Methods: A total of 34 female Sprague Dawley rats, aged 18 days old, weighing 40 to 45 g, were randomly divided into negative control, positive control, and treatment groups. A daily dose of 1500 mg/kg per body weight of FSA extract was administrated orally to rats in the treatment group for 13 days. On day eight of the study, OHSS was induced in both positive control and treated groups by subcutaneous injection of pregnant mare's serum gonadotropin 50 IU for four consecutive days, followed by human chorionic gonadotropin 25 IU on the fifth day. The effect of FSA extract was evaluated by measuring the concentration of serum E2 using the enzyme-linked immunosorbent assay.
Results: FSA extract reduced serum E2 level significantly in the treated OHSS model (p-value < 0.050) compared to the positive control group.
Conclusions: The finding has important implications on the development of female infertility adjuvant drugs for safe assisted reproduction technology cycles in terms of OHSS prevention.
METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.
RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.
CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).