Daniel D. Gretler

Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension.

The renal and hemodynamic effects of intravenously administered fenoldopam mesylate, a novel dopamine-1 receptor agonist, were compared with those of sodium nitroprusside in 28 patients (18 male; 26 black, two white; average age, 49 +/- 3 years) with an average blood pressure of 219/137 mm Hg, most of whom presented with acute target organ damage. Fenoldopam and nitroprusside lowered blood pressure safely to an average pressure of 176/105 mm Hg; highly significant dose-response relations were found for the 13 patients receiving fenoldopam and the 15 receiving nitroprusside. Volume and sodium, potassium, and creatinine concentrations were measured in freely voided urine specimens both before and during intravenous therapy. In the fenoldopam-treated patients, there were significant increases in urinary flow (92 +/- 21 to 168 +/- 37 ml/hr, p less than 0.003), sodium excretion (227 +/- 73 to 335 +/- 90 mu eq/min, p less than 0.001), and creatinine clearance (70 +/- 11 to 93 +/- 13 ml/hr, p less than 0.003). In the nitroprusside-treated group, however, all these parameters decreased, but not significantly. For direct comparison of the two agents, the increments in urinary flow rate (+76 +/- 20 vs. -16 +/- 15 ml/hr, fenoldopam vs. nitroprusside), sodium excretion (+109 +/- 28 vs. -39 +/- 28 mu eq/min), and creatinine clearance (+23 +/- 6 vs. -11 +/- 7 ml/min) were significantly greater (p less than 0.001 for each) in the fenoldopam-treated group. Significant differences were also obtained when these parameters were calculated as percentage increase over baseline. Fenoldopam and nitroprusside are effective therapies for severe, accelerated, or malignant hypertension, but fenoldopam had additional salutary renal effects in these patients.

Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa)

Aims Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. Methods and results Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0–3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. Conclusion Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.

Noninvasive method for determination of arterial compliance using Doppler echocardiography and subclavian pulse tracings. Validation and clinical application of a physiological model of the circulation.

BACKGROUND The Poiseuillian model of the arterial system currently applied in clinical physiology does not explain how arterial pressure is maintained during diastole after cessation of pulsatile aortic inflow. Arterial pressure-flow relations can be more accurately described by models that incorporate arterial viscoelastic properties such as arterial compliance. Continuous pressure and flow measurements are needed to evaluate these properties. Since the techniques used to date to acquire such data have been invasive, physiological models of the circulation that incorporate these properties have not been widely applied in the clinical setting. The purpose of this study was (1) to validate noninvasive methods for continuous measurement of central arterial pressure and flow and (2) to determine normal reference values for arterial compliance using physiological models of the circulation applied to the noninvasively acquired pressure and flow data. METHODS AND RESULTS Simultaneously acquired invasive and noninvasive aortic pressures (30 patients), flows (8 patients), and arterial mechanical properties (8 patients) were compared. Pressure was measured by high-fidelity catheter aortic micromanometer (invasive) and calibrated subclavian pulse tracing (noninvasive). Aortic inflow was determined from thermodilution-calibrated electromagnetic flow velocity data (invasive) and echo-Doppler data (noninvasive). Arterial compliance was determined for two- and three-element windkessel models of the circulation using the area method and an iterative procedure, respectively. Once validated, the noninvasive methodology was used to determine normal compliance values for a reference population of 70 subjects (age range, 20 to 81 years) with normal 24-hour ambulatory blood pressures and without Doppler-echocardiographic evidence for structural heart disease. The limits of agreement between invasive and noninvasive pressure data, compared at 10% intervals during ejection and nonejection, were narrow over a wide range of pressures, with no significant differences between methods. Invasive and noninvasive instantaneous aortic inflow values differed slightly but significantly at the start of ejection (P < .05), but during the latter 90% of ejection, values for the two methods were similar, with narrow limits of agreement. Total vascular resistance and arterial compliance values derived from invasive and noninvasive data were similar. Arterial compliance values for the normal population using the two-element model (C2E) ranged from 0.74 to 2.44 cm3/mm Hg (mean, 1.57 +/- 0.38 cm3/mm Hg), with a beat-to-beat variability of 5.2 +/- 3.9%. C2E decreased with increasing age (r = -.73, P < .001) and tended to be higher in men (1.67 +/- 0.41 cm3/mm Hg) than in women (1.51 +/- 0.35 cm3/mm Hg, P = .07). Compliance values for the three-element model (C3E) were predictably smaller than for the two-element model (mean, 1.23 +/- 0.30; range, 0.59 to 2.16 cm3/mm Hg, P < .001 versus C2E) but correlated with C2E values (r = .81, P < .001) and were also inversely related to age (r = -.56, P < .001). Ridge regression and principal component analyses both showed the compliance value to be a composite function whose variation could be best predicted by consideration of simultaneous values for five major hemodynamic determinants: heart rate, mean flow, mean aortic pressure, minimal diastolic pressure, and end-systolic pressure. Multivariate analysis revealed age and sex to be independent predictors of compliance (P < .01 for both). There were no differences in compliance between black and white subjects. CONCLUSIONS Noninvasive methods can be used to acquire the hemodynamic data necessary for clinical application of physiological models of the circulation that incorporate arterial viscoelastic properties such as arterial compliance. The strong inverse linear relation between model-based compliance estimates and age mandates incorporation of this demographic parameter in

