The Antipsychotic Thioridazine Shows Promising Therapeutic Activity in a Mouse Model of Multidrug-Resistant Tuberculosis

Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobia...

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Veröffentlicht in:PloS one Jg. 5; H. 9; S. e12640
Hauptverfasser: van Soolingen, Dick, Hernandez-Pando, Rogelio, Orozco, Hector, Aguilar, Diana, Magis-Escurra, Cecile, Amaral, Leonard, van Ingen, Jakko, Boeree, Martin J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 09.09.2010
Public Library of Science (PLoS)
Schlagworte:
Analysis
Animal models
Animals
Antimicrobial agents
Antipsychotic Agents - administration & dosage
Antipsychotics
Antitubercular Agents - administration & dosage
Bacilli
Bacterial infections
Chronic illnesses
Disease Models, Animal
Drug resistance
Drug Resistance, Bacterial
Drug therapy
Drugs
Health aspects
Humans
Infectious Diseases/Antimicrobials and Drug Resistance
Infectious Diseases/Respiratory Infections
Isoniazid
Kinases
Lung - microbiology
Lungs
Male
Mice
Mice, Inbred BALB C
Microbial drug resistance
Multidrug resistance
Multidrug resistant organisms
Mycobacterium
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - physiology
Oral administration
Pharmacology
Pharmacology/Drug Development
Phenothiazines
Psychotropic drugs
Public health
Pyrazinamide
Respiratory Medicine/Respiratory Infections
Rifampin
Synergistic effect
Thioridazine
Thioridazine - administration & dosage
Treatment Outcome
Tuberculosis
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
Mexico
Netherlands
ISSN:1932-6203, 1932-6203
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Zusammenfassung:Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.
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Conceived and designed the experiments: DvS RHP CME LA JvI MJB. Performed the experiments: HOE DAL. Analyzed the data: RHP HOE DAL. Contributed reagents/materials/analysis tools: DvS RHP. Wrote the paper: DvS RHP CME LA JvI MJB.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0012640