Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

[Quantitative analysis of the exposure of suboccipital far-lateral approach and postauricular transtemporal approach to the jugular foramen region].

OBJECTIVE: To study the exposure of suboccipital far-lateral approach and postauricular transtemporal approach to the jugular foramen region based on quantitative measurements, and provide reliable anatomic data for selecting surgical approach individually and protecting the function of important structures. METHODS: The complete approach of the suboccipital far-lateral approach and the postauricular transtemporal approach were reproduced in twelve (twenty-four sides) head-neck specimens of adults be fixed in 10% formalin. The exposure area to the jugular foramen region was obtained using a stereotactic device, and the length of exposure of the clivus and the trigeminal nerve were measured using a vernier caliper. RESULTS: In the suboccipital far-lateral approach, the significant increase in exposure was noted after removal of the jugular process and partial resection of occipital condyle. In the postauricular transtemporal approach, the exposure increased significantly after complete retrolabyrinthine approach, partial labyrinthectomy and transcochlear approach. CONCLUSIONS: Resection of jugular process is the key to expose the jugular foramen through the far-lateral approach. The infralabyrinthine approach and the partial labyrinthectomy approach are ideal approaches to expose the jugular foramen region laterally.

[Total mesorectal excision versus conventional radical surgery for rectal cancer: a meta analysis].

OBJECTIVE: To compare treatment outcomes of total mesorectal excision (TME) with those of conventional radical surgery (CRS) for rectal cancer. METHODS: Literature reviews were performed with key words, such as rectal cancer, total mesorectal excision, TME on all studies reported on TME versus CRS for rectal cancer between January 1986 to May 2006. According to the same screening criteria, 17 clinical studies were included in our systematic reviews. Two of our co-authors drew the details of trial design, characteristics of participants, results and so on from the studies included. Data analyses were performed by using RevMan 4.2. RESULTS: Sample volume in this Meta analysis was 5267 rectal cancer cases. Quality and quantity analyses were performed within all included studies, prospective studies (prospective nonrandomized studies and multicenter prospective nonrandomized studies) and retrospective studies. The results showed that postoperative survival rate was significantly increased [OR 1.81 (95%CI 1.55-2.11, P<0.00001), OR 1.79 (95%CI 1.49-2.15, P<0.00001) and OR 1.84 (95%CI 1.39-2.45, P<0.00001)] and local recurrence rate was significantly reduced [OR 0.35 (95%CI 0.29-0.43, P<0.00001), OR 0.41 (95%CI 0.32-0.53, P<0.00001) and OR 0.29 (95%CI 0.22-0.39, P<0.00001)] after TME was used. The results of all study analyses agreed with those from prospective studies analyses, in which postoperative mortality was significantly reduced [OR 0.51 (95%CI 0.32-0.87, P=0.007) and OR 0.56 (95%CI 0.33-0.94, P=0.04)] after TME treatment, meanwhile the results of retrospective study analyses indicated that there was no significant difference between TME group and CRS group in postoperative mortality [OR 0.39 (95%CI 0.14-1.10, P=0.07)]. TME was a risk factor for postoperative anastomotic leak according to the results of all included studies and prospective study analyses, but no difference between TME group and CRS group had been found [OR 1.24 (95%CI 0.84-1.83, P=0.29) OR 1.98 (95%CI 0.85-4.61, P=0.11)]. CONCLUSIONS: TME is still the standard operative technique for rectal cancer. As compared with CRS, TME results in lower postoperative local recurrence rate and higher survival rate.