Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

Soy phosphatidylinositol (PI) containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain deleted Factor VIII (BDD FVIII) in Hemophilia A (HA) mice. We hypothesize that PI associated BDD FVIII is more potent than the free protein, and using mathematical modeling, have projected that PI associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. 2 HA dogs were administered a 50 U/kg iv dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses like whole blood clotting time (WBCT) and thromboelastography (TEG) were conducted on recovered plasma and whole blood samples. PI association decreased clearance (~25%) and increased plasma exposure (~1.4 fold) of rcFVIII. PI-rcFVIII treated animals had prolonged improvements in WBCTs and TEG parameters compared to free rcFVIII treated animals. Since rcFVIII is a BDD form of FVIII, these studies provide proof-of-principle that observations with human BDD FVIII in mice translate to higher animal species. Additionally, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients

Which method is best for the induction of labour?: A systematic review, network meta-analysis and cost-effectiveness analysis

Background: More than 150,000 pregnant women in England and Wales have their labour induced each year. Multiple pharmacological, mechanical and complementary methods are available to induce labour. Objective: To assess the relative effectiveness, safety and cost-effectiveness of labour induction methods and, data permitting, effects in different clinical subgroups. Methods: We carried out a systematic review using Cochrane methods. The Cochrane Pregnancy and Childbirth Group’s Trials Register was searched (March 2014). This contains over 22,000 reports of controlled trials (published from 1923 onwards) retrieved from weekly searches of OVID MEDLINE (1966 to current); Cochrane Central Register of Controlled Trials (The Cochrane Library); EMBASE (1982 to current); Cumulative Index to Nursing and Allied Health Literature (1984 to current); ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Portal; and hand-searching of relevant conference proceedings and journals. We included randomised controlled trials examining interventions to induce labour compared with placebo, no treatment or other interventions in women eligible for third-trimester induction. We included outcomes relating to efficacy, safety and acceptability to women. In addition, for the economic analysis we searched the Database of Abstracts of Reviews of Effects, and Economic Evaluations Databases, NHS Economic Evaluation Database and the Health Technology Assessment database. We carried out a network meta-analysis (NMA) using all of the available evidence, both direct and indirect, to produce estimates of the relative effects of each treatment compared with others in a network. We developed a de novo decision tree model to estimate the cost-effectiveness of various methods. The costs included were the intervention and other hospital costs incurred (price year 2012–13). We reviewed the literature to identify preference-based utilities for the health-related outcomes in the model. We calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit. We represent uncertainty in the optimal intervention using cost-effectiveness acceptability curves. Results: We identified 1190 studies; 611 were eligible for inclusion. The interventions most likely to achieve vaginal delivery (VD) within 24 hours were intravenous oxytocin with amniotomy [posterior rank 2; 95% credible intervals (CrIs) 1 to 9] and higher-dose (≥ 50 μg) vaginal misoprostol (rank 3; 95% CrI 1 to 6). Compared with placebo, several treatments reduced the odds of caesarean section, but we observed considerable uncertainty in treatment rankings. For uterine hyperstimulation, double-balloon catheter had the highest probability of being among the best three treatments, whereas vaginal misoprostol (≥ 50 μg) was most likely to increase the odds of excessive uterine activity. For other safety outcomes there were insufficient data or there was too much uncertainty to identify which treatments performed ‘best’. Few studies collected information on women’s views. Owing to incomplete reporting of the VD within 24 hours outcome, the cost-effectiveness analysis could compare only 20 interventions. The analysis suggested that most interventions have similar utility and differ mainly in cost. With a caveat of considerable uncertainty, titrated (low-dose) misoprostol solution and buccal/sublingual misoprostol had the highest likelihood of being cost-effective. Limitations: There was considerable uncertainty in findings and there were insufficient data for some planned subgroup analyses. Conclusions: Overall, misoprostol and oxytocin with amniotomy (for women with favourable cervix) is more successful than other agents in achieving VD within 24 hours. The ranking according to safety of different methods was less clear. The cost-effectiveness analysis suggested that titrated (low-dose) oral misoprostol solution resulted in the highest utility, whereas buccal/sublingual misoprostol had the lowest cost. There was a high degree of uncertainty as to the most cost-effective intervention

Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

Soy phosphatidylinositol (PI) containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain deleted Factor VIII (BDD FVIII) in Hemophilia A (HA) mice. We hypothesize that PI associated BDD FVIII is more potent than the free protein, and using mathematical modeling, have projected that PI associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. 2 HA dogs were administered a 50 U/kg iv dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses like whole blood clotting time (WBCT) and thromboelastography (TEG) were conducted on recovered plasma and whole blood samples. PI association decreased clearance (~25%) and increased plasma exposure (~1.4 fold) of rcFVIII. PI-rcFVIII treated animals had prolonged improvements in WBCTs and TEG parameters compared to free rcFVIII treated animals. Since rcFVIII is a BDD form of FVIII, these studies provide proof-of-principle that observations with human BDD FVIII in mice translate to higher animal species. Additionally, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients