Pulmonary emboli imaging with (99m)Tc-labelled anti-D-dimer (DI-80B3) Fab' followed by SPECT.

OBJECTIVES: Pre-clinical experiments demonstrated that intravenous (99m)Tc labelled DI-DD-3B6/22-80B3 humanised anti-fibrin-D-dimer Fab' fragments ((99m)Tc-DI-80B3) allowed scintigraphic imaging of acute pulmonary emboli (PE). The aims of this clinical study were to determine the safety of (99m)Tc-DI-80B3 in patients with PE and evaluate the resulting scintigraphic images for the localisation of acute PE. MATERIALS/PATIENTS AND METHODS: (99m)Tc-DI-80B3 (0.5mg, 710-850MBq) was administered intravenously to subjects (n=14) with segmental or larger PE on recent contrast-enhanced helical CT scans. Thoracic SPECT scans were acquired 15 minutes, 2 hours and 4 hours afterwards. Subjects were followed for 90 days subsequently. RESULTS: There were no serious adverse events or antibody responses associated with (99m)Tc-DI-80B3 administration. Focal accumulations of (99m)Tc-DI-80B3 on the SPECT images of the thorax acquired at four hours corresponded to pulmonary emboli detected by CT. Two independent "blinded" SPECT readers identified 79% and 71% (respectively) of the right lung and 79% and 64% (respectively) of the left lung in which CT scans disclosed PE. CONCLUSIONS: (99m)Tc-DI-80B3 is well-tolerated in patients with acute PE and does not induce an immune response. (99m)Tc-DI-80B3 may offer a novel approach to imaging PE in a clinically acceptable timeframe without exposure to potentially nephrotoxic radiographic contrast agents.

A retrospective study of positive antibody screens at delivery in Rh-negative parturients.

PURPOSE: Rhesus- (Rh-) negative women receiving anti-D antibodies antenatally often have a positive antibody screen at delivery. We investigated the incidence of positive antibody screens at delivery in this population and examined how the presence of positive antibody screens affected the time required to obtain type and screen or type and crossmatch results. METHODS: Records of parturients who had type and screen or type and crossmatch done upon presentation for delivery from June to October 2007 were examined to determine estimated gestational age at admission, Rh-status, the presence of positive antibody screens, and the time interval from receipt of specimen in the blood bank to the availability of antibody screen results. RESULTS: Of the 480 specimens sent for type and screen or type and crossmatch, 20% of parturients were Rh-negative, with 57% of those demonstrating a positive antibody screen compared with 4% of the Rh-positive parturients (P < 0.01). In the Rh-negative group, 100% (95% CI 98-102) of positive antibody screens were anti-D antibodies. There was a longer median laboratory time for Rh-negative vs Rh-positive parturients (146 vs 65 min), for antibody positive vs antibody negative parturients (243 vs 65 min) (P < 0.001 for both), but not for Rh-positive/antibody positive vs Rh-negative/antibody positive patients (312 vs 218 min) (P = 0.09). The antibody screen was positive in 100% of Rh-negative parturients until 37 weeks gestation, after which there was a decline. CONCLUSIONS: Rh-negative parturients who receive anti-D antibodies antenatally have a higher incidence of positive antibody screens at delivery than Rh-positive parturients due to the presence of anti-D antibodies.

Imaging of deep venous thrombosis in patients using a radiolabelled anti-D-dimer Fab' fragment (99mTc-DI-DD3B6/22-80B3): results of a phase I trial.

PURPOSE: (99m)Tc-DI-DD3B6/22-80B3 (ThromboView, hereafter abbreviated to (99m)Tc-DI-80B3 Fab') is a radiolabelled humanised monoclonal Fab' fragment with affinity and specificity for D-dimer domains of cross-linked fibrin. Detection of thromboembolic events has been demonstrated in canine models. The study objectives were evaluation of safety and characterisation of biodistribution, immunogenicity and pharmacokinetic profile of increasing doses of (99m)Tc-DI-80B3 Fab' in subjects with acute lower-limb DVT. METHODS: Twenty-six patients with acute lower limb DVT were enrolled. Of these, 21 received a single intravenous dose of 0.5 mg (n = 6), 1.0 mg (n = 9) or 2 mg (n = 6) (99m)Tc-DI-80B3 Fab'. Blood and urine samples and gamma camera images were collected to 24 h after administration for pharmacokinetic and dosimetry analysis. Vital signs, electrocardiography, hematological and biochemical data and human anti-human antibody (HAHA) levels were monitored for up to 30 days following administration. Patients were assigned to either planar or single photon emission computed tomographic (SPECT) imaging of the thorax at 4 h following injection. RESULTS: Thirty-five adverse events were reported in 15 of the 21 subjects. Those deemed possibly related to administration of (99m)Tc-DI-80B3 Fab' included mild hypertension, mild elevation of LD (lactate dehydrogenase) and moderate elevation of ALT (alanine transaminase). HAHA assays remained negative. Pharmacokinetics and organ dosimetry were comparable to prior normal volunteer data. Localisation of Thromboview to sites of known thrombus was evident as early as 30 min post-injection. CONCLUSIONS: In subjects with acute DVT, (99m)Tc-DI-80B3 Fab' was well tolerated with favourable characteristics for the detection of acute venous thrombosis.

Overcoming Barriers to Development of Novel Therapies for Cardiovascular Disease: Insights From the Oncology Drug Development Experience.

