As the pathophysiology of acute coronary syndromes (ACS) has been clarified in recent years, major advances have been made in the management of the disease. The magnitude of the thrombotic process triggered upon plaque disruption is modulated by different elements that determine plaque and blood thrombogenicity. Thrombin plays a pivotal role in ACS because of its extensive procoagulant and prothrombotic actions. Antithrombotic therapy and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI), have become central in the management of ACS. A number of options for anticoagulation regimens are available. However, many agents currently used have significant limitations, recognition of which has led to the development, evaluation and clinical introduction of the class of thrombin-specific anticoagulant agents. This paper will discuss the clinical development of the direct thrombin inhibitor bivalirudin as the core anticoagulant in the contemporary PCI setting and the implications for its use in ACS.

Background Despite therapy, arterial hypertension continues to be a risk factor of coronary artery disease (CAD). T h e role of oxidative stress, an important source of vascular injury, in the genesis of this increased risk also needs to be defined, because several antihypertensive drugs have demonstrated antioxidant effects. This study tested the existence of oxidative stress in young (<40 years) untreated patients with uncomplicated essential hypertension (EH).Methods Lipid peroxidation (LP) products (diene conjugates, basal and Fe-stimulated levels of thiobarbituric acid reactive substances) were detected spectrophotometrically in serum together with markers of antioxidant status (serum antioxidative capacity (AOC), red blood cell (RBC) glutathione) in 32 patients with mild-to-moderate EH and in 26 matched normotensive controls. ResultsAll L P products were elevated (P < 0.01), while serum AOC was decreased (P < 0.001) and RBC glutathione increased (P < 0.05) in EH patients compared with controls. T h e presence of hypercholesterolaemia was not found to influence the differences in the measured parameters between hypertensive patients and controls significantly.Conclusions T h e results indicate that oxidative stress occurs in young patients with uncomplicated EH. Therefore antihypertensive treatment, especially in patients whose vascular disease is still reversible, should provide antioxidant protection.introduction Despite therapy, arterial hypertension continues to be a risk factor of coronary artery disease, suggesting that factors beyond high blood pressure (BP) contribute to the development of atherosclerosis in hypertensive patients [ 11. T h e role of oxidative stress in the development of hypertensive vascular changes has been examined recently [2,3]. Oxidative stress is a potentially harmful imbalance between the levels of pro-oxidants and antioxidants in favour of the former [4]. Free radicals and other reactive oxygen species (ROS) are recognized as important sources of endothelial injury, the crucial event in the initiation of atherogenesis [ 5 ] .Ox'idative damage via lipid peroxidation-mediated processes modifies low-density lipoprotein (LDL)-cholesterol, rendering it atherogenic [6]. In addition, vasodilation mediated by endothelium has proven to be very sensitive to inhibition by ROS [7-91.T h e contribution of oxidative stress to hypertensive disease therefore needs to be defined. T h e attractive possibilities that antioxidants might offer endothelial cytoprotection, as well as the fact that several antihypertensive agents have demonstrated antioxidant effects in experimental models [lO,ll], also emphasize the necessity to evaluate further the link between oxidative stress and arterial hypertension.This study was designed to test the existence of oxidative stress in young, untreated patients with uncomplicated essential hypertension by evaluating simultaneously markers of lipid peroxidation and antioxidant status. Materials and methods Study subjectsThirty-two untreated patients with mild-to...

8539 Background: TAK-079 is a subcutaneously (SC) administered mAb with multiple modes of action for killing target cells. Here we report data from an ongoing dose finding study of TAK-079 monotherapy in patients with RRMM (NCT03439280). Methods: Pt were eligible after ≥ 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid; prior anti-CD38 therapy allowed. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. TAK-079 given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity. SC injection was 2 mL administered in ≤ 1 minute. Results: 34 patients were enrolled across 5 fixed dose cohorts (TAK-079 45-135-300-600-1200 mg SC) as of 09 December 2019. Median age was 65 (50–81) years. At study entry, 65% were refractory to both an IMiD and PI; 82% refractory to last line of therapy, 21% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody. Median number of prior therapies was 4 (2,12). No ≥ Grade 1 early or late systemic infusion reactions (IRR) reported. Three ( < 1%) injection site reactions described in > 1200 injections administered; 2 mild pruritis and 1 moderate swelling. Drug related adverse events (AEs), any grade, occurring in at least 10% of patients were: fatigue (21%), anemia (18%), neutropenia (18%), leukopenia (15%). Neutropenia was the only drug related grade 3 AEs in 2 or more patients (n = 2); only drug related SAE was 1 Grade 3 diverticulitis. No drug-related grade 4 AEs, AEs leading to study discontinuation, or on-study deaths reported. Recommended phase 2 dose (RP2) is to be 600 mg based on no reported DLTs, no MTD identified, and preliminary efficacy (PFS and response [ORR]). At the RP2 dose, 9 patients received at least 6 cycles of therapy by the data cutoff; their ORR was 33%, median duration of response was not estimable. The clinical benefit rate (minimal response or better) in all 12 patients enrolled at the RP2 dose was 67%. At a median follow-up of 7.5 months, PFS not estimable at the RP2 dose. Conclusions: TAK-079 monotherapy is safe, generally well tolerated, and active in patients with RRMM through tested doses. Clinical activity occurred early and was durable. With no MTD identified, no IRRs, no significant hematologic toxicity, the RP2 dose is 600 mg. PFS, with a median FU of 7.5 months at the data-cut off, is not estimable at the RP2 dose. Updated safety and efficacy data will be presented. Clinical trial information: NCT03439280 .

Essential hypertensive patients with a high renin profile display more pronounced dyslipidaemia and higher levels of plasma insulin than patients with a low renin profile. This may be one explanation for higher incidence of cardiovascular disease previously reported in high PRA group.