Dataset Information

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

ABSTRACT: Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.

SUBMITTER: Weeks JC

PROVIDER: S-EPMC5772060 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

Weeks Janis C JC Roberts William M WM Leasure Caitlyn C Suzuki Brian M BM Robinson Kristin J KJ Currey Heather H Wangchuk Phurpa P Eichenberger Ramon M RM Saxton Aleen D AD Bird Thomas D TD Kraemer Brian C BC Loukas Alex A Hawdon John M JM Caffrey Conor R CR Liachko Nicole F NF

Scientific reports 20180117 1

Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae ...[more]

PMID: 29343694

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Project description:PurposeTo compare treatment outcomes in patients with major depressive disorder treated with duloxetine, escitalopram, fluoxetine, paroxetine, or sertraline for up to 6 months.Patients and methodsData were taken from a 6-month prospective, observational study that included 1,549 major depressive disorder patients without sexual dysfunction in 12 countries. We report the overall results and those from Asian countries. Depression severity was measured using the Clinical Global Impression and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Clinical and functional remissions were defined as having a QIDS-SR16 <6, and as having a rating of <3 on all three Sheehan Disability Scale items and no reduced productivity, respectively. Mixed effects modeling with repeated measures analysis and generalized estimating equation models were used. Propensity scores were included in the models.ResultsThe mixed effects modeling with repeated measures regression models showed that the Clinical Global Impression rating during follow-up was significantly lower in those patients treated with duloxetine compared with escitalopram (0.40, 95% CI 0.25 to 0.56); fluoxetine (0.22, 95% CI 0.05 to 0.38); paroxetine (0.38, 95% CI 0.23 to 0.54); and sertraline (0.32, 95% CI 0.16 to 0.49). The QIDS-SR16 of duloxetine-treated patients was significantly lower than those treated with escitalopram (1.58, 95% CI 1.03 to 2.12); fluoxetine (1.48, 95% CI 0.90 to 2.06); paroxetine (1.53, 95% CI 1.00 to 2.07); and sertraline (1.19, 95% CI 0.61 to 1.78). The probability of clinical remission of the patients treated with escitalopram, fluoxetine, paroxetine, and sertraline was lower than those treated with duloxetine (OR 0.46, 95% CI 0.33 to 0.64; OR 0.42, 95% CI 0.29 to 0.61; OR 0.40, 95% CI 0.29 to 0.56; OR 0.50, 95% CI 0.35 to 0.71; respectively). The regression analysis of functional remission also showed more favorable results for duloxetine, with OR ranging from 0.43, 95% CI 0.31 to 0.60 for paroxetine to 0.49, 95% CI 0.35 to 0.70 for sertraline. The results for the Asian countries were generally consistent.ConclusionDuloxetine-treated patients had better 6-month outcomes in terms of depression severity and clinical and functional remission, compared with selective serotonin reuptake inhibitor-treated patients.

Project description:Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.

Dataset Information

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

Publications

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

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