Despite the fact that cardiovascular disease (CVD) is the number 1 cause of death globally, investment in drug development and new drug approvals for CVD are precipitously declining. In contrast, the trajectory of both investment in development as well as new drug approvals for oncology have been increasing steadily over the same time frame. The factors that have spurred drug development in oncology may be applicable to new efforts to overcome barriers to drug development for CVD. Greater investment in basic research and application of expedited regulatory pathways have contributed to a lowering of development barriers in oncology. Barriers in implementation are also critical. More rapid adoption of guideline-based therapies and lower access barriers by payers have contributed to fewer implementation barriers for oncology therapeutics. There is substantially greater advocacy among patients and physicians for new oncology therapeutics, and such advocacy efforts are likely to have had a meaningful impact on lowering barriers to develop new oncology therapeutics. Broad support of patient and physician advocacy efforts directed towards CVD may help overcome existing development and implementation barriers to new drug development, thereby spurring more rapid progress in the fight to eradicate cardiovascular disease.

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

OBJECTIVES: The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. BACKGROUND: Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. METHODS: In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). RESULTS: The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. CONCLUSIONS: Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565).

Aurintricarboxylic acid attenuates intimal thickening after balloon injury of the rabbit aorta.

Injury to the arterial wall initiates a cascade of events including platelet deposition and an increase in procoagulant activity of the vessel wall that is associated with intimal thickening and vascular wall remodeling. This study was designed to characterize the effects of aurintricarboxylic acid (ATA), an inhibitor of von Willebrand factor function, on vascular procoagulant activity and the development of intimal thickening after balloon-induced injury to the rabbit aorta. Treatment with ATA, aspirin, or the combination of agents at doses that attenuated platelet aggregation decreased platelet deposition and procoagulant activity bound to the vessel wall after injury. Treatment with ATA reduced the intimal thickening observed 2 weeks after injury. Surprisingly, aspirin treatment had no effect on intimal thickening. These data indicate that inhibition of platelet deposition, while it is able to attenuate local thrombin elaboration, is not alone sufficient to attenuate subsequent intimal thickening that occurs in response to arterial injury.

Perioperative complications of cardiac surgery and postoperative care.

The care of the cardiac surgical patient postoperatively is fraught with several complications because of the nature of the surgical procedure itself and the common comorbidities of this patient population. Most complications occurring in the immediate postoperative period are categorized by organ system, and their pathophysiology is presented. Current diagnostic approaches and treatment options are offered. Preventive measures, where appropriate, are also included in the discussion.

Accuracy and safety of (99m)Tc-labeled anti-D-dimer (DI-80B3) Fab' fragments (ThromboView®) in the diagnosis of deep vein thrombosis: a phase II study.

BACKGROUND: The assessment of patients with suspected deep vein thrombosis (DVT) remains challenging despite current diagnostic algorithms. (99m)Tc-labelled DI-DD3B6/22-80B3 Fab´ fragments ((99m)Tc-DI-80B3, ThromboView®) is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect DVT. This test has an anatomic component to locate DVT and a functional component to differentiate acute (newly formed) thrombus from inactive (old) thrombus. METHODS: In a multi-centre prospective cohort trial we investigated the diagnostic accuracy and safety of (99m)Tc-DI-80B3 in consecutive patients with suspected DVT who had the diagnosis confirmed or excluded by venography. RESULTS: We enrolled 94 patients with suspected DVT of whom 12 did not have (99m)Tc-DI-80B3 imaging, leaving 82 patients for the safety analysis. Of these patients, there were 16 with non-evaluable imaging (11 venography, 7 (99m)Tc-DI-80B3, both in two patients) leaving 66 patients for the accuracy analysis. (99m)Tc-DI-80B3 imaging was well-tolerated: 2 patients developed urticaria; none developed serious adverse events. For proximal DVT, the sensitivity (84.2%; 95% confidence interval [CI]: 62.4-94.5) and specificity (97.6%; CI: 83.3-99.4) were highest when the combined 0.25-hour and 3-hour (99m)Tc-DI-80B3 images were used. The accuracy was lower for distal DVT, irrespective of the images used. There were insufficient patients to comment on the accuracy of (99m)Tc-DI-80B3 imaging for suspected recurrent DVT. CONCLUSIONS: (99m)Tc-DI-80B3 (ThromboView®) is a novel diagnostic modality for patients with suspected DVT with a promising accuracy and safety profile that justifies additional clinical development in diagnostic accuracy and clinical management studies.

Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab'.

PURPOSE: (99m)Tc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to (99m)Tc-DI-80B3 Fab') is a humanised, radiolabelled monoclonal antibody Fab' fragment with high affinity and specificity for the D-dimer domain of cross-linked fibrin. The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of (99m)Tc-DI-80B3 Fab' in healthy volunteers. METHODS: Thirty-two healthy volunteers (18-70 years; 16 male, 16 female) received a single intravenous injection of 0.5, 1.0, 2.0 or 4.0 mg of (99m)Tc-DI-80B3 Fab'. Safety outcomes (vital signs, electrocardiography, haematology, biochemistry, adverse events and development of human anti-human antibodies) were assessed up to 30 days post injection. Blood and urine samples were collected up to 48 h post injection. Gamma camera images were acquired at 0.5, 1, 2, 4, 6 and 24 h post injection. Dosimetry was performed using standard MIRD methodology. RESULTS: No adverse events considered to be drug related were observed. Human anti-human antibody was not detectable in any subject during the follow-up period. (99m)Tc-DI-80B3 Fab' had a rapid initial plasma clearance (t (1/2)alpha=1 h). The pharmacokinetic profile of the Fab' fragment was generally linear across the four dose cohorts. By 24 h, 30-35% of the administered radioactivity appeared in the urine. There was marked renal accumulation with time, but no specific uptake was identified within other normal tissues. The effective dose was 9 mSv/750 MBq. CONCLUSIONS: (99m)Tc-DI-80B3 Fab' is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry-characteristics well suited to a potential thrombus imaging agent.