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Antimicrobial Agents and Chemotherapy Mar 2020Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some...
Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on , reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against but also against some spp., in particular against In parallel, we identified drugs that had antifungal activity against and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.
Topics: Amphotericin B; Animals; Antifungal Agents; Auranofin; Candida albicans; Candidiasis; Cell Line; Ciclopirox; Cryptococcosis; Cryptococcus neoformans; Drug Evaluation, Preclinical; Drug Repositioning; Drug Synergism; Erythromycin; Flucytosine; Humans; Mice; Microbial Sensitivity Tests; Opportunistic Infections; RAW 264.7 Cells; Zebrafish
PubMed: 31988099
DOI: 10.1128/AAC.01921-19 -
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 -
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 -
Cancer Medicine Nov 2019Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key...
BACKGROUND
Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment.
METHODS
We used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case-control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning.
RESULTS
The regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival.
CONCLUSION
Using an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.
Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Case-Control Studies; Drug Repositioning; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; Phenotype; Prognosis; Survival Analysis; Transcription Factors
PubMed: 31503425
DOI: 10.1002/cam4.2493 -
Oxford Medical Case Reports Mar 2019Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients. Neuroleptic malign syndrome...
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients. Neuroleptic malign syndrome (NMS) is an idiosyncratic drug reaction showing fever, dysautonomia and rigidity with increased levels of Creatinine-phosphokinase (CPK) dependent on leakage of muscle contents into the circulation and defined as rhabdomyolysis. Although different diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur, particularly during treatment with atypical antipsychotics. We here present a case report of a psychiatric patient affected by a SIADH complicated with NMS/rhabdomyolysis, induced by second-generation (atypical) antipsychotic drugs in combination with carbamazepine and promazine.
PubMed: 30949348
DOI: 10.1093/omcr/omz010 -
Analytical Sciences : the International... Jun 2019Molecularly imprinted polymers (MIPs) for promazine (PZ) and chlorpromazine (CPZ), MIP and MIP, were prepared by multi-step swelling and polymerization using methacrylic...
Preparation and Evaluation of Molecularly Imprinted Polymers for Promazine and Chlorpromazine by Multi-step Swelling and Polymerization: the Application for the Determination of Promazine in Rat Serum by Column-switching LC.
Molecularly imprinted polymers (MIPs) for promazine (PZ) and chlorpromazine (CPZ), MIP and MIP, were prepared by multi-step swelling and polymerization using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a crosslinker. The retention and molecular-recognition properties of MIP and MIP were evaluated using a mixture of potassium phosphate buffer and acetonitrile, or a mixture of ammonium formate and acetonitrile as the mobile phase in LC. PZ and CPZ gave the maximal retentions on MIP and MIP at an apparent pH 8.2 using a mixture of potassium phosphate buffer and acetonitrile as the mobile phase. The retentions of PZ and CPZ decreased with an increase of acetonitrile contents from 70 to 90 vol% using a mixture of ammonium formate and acetonitrile as the mobile phase. The template molecules (PZ and CPZ, respectively) were recognized the most on the respective MIPs, and the imprinting factor of PZ was higher on MIP than on MIP. These results indicate that in addition to shape recognition, ionic and hydrophobic interactions seem to work for the retention and molecular-recognition of PZ and CPZ on the MIPs. MIP was successfully utilized for the selective extraction of PZ in rat-serum samples in column-switching LC with fluorescence detection.
PubMed: 30773513
DOI: 10.2116/analsci.19P011 -
RSC Advances Feb 2018Ionic liquids (ILs) and deep eutectic solvents (DESs) are receiving increased attention from both academic and industrial research due to their immense application...
Ionic liquids (ILs) and deep eutectic solvents (DESs) are receiving increased attention from both academic and industrial research due to their immense application potential. These designer solvents are environmentally friendly in nature with tunable physicochemical properties. In the present investigation, we have studied the aggregation behavior of a short-chain IL 1-butyl-3-methylimidazolium octylsulphate [Bmim][OS] within aqueous DESs using fluorescence, UV-vis, dynamic light scattering (DLS) and FT-IR spectroscopic techniques. We have prepared two DESs, ChCl-urea and ChCl-Gly, which are obtained by heating a mixture of an ammonium salt choline chloride with hydrogen bond donor urea or glycerol, respectively, in 1 : 2 molar ratios. The local microenvironment and size of the aggregates are obtained from steady state fluorescence (using pyrene and pyrene-1-carboxaldehyde as polarity probes) and DLS measurements, respectively. DLS results shows that IL [Bmim][OS] forms relatively larger micelles within the aqueous solution of DES ChCl-urea (avg. hydrodynamic radii = 209 nm) than compared to ChCl-Gly (avg. hydrodynamic radii = 135 nm). A significant decrease in the critical micelle concentration and increase in the aggregation number ( ) are observed within DES solutions as compared to that in water, thus indicating that the micellization process of the IL [Bmim][OS] is much favored in the DES solutions. Molecular interactions of [Bmim][OS] in DESs are revealed from FT-IR spectroscopic investigation. Furthermore, these systems were applied to study the IL-drug binding of the antidepressant drug promazine hydrochloride (PH).
PubMed: 35542011
DOI: 10.1039/c7ra13557b -
PloS One 2018Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described...
Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity.
Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicrobial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity, which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration-a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.
Topics: Anti-Bacterial Agents; Antipsychotic Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; In Vitro Techniques; Lipids; Microbial Sensitivity Tests; Nanocapsules
PubMed: 29298353
DOI: 10.1371/journal.pone.0189950 -
Cureus Feb 2017In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved...
In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved based on clinical trials in adult patients only. Preliminary studies have shown that the "off-label" use of these drugs in pediatric and geriatric populations may result in adverse events not found in adults. In this study, we utilized the large-scale U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) database to look at differences in adverse events from antipsychotics among adult, pediatric, and geriatric populations. We performed a systematic analysis of the FDA AERS database using MySQL by standardizing the database using structured terminologies and ontologies. We compared adverse event profiles of atypical versus typical antipsychotic medications among adult (18-65), pediatric (age < 18), and geriatric (> 65) populations. We found statistically significant differences between the number of adverse events in the pediatric versus adult populations with aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene, and between the geriatric versus adult populations with aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone (p < 0.05, with adjustment for multiple comparisons). Furthermore, the particular types of adverse events reported also varied significantly between each population for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (Chi-square, p < 10). Diabetes was the most commonly reported side effect in the adult population, compared to behavioral problems in the pediatric population and neurologic symptoms in the geriatric population. We also found discrepancies between the frequencies of reports in AERS and in the literature. Our analysis of the FDA AERS database shows that there are significant differences in both the numbers and types of adverse events among these age groups and between atypical and typical antipsychotics. It is important for clinicians to be mindful of these differences when prescribing antipsychotics, especially when prescribing medications off-label.
PubMed: 28465867
DOI: 10.7759/cureus.1059 -
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