-
International Journal of Molecular... Dec 2021Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the...
Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the emergence of drug-resistant parasites. Because protozoan tubulin can be selectively disrupted by small molecules to inhibit parasite growth, we assembled an in vitro testing cascade to fully delineate effects of candidate tubulin-targeting drugs on and vertebrate host cells. Using this analysis, we evaluated clemastine, an antihistamine that has been previously shown to inhibit growth by competitively binding to the CCT/TRiC tubulin chaperone as a proof-of-concept. We concurrently analyzed astemizole, a distinct antihistamine that blocks heme detoxification in . Both drugs have EC values of ~2 µM and do not demonstrate cytotoxicity or vertebrate microtubule disruption at this concentration. Parasite subpellicular microtubules are shortened by treatment with either clemastine or astemizole but not after treatment with pyrimethamine, indicating that this effect is not a general response to antiparasitic drugs. Immunoblot quantification indicates that the total α-tubulin concentration of 0.02 pg/tachyzoite does not change with clemastine treatment. In conclusion, the testing cascade allows profiling of small-molecule effects on both parasite and vertebrate cell viability and microtubule integrity.
Topics: Animals; Antiparasitic Agents; Apicoplasts; Cells, Cultured; Clemastine; Histamine Antagonists; Humans; Microtubules; Parasites; Protozoan Proteins; Tubulin
PubMed: 35008492
DOI: 10.3390/ijms23010068 -
Microsystems & Nanoengineering 2021Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious...
Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious CVD that can lead to sudden death or heart failure. Conventional cardiomyocyte-based biosensors can record extracellular potentials and mechanical beating signals. However, parameter extraction and examination by the naked eye are the traditional methods for analyzing arrhythmic beats, and it is difficult to achieve automated and efficient arrhythmic recognition with these methods. In this work, we developed a unique automated template matching (ATM) cardiomyocyte beating model to achieve arrhythmic recognition at the single beat level with an interdigitated electrode impedance detection system. The ATM model was established based on a rhythmic template with a data length that was dynamically adjusted to match the data length of the target beat by spline interpolation. The performance of the ATM model under long-term astemizole, droperidol, and sertindole treatment at different doses was determined. The results indicated that the ATM model based on a random rhythmic template of a signal segment obtained after astemizole treatment presented a higher recognition accuracy (100% for astemizole treatment and 99.14% for droperidol and sertindole treatment) than the ATM model based on arrhythmic multitemplates. We believe this highly specific ATM method based on a cardiomyocyte beating model has the potential to be used for arrhythmia screening in the fields of cardiology and pharmacology.
PubMed: 34567738
DOI: 10.1038/s41378-021-00251-4 -
British Journal of Clinical Pharmacology Mar 1997The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
AIMS
The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied.
METHODS
Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration.
RESULTS
Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session.
CONCLUSIONS
Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Topics: Administration, Oral; Adult; Analysis of Variance; Antifungal Agents; Astemizole; Blood Pressure; Cross-Over Studies; Double-Blind Method; Electrocardiography; Heart Rate; Histamine H1 Antagonists; Humans; Itraconazole; Linear Models; Male
PubMed: 9088588
DOI: 10.1046/j.1365-2125.1997.00548.x -
Blood Cancer Journal Jun 2018Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse....
Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.
Topics: Apoptosis; Biomarkers; Biomarkers, Tumor; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Computational Biology; Cytarabine; Drug Discovery; Drug Screening Assays, Antitumor; Gene Expression Profiling; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Neoplastic Stem Cells; Transcriptome
PubMed: 29921955
DOI: 10.1038/s41408-018-0087-2 -
Proceedings of the National Academy of... Apr 2017Prion diseases, like Alzheimer's disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and...
Prion diseases, like Alzheimer's disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp-Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.
Topics: Animals; Diffusion; Hydrophobic and Hydrophilic Interactions; Mesocricetus; Models, Molecular; Prion Proteins; Protein Aggregates; Protein Conformation; Protein Unfolding; Rabbits
PubMed: 28320943
DOI: 10.1073/pnas.1620400114 -
Clinical Cardiology Jan 1994
Topics: Astemizole; Drug Interactions; Drug Therapy, Combination; Humans; Long QT Syndrome; Terfenadine
PubMed: 8149675
DOI: No ID Found -
Frontiers in Pharmacology 2022Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of...
Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of novel drugs. A concept of the Connectivity Map (CMap) was previously proposed to connect genes, drugs, and disease states based on the common gene-expression signatures. For a new query compound, the CMap-based method can infer its potential targets by searching similar drugs with known targets (reference drugs) and measuring the similarities into their specific transcriptional responses between the query compound and those reference drugs. However, the available methods are often inefficient due to the requirement of the reference drugs as a medium to link the query agent and targets. Here, we developed a general procedure to extract target-induced consensus gene modules from the transcriptional profiles induced by the treatment of perturbagens of a target. A specific transcriptional gene module pair (GMP) was automatically identified for each target and could be used as a direct target signature. Based on the GMPs, we built the target network and identified some target gene clusters with similar biological mechanisms. Moreover, a gene module pair-based target identification (GMPTI) approach was proposed to predict novel compound-target interactions. Using this method, we have discovered novel inhibitors for three PI3K pathway proteins PI3Kα/β/δ, including PU-H71, alvespimycin, reversine, astemizole, raloxifene HCl, and tamoxifen.
PubMed: 36726786
DOI: 10.3389/fphar.2022.1089217 -
Drug Discovery Today. Therapeutic... 2011Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we...
Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.
PubMed: 22368688
DOI: 10.1016/j.ddstr.2011.10.002 -
The Journal of General Physiology Oct 2004Ether à go-go (Eag; KV10.1) voltage-gated K+ channels have been detected in cancer cell lines of diverse origin and shown to influence their rate of proliferation. The...
Ether à go-go (Eag; KV10.1) voltage-gated K+ channels have been detected in cancer cell lines of diverse origin and shown to influence their rate of proliferation. The tricyclic antidepressant imipramine and the antihistamine astemizole inhibit the current through Eag1 channels and reduce the proliferation of cancer cells. Here we describe the mechanism by which both drugs block human Eag1 (hEag1) channels. Even if both drugs differ in their affinity for hEag1 channels (IC50s are approximately 2 microM for imipramine and approximately 200 nM for astemizole) and in their blocking kinetics, both drugs permeate the membrane and inhibit the hEag1 current by selectively binding to open channels. Furthermore, both drugs are weak bases and the IC50s depend on both internal an external pH, suggesting that both substances cross the membrane in their uncharged form and act from inside the cell in their charged forms. Accordingly, the block by imipramine is voltage dependent and antagonized by intracellular TEA, consistent with imipramine binding in its charged form to a site located close to the inner end of the selectivity filter. Using inside- and outside-out patch recordings, we found that a permanently charged, quaternary derivative of imipramine (N-methyl-imipramine) only blocks channels from the intracellular side of the membrane. In contrast, the block by astemizole is voltage independent. However, as astemizole competes with imipramine and intracellular TEA for binding to the channel, it is proposed to interact with an overlapping intracellular binding site. The significance of these findings, in the context of structure-function of channels of the eag family is discussed.
Topics: Astemizole; Cell Membrane; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Hydrogen-Ion Concentration; Imipramine; Ion Channel Gating; Kidney; Membrane Potentials; Models, Biological; Potassium Channels, Voltage-Gated; Recombinant Proteins; Structure-Activity Relationship
PubMed: 15365094
DOI: 10.1085/jgp.200409041 -
Scientific Reports Apr 2016The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting...
The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that a reduction of FET proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired motor phenotypes. FET proteins are also involved in the regulation of lifespan and stress resistance, acting partially through the insulin/IGF-signalling pathway. We propose that FET proteins are involved in the maintenance of lifespan, cellular stress resistance and neuronal integrity.
Topics: Animals; Astemizole; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Insulin; Longevity; Mutation; Neurons; Signal Transduction; Somatomedins; Stress, Physiological
PubMed: 27117089
DOI: 10.1038/srep25159