Tuberculosis Medicines Research Articles

Structural basis of mapping the spontaneous mutations with 5-flurouracil in uracil phosphoribosyltransferase from Mycobacterium tuberculosis

Tuberculosis (TB) remains the second leading cause of death from an infectious disease globally, despite the incessant efforts to control it. Research and development into new TB medicines is imperative for effective TB control; however, new strategies for the rational use of existing drugs, such as through the identification of new drug targets, could also significantly enhance this process. Key enzymes involved in the essential metabolic and regulatory pathways are usually sought in the pursuit of potential drug targets. Uracil phosphoribosyltransferase (UPRT) is a key salvage pathway enzyme in the synthesis of uridine 5′-monophosphate (UMP) and a probable target of 5-fluorouracil (5-FU) in Mycobacterium tuberculosis (Mtb). To date, there is no structure available for UPRT from Mtb (MtUPRT) that would assist in the identification of appropriate inhibitors for the enzyme. Here we report the structure of MtUPRT along with its spontaneous mutational studies in the presence of 5-FU. We further mapped these four single nucleotide polymorphisms (SNPs) onto the MtUPRT structure, with two residues found to be conserved among the MtUPRT homologs. Notably, none of these SNPs are located in the 5-FU binding pocket. However, the mutants harboring these mutations showed increased MICs (minimum inhibitory concentration) as compared to wild type strains. The present study will aid in the screening of inhibitors of MtUPRT and thus assist in TB drug design and development.

English

In Sub Saharan Africa, human immunodeficiency virus (HIV) and tuberculosis (TB) co-infections are common, and patients often find out about their HIV positive status during consultation for pulmonary tuberculosis. Reports from the HIV and TB hospital unit in Swaziland indicate that many deaths are related to low uptake of antiretroviral therapy among patients co-infected with TB, and anecdotal evidence suggests reluctance and refusal by some TB/HIV co-infected patients to initiate antiretroviral therapy (ART) before completing TB treatment, and this phenomenon is not well understood. The aim of this study was to explore the reasons for refusing antiretroviral therapy among HIV co-infected tuberculosis patients, prior to the completion of tuberculosis treatment, at a regional hospital in Swaziland. A qualitative descriptive study was conducted to understand patients’ views and concerns, which results in their refusing to initiate ART before completing tuberculosis treatment. A sample of convenience, consisting of nineteen HIV/TB co-infected patients was selected to answer the research question. Reasons given were the clients’ un-readiness for ART, the perception that one was still in good health, the fear of adverse outcomes being precipitated by combining ART with TB medicines, preference for traditional medicines, and health systems-related problems. Key words: Antiretroviral therapy, human immunodeficiency virus (HIV)/tuberculosis (TB) co-infections, tuberculosis, HIV.

Integration of HIV and Tuberculosis in the Community

Current strategies are insufficient to contain the growing tuberculosis (TB) epidemic in areas of high HIV prevalence such as sub-Saharan Africa. Due to the increased risk of morbidity and mortality among those coinfected, early detection is critical. However,strategies dependent on passive, facility-based case finding have failed due to severe limitations in the HIV-positive population.There is growing evidence from multiple clinical trials that early initiation of antiretroviral therapy (ART) in patients coinfected with HIV and TB reduces mortality. Integration of community-based distribution of ART and TB medicines should be considered for coinfected patients to help improve retention in care and to off-load busy health systems. Several models of integration of HIV and TB care in sub-Saharan Africa have been successful. This review article examines the concepts of HIV and TB integration of testing and treatment at the community level.

An observation on tuberculosis associated with HIV infection in Japan

To observe the reported cases of tuberculosis (TB) with HIV infection in Japan, in terms of their main clinical features and related factors. A voluntary reporting network has been organized by the authors who are specialists of TB or respiratory medicine in tuberculosis institutions located roughly all over the country. The members have been encouraged to report not only their own cases but cases seen by their friends or in other institutions. By the end of 1996, a total of 71 cases have been reported of which 59 were TB and 12 NTM cases. Nationality of the cases were; Japan 48, Other Asian countries 16, Others 7. All of the NTM cases were Japanese. 30% of the cases were aged less than 30 years, 24% were thirties, 24% forties, 17% fifties and 6% were those aged 60 years or older. The cases were clearly younger than the TB cases in the national TB registry, and older than HIV-infected persons as known from the HIV surveillance system. 97% of the TB cases were bacteriologically confirmed cases. Eight of NTM cases were positive for MAC, others for M.kansasii. 42% of the cases had extra-pulmonary disease, including disseminated infections seen among 19%. Of TB cases 25% were excreting bacilli resistant to any of the anti-TB drugs which was higher than in the case of general TB population (10-15%). 11% of TB cases had past history of TB treatment. The cases had severe immunological impairment, 79% of the cases having CD4+ cell count less than 100. The route of HIV infection were; 51% heterosexual, 13% homosexual, 13% through blood preparations, etc. Although there may be many cases not included in this observation, it is considered to well reflect the real situation of the problem of Japan. More attention should be paid to HIV infection of the patients in the clinical practice of TB in Japan.

Patient satisfaction, feasibility and reliability of satisfaction questionnaire among patients with pulmonary tuberculosis in urban Uganda: a cross-sectional study

BackgroundA comprehensive understanding of the barriers to and facilitators of poor tuberculosis (TB) treatment outcome is still lacking; posing a major obstacle to finding effective solutions. Assessment of patient satisfaction in TB programs would contribute to the understanding of gaps in healthcare delivery and the specific needs of individual patients. However, tools for assessing patient satisfaction are lacking.ObjectiveTo establish patient satisfaction, the feasibility and reliability of a questionnaire for healthcare service satisfaction and a questionnaire for satisfaction with information received about TB medicines among adult TB patients attending public and private program clinics in Kampala, Uganda.MethodsIn a cross-sectional study, we recruited 133 patients of known HIV status and confirmed pulmonary TB receiving care at the public and private hospitals in Kampala, Uganda. Participants were enrolled based on length of TB treatment as follows: starting therapy, completed two months of therapy, and completed eight months of therapy. A translated and standardized 13-item patient healthcare service satisfaction questionnaire (PS-13) and the Satisfaction with Information about Medicines Scale (SIMS) tool were administered by trained interviewers. Factor analysis was used to systematically group the PS-13 questionnaire into three factors of technical quality of care, responsiveness to patient preference, and management of patient preference satisfaction subscales. The SIMS tool was analyzed with two subscales of information about the action and usage of medication and the potential problems with medication.ResultsOf the 133 participants, 35% (46/133) were starting, 33% (44/133) had completed two months, and 32% (43/133) had completed eight months of TB therapy. The male to female and public to private hospital ratios in the study population were 1:1. The PS-13 and the SIMS tools were highly acceptable and easily administered. Both scales and the subscales demonstrated acceptable internal consistency with Cronbach's alpha above 0.70. Patients that were enrolled at the public hospital had relatively lower PS-13 satisfaction scores (0.48 (95% confidence interval (CI), 0.42 - 0.52)), (0.86 (95% CI, 0.81 - 0.90)) for technical quality of care and responsiveness to patient preferences, respectively compared to patients that were enrolled at the private hospital. For potential problems SIMS subscale, male patients that were recruited at the public hospital had relatively lower satisfaction scores (0.58 (95% CI, 0.40 - 0.86)) compared to female patients after adjusting for other factors. Similarly, patients that had completed eight months of TB treatment had relatively higher satisfaction scores (1.23 (95% CI, 1.06 - 1.44)) for action and usage SIMS subscale, and higher satisfaction scores (1.09 (95% CI, 1.03 - 1.16)) for management of patient preference (PS-13 satisfaction subscale) compared to patients that were starting treatment, respectively.ConclusionThe study provides preliminary evidence that the PS-13 service satisfaction and the SIMS tools are reliable measures of patient satisfaction in TB programs. Satisfaction score findings suggest differences in patient satisfaction levels between public and private hospitals; between patients starting and those completing TB therapy.

From the Zulu medicine to the European phytomedicine Umckaloabo®

Among the Zulus of South Africa a crude root drug of initially unknown botanical origin was used for the treatment of pulmonary diseases and tuberculosis (TB). An English TB patient called "Stevens" heard about it and travelled to South Africa where, according to his account, he was cured by taking an extract of the crude drug. It was extremely difficult to establish the imported crude herbal drug as a "new TB medicine", as neither the plant from which the drug originated was identified nor were the constituents and pharmacological effects known at that time. It was only after a professional search and initial chemical and taxonomic investigations enabled the identity of the plant to be determined that the requirements were met for comprehensive chemical, pharmacological and clinical research into the crude drug. The following report traces the long and difficult path of this "mystery drug" from the Zululand of South Africa to the laboratories of Europe.

Meeting the need for treatment: the initiatives

Many diseases prevail because are old and ineffective, or simply do not exist. Tuberculosis (TB) is a major killer in poor countries, but no new anti-TB drug has been developed since the 1960s. There are rare, often life-threatening diseases, defined in Europe as affecting fewer than one in 2000 people, for which more orphan drugs need to be developed. There are diseases that are highly prevalent, such as HIV/AIDS in southern Africa, but while new, effective medicines exist, millions of people and their governments cannot afford them or they are not available at all. Neglected tropical diseases, such as malaria, affect millions of people, but most are too poor to constitute a market that is lucrative enough to justify drug research and development (RD 46 such projects were in the pipeline in 2005, according to a Wellcome Trust report. The generic industry provides cheap copies of brand-name medicines, has pushed down drug prices overall through competition. Access-to-medicines campaigners and generic companies argue that patents are a major barrier to meet the huge demand for affordable drugs, vaccines and diagnostics in developing countries. In contrast, the R&D-based pharmaceuticals industry, which comes up with innovations and patents them to recoup the R&D costs, argues that the bottleneck is not the fault of patent restrictions, but the lack of funds to buy these products and inadequate infrastructure to deliver them. Generic industry The global generic pharmaceuticals industry produces cheap copies of patented medicines for diseases such as HIV/AIDS, often pushing down the prices of the original patented medicines in the process. India is a major exporter of generic medicines to other developing countries. Of the more than 60 000 HIV/AIDS patients in nearly 30 countries in Medecins Sans Frontieres' projects, 84% receive generic medicines made in India. The generic industry helped establish the US Orphan Drug Act of 1983 to promote the development of medicines for small patient populations by providing incentives, such as tax benefits and exclusive marketing protection. Some say this model could be used to promote the R&D for for neglected diseases. The generic industry sees several threats to its business model, such as evergreening by pharmaceutical companies to extend their patent rights and data exclusivity, i.e. denying the release of information required to advance science. Public-private partnerships Public-private partnerships show that costly drug development can be combined with social responsibility. Under a 2002 agreement with US pharmaceuticals company Chiron Corporation, the Global Alliance for TB Drug Development obtained exclusive world rights to the compound, PA-824, and its derivatives, which may be developed into a new TB medicine. Chiron agreed to make the compounds royalty free in endemic countries, while retaining the right to develop and commercialize them for non-TB indications. Another example is a 2004 agreement between the International Partnership for Microbicides and Tibotec Pharmaceuticals, a Belgian subsidiary of pharmaceutical company Johnson & Johnson, to develop a microbicide to protect women from infection with HIV. …