European Society of Mycobacteriology - Instituto Nacional de Saúde ...

OP-26
THIORIDAZINE SHOWS PROMISING ACTIVITY IN A
MURINE MODEL OF MULTIDRUG-RESISTANT TUBERCULOSIS
Jakko van Ingen 1,2 , Martin Boeree 1 , Leonard Amaral 3 , Rogelio Hernandez Pando 4 , Dick van Soolingen 2
1 - Department of Pulmonary Diseases, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
2 - National Mycobacteria Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven,
the Netherlands
3 - Mycobacteriology Unit, Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Lisbon, Portugal
4 - Experimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition
Salvador Zubiràn, Mexico City, Mexico
Background
Multidrug-resistant tuberculosis (MDR-TB) is a threat to TB control efforts worldwide for which very few active drugs
are currently available. The phenothiazines are antipsychotic agents that have potential as anti-tuberculosis drugs, at least
in vitro. Within this pharmacological class thioridazine is the most efficacious and causes the mildest side-effects when
used as an antipsychotic agent. Thioridazine is active against mycobacteria by targeting the type II NADH dehydrogenase,
succinate dehydrogenase, the binding of calcium to proteins and disruption of aerobic respiration under micro-aerobic
conditions. We tested its in vivo activity in a murine model.
Methods
We infected 3 groups of 40 Balb/c mice with pansusceptibe M. tuberculosis H37Rv. After 60 days, 20 mice in each group
started 2 months of thioridazine monotherapy at 16, 32 and 70 mg/kg dosages; the remaining 20 served as controls. This
experiment was repeated using a clinical multidrug-resistant M. tuberculosis (MDR-TB) isolate and two months daily oral
administration of 32 and 70 mg/kg. In a third experiment, 3 groups of 20 mice were infected with M. tuberculosis H37Rv;
one group received rifampicin, isoniazid and pyrazinamide, another received these 3 drugs and thioridazine, one untreated
group served as controls. In all experiments, groups of five mice per group were sacrificed after 2, 4 and 8 weeks
of treatment; lung tissue was homogenized for quantitative cultures. The bacillary load of the lungs was determined by
colony forming units (CFU) quantification; histological damage was observed by microscopic examination.
Results
In both the M. tuberculosis H37Rv and MDR-TB infection, monotherapy with 32 and 70mg/kg thioridazine lead to significant
reductions in CFU counts from the lung tissue homogenates and in the extent of histological damage, at all time
points. Moreover, when 32 mg/kg of thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide
for susceptible tuberculosis, a significant synergistic effect was achieved.
Conclusions
Thioridazine shows promising activity in our murine model. It has a potential effect in the treatment of susceptible
and MDR-TB, where few active drugs are available. The low price of this out of patent drug enables extended use in
resource–poor settings where the burden of multidrug-resistance is most grave.
European Society of Mycobacteriology | 30 th Annual Congress | July 2009 | Porto - Portugal
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