Cerebral blood flow during the acute therapy of severe hypertension with oral clonidine

A major risk associated with the acute treatment of severe hypertension is a reduction in cerebral blood flow (CBF) with ischemic injury to the central nervous system. The authors studied CBF before and after the acute treatment of severe hypertension (diastolic blood pressure greater than 115 mm Hg) with clonidine in 13 patients. One patient did not reach goal blood pressure (diastolic blood pressure 105 mm Hg or a decrease by 30 mm Hg) after clonidine alone. In the remaining 12 patients, oral clonidine reduced supine blood pressure from 201.7 +/- 5.0/126.3 +/- 2.1 mm Hg to 149.4 +/- 5.3/96.8 +/- 1.7 mm Hg over an average time period of 85 +/- 7 minutes. Although mean CBF for the group did not change (72.6 +/- 4.2 v 73.7 +/- 3.5 mL/100 mg/min), a significant (greater than 10%) change occurred in 9 of the 12 patients (5 increases and 4 reductions). The magnitude and direction of the change were dependent upon initial CBF (r = -0.65, P less than .05); patients with low pretreatment CBF experienced an increase, whereas those with high initial flow exhibited a decrease. No significant adverse effects were observed. These data confirm previous reports that clonidine is effective in the acute treatment of severe hypertension and demonstrate that its effects on CBF are determined by the pretreatment levels of flow.

Absence of QTc prolongation with betrixaban: a randomized, double-blind, placebo- and positive-controlled thorough ECG study

Objective: To evaluate the effects of the anticoagulant betrixaban on individual heart rate-corrected QT (QTcI). Research design and methods: Ninety-six healthy adults were randomly assigned to single-dose betrixaban 80 and 140 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin 400 mg (positive control) in a four-period crossover study. Electrocardiograms were recorded at pre-dose and post-dose hours 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24. Main outcomes measures: An analysis of covariance determined the placebo-corrected, time-matched mean change from baseline QTcI at the 95% upper confidence interval (UCI; one-sided). The pre-specified clinically significant change for betrixaban-treated groups was > 10 ms (95% UCI, one-sided). Subjects were monitored for safety and tolerability. Results: Mean QTcI change was < 10 ms for both betrixaban groups at all time points; expected changes were observed for moxifloxacin, establishing assay sensitivity. Correlation between betrixaban plasma concentration and QTcI duration confirmed the absence of effect on QT. Conclusions: Betrixaban at therapeutic and supratherapeutic doses did not cause clinically relevant changes in QTcI intervals or other electrocardiographic parameters. Betrixaban was well tolerated.

Influence of Diuretic Therapy on the Clonidine Suppression Test

Moduretic has been reported to inhibit the suppression of plasma norepinephrine (NE) levels by the alpha2 adrenoceptor agonist, clonidine. To determine whether plasma volume reduction by hydrochlorothiazide (HCTZ) or antagonism of Na+/H+ exchange by amiloride (the constituents of Moduretic) is responsible, the authors performed a modified clonidine suppression test (CST) in nine normal volunteers (aged 25 ± 2 years), pretreated for 1 week with HCTZ 50 mg daily, amiloride 10 mg daily, or placebo, in a randomized, double‐blind, crossover study. Baseline characteristics were identical on all study days, except serum [K+] and weight, which were lowest on HCