ABSTRACT
OBJECTIVE: To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4-mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A total of 93 intensive care units worldwide. PATIENTS: A total of 274 patients with severe sepsis and shock or respiratory failure. INTERVENTIONS: Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242 1.2 mg/kg/day, or TAK-242 2.4 mg/kg/day. MEASUREMENTS AND MAIN RESULTS: The primary pharmacodynamic end point was change in serum interleukin-6 levels relative to baseline, with 28-day all-cause mortality rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242 did not suppress interleukin-6 as measured by 0- to 96.5-hr area under the interleukin-6 concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242 1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p = .63 and .15, respectively). The 28-day mortality rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p = .26 for placebo vs. high dose). A nonsignificant reduction in mortality rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p = .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242 treatment in 30.1% of the patients. CONCLUSIONS: TAK-242 failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242 resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant.
Subject(s)
Hospital Mortality/trends , Sepsis/drug therapy , Sepsis/mortality , Sulfonamides/administration & dosage , Adult , Aged , Cytokines/drug effects , Cytokines/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Infusions, Intravenous , Male , Middle Aged , Multiple Organ Failure/prevention & control , Probability , Pulse Therapy, Drug , Reference Values , Risk Assessment , Sepsis/diagnosis , Sulfonamides/adverse effects , Survival Analysis , Treatment OutcomeSubject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Rifampin/pharmacokinetics , Taurine/pharmacology , Cell Line , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , Enzyme Induction , Humans , Phenobarbital/pharmacology , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The human pregnane X receptor (hPXR) plays a key role in the regulation of both drug metabolism and efflux by inducing the expression of CYP3A4 and MDR1 gene. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we identified seven novel splicing variants of hPXR in tissue from a single human liver. The expression of hPXR-related transcripts in the liver samples of 15 Caucasian individuals was subsequently determined by RT-PCR assays. The pattern of expression levels of these transcripts varied among liver samples. These results suggest that the hPXR is expressed as several different transcripts in liver tissues, apparently due to alternative as well as defective gene splicing. Furthermore, because this study provides the possibility of interindividual differences in hPXR transcript profiles, these alternative splicings for hPXR may largely contribute to the interindividual variability in CYP3A4 and P-glycoprotein induction.
Subject(s)
Alternative Splicing , Liver/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/genetics , Base Sequence , DNA Primers , Humans , Pregnane X Receptor , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Taurine is not only present in foods, tonics and nutrient drinks but is also used as a medicinal agent mainly for treatment of chronic heart failure and liver disease. However, little is known about its influence on drug-metabolizing enzymes, especially cytochrome P450 (CYP), in human. We examined whether taurine could affect the expression of CYP3A4 mRNA in the presence or absence of rifampicin (RFP), which is a potent inducer of CYPs, with HepG2 cells. Taurine enhanced twice the induction of CYP3A4 mRNA by RFP, but did not affect the expression by itself. This effect was both concentration- and time-dependent. On the other hand, taurine did not affect the induction by phenobarbital. Taurine did not increase intracellular uptake of RFP. Therefore, we conclude that taurine is an enhancer for the induction of CYP3A4 by RFP.
