Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

The association between cytomegalovirus immune globulin and long-term recipient and graft survival following liver transplantation.

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and long-term clinical outcomes has not been well defined. We examined the association between CMVIG and long-term recipient and graft survival in liver transplant recipients. Data were from the Scientific Registry of Transplant Recipients and included recipients transplanted between January 1995 and October 2008; follow-up was through March 2009. All recipients≤80 years of age with primary, single-organ liver transplants, given CMVIG with (n=2350) or without antivirals (n=455), antivirals without CMVIG (n = 32,939), or no CMV prophylaxis (n=28,508) before discharge were included. Kaplan-Meier analysis was used to examine rates of acute rejection (AR), graft loss, and death, over 7 years post transplantation. The adjusted risk of AR, graft loss, and death associated with CMVIG with and without antivirals vs. no prophylaxis was estimated using the Cox proportional hazards regression. In the univariate analysis, CMVIG, with and without antivirals, was associated with increased AR rates, but decreased mortality; CMVIG with antivirals was also associated with decreased graft loss compared with no prophylaxis. From the multivariable model, CMVIG with antivirals was associated with increased risk for AR, but decreased risk for graft loss and death; after adjustment, the association between CMVIG alone and mortality was not significant. CMVIG with antivirals is associated with increased risk of AR but greater long-term patient and graft survival after liver transplantation.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.

Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.

Diagnostic precision of Doppler flow echocardiography in fetuses at risk for atrioventricular block.

OBJECTIVE: To investigate the diagnostic precision of three Doppler methods in their ability to predict postnatal first-degree atrioventricular (AV) block. METHODS: This was a prospective, observational study carried out from December 1999 to March 2008, including 95 fetuses of anti-SSA/Ro positive mothers undergoing weekly fetal echocardiograms at 18-24 weeks' gestation. Doppler-derived AV time intervals for left ventricular inflow (MV), inflow and outflow (MV-Ao) and superior vena cava a-wave to aortic flow (SVC-Ao) were compared with the PR interval on postnatal electrocardiography. Reference values for MV intervals were established from 102 healthy fetuses, with previously published reference ranges used for the two other methods. Bayesian and receiver-operating characteristics (ROC) curve analyses were performed. RESULTS: The prevalence of first-degree AV block at birth was 13.8%. Using a cut-off at the upper 95% confidence limit, MV-Ao and SVC-Ao time intervals had a sensitivity of 91.7%, and negative predictive value and negative likelihood ratio of 98.4% and 0.10, respectively. The corresponding positive predictive value/positive likelihood ratio for MV-Ao and SVC-Ao were 42.3%/4.5 and 47.8%/5.7, respectively. The areas under the ROC curve (AUC) for MV-Ao and SVC-Ao were 0.87 and 0.89, respectively (both P < 0.001), with generated cut-offs for abnormal AV time intervals at 134-138 and 132-138 ms. MV time intervals using a cut-off at the upper 95% confidence limit had a sensitivity of just 50% and an AUC of 0.74 (P < 0.01). CONCLUSION: The MV-Ao and SVC-Ao Doppler methods make it possible to identify nearly all fetuses with first-degree AV block at birth and to exclude conduction disturbances in the case of a normal AV time measurement but at the cost of a positive predictive value of 50%.

Clinical feasibility of a magnetic resonance tracking system to guide the position of the scan plane during physiologic joint motion.

PURPOSE: Unrestricted physiologic joint motion results in multidirectional displacement of the anatomic structures. When performing real-time magnetic resonance (MR) imaging of such a joint motion, continuous adjustment of the scan plane position may be required. The purpose of this study was to evaluate the clinical feasibility of a method to guide the scan plane position during dynamic-motion MR imaging of freely moving joints. MATERIALS AND METHODS: The location of a small tracker device (dedicated hardware) placed on the patient's skin overlying a joint was determined by an ultrashort MR sequence and used to automatically adjust the scan plane position prior to each dynamic-motion MR image. Using a vertically open MR unit, this MR tracking system was applied in ten dynamic-motion MR examinations to evaluate flexion/extension manoeuvres in the weight-bearing knee joint, and in ten dynamic-motion MR examinations of the shoulder joint to evaluate manoeuvres such as internal/external rotation of the humerus, stress testing of the glenohumeral joint and abduction/adduction manoeuvres. Average number of manoeuvre repetitions, total number of images and percentage of useful images per manoeuvre were calculated. Imaging time per scan plane for each manoeuvre was recorded. RESULTS: Average repetition of manoeuvres varied between 1.6 and 5.8, with an average number of 7 to 18 images per manoeuvre. Average percentage of useful images varied between 61% and 89%. Total imaging time per scan plane ranged between 1 min 10 s and 4 min 51 s. CONCLUSIONS: The MR tracking system to guide the slice position for each consecutive dynamic-motion MR image of the freely but slowly moving shoulder or knee joint was feasible for clinical use, providing a high percentage of useful images for each manoeuvre within a clinically acceptable time frame.

Anti-Ro52/SSA antibody-exposed fetuses with prolonged atrioventricular time intervals show signs of decreased cardiac performance.

OBJECTIVE: To investigate if anti-Ro/SSA antibody-exposed fetuses with prolonged atrioventricular (AV) time intervals also have prolongation of the isovolumetric contraction time (ICT). METHODS: Seventy-eight anti-Ro/SSA (including 70 anti-Ro52) antibody-exposed fetuses at risk for congenital heart block (CHB) were followed weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to detect signs of first-degree AV block. One of these AV time measurements, using hemodynamic events from the mitral valve and aortic outflow as indirect markers of atrial and ventricular depolarization (MV-Ao), was also used to calculate a time interval representing an early phase of systolic cardiac performance, i.e. the ICT. Two hundred and eighty-four women with normal pregnancies served as controls for AV time intervals and another 106 were used to establish an ICT reference range. RESULTS: Strong positive relationships were found between ICT and MV-Ao time intervals (r = 0.91, P < 0.001), as well as between ICT and time intervals obtained from the superior vena cava and aorta (r = 0.85, P < 0.001). The ICT was estimated to contribute more than 50% of the total AV time prolongation. Abnormal AV time and ICT intervals were only seen in anti-Ro52 positive pregnancies. CONCLUSIONS: The ICT is an important contributor to prolongation of AV time intervals. This observation suggests that anti-Ro52/SSA antibody-exposed fetal hearts have not only disturbed electrical conduction but also decreased mechanical performance. Moreover, our findings have implications for the interpretation of AV time intervals used for surveillance of fetuses at risk for developing CHB.

Genomic instability in the type II TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells.

Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-beta1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-beta1 (TbetaR-II), causing acquired resistance to TGF-beta1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A10 microsatellite within TbetaR-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in TbetaR-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-beta1. We propose that microsatellite instability in TbetaR-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions.

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Heart rate adjustment of the time-voltage ST segment integral: identification of coronary disease and relation to standard and heart rate-adjusted ST segment depression criteria.

To assess the effect of heart rate adjustment of the magnitude of the ST integral (ST-HR integral) on exercise test performance, the exercise electrocardiogram (ECG) of 50 clinically normal subjects and 100 patients with known or suspected coronary artery disease was analyzed. At matched specificity of 96% with standard ECG criteria (greater than or equal to 0.1 mV of additional horizontal or downsloping ST segment depression), an unadjusted ST integral partition of 16 microV-s identified coronary disease in the 100 patients with known or suspected disease with a sensitivity of only 41%, a value significantly lower than the 59% sensitivity of standard ECG criteria (p less than 0.01) and the 65% sensitivity of an ST depression partition of 130 microV (p less than 0.001). However, test performance of the ST integral was greatly improved by simple heart rate adjustment: at a matched specificity of 96%, an ST-HR integral partition of 0.154 microV-s/beat per min identified coronary disease in the 100 patients with a sensitivity of 90%, a value significantly greater than the 59% sensitivity of standard criteria and 65% sensitivity of ST depression criteria (each p less than 0.001) and similar to the 91% sensitivity of the ST-HR index and 93% sensitivity of the ST-HR slope (each p = NS). Comparison of receiver-operating characteristic curves confirmed the superior overall test performance of the ST-HR integral relative to the ST integral and ST segment depression, and demonstrated improved performance that was comparable with that of the ST-HR index and the ST-HR slope.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement variables for optimal performance of the ST integral.

OBJECTIVES: This study examined the effect of varied onset and offset of ST measurement on performance of the ST integral for the detection of coronary artery disease. BACKGROUND: The J point and other early ST segment measurements may significantly reduce the accuracy of ST segment depression criteria. METHODS: The exercise electrocardiograms (ECGs) from 112 normal subjects and 163 patients with known or likely coronary disease were analyzed, using the J point or 20 ms after the J point onset and 60 or 80 ms after the J point offset of ST integral calculation. RESULTS: At a matched specificity of 97%, incorporation of J point measurements into the ST integral significantly reduced test performance. The ST integrals measured from the J point to 80 and to 60 ms after the J point were significantly less sensitive (31% and 25%, respectively) than those measured from 20 to 80 ms and 20 to 60 ms after the J point (39% and 31%, p < 0.001 and p < 0.01, respectively). For either J point or 20 ms after the J point onset of the ST integral measurement, the sensitivity was higher using 80 ms than 60 ms after the J point offset (31% vs. 25%, p < 0.01 and 39% vs. 31%, respectively, p < 0.001). Comparison of areas under receiver operating characteristic curves confirmed the superior performance of the ST integral measured from 20 to 80 ms after the J point relative to the other measurement intervals. CONCLUSIONS: These findings demonstrate that J point and early repolarization phase time-voltage measurements reduce performance of the ST integral for the identification of coronary artery disease and provide further evidence that optimal signal to noise content of repolarization for the identification of ischemia can be localized to later phases of the ST segment.

