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Ginsberg A.M.,Global Alliance for TB Drug Development
Drugs | Year: 2010

Tuberculosis (TB) drug research and development efforts have resurged in the past 10 years to meet urgent medical needs, but enormous challenges remain. These urgent needs are largely driven by the current long and arduous multidrug regimens, which have significant safety, tolerability and compliance issues; rising and disturbing rates of multidrug- and extensively drug-resistant TB; the existence of approximately 2 billion individuals already latently infected with Mycobacterium tuberculosis, the causative pathogen of TB; and a global TB-HIV co-epidemic. Stakeholders in TB drug development are moving to enable and streamline development and registration of novel, multidrug treatment regimens, comprised of multiple new chemical entities with novel mechanisms of action that do not demonstrate cross-resistance to current first- and second-line TB drugs. Ideally, these new regimens will ultimately provide a short, simple treatment suitable for essentially all TB patients, whether sensitive or resistant to the current anti-TB agents, whether HIV-positive or -negative, and irrespective of patient age.This article reviews the challenges faced by those trying to develop these novel regimens and the key agents currently in clinical testing for TB; the latter are organized for discussion into three categories: (i) novel drugs (TMC207, SQ109, sudoterb LL3858); (ii) present first-line TB drugs being re-evaluated to optimize their efficacy (rifampicin, rifapentine); and (iii) currently licensed drugs for other indications and 'next-generation' compounds of the same chemical class being repurposed for TB (gatifloxacin and moxifloxacin; linezolid, PNU100480 and AZD5847; metronidazole, OPC-67683 and PA-824). © 2010 Adis Data Information BV. All rights reserved. Source


Dodd P.J.,University of Sheffield | Gardiner E.,Global Alliance for TB Drug Development | Coghlan R.,TESS Development Advisors | Seddon J.A.,Imperial College London
The Lancet Global Health | Year: 2014

Background: Confirmation of a diagnosis of tuberculosis in children (aged <15 years) is challenging; under-reporting can result even when children do present to health services. Direct incidence estimates are unavailable, and WHO estimates build on paediatric notifications, with adjustment for incomplete surveillance by the same factor as adult notifications. We aimed to estimate the incidence of infection and disease in children, the prevalence of infection, and household exposure in the 22 countries with a high burden of the disease. Methods: Within a mechanistic mathematical model, we combined estimates of adult tuberculosis prevalence in 2010, with aspects of the natural history of paediatric tuberculosis. In a household model, we estimated household exposure and infection. We accounted for the effects of age, BCG vaccination, and HIV infection. Additionally, we tested sensitivity to key structural assumptions by repeating all analyses without variation in BCG efficacy by latitude. Findings: The median number of children estimated to be sharing a household with an individual with infectious tuberculosis in 2010 was 15319701 (IQR 13766297-17061821). In 2010, the median number of Mycobacterium tuberculosis infections in children was 7591759 (5800053-9969780), and 650977 children (424871-983118) developed disease. Cumulative exposure meant that the median number of children with latent infection in 2010 was 53234854 (41111669-68959804). The model suggests that 35% (23-54) of paediatric cases of tuberculosis in the 15 countries reporting notifications by age in 2010 were detected. India is predicted to account for 27% (22-33) of the total burden of paediatric tuberculosis in the 22 countries. The predicted proportion of tuberculosis burden in children for each country correlated with incidence, varying between 4% and 21%. Interpretation: Our model has shown that the incidence of paediatric tuberculosis is higher than the number of notifications, particularly in young children. Estimates of current household exposure and cumulative infection suggest an enormous opportunity for preventive treatment. Funding: UNITAID and the US Agency for International Development. © 2014 Dodd et al. Open Access article distributed under the terms of CC BY. Source


Ginsberg A.M.,Global Alliance for TB Drug Development
Tuberculosis | Year: 2010

Tuberculosis (TB) drug development has made substantial progress in the past decade. There are currently at least ten drugs being evaluated in clinical trials. Some belong to chemical classes already employed in first- or second-line treatment regimens and are being explored for more optimized use at higher doses or in new drug combinations (rifamycins, fluoroquinolones and oxazolidinones), while others represent potential novel members of the TB drug arsenal, killing Mycobacterium tuberculosis through previously untried mechanisms of action (nitroimidazoles, diarylquinolines, ethylene diamines and pyrroles). The typical challenges of drug development are augmented in TB by the complexity of the disease, the requirement for multi-drug regimens, the relative lack of TB drug development for the past several decades, and inadequate resources being brought to bear despite the urgency of the global medical need. Yet in the face of these challenges, for the first time in history, there is a robust enough pipeline of drugs in development to potentially enable identification of a novel, three-drug regimen capable of curing patients in three months or less, whether they are infected with a strain of M. tuberculosis sensitive or resistant to the current first and second-line drugs. Realizing this potential will require innovation, persistence, cooperation and resources. A fine balance will need to be achieved between protecting novel drugs so that resistance to them doesn't develop and ensuring the regimens are low in cost, readily available, and adopted by healthcare systems and providers. © 2010 Elsevier Ltd. All rights reserved. Source


Patent
Global Alliance For Tb Drug Development | Date: 2010-07-30

The current invention pertains to nitroimidazooxazine and nitroimidazooxazole analogues, their methods of preparation, and uses of the compounds as treatment for


Patent
Global Alliance For Tb Drug Development | Date: 2014-05-01

The present invention relates to riminophenazines having heteroaromatic substitutions, including those with 2-heteroaryl-amino substituents, to their preparation, and to their use as drugs for treating

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