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.     

Massive Immune Hemolysis Caused by Anti-D After Dual Kidney Transplantation

Massive immune hemolysis due to passenger lymphocyte-derived anti-D has not been reported in renal transplantation. A 50-year-old (B-positive) male received a dual deceased-donor kidney transplant (B-negative) for diabetic renal failure. Two weeks post-transplant, the patient developed severe hemolytic anemia. The donor anti-D titer was 1:8. The recipient anti-D titer (zero pre-transplant) increased from 1:4 to 1:16 over 4 days. Rapid hemolysis caused severe anemia, minimum Hb = 4.2 g/dL, while selectively lysing the patient's autologous red cells during this time. The hemolytic anemia did not impair the allografts and subsided without monoclonal B-cell pharmacotherapy or apheresis. The anti-D titer decreased to barely detectable levels at four months and had cleared when checked 2 years post-transplant. Transfusion support subsided after two months. If complications of anemia can be avoided, the deleterious effects of hemolysis may be well tolerated by renal allografts using antigen negative transfusion alone.     

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.     

Radiation therapy in proliferative vitreoretinopathy

In a prospective study of the effect of postoperative radiation therapy for the prevention of reproliferation of membranes and recurrent proliferative vitreoretinopathy (PVR) two similar groups of patients with retinal detachment and PVR grade D1 to D3 in one eye were compared. Half the eyes (30) received a total dose of 3000 cGy after surgery; the other half remained untreated. After a followup of 6 months and 14 months or more (maximum 36 months) the anatomical and functional results of each group were compared. After 6 months in the unirradiated group 57% (17/30) remained attached and 43% (13/30) had detached again. In the irradiated group 63% (19/30) were attached and 37% (11/30) had detached. However, there was no statistically significant difference between the two groups (P=0.479, Fisher's Exact Test). After 14 months the number of cured and uncured eyes remained the same in the unirradiated group, while in four of the eyes in the irradiated group a later onset of reproliferation and detachment occurred (after 7, 8, 12 and 14 months, respectively). A final cure rate of 57% (17/30) was achieved in the unirradiated group and a 50% (15/30) cure rate in the irradiated group. Thus the failure rate was 43% (13/30) in the unirradiated group and 50% (15/30) in the irradiated group (P=0.473, Fisher's Exact Test). No side effects from the radiation were observed in any case and no radiation retinopathy occurred during an observation period of up to 3 years. The visual acuity of the cured treated and cured untreated eyes was similar in the two groups. From these results we conclude that immediate radiation treatment does not improve the long-term results and does not reduce the number of reoperations. In a considerable number of treated eyes the onset of reproliferation was delayed from 7 to 14 months, whereas in the untreated group reproliferation was always observed during the first 6 months. A combination of various antiproliferative and antiinflammatory therapies are needed to suppress recurrent PVR after succesful vitreoretinal surgery and to minimize the side effects of these treatments.Presented in part at the XVIIth Meeting of the Club Jules Gonin, 1–6 September 1990, Lausanne