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Prospects for cureently antitubercular drugs
The inexorable rise in cases of tuberculosis worldwide, fuelledby the HIV epidemic, highlights the need for new drugs andparticularly those that can shorten the duration of treatment.Clinical trials of existing broad-spectrum agents such asthe fluoroquinolone moxifloxacin are proceeding, on thebasis of efficacy in models of infection and preliminaryclinical data. These may provide a stopgap, but the realbreakthrough will come when novel agents with potentsterilising activity are discovered. Few such novel pre-clinicaldrug candidates exist and therefore considerable effort isbeing exerted to employ new tools to identify drug targetsessential for survival of Mycobacterium tuberculosis.
According to a recent report compiled by the WorldHealth Organization (WHO), the total number of newcases of tuberculosis (TB) worldwide in 2002 had risento approximately 9 million [1]. This is despite theundoubted success of widespread implementation ofthe ‘DOTS' (directly observed therapy, short-course)strategy, now covering 180 countries and accessible byover 70% of the world's population. A key driver of theincrease is synergy with the HIV epidemic, which ishaving a devastating impact in some parts of the worldsuch as the WHO African Region, where 31% of new TBcases were attributable to HIV co-infection [2]. Furthermore,the emergence of strains of Mycobacterium tuberculosis(MDR-TB), resistant to all the first-line drugs iscausing serious concern in some countries [3].No new classes of drugs for TB have been developed inthe past 30 years, reflecting the inherent difficulties indiscovery and clinical testing of new agents and the lackof pharmaceutical industry research in the area [4]. TheGlobal Alliance for TB Drug Development (GATB;www.tballiance.org) was established to address this need.Its top priority is the development of a new agent that willshorten the duration of chemotherapy from the current6–8 months to two months or less, although new drugswith activity against MDR-TB and latent TB are alsoneeded [5]. There has also been considerable investmentby both the private and public sector in the developmentof new agents for the treatment of TB but fundamentaluncertainties in many aspects of the biology of the organismhave substantially hampered the ability to identifycritical targets whose inhibition would correlate withsterilising activity (Table 1). Sterilizing activity refersto the ability of a drug (such as pyrazinamide or rifampicin)to kill those organisms, known as ‘persisters', thatsurvive treatment with agents targeting essential processesin dividing bacteria. It is only by discoveringnew agents with improved sterilising activity that ashorter treatment regimen can be developed.In this review, we discuss the drug candidates that are inclinical development and the efforts being made in preclinicalresearch to exploit alternative delivery systemsand to identify new drug targets.Clinical studiesThere have been no recent reports on the outcome ofclinical studies with truly novel antitubercular agents,reflecting the previous lack of investment in drug discoveryefforts. However, derivatives of known drugs ordrugs developed originally for other antibacterial indicationshave been tested in TB patients.RifamycinsThe most prominent of the new rifamycins is rifapentine.Its long serum half-life may permit establishment of anintermittent regimen, thus reducing the total number ofdosages to be taken under DOTS supervision. However,it does not benefit from activity against rifampicin-resistantstrains and is therefore unlikely to provide a breakthroughin therapy. In a pivotal phase III clinical study,rifapentine and isoniazid once per week was comparedwith rifampicin and isoniazid twice a week in patients who had completed two months of standard chemotherapy,that is during the continuation phase of treatment.The rifapentine regimen was found to be less effective inthat a higher rate of drug-susceptible relapse was detectedin HIV-negative patients, which correlated with theextent of cavitation [6]. In a follow-up pharmacokineticstudy, low plasma levels of isoniazid were found to beassociated with treatment failure or relapse, suggestingthat an alternative companion drug may need to beidentified for the intermittent rifapentine regimen tobe fully effective [7].Another rifamycin with a long half-life, rifalazil (previouslyknown as KRM-1648), was investigated in a PhaseII study. Patients were treated with rifalazil (10 mg or40 mg) plus isoniazid for two weeks and compared withgroups treated with isoniazid alone or isoniazid plusrifampicin. Comparable reductions in sputum bacillaryload were found, and there were few drug-related adverseevents [8].
1. World Health Organisation: Global Tuberculosis Control:Surveillance, Planning, Financing. WHO Report 2004.ISBN 92 4 156264 1. 2004. Geneva, Switzerland.2. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG,Raviglione MC, Dye C: The growing burden of tuberculosis:global trends and interactions with the HIV epidemic.Arch Intern Med 2003, 163:1009-1021.3. Espinal MA: The global situation of MDR-TB. Tuberculosis 2003,83:44-51.4. O'Brien RJ, Nunn PP: The need for new drugs againsttuberculosis. Obstacles, opportunities, and next steps.Am J Respir Crit Care Med 2001, 163:1055-1058.5. Global Alliance for TB Drug Development: Tuberculosis.Scientific blueprint for tuberculosis drug development.Tuberculosis 2001, 81(Suppl 1):1–52.6. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A,Chaisson R, Gordin F, Horsburgh CR, Horton J, Khan A et al.:Rifapentine and isoniazid once a week versus rifampicin andisoniazid twice a week for treatment of drug-susceptiblepulmonary tuberculosis in HIV-negative patients: arandomised clinical trial. Lancet 2002, 360:528-534.7. Weiner M, Burman W, Vernon A, Benator D, Peloquin CA,Khan A, Weis S, King B, Shah N, Hodge T et al.: Low isoniazidconcentrations and outcome of tuberculosis treatmentwith once-weekly isoniazid and rifapentine. Am J RespirCrit Care Med 2003, 167:1341-1347.8. Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C,Rose L, Eisenach K, Ellner JJ: Safety and bactericidal activity ofrifalazil in patients with pulmonary tuberculosis. AntimicrobAgents Chemother 2001, 45:1972-1976.
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Pivot 3 Can somebody Please Help!?
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