Angiographic findings and clinical correlates in patients with cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?

OBJECTIVES: We sought to delineate the angiographic findings, clinical correlates and in-hospital outcomes in patients with cardiogenic shock (CS) complicating acute myocardial infarction. BACKGROUND: Patients with CS complicating acute myocardial infarction carry a grave prognosis. Detailed angiographic findings in a large, prospectively identified cohort of patients with CS are currently lacking. METHODS: We compared the clinical characteristics, angiographic findings, and in-hospital outcomes of 717 patients selected to undergo angiography and 442 not selected, overall and by shock etiology: left or right ventricular failure versus mechanical complications. RESULTS: Patients who underwent angiography had lower baseline risk and a better hemodynamic profile than those who did not. Overall, 15.5% of the patients had significant left main lesions on angiography, and 53.4% had three-vessel disease, with higher rates of both for those with ventricular failure, compared with patients who had mechanical complications. Among patients who underwent angiography, those with ventricular failure had significantly lower in-hospital mortality than patients with mechanical complications (45.2% vs. 57.0%; p = 0.021). Importantly, for patients with ventricular failure, in-hospital mortality also correlated with disease severity: 35.0% for no or single-vessel disease versus 50.8% for three-vessel disease. Furthermore, mortality was associated with the culprit lesion location (78.6% in left main lesion, 69.7% in saphenous vein graft lesions, 42.4% in circumflex lesions, 42.3% in left anterior descending lesions, and 37.4% in right coronary artery lesions), and Thrombolysis In Myocardial Infarction (TIMI) flow grade (46.5% in TIMI 0/1, 49.4% in TIMI 2 and 26% in TIMI 3). CONCLUSIONS: Patients who underwent angiographic study in the SHOCK Trial Registry had a more benign cardiac risk profile, more favorable hemodynamic findings and lower in-hospital mortality than those for whom angiograms were not obtained. Patients with CS caused by ventricular failure had more severe atherosclerosis, and a different distribution of culprit vessel involvement but lower in-hospital mortality, than those with mechanical complications. Overall in-hospital survival correlates with the extent of coronary artery obstructions, location of culprit lesion and baseline coronary TIMI flow grade.

A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.

Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery, and safety in patients with hemophilia B.

Highly purified factor IX, produced by a monoclonal antibody immunoaffinity technique, contains a high concentration of factor IX with negligible amounts of other vitamin K-dependent coagulation factors. When infused in patients with hemophilia B, monoclonal factor IX concentrate yielded a mean half-life of 34.6 +/- 13.1 (+/- SD) hours and in vivo recovery of 0.67 +/- 0.14 U/dL rise per each U/kg of factor IX infused. Unlike prothrombin complex concentrate (PCC) infusion, monoclonal IX infusion was not associated with rises in factors II, VII, and X, but achieved in vivo recovery and half-life at least comparable to PCC. Long-term use of monoclonal IX as a home-care product provided excellent response in the control of bleeding episodes and was equivalent to previous patient experience with PCC. The results indicate that monoclonal IX concentrate raises factor IX levels effectively, while avoiding extraneous thrombogenic components.

Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients.

BACKGROUND: Chemotherapy and radiation therapy result in increased free radical formation and depletion of tissue antioxidants. It is not known whether parenteral nutrition (PN) administered during bone marrow transplantation (BMT) supports systemic antioxidant status. OBJECTIVE: The aims of the study were to determine 1) whether high-dose chemotherapy decreases concentrations of major circulating antioxidants in patients undergoing BMT and 2) whether administration of standard PN maintains systemic antioxidant concentrations compared with PN containing micronutrients and minimal lipids alone. DESIGN: Twenty-four BMT patients were randomly assigned to receive either standard PN containing conventional amounts of dextrose, amino acids, micronutrients, and lipid (120 kJ/d) or a solution containing only micronutrients (identical to those in standard PN) and a small amount of lipid (12 kJ/d). Plasma antioxidant status was measured before conditioning therapy and serially at days 1, 3, 7, 10, and 14 after BMT. RESULTS: Plasma glutathione (GSH) and alpha- and gamma-tocopherol concentrations decreased and the GSH redox state became more oxidized after conditioning chemotherapy. Plasma cysteine concentrations were unchanged, whereas cystine concentrations increased. Plasma vitamin C and zinc concentrations and GSH peroxidase activity increased over time. Plasma alpha-tocopherol concentrations were lower in patients given standard PN. There were no differences in other plasma antioxidants between groups. CONCLUSIONS: A significant decline in GSH-glutathione disulfide, cysteine-cystine, and vitamin E status occurs after chemotherapy and BMT. Standard PN does not improve antioxidant status compared with administration of micronutrients alone. Further evaluation of PN formulations to support patients undergoing high-dose chemotherapy and BMT are needed.

