Data on antituberculosis drug-induced hepatotoxicity in sub Saharan Africa are limited, probably ... more Data on antituberculosis drug-induced hepatotoxicity in sub Saharan Africa are limited, probably because liver function tests are not carried out routinely during tuberculosis treatment in most African countries. We monitored the liver function of 112 Tanzanian hospitalized pulmonary tuberculosis patients during the first 2 months (i.e. the intensive phase) of tuberculosis treatment. The rate of hepatotoxicity in our study was 0.9% (95% CI 0.04-4.3%). It is encouraging to find a lower rate of antituberculosis drug-induced hepatotoxicity than one would expect based on the high prevalence of risk factors such as HIV and hepatitis B.
Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and m... more Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and mosquito infection. However, molecular techniques have recently revealed high prevalences of submicroscopic gametocytemia. Our objective here was to determine the effect of sulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plus artesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia and infectiousness.
The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazina... more The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis druginduced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.
International Journal of Antimicrobial Agents, 2008
Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patient... more Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patients treated for active tuberculosis (TB). Knowledge regarding the mechanism of toxicity is still incomplete. Metabolism and the formation of toxic metabolites of the TB drugs may play an important role in the development of ATDH. We studied hepatotoxicity and interactions between isoniazid (INH), its toxic metabolite hydrazine (HYD), rifampicin (RIF) and pyrazinamide (PZA) in human hepatoma cells (HepG2). After 24 h pre-treatment with a non-toxic concentration of one of the four compounds, cells were exposed to increasing concentrations of INH, HYD, RIF or PZA. To determine whether pre-treatment increased toxicity, changes in the concentration at which 50% of cell growth was inhibited (IC 50 ) were quantified using the WST-1 cytotoxicity assay. Pre-treatment with INH, HYD or RIF decreased the INH IC 50 by 24%, 26% and 15%, respectively, meaning that INH toxicity was increased. INH and HYD pre-treatment decreased the PZA IC 50 by 30% and 38%, respectively. HYD and RIF toxicity were not affected by the pre-treatments. The present study is the first to demonstrate that pre-treatment with INH or its toxic metabolite HYD increases the in vitro toxicity of PZA. In addition, pre-treatment with INH, HYD or RIF increases the in vitro toxicity of INH. These results give us greater insight into the development of ATDH.
Outbreaks in which most or all persons were exposed to the same suspected source of infection, so... more Outbreaks in which most or all persons were exposed to the same suspected source of infection, so-called universal exposure, are common. They represent a challenge for public health specialists because conducting analytical studies in such investigations is complicated by the absence of a nonexposed group. We describe different strategies that can support investigations of outbreaks with universal exposure. The value of descriptive epidemiology, extensive environmental investigation, and the hypothesis-generation phase cannot be overemphasized. An exposure that seems universal may in fact not be universal when additional aspects of the exposure are taken into account. Each exposure has unique characteristics that may not be captured when investigators rely on the tools readily at hand, such as standard questionnaires. We therefore encourage fi eld epidemiologists to be creative and consider the use of alternative data sources or original techniques in their investigations of outbreaks with universal exposure.
Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the m... more Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in vitro pyrazinamide toxicity in HepG2 cells, which suggests that the hydroxy metabolites of pyrazinamide are probably not fully responsible for pyrazinamide-induced
Data on antituberculosis drug-induced hepatotoxicity in sub Saharan Africa are limited, probably ... more Data on antituberculosis drug-induced hepatotoxicity in sub Saharan Africa are limited, probably because liver function tests are not carried out routinely during tuberculosis treatment in most African countries. We monitored the liver function of 112 Tanzanian hospitalized pulmonary tuberculosis patients during the first 2 months (i.e. the intensive phase) of tuberculosis treatment. The rate of hepatotoxicity in our study was 0.9% (95% CI 0.04-4.3%). It is encouraging to find a lower rate of antituberculosis drug-induced hepatotoxicity than one would expect based on the high prevalence of risk factors such as HIV and hepatitis B.
Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and m... more Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and mosquito infection. However, molecular techniques have recently revealed high prevalences of submicroscopic gametocytemia. Our objective here was to determine the effect of sulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plus artesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia and infectiousness.
The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazina... more The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis druginduced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.
International Journal of Antimicrobial Agents, 2008
Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patient... more Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patients treated for active tuberculosis (TB). Knowledge regarding the mechanism of toxicity is still incomplete. Metabolism and the formation of toxic metabolites of the TB drugs may play an important role in the development of ATDH. We studied hepatotoxicity and interactions between isoniazid (INH), its toxic metabolite hydrazine (HYD), rifampicin (RIF) and pyrazinamide (PZA) in human hepatoma cells (HepG2). After 24 h pre-treatment with a non-toxic concentration of one of the four compounds, cells were exposed to increasing concentrations of INH, HYD, RIF or PZA. To determine whether pre-treatment increased toxicity, changes in the concentration at which 50% of cell growth was inhibited (IC 50 ) were quantified using the WST-1 cytotoxicity assay. Pre-treatment with INH, HYD or RIF decreased the INH IC 50 by 24%, 26% and 15%, respectively, meaning that INH toxicity was increased. INH and HYD pre-treatment decreased the PZA IC 50 by 30% and 38%, respectively. HYD and RIF toxicity were not affected by the pre-treatments. The present study is the first to demonstrate that pre-treatment with INH or its toxic metabolite HYD increases the in vitro toxicity of PZA. In addition, pre-treatment with INH, HYD or RIF increases the in vitro toxicity of INH. These results give us greater insight into the development of ATDH.
Outbreaks in which most or all persons were exposed to the same suspected source of infection, so... more Outbreaks in which most or all persons were exposed to the same suspected source of infection, so-called universal exposure, are common. They represent a challenge for public health specialists because conducting analytical studies in such investigations is complicated by the absence of a nonexposed group. We describe different strategies that can support investigations of outbreaks with universal exposure. The value of descriptive epidemiology, extensive environmental investigation, and the hypothesis-generation phase cannot be overemphasized. An exposure that seems universal may in fact not be universal when additional aspects of the exposure are taken into account. Each exposure has unique characteristics that may not be captured when investigators rely on the tools readily at hand, such as standard questionnaires. We therefore encourage fi eld epidemiologists to be creative and consider the use of alternative data sources or original techniques in their investigations of outbreaks with universal exposure.
Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the m... more Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in vitro pyrazinamide toxicity in HepG2 cells, which suggests that the hydroxy metabolites of pyrazinamide are probably not fully responsible for pyrazinamide-induced
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