RESUMO
PURPOSE: A specific and efficacious method for treatment of pneumonia-derived sepsis is lacking. Chengqi decoction has been used for treatment of pneumonia-derived sepsis, but a clinical trial on patients with pneumonia-derived sepsis is lacking, a gap in the literature that we sought to fill. Patients and Methods. 282 patients with pneumonia-derived sepsis admitted to the intensive care unit of our hospital were selected. They were divided into the treatment group (141 cases) and control group (141 cases). Both groups underwent conventional treatment, but Chengqi decoction (in the form of enema) was given to the treatment group. Mortality, morbidity (abdominal distension and gastrointestinal bleeding), duration of antibiotic use, and use of vasoactive agents were documented 28 days after the drug was used. RESULTS: The treatment group reduced mortality and morbidity (abdominal distension) (P < 0.05). After adjustment for significant covariates, 28-day survival was similar for the whole group (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.23-0.97; P=0.037), for the subgroup (n = 120) with Acute Physiology and Chronic Health Evaluation II score ≥25 (HR: 0.180; 95% CI: 0.032-0.332; P=0.039) and for the subgroup (n = 66) with N-terminal B-type natriuretic peptide <1800 (0.059, 0.004-0.979, and 0.019). There was no difference between the two groups for the duration of antibiotic use, major bleeding, or use of vasoactive drugs. CONCLUSIONS: Chengqi decoction improved 28-day survival and reduced the prevalence of abdominal distension in patients with pneumonia-derived sepsis.
RESUMO
Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8- and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6- and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways.