).
PubMed: 35647432
DOI: 10.1021/acsomega.1c07382 -
BMB Reports Mar 2020A chemical library comprising 2,354 drug-like compounds was screened using a transcription and replication-competent viruslike particle (trVLP) system implementing the...
A chemical library comprising 2,354 drug-like compounds was screened using a transcription and replication-competent viruslike particle (trVLP) system implementing the whole Ebola virus (EBOV) life cycle. Dose-dependent inhibition of Ebola trVLP replication was induced by 15 hit compounds, which primarily target different types of G protein-coupled receptors (GPCRs). Based on the chemical structure, the compounds were divided into three groups, diphenylmethane derivatives, promazine derivatives and chemicals with no conserved skeletons. The third group included sertindole, raloxifene, and ibutamoren showing prominent antiviral effects in cells. They downregulated the expression of viral proteins, including the VP40 matrix protein and the envelope glycoprotein. They also reduced the amount of EBOV-derived tetracistronic minigenome RNA incorporated into progeny trVLPs in the culture supernatant. Particularly, ibutamoren, which is a known agonist of growth hormone secretagogue receptor (GHSR), showed the most promising antiviral activity with a 50% effective concentration of 0.2 μM, a 50% cytotoxic concentration of 42.4 μM, and a selectivity index of 222.8. Here, we suggest a strategy for development of anti-EBOV therapeutics by adopting GHSR agonists as hit compounds. [BMB Reports 2020; 53(3): 166-171].
Topics: Antiviral Agents; Ebolavirus; Genome, Viral; HEK293 Cells; Humans; Imidazoles; Indoles; RNA; Raloxifene Hydrochloride; Small Molecule Libraries; Viral Proteins; Virus Replication
PubMed: 31964466
DOI: 10.5483/BMBRep.2020.53.3.175 -
BMC Nursing Jan 2023Animal models are increasingly used in Nursing science to study care approaches. Despite the scientific relevance and the ethical debate surrounding the use of...
BACKGROUND
Animal models are increasingly used in Nursing science to study care approaches. Despite the scientific relevance and the ethical debate surrounding the use of experimental animals, there is a scarcity of scholarly literature exploring this topic in Nursing Schools.
AIM
To evaluate perceptions and attitudes of nursing students enrolled in a Pharmacology course on the use of experimental animals and implementation of alternative methods, by comparing the experience for two academic years. An interdisciplinary collaboration has also been developed.
METHODS
A descriptive cross-sectional, quantitative study was developed. Undergraduate nursing students were enrolled in the Pharmacology subject at the University of Leon (Spain). The study was carried out in the Pharmacology facilities. Students followed a two-session practical class regarding experimental animals and alternative methods in the Pharmacology course (Degree in Nursing) in two different academic years (2019-20/2020-21). At the end of the activity, they answered a questionnaire to assess their opinions on the use of experimental animals and alternative methods in Pharmacology and the 3Rs principle.
RESULTS
A comparison of the students' perception with and without direct participation in the evaluation of promazine effects in mice was made. A total of 190 students participated in the teaching experience, providing high scores in all items (4-5 out of 5 points) regarding the teaching experience. Students became also aware of the advantages and disadvantages on the use of experimental animals, as well as the ethical considerations to bear in mind for their use and the need for alternative methods.
CONCLUSIONS
In the students' opinion, the total replacement of animals by alternative techniques was very difficult, and they preferred to do the practice face-to-face. The alternative method designed was useful for the students to accept the employment of experimental animals in biomedical research and education, and know the legislation applied in the protection of animals.
PubMed: 36639785
DOI: 10.1186/s12912-023-01172-5 -
Journal of Materials Chemistry. B Nov 2023A nanocomposite of (2-aminoethyl)piperazine ligand substituted with zinc(II) tetra carboxylic acid phthalocyanine (ZnTEPZCAPC) and MWCNTs was constructed and employed to...
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 cm), 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.
Topics: Antipsychotic Agents; Promazine; Spectroscopy, Fourier Transform Infrared; Reproducibility of Results; Zinc; Piperazines
PubMed: 37917006
DOI: 10.1039/d3tb01859h -
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 -
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 -
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