Therapy Of XDR TB with thioridazine a drug beyond patent protection but eligible for patent "as new use".
Mycobacterium tuberculosis that is resistant to Isoniazid (INH) and Rifampin (Rif) and hence, multi-drug resistant (MDR) has progressed to extensive drug resistant (XDR) status. XDR strains of Mycobacterium tuberculosis (XDR Mtb) are resistant, in addition to INH and Rif, to any fluoroquinolone, streptomycin and to any of the injectable anti-TB drugs kanamycin, amikacin and capreomycin. Therapy of the XDR TB patient, even under the best conditions, is problematic and at least 20% of XDR TB patients die within one year after diagnosis. Mortality among XDR TB patients co-infected with HIV or presenting with AIDS is considerably higher reaching levels of 80% or higher. Drugs that are to prove effective against XDR Mtb must be able to reach the organism at the site where it mainly resides-the pulmonary macrophage. However, experience tells us that no matter how effective a drug may be, it will be followed by resistance. We have been able to demonstrate that thioridazine, a neuroleptic in safe use for over forty years, enhances the killing of phagocytosed Mycobacterium tuberculosis regardless of its antibiotic susceptibility profile and cure the mouse of a Mycobacterium tuberculosis pulmonary infection. Most recently, others have employed our studies for the therapy of the XDR TB patient with thioridazine and cured 10 out of 12 XDR TB patients of an XDR Mtb infection. Although thioridazine is beyond patent protection, its use for the therapy of XDR TB is new and therefore, a patent may be sought for "use as an anti-XDR TB agent".
Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa. Lisbon, Portugal. lamaral@ihmt.unl.pt
Leonard
L
Amaral
Joseph
J
Molnar
D000277:Adjuvants, Pharmaceutic / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D057176:Compassionate Use Trials / Q000379:methods; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004359:Drug Therapy, Combination / Q000379:methods; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010330:Patents as Topic; D013881:Thioridazine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000277:Adjuvants, Pharmaceutic; D000995:Antitubercular Agents; D013881:Thioridazine