Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.

Summary. Congenital factor XIII (FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, openlabel study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg À1 in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥85%) had trough FXIII activity levels ≥10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product. Clinical trial registration: www.clinicaltrials.gov/ct2/show/NCT00885742.

BACKGROUND:Patients with congenital Factor XIII (FXIII) deficiency have impaired fibrin stabilization and are at high risk for surgical bleeding. Data regarding the use of FXIII concentrates before and during surgery are lacking. The objective of this study was to report the use of plasma-derived FXIII concentrate (Corifact in the United States; Fibrogammin P in other countries) in patients with congenital FXIII deficiency undergoing surgical procedures. STUDY DESIGN AND METHODS: FXIII concentrate at preoperative doses ranging from 25 to 40 U/kg was administered to six patients with congenital FXIII deficiency undergoing major or minor surgeries. RESULTS: FXIII concentrate was administered immediately before surgery for five surgical cases; three of these patients achieved excellent hemostasis during and after surgery, while two had intraoperative bleeding. In one surgical case, a regular prophylactic dose of FXIII concentrate was administered to the patient 1 week before minor surgery. FXIII concentrate provided rapid replacement of FXIII activity. In all but one of the patients given a dose of FXIII designed to increase FXIII levels more than 50%, there was satisfactory intraoperative and postoperative hemostasis. One patient undergoing aortic valve replacement on cardiopulmonary bypass (CPB) was the exception. Intraoperative bleeding in this patient was associated with lower-than-expected blood levels of FXIII. CONCLUSION: Preoperative plasma-derived FXIII concentrate allowed for sufficient hemostasis in most patients with FXIII deficiencies. Additional doses were necessary to achieve hemostasis in one patient who underwent a CPB procedure. F actor XIII (FXIII) deficiency is a rare autosomal recessive congenital bleeding disorder resulting from defects in genes encoding the "A"-chain or "B"-chain subunits of the FXIII coagulation protein.1 FXIII is capable of cross-linking a variety of proteins, but its function in cross-linking fibrin is crucial for clot stabilization and the prevention of bleeding. The incidence of severe FXIII deficiency (<1% FXIII) is estimated to be one in 5 million people, 2 but the true incidence of FXIII deficiency is unknown, as heterozygous patients will have higher baseline FXIII levels and may not exhibit overt symptoms.1 Patients with severe FXIII deficiencies usually present with umbilical cord bleeding, mucosal bleeding, poor wound healing, primary intracranial hemorrhage, or spontaneous miscarriage. Patients with less severe FXIII deficiency (with levels from 2%-50% activity) are rarely symptomatic, and may only be diagnosed after an invasive procedure or other hemostatic challenge. Traditionally, FXIII deficiency has been assessed qualitatively by plasma clot solubility in concentrated urea, acetic acid, or monochloroacetic acid.3 However, since clot solubility ABBREVIATION: CPB = cardiopulmonary bypass. Although not licensed in Canada, Fibrogammin P has been widely used under the Special Access Programme of Health Canada. In 2013, the US Food and Drug Administration approve...

We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57±+14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p<0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20,18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively;p <0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion. Quinidine uniformly increased the ventricular refractory periods by about 9-11% above the control values regardless of the pacing cycle lengths and the action potential durations. Although quinidine generally had no effect on the ratio of ventricular effective refractory period to the action potential duration, a strong trend emerged showing that quinidine increased the ratio as the pacing cycle lengths shortened (p=0.07). Our data demonstrate that at slower heart rates quinidine has a significant effect on the action potential duration, repolarization, and voltage-dependent refractory period. As the heart rate increased, quinidine's effect on these variables diminished, but its effect on the time-dependent refractory period became more pronounced. In contrast to quinidine's effect on the action potential duration, the drug prolonged the QRS duration in a use-dependent manner. (Circulation 1990;81:790-796) C hanges in heart rate affect many facets of cardiac electrical activity.' In particular, the repolarization phase of the cardiac action Presented in part at the 61st Scientific Sessions of the American Heart Association, Washington, DC, November 14-17, 1988

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