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.).
Objective: To investigate the acceptability and pharmacokinetics (PK) of SC injection of TU.
Design: Randomized sequence, crossover clinical study of SC vs IM TU injections.
Setting: Ambulatory clinic of an academic andrology center.
Participants: Twenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) sampling.
Results: Pain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection.
Conclusions: We conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.
Methods: Pseudopregnancy (pc) was induced in cyclic Sprague-Dawley rats by sterile mating. Subcutaneous injection of nicotine tartrate (7.5 mg/kg/day) was scheduled from day 1 through day 5, day 5 through day 9 or day 1 through day 9 of pc. In another group of pseudopregnant rats, concomitant treatment of nicotine tartrate concurrently with progesterone (2 mg/day) was scheduled from day 1 through day 9 pc. Control groups received subcutaneous injections of vehicle only. Endometrial decidualization was induced on day 5 pc. On day 10 pc, animals were sacrificed.The degree of decidual growth and circulating levels of estrogen and progesterone were measured.
Results: The decidual growth in all the first three nicotine-treated groups of animals was significantly reduced, particularly in the animals treated with nicotine from day 1 through day 9 pc. Plasma estrogen levels were significantly elevated in animals treated with nicotine from day 1 through day 9 pc. Conversely, levels of plasma progesterone were found to be significantly attenuated in the same group of nicotine-treated animals compared to controls. Exogenous replacement of progesterone, however, caused a higher degree of endometrial decidualization compared to the nicotine-treated group but it was slightly less than when compared to control.
Conclusions: In conclusion, nicotine-induced progesterone deficiency with a corresponding elevation of estrogen may possibly attenuate the degree of endometrial decidualization in pseudopregnant rats.
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.