Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paditaxel is metabolized by the liver and the pharmacokinetcs of paclitaxel in cancer patients with liver involvement or impairment may be important clinicalty. Pharmacokinetic study was completed in 13 HCC patients. The pacitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

cRelatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA-and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P < 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P < 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.

SummaryThe aim of this study was to investigate the pharmacokinetics of sevoflurane uptake into the brain and body by comparing sevoflurane concentrations in internal jugular-bulb blood (Jsev), arterial blood (Asev) and pulmonary arterial blood (PAsev) over a fixed inspired sevoflurane concentration. Ten patients (aged 51-73 years), undergoing coronary artery bypass grafting surgery were enrolled in this study. They were anaesthetised using a constant 3.5% inspired sevoflurane concentration (C I sev) during the first hour of anaesthesia. During constant volume-controlled ventilation, we measured C I sev and end-tidal sevoflurane (C E sev) using infrared analysis. The sevoflurane concentration in the blood was analysed using gas chromatography, and cardiac output was measured using an Opti-Q pulmonary artery catheter. We found that it took 40 min for the brain concentration to equilibrate with arterial blood (Asev). Both C I sev-C E sev and Asev-PAsev gradients persisted during the study period. There was no further uptake of sevoflurane into the brain after 40 min; however, there was near-constant uptake into the body. Sevoflurane is widely used in clinical anaesthesia because of its relative lack of airway irritation or myocardial suppression effects. It has rapid induction and emergence characteristics compared with other available inhalation anaesthetic agents [1][2][3]. Sevoflurane, has a low blood ⁄ gas solubility coefficient and has been thought to have rapid uptake pharmacokinetics in human volunteers [4,5]. The brain ⁄ blood partition coefficient of volatile anaesthetics is important in determining the rate of brain tissue wash-in and wash-out, and wash-in and wash-out characteristics are the main determinants of the rate of induction of and recovery from anaesthesia.The uptake pattern of sevoflurane remains poorly quantified and its uptake into the brain and body has not yet been fully elucidated. However, it has been shown that there is a well-defined relationship between volatile anaesthetic partial pressure in the brain and anaesthetic effects [6,7]. The aim of inhalation anaesthesia is to produce, safely and conveniently, a partial pressure adequate for anaesthesia. The aim of this study was to establish the time required for sevoflurane changes in arterial blood (Asev), right internal jugular-bulb blood (Jsev) and pulmonary arterial blood (PAsev) under constant inspired concentrations of sevoflurane during the first hour of anaesthesia. The primary purpose of this study was to explore the relationship among end-tidal sevoflurane concentrations (C E sev), Asev, PAsev and Jsev at a fixed inspired sevoflurane concentration during the first hour of sevoflurane anaesthesia. Second, we compared the different uptake patterns of sevoflurane in the Anaesthesia, 2003, 58, pages 951-956

No abstract

Abstract. Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg −1 day −1 . Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31-to 0.48-fold (p<0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p<0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry--Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.

No abstract

No abstract