Library

Notes: Summary.  This prospective, open-label, non-randomized study evaluated the safety and efficacy of factor VIII (FVIII)/von Willebrand Factor (VWF) concentrate (Humate-P®) using treatment regimens based on VWF:ristocetin cofactor (VWF:RCo) activity in patients with von Willebrand Disease (VWD) in (i) urgent bleeding episodes, or (ii) in patients undergoing urgent and necessary surgery. This article summarizes the results of treatment for the 33 patients with 53 urgent bleeding events. The median loading dose of FVIII/VWF concentrate was 67.0 international units per kilogram (IU kg−1) VWF:RCo (range 25.7–143.2 IU kg−1), and the median daily maintenance dose per infusion was 74.0 IU kg−1 (range 16.4–182.9 IU kg−1) for a median duration of 2 days (range 1–34 days). The overall efficacy (achievement of haemostasis) of FVIII/VWF concentrate was rated as excellent/good for 98% of the urgent bleeding events. No unexpected treatment-related adverse events or serious drug-related adverse events (AEs) were observed. This study supports the safety and efficacy of Humate-P® administered in doses calculated in VWF:RCo units for the treatment of urgent bleeding episodes in patients with VWD.

Notes: Summary.  To determine the dosing needed to maintain a prophylactic level of factor IX (FIX) ≥2%, 15 non-inhibitor severe (≤1% FIX) deficient subjects participated in a double-blind, two-period crossover study to assess the pharmacokinetics of two FIX concentrates, Mononine (pd-FIX), an ultra-high-purity plasma-derived concentrate, and BeneFix (r-FIX), a recombinant product. The median recovery in the pd-FIX group was 1.67 IU dL−1 per IU kg−1±1.07 vs. 0.86 IU dL−1 per IU kg−1±0.32 in the r-FIX group (P = 0.0002). The median half-life for pd-FIX was 12.9 ±1.7 h compared with 13.7 ± 2.9 h for r-FIX (P = 0.016). Fitted dose activity curves were computer-simulated to depict multiple-dose activity curves for each patient with each product that would maintain prophylactic levels of ≥2%. Based on pharmacokinetic analysis the median amount of concentrate needed to maintain a prophylactic level ≥2% for 30 days when administered every third day is 677 IU kg−1 pd-FIX (range 388–6005 IU kg−1 pd-FIX) compared with 1168 IU kg−1 r-FIX (range 268–13085 IU kg−1 r-FIX). The median cost for 30 days of prophylaxis of an average 25-kg 8-year-old child at the current University of Iowa Price ($0.87 Mononine/$0.86 BeneFix as of December 2002) if given every third day would be $19 972 and $34 456 for r-FIX. However, because of wide inter-patient variability in recovery and half-life, pharmacokinetic evaluation of each patient is necessary to determine the appropriate dosing schedule and product best suited for prophylaxis.

Notes: Summary.  This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine®, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4–1.0 IU mL−1 (i.e. 40–100%). A median intravenous bolus dose of 54.2 IU kg−1 FIX was administered to a subset of 13 non-emergency patients 7–21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg−1) (range, 12.4–108.3), followed by a median total CIV infusion dose of 396.4 IU kg−1 (range, 44.9–785.5) was administered at a median rate of 3.84 IU kg−1 h−1 (range, 1.74–7.33) for 107.17 h (range, 31.75–144). Twenty-four patients completed 72–120 h of FIX CIV infusion. Overall, ‘excellent’ (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and ‘good’ (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72–86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.

Notes: Summary.  von Willebrand disease (VWD) is characterized by insufficient von Willebrand factor (VWF) activity. It has been proposed that VWF:ristocetin cofactor (VWF:RCo) activity may be useful in evaluating the response to VWD treatment in patients who require replacement therapy. This prospective, open-label, non-randomized study evaluated the safety and efficacy of a factor VIII (FVIII)/VWF concentrate (Humate-P®) used in treatment regimens based on VWF:RCo activity in subjects with VWD in situations requiring urgent and necessary surgery. This article summarizes the results for 39 subjects with 42 evaluable surgical treatment events, 100% of which were rated as excellent/good for overall efficacy (achievement of haemostasis). The median loading dose based upon VWF:RCo activity was 82.3 international units/kilogram (IU kg−1; range 32.5–216.8 IU kg−1), and the median maintenance dose per infusion was 52.8 IU kg−1 (range 24.2–196.5 IU kg−1) for a median of 3 days (range 1–50 days). The median number of infusions per event was 6 (range 1–67 infusions). Three unanticipated adverse events (peripheral oedema, extremity pain and pseudo-thrombocytopenia) from two surgical treatment events were reported that were potentially treatment-related. No serious drug-related adverse events (AEs) were observed, and no thrombotic events were reported in this study. This study supports the safety and efficacy of the FVIII/VWF concentrate Humate-P® for the prevention of surgical haemorrhage in patients with VWD when administered in doses calculated in VWF:RCo units.

Notes: Abstract Objectives: To evaluate whether dimercaptosuccinic acid (DMSA) -chelatable lead, an estimate of current bioavailable lead stores, is a better predictor of lead-related symptoms than are other commonly used lead biomarkers. Methods: A total of 95 male lead workers from three lead industries (one secondary lead smelting facility, one polyvinyl chloride-stabilizer manufacturing plant, and one lead-acid storage battery factory), and 13 workers without occupational lead exposure recruited from an occupational health institute, were studied. Blood lead, blood zinc protoporphyrin (ZPP), 4 h DMSA-chelatable lead (after oral administration of 10 mg/kg DMSA), urine lead, and urinary δ-aminolevulinic acid levels were evaluated as predictors of 15 lead-related symptoms, assessed by self-administered questionnaire, with linear and logistic regression controlling for covariates. Total symptoms and symptoms in three categories (gastrointestinal, neuromuscular, and general) were evaluated. Results: The mean (SD) 4 h DMSA-chelatable lead level was 288.7 (167.7) μg, with a range from 32.4 to 789 μg in the 95 lead workers. The mean (SD) in the non-exposed subjects was 23.7 (11.5) μg with a range from 10.5 to 43.5 μg. Blood lead, blood ZPP, and spot urine lead levels ranged from 21.4 to 78.4 μg/dl, 40 to 331 μg/l, and 7.5 to 153.0 μg/l, respectively, in the lead workers, and from 4.0 to 7.2 μg/dl, 27 to 52 μg/l, and 2.9 to 15.5 μg/l in the non-exposed controls, respectively. The overall mean symptom score (SD), derived as the sum of 0 or 1 point for absence or presence of 15 symptoms, of the lead workers was 3.7 (2.0), compared to 1.2 (1.5) for the non-exposed workers. DMSA-chelatable lead was the best predictor of symptom scores in both crude and adjusted analyses, compared with the other biomarkers. Lead workers with DMSA-chelatable lead values greater than the median (260.5 μg) were 6.2 times more likely to have frequent tingling or numbness of the arms or legs and 3.3 times more likely to have muscle pain than subjects with lower chelatable lead values. Three symptoms (tingling or numbness of arm or leg, muscle pain, and feeling irritation at the slightest disturbance) evidenced a dose-dependent relationship with DMSA-chelatable lead levels. Conclusions: DMSA-chelatable lead was found to be the best predictor of lead-related symptoms, particularly of both total symptom scores and neuromuscular symptoms, than were the other other lead biomarkers.