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

AbstractOBJECTIVES:
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.
AuthorsNoton K Dutta, Michael L Pinn, Ming Zhao, Michelle A Rudek, Petros C Karakousis
JournalThe Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 68 Issue 6 Pg. 1327-30 (Jun 2013) ISSN: 1460-2091 [Electronic] England
PMID23463208 (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)

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