Variability of in vivo recovery of factor IX after infusion of monoclonal antibody purified factor IX concentrates in patients with hemophilia B. The Mononine Study Group.

Monoclonal antibody purified factor IX concentrate, Mononine (Armour Pharmaceutical Company, Kankakee, Illinois, USA), is a recently developed replacement factor concentrate for the treatment of patients with hemophilia B. The pharmacokinetic properties of monoclonal antibody purified factor IX concentrate (MAb Factor IX concentrate) have been evaluated in only small samples of patients, and little is known about those factors that might influenced in vivo recovery of factor IX after infusion is a larger patient population. In vivo recovery of factor IX was therefore evaluated for 80 different indications in 72 patients who received MAb Factor IX concentrate for the management of spontaneous or trauma-induced bleeding, or as prophylaxis with surgery. The average recovery after infusions for presurgical pharmacokinetic analysis (mean +/- standard deviation) was 1.28 +/- 0.56 U/dl rise per U/kg infused (range 0.41-2.80), and the average recovery after all infusions for treatment was 1.23 +/- 0.49 U/dl rise per U/kg infused (range - 0.35-2.92). Recovery values for multiple MAb Factor IX doses in a given patient were also variable; the average recovery was 1.22 +/- 0.53 U/dl rise per U/kg given, and standard deviations ranged from 0.03 to 1.26. Patient age, weight, and MAb Factor IX concentrate dose minimally but significantly influenced factor IX recovery. There was no significant effect of either race, history of previous thrombotic complications during treatment with other replacement factor concentrates, or bleeding state on recovery. All of the patients treated with this preparation experienced excellent hemostasis, and no thrombotic complications were observed.

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Effectiveness of aspirin and clopidogrel combination therapy in coronary stenting.

Two hundred fifty consecutive patients underwent coronary stenting and received a 2-week course of clopidogrel (75 mg orally each day after a loading dose of 150 mg) and aspirin. There was 1 (0.4%) in-hospital death, 1 (0.4%) acute stent thrombosis, and 2 (0.8%) subacute stent thromboses. There were no Q-wave myocardial infarctions, vascular complications, or repeat interventions at 30-day follow-up.

Electrophysiologic, hemodynamic and metabolic effects of intravenous bepridil hydrochloride.

Bepridil, a fast and slow channel blocking drug, was administered intravenously over 5 minutes in a dose of 3 mg/kg body weight to 19 patients. Ten patients received intravenous bepridil during electrophysiologic study, performed for the investigation of known or suspected cardiac arrhythmias. Sinus cycle length increase from 764 +/- 56 to 886 +/- 62 ms (p less than 0.002). AH interval increased from 101 +/- 6.9 to 137 +/- 11.9 ms (p less than 0.01). HV and QRS durations were not significantly affected. QTc interval increased from 395 +/- 13 to 423 +/- 13 ms (p less than 0.001). Atrial effective refractory period increased from 211 +/- 8 to 242 +/- 8.7 ms (p less than 0.005), and atrioventricular nodal effective refractory period increased from 299 +/- 26 to 366 +/- 30 ms (p less than 0.02). Right ventricular effective refractory period increased from 233 +/- 9.3 to 259 +/- 8.1 ms (p less than 0.001). In an additional 9 patients with coronary artery disease, a hemodynamic and metabolic study was performed. A transient mean decrease dP/dt max from 1,646 +/- 164 to 1,506 +/- 238 mm Hg/s (p less than 0.05) and a mean increase of 2.6 mm Hg (p less than 0.05) in left ventricular end-diastolic pressure were observed. Both values had returned to control levels 15 minutes after drug infusion. Blood pressure, cardiac output, coronary sinus blood flow and myocardial lactate extraction ratio did not change significantly. This profile of powerful electrophysiologic and minor hemodynamic changes indicates a potentially useful role for bepridil in the acute management of supraventricular arrhythmias and, possibly, ventricular arrhythmias.