Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis.

Abstract

OBJECTIVES:

The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts.

METHODS:

Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ∼100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid.

RESULTS:

The human-equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ∼6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg.

CONCLUSIONS:

Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined.

• Authors: Noton K Dutta, Michael L Pinn, Ming Zhao, Michelle A Rudek, Petros C Karakousis
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 68 Issue 6 Pg. 1327-30 (Jun 2013) ISSN: 1460-2091 [Electronic] England
• PMID: 23463208 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aerosols
• Antipsychotic Agents
• Thioridazine

Topics

• Aerosols
• Animals
• Antipsychotic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Dose-Response Relationship, Drug
• Endpoint Determination
• Extracellular Space
• Female
• Guinea Pigs
• Humans
• Mice
• Mycobacterium tuberculosis (drug effects)
• Organ Size (drug effects)
• Thioridazine (adverse effects, pharmacokinetics, therapeutic use)
• Tuberculosis (drug therapy, microbiology, pathology)