Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey.

Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC-MS-MS and (1)H NMR. The major metabolic pathways of BA-j, by capturing oxygen free radicals ((.)O2(-)) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t1/2(ß) of 4.2h, Cmax 25.4µM at 2h, and Vd 12.6L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood-brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor.

Glutamine supplementation for critically ill adults.

BACKGROUND: Glutamine is a non-essential amino acid which is abundant in the healthy human body. There are studies reporting that plasma glutamine levels are reduced in patients with critical illness or following major surgery, suggesting that glutamine may be a conditionally essential amino acid in situations of extreme stress. In the past decade, several clinical trials examining the effects of glutamine supplementation in patients with critical illness or receiving surgery have been done, and the systematic review of this clinical evidence has suggested that glutamine supplementation may reduce infection and mortality rates in patients with critical illness. However, two recent large-scale randomized clinical trials did not find any beneficial effects of glutamine supplementation in patients with critical illness. OBJECTIVES: The objective of this review was to:1. assess the effects of glutamine supplementation in critically ill adults and in adults after major surgery on infection rate, mortality and other clinically relevant outcomes;2. investigate potential heterogeneity across different patient groups and different routes for providing nutrition. SEARCH METHODS: We searched the Cochrane Anaesthesia Review Group (CARG) Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1950 to May 2013); EMBASE (1980 to May 2013) and Web of Science (1945 to May 2013). SELECTION CRITERIA: We included controlled clinical trials with random or quasi-random allocation that examined glutamine supplementation versus no supplementation or placebo in adults with a critical illness or undergoing elective major surgery. We excluded cross-over trials. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the relevant information from each included study using a standardized data extraction form. For infectious complications and mortality and morbidity outcomes we used risk ratio (RR) as the summary measure with the 95% confidence interval (CI). We calculated, where appropriate, the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH). We presented continuous data as the difference between means (MD) with the 95% CI. MAIN RESULTS: Our search identified 1999 titles, of which 53 trials (57 articles) fulfilled our inclusion criteria. The 53 included studies enrolled a total of 4671 participants with critical illness or undergoing elective major surgery. We analysed seven domains of potential risk of bias. In 10 studies the risk of bias was evaluated as low in all of the domains. Thirty-three trials (2303 patients) provided data on nosocomial infectious complications; pooling of these data suggested that glutamine supplementation reduced the infectious complications rate in adults with critical illness or undergoing elective major surgery (RR 0.79, 95% CI 0.71 to 0.87, P ＜ 0.00001, I² = 8%, moderate quality evidence). Thirty-six studies reported short-term (hospital or less than one month) mortality. The combined rate of mortality from these studies was not statistically different between the groups receiving glutamine supplement and those receiving no supplement (RR 0.89, 95% CI 0.78 to 1.02, P = 0.10, I² = 22%, low quality evidence). Eleven studies reported long-term (more than six months) mortality; meta-analysis of these studies (2277 participants) yielded a RR of 1.00 (95% CI 0.89 to 1.12, P = 0.94, I² = 30%, moderate quality evidence). Subgroup analysis of infectious complications and mortality outcomes did not find any statistically significant differences between the predefined groups. Hospital length of stay was reported in 36 studies. We found that the length of hospital stay was shorter in the intervention group than in the control group (MD -3.46 days, 95% CI -4.61 to -2.32, P < 0.0001, I² = 63%, low quality evidence). Slightly prolonged intensive care unit (ICU) stay was found in the glutamine supplemented group from 22 studies (2285 participants) (MD 0.18 days, 95% CI 0.07 to 0.29, P = 0.002, I² = 11%, moderate quality evidence). Days on mechanical ventilation (14 studies, 1297 participants) was found to be slightly shorter in the intervention group than in the control group (MD - 0.69 days, 95% CI -1.37 to -0.02, P = 0.04, I² = 18%, moderate quality evidence). There was no clear evidence of a difference between the groups for side effects and quality of life, however results were imprecise for serious adverse events and few studies reported on quality of life. Sensitivity analysis including only low risk of bias studies found that glutamine supplementation had beneficial effects in reducing the length of hospital stay (MD -2.9 days, 95% CI -5.3 to -0.5, P = 0.02, I² = 58%, eight studies) while there was no statistically significant difference between the groups for all of the other outcomes. AUTHORS' CONCLUSIONS: This review found moderate evidence that glutamine supplementation reduced the infection rate and days on mechanical ventilation, and low quality evidence that glutamine supplementation reduced length of hospital stay in critically ill or surgical patients. It seems to have little or no effect on the risk of mortality and length of ICU stay, however. The effects on the risk of serious side effects were imprecise. The strength of evidence in this review was impaired by a high risk of overall bias, suspected publication bias, and moderate to substantial heterogeneity within the included studies.

[Clinical study on sodium ferulate for intracerebral hemorrhage in early stage].

OBJECTIVE: To evaluate the clinical application value of sodium ferulate for intracerebral hemorrhage in early stage. METHOD: Sixty patients with cerebral hemorrhage in basal ganglia onset within 24 h were randomly divided into two groups. The two groups showed no evident differences in age, hematoma volume and edema volume, computerized tomography number, and Chinese Stroke Scale. Both groups were given basic treatment with dehydrating, cytidine diphosphocholine, controlling blood pressure, blood sugar and complicating diseases, while the observation group added the treatment of sodium ferulate intravenous drip after 24 h. The hematoma volume, edema volume, and computerized tomographynumber were examined in the 1st day and 14th day, Chinese Stroke Scale in the 1st day, 14th day and 28th day, and the level of serum endothelin in the 1, 3, 5, 7, 14th day. RESULT: After treatment, edema volume and computerized tomography number in the observation group were lower than those in the control group (P < 0.01, P < 0.05). Patients' recovery of neural function were markedly improved in the observation group better than that in the control group (P < 0.05), and also the therapeutic effectiveness (P < 0.05). The serum endothelin level of the 60 patients showed higher significantly than the healthy group in 24 h after hemorrhage (P < 0.01). The control group kept higher in 14 days (P < 0.05), while the observation group showed declined significantly in the 3rd day and close to the healthy group, and lower than the healthy group in the 14th day (P < 0.05). CONCLUSION: With the basic medical therapy, applying sodium ferulate can effectually improve the resolution of the haematoma, reduce the peripheral edema, and enhance the recovery of neural function for the patients with intracerebral hemorrhage in early stag. The therapeutic effectiveness of adding sodium ferulate in patients with intracerebral hemorrhage in early stage is better than that of the basic medical therapy in most of the fields as the above. No evident effect on secondary hemorrhage, or harmful impact on heart, liver and kidney function was found.