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      Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats

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          Abstract

          Bedaquiline (TMC-207) is a key anti-tubercular drug to fight against multidrug resistance tuberculosis. Little information is available till date on the impact of any disease state toward its pharmacokinetic behavior. The present research work aimed to investigate the effect of renal impairment and diabetes mellitus on the oral pharmacokinetics of bedaquiline in the rat model. Renal impairment and diabetes mellitus were induced in the Wistar rat model separately using cisplatin and streptozotocin, respectively, and thereafter, an oral pharmacokinetic study of bedaquiline was carried out in the individual disease models as well as in the normal rat model. Pharmacokinetic parameters of bedaquiline were not altered markedly in cisplatin-induced renal-impaired rats compared to normal rats except an area under the curve (AUC) for plasma concentration of bedaquiline in the experimental time frame (AUC 0– t ) reduced to 3477 ± 228 from 4984 ± 1174 ng h/mL, respectively. Maximum plasma concentrations of bedaquiline (259 ± 77 ng/mL), AUC 0– t (3112 ± 1046 ng h/mL), and AUC 0–∞ (3673 ± 1493 ng h/mL) were significantly reduced along with an increase in the clearance of bedaquiline (3.1 ± 1.1 L/h/kg) in the case of streptozotocin-induced diabetic rats compared to respective pharmacokinetic parameters of bedaquiline (482 ± 170 ng/mL, 4984 ± 1174 ng h/mL, and 6137 ± 1542 ng h/mL) in the normal rats. Preclinical findings suggest that dose adjustment of bedaquiline is required in the diabetes mellitus condition to prevent the therapeutic failure of bedaquiline treatment, but clinical exploration is needed to establish the fact. It is the first report for the consequence of renal impairment and diabetes mellitus on the pharmacokinetics of bedaquiline in the preclinical model.

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          Kidney disease and increased mortality risk in type 2 diabetes.

          Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ≥30 mg/g and/or estimated GFR ≤60 ml/min per 1.73 m(2), was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%-8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%-15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%-7.7%), adjusted for demographics, and 3.4% (95% CI, -0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%-37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%-29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.
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            Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence

            Background Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example. Methods We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence, and to the difference between tuberculosis incidence in urban and rural areas. Results In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2% (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis. We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas – over a fifth of the estimated total difference. Conclusion Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially carries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.
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              Tuberculosis: A Global Health Problem

              K. Zaman (2010)
              Tuberculosis (TB) is an ancient disease that has affected mankind for more than 4,000 years (1). It is a chronic disease caused by the bacillus Mycobacterium tuberculosis and spreads from person to person through air. TB usually affects the lungs but it can also affect other parts of the body, such as brain, intestines, kidneys, or the spine. Symptoms of TB depend on where in the body the TB bacteria are growing. In the cases of pulmonary TB, it may cause symptoms, such as chronic cough, pain in the chest, haemoptysis, weakness or fatigue, weight loss, fever, and night-sweats. TB remains a leading cause of morbidity and mortality in developing countries, including Bangladesh. With the discovery of chemotherapy in the 1940s and adoption of the standardized short course in the 1980s, it was believed that TB would decline globally. Although a declining trend was observed in most developed countries, this was not evident in many developing countries (2). In developing countries, about 7% of all deaths are attributed to TB which is the most common cause of death from a single source of infection among adults (3). It is the first infectious disease declared by the World Health Organization (WHO) as a global health emergency (4). In 2007, it was estimated globally that there were 9.27 million incident cases of TB, 13.7 million prevalent cases, 1.32 million deaths from TB in HIV-negative and 0.45 million deaths in HIV-positive persons (5). Asia and Africa alone constitute 86% of all cases (5). Bangladesh ranked the 6th highest for the burden of TB among 22 high-burden countries in 2007, with 353,000 new cases, 70,000 deaths, and an incidence of 223/100,000 people per year (5). Implementation of directly-observed therapy short course (DOTS) has been a ‘breakthrough’ in the control of tuberculosis. In many countries, it has become the cornerstone in the treatment of tuberculosis. The number of countries and the coverage of DOTS within the countries have increased over the years (5). Over the last 15 years, about 35 million people have been cured, and eight million deaths have been averted with the adoption of DOTS (6). Implementation of DOTS was started in 1993 in Bangladesh, and it gradually covered the whole country (7). Men are more commonly affected than women. The case notifications in most countries are higher in males than in females. There were 1.4 million smear-positive TB cases in men and 775,000 in women in 2004 (8). The ratio of female to male TB cases notified globally is 0.47:0.67 (9). The reasons for these gender differences are not clear. These may be due to differences in the prevalence of infection, rate of progression from infection to disease, under-reporting of female cases, or the differences in access to services. The association between poverty and TB is well-recognized, and the highest rates of TB were found in the poorest section of the community (10). TB occurs more frequently among low-income people living in overcrowded areas and persons with little schooling (11). Poverty may result in poor nutrition which may be associated with alterations in immune function. On the other hand, poverty resulting in overcrowded living conditions, poor ventilation, and poor hygiene-habits is likely to increase the risk of transmission of TB (12). Various surveys have been conducted to understand the knowledge, attitudes, and practices regarding tuberculosis (13–14). One survey in India reported that most (93%) people had heard of TB but only 20.5% of the people demonstrated sufficient knowledge of TB (13). This issue of the Journal includes an article by Rundi who explored healthcare-seeking behaviour with regard to TB among the people of Sabah in East Malaysia and the impact of TB on patients and their families (15). The author used qualitative methods and interviewed patients with TB and their relatives. It was found that most (96%) respondents did not know the cause of TB. TB also affected life-styles of the people. The author emphasized the need to understand the reasons for misconceptions about TB and to address it through health education. Better understanding of the prevalence of drug resistance against tuberculosis is one of the key elements in the control of TB. Drug resistance, in combination with other factors, results in increased morbidity and mortality due to tuberculosis. Drug-resistant strains of TB is rapidly emerging worldwide (16). The WHO reported alarming rise of not only multidrug-resistant (MDR) TB but also of XDR TB (extreme drug-resistant TB) globally. Both treatment and management of such cases are well beyond the capacity of any developing country. Globally, there were about 0.5 million cases of MDR TB. In Bangladesh, the MDR rate is 3.5% among new cases and 20% among previously-treated cases (5). The death rate in MDR cases is high (50–60%) and is often associated with a short span of disease (4–16 weeks) (17). Several factors have been identified for the development of MDR cases. These include non-adherence to therapy, lack of direct observed treatment, limited or interrupted drug supplies, poor quality of drugs, widespread availability of anti-TB drugs without prescription, poor medical management, and poorly-managed national control programmes (18–20). Continuation of the existing MDR surveillance is important to effectively plan for the treatment of MDR cases and implementation of the DOTS-Plus strategy. It requires rapid, concerted action and close collaboration among government, non-government and private organizations to control MDR tuberculosis (21). The diagnosis of TB among children is difficult. Moreover, young children cannot produce sputum. Estimates indicate that children constitute about 10% of all new cases in high-burden areas (8). Clinical signs and symptoms and scoring system have been used for the diagnosis of TB among children (22). Various diagnostic techniques have been used for improving the diagnosis among children. These include culture, serodiagnosis, and nucleic acid amplification (23). Many countries use BCG vaccine as part of their TB-control programme. The protective efficacy of BCG viccine against all forms of TB is about 50% but it was more in serious forms of infection (64% in cases of tuberculosis meningitis and 78% in disseminated infection) (24). Several new vaccines against TB are being developed. These vaccines are now being field-tested in different countries in different phases (25). There are several challenges which need to be addressed for effective control of TB, particularly in developing countries. These include the development of an effective surveillance system, accelerated identification of cases, expansion of DOTS to hard-to-reach areas, strengthening of DOTS in urban settings, ensuring adequate staff and laboratory facilities, involvement of private practitioners, treatment facilities for MDR cases, identification of TB among children and extra-pulmonary cases, and effective coordination among healthcare providers (5, 26–27). Moreover, the prevalence of TB is influenced by HIV, and effective control measures are needed for both the diseases. Further research is warranted to improve diagnostics, develop new drugs and vaccines, simple and effective regimen for simultaneous treatment of TB and HIV, ways to improve programme effectiveness, and better understanding of the relationship between TB and chronic diseases, e.g. diabetes and smoking, and identify social and behavioural factors which limit the detection of cases (8, 28).
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                Author and article information

                Journal
                ACS Omega
                ACS Omega
                ao
                acsodf
                ACS Omega
                American Chemical Society
                2470-1343
                03 March 2021
                16 March 2021
                : 6
                : 10
                : 6934-6941
                Affiliations
                []PK-PD, Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine , Jammu, Jammu and Kashmir 180001, India
                []Academy of Scientific and Innovative Research (AcSIR) , Ghaziabad, Uttar Pradesh 201 002, India
                [§ ]Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine , Jammu, Jammu and Kashmir 180001, India
                Author notes
                Article
                10.1021/acsomega.0c06165
                7970569
                33748607
                c69e3d43-e938-41e1-bf59-a6643acb0504
                © 2021 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 December 2020
                : 29 January 2021
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