Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Operative Behandlung von Rektumkarzinomen im Vergleich

BACKGROUND: The laparoscopic resection of rectal cancer shows morbidity and oncological safety comparable to the open approach, but morbidity increases after conversion to open resection. No oncological long-term results are available for the latter patients. METHODS: From 01/01/2000-31/12/2002, patients with curatively resected rectal cancer enrolled in a observational study were evaluated for morbidity, mortality, tumor- and local recurrence rate, paying attention to patients with conversion from laparoscopic to open resection. RESULTS: 237 (3.3%) of 7,189 patients underwent laparoscopic resection (ITT). These patients showed significantly more T1/2 tumors (P<0.001) in earlier UICC stages (P<0.001) than open resected patients. 35 (14.8%) of 237 laparoscopic procedures were converted. Compared with patients receiving complete laparoscopic or open resection, these patients showed significantly higher frequencies of intraoperative (P<0.001) and general postoperative complications (P=0.003) as well as the highest overall morbidity (P=0.031). After a median follow-up of 30.1 months, the highest 5-year local recurrence rate was found in the converted group (16.0%). The laparoscopically resected patients showed a local recurrence rate of 3.3%, patients with open resection of 12.4% (P=0.082). The disease-free survival rate did not differ between the groups (P=0.585). CONCLUSION: Laparoscopic resection of rectal cancer provides oncological results similar to open resection. After conversion, the short and oncological long-term outcomes were worse. Considering a conversion rate of 15%, only a strict indication for the laparoscopic approach can be allowed, and laparoscopic resection should be performed at centers.     

Early postoperative results of surgery for rectal carcinoma as a function of the distance of the tumor from the anal verge: results of a multicenter prospective evaluation

BACKGROUND: The problems associated with rectal surgery are frequently discussed with no reference being made to the distance of the tumor from the anal verge. This study examined the effect of the location of the tumor on early postoperative results. PATIENTS AND METHODS: This was a multicenter study involving 75 German hospitals and 3756 patients, of whom 1463 had rectal carcinoma. On the basis of the location of the tumor (distance from the anal verge), four groups were distinguished: <4, 4-7.9, 8-11.9, and 12-16 cm. RESULTS: Resection and abdominoperineal resection rates and the incidence of postoperative complications depended on the location of the tumor. Significantly higher resection rates and fewer specific complications, and a significant reduction in overall postoperative morbidity were found with tumor locations more than 8 cm from the anal verge. The highest anastomotic leak rate was observed with anastomoses less than 7 cm from the anal verge. The logistic regression showed that the distance of the tumor from the anal verge is an independent variable for the development of an anastomotic leak. CONCLUSIONS: Early results are greatly affected by the location of the rectal carcinoma. This applies to both abdominoperineal resection rates and specific postoperative complications, such as anastomotic leak rate and operation morbidity in general.     

Polymorphonuclear leucocyte motility in patients with severe burns

Chemotaxis, chemokinesis and cellular orientation were measured for unstimulated and 10(-7) n-formyl methionyl leucyl phenylalanine (F-met-leu-phe) stimulated polymorphonuclear leucocytes (PMNS) of nine patients with recent 10-80 per cent burns using a computer-assisted image analysis technique. The technique records PMN movement, as viewed with a phase-contrast microscope on videotapes, and then uses computer programs to calculate the speed and direction of up to 50 PMNS over a 5-min period. Orientation was determined visually. Cellular adherence was also measured by attachment methods. PMNS from burn patients were slower (av. speed 16.8 microns/min), responded less well to F-met-leu-phe (av. speed 20.9 microns/min, av. McCutcheon index 0.32), were less often oriented towards the chemoattractant (av. 39 per cent) and were more adherent (av. 50 per cent) than control cells (av. speed 21.8 microns/min; av. speed F-met-leu-phe 32.2 microns/min; McCutcheon index 0.61; oriented 59 per cent adherent; 16 per cent). Thus PMNS from burn patients orient less well, are significantly slower and have less directionality in response to a chemoattractant, and are more adherent suggesting activation.     

Incretin mimetics as a novel therapeutic option for hepatic steatosis.

BACKGROUND: Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes. CASE REPORT: A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis. CONCLUSION: This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.