Pharmacokinetics, efficacy and safety of IMMUNATE solvent/detergent (IMMUNATE S/D) in previously treated patients with severe hemophilia A: results of a prospective, multicenter, open-label phase III study.

BACKGROUND: IMMUNATE Solvent/Detergent (S/D) is a plasma-derived, human factor VIII (FVIII)/von Willebrand factor (VWF) complex subjected to S/D and vapor heat treatment. METHODS: This prospective clinical study evaluated the pharmacokinetics (PK) (compared to IMMUNATE), efficacy and safety of IMMUNATE S/D in 56 previously treated patients with severe hemophilia A. Subjects received IMMUNATE S/D either on-demand (47/56), as a prophylactic regimen (49/56), or both (40/56). RESULTS: IMMUNATE and IMMUNATES/D were equivalent with respect to the FVIII and VWF PK parameters assessed. Bleeding episodes (623) were reported in 47/56 subjects. For 89% of episodes, subjects required only 1 infusion with a mean dose of 29.6 IU/kg and 96% of episodes had an excellent or good response. The duration of prophylaxis ranged from 0.1 to 5.2 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). No FVIII inhibitory antibodies were observed in 56 subjects after 2,646 treatment exposure days. No related serious adverse events were reported. CONCLUSION: The introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules in IMMUNATE S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures and prophylaxis.

Evaluation of pharmacokinetics, efficacy and safety of Immunate solvent detergent in previously treated patients with severe haemophilia A.

Immunate Solvent Detergent (S/D) is a plasma derived, purified, human factor VIII (FVIII) - von Willebrand factor (VWF) complex subjected to two virus inactivation/removal processes: S/D and vapor heat treatment. This prospective, multicentre, three-part clinical study evaluated the pharmacokinetics (in comparison to the predecessor product Immunate), efficacy and safety of Immunate S/D in 56 previously treated patients with severe haemophilia A. Subjects received Immunate S/D on-demand, as a prophylactic regimen or both. The results of the pharmacokinetic population demonstrate that Immunate and Immunate S/D were equivalent with respect to the FVIII - and to the retrospectively VWF - parameters assessed. A total of 623 bleeding episodes were reported in 47/56 subjects. The duration of prophylaxis ranged from 0.1-5.2 months with a total of 175.6 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). Ninety-six percent of bleeding episodes were rated as having an excellent or good response. For most bleeding episodes (89%), subjects required only one infusion with a mean dose of 29.6 IU kg(-1). No FVIII inhibitory antibodies were observed in any subject. No related serious adverse events were reported. Thus, the introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules of Immunate S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures, and prophylaxis.

Randomized double-blind placebo-controlled multicenter evaluation of efficacy and dose finding of midodrine hydrochloride in women with mild to moderate stress urinary incontinence: a phase II study.

Midodrine is a potent and selective alpha1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.

Comparison of acid inhibition by either oral high-dose ranitidine or omeprazole.

BACKGROUND: High-dose once daily oral omeprazole dosing can inhibit acid secretion almost completely but several days elapse before maximum efficacy is established. The acid inhibitory effect obtained with high doses of a histamine H2-receptor antagonist is built up rapidly but has the tendency to fade--the term 'tolerance' has been applied to characterize this phenomenon. METHODS: To obtain more information on the dynamics of acid inhibition during prolonged dosing, we compared the acid suppressory effects of oral high-dose omeprazole with high-dose ranitidine. Twenty-eight healthy volunteers were randomly assigned to a 2-week dosing with omeprazole or ranitidine in a double-blind, double-dummy, parallel-group study design. Omeprazole was given as 1 capsule of 40 mg mane and ranitidine as 2 tabs of 150 mg q.d.s. The median 24-h pH, daytime pH and night-time pH were measured by ambulatory continuous 24-h pH metry on days -8, -6, 1, 2, 7 and 14. RESULTS: High reproducibility was observed for the two baseline acidity measurements. Ranitidine exerted its peak acid suppressant effect on day 1 of dosing; the degree of acid inhibition faded from day 2 to 7, with no significant change thereafter. The decline in antisecretory activity was more pronounced during the day than the night. In contrast, acid inhibition by omeprazole increased throughout the first week, and antisecretory activity was stable thereafter. Despite the considerable differences in median intragastric pH values at the end of the 14-day study, plasma gastrin levels were elevated to a similar degree with both medications. CONCLUSIONS: This study confirms the 'tolerance' phenomenon previously observed with high-dose histamine H2-receptor antagonist dosing. The dynamics with which it occurs exclude a typical exaggerated first-dose response. Prolonged high-dose histamine H2-receptor dosing compromises the feedback mechanism regulating gastrin release, whilst this is maintained during dosing with omeprazole.