Veränderungen des Äthioniamides und seines Sulfoxydes in vitro

Grunert, M; Werner, Eric; Iwainsky, H; Eule, H

doi:10.1007/bf02092587

Cited by 3 publications

(1 citation statement)

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“…There is evidence that ETH can produce a bactericidal effect in concentrations of 2.5 to 5.0 g/ml in vitro, with a 99% killing of M. tuberculosis (15). In vivo, ETH is metabolized mainly to ETHsulfoxide, which is less stable than ETH but also has antimycobacterial activity and might add to the therapeutic efficacy of ETH (12). At this stage, it is unknown whether higher in vivo ETH serum concentrations (e.g., above 2.5 g/ml) increase the bactericidal activity or if lower ETH levels are sufficient in the presence of this active metabolite.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ethionamide in Children

Thee

Seifart

Rosenkranz

et al. 2011

Antimicrob Agents Chemother

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Ethionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration (C max ), time to C max (T max ), and area under the time-concentration curve from 0 to 6 h (AUC 0-6 ) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month (r ‫؍‬ 0.50, P ‫؍‬ 0.001) and 4 months (r ‫؍‬ 0.63, P ‫؍‬ 0.001) of therapy. There was no difference in the AUC or C max between children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy.The thioamides, ethionamide (ETH) and prothionamide, are among the most frequently used second-line drugs for the management of pediatric tuberculosis (TB) and are active against several species of mycobacteria. They are oral drugs recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) and also used to treat drug-susceptible tuberculous meningitis (TBM) and miliary disease due to good cerebrospinal fluid penetration (8,19). Absorption of ETH from the intestinal tract is almost complete, and food and antacids appear to have little effect on this process (2). Protein binding is approximately 30% (9). ETH is distributed with ease throughout the body (28). In adults, peak plasma concentrations of ETH occur at approximately 2 h postdosing (2, 10, 29). For clinical purposes, the suggested serum levels for susceptible strains of Mycobacterium tuberculosis vary in the literature, as follows: 2.5 g/ml or between 1 and 5 g/ml (13,14,22). There is evidence that ETH has a bactericidal effect in higher doses (15). Higher doses are often poorly tolerated, limiting the dose in adults to 500 to 1,000 mg per day. A very small proportion of the drug is excreted unchanged, and the first step in thioamide metabolism in the liver is transformation to the active sulfoxide metabolites by monooxygenases (17). These monooxygenases have many properties in common with the cytochrome P450 sy...

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Section: Discussionmentioning

confidence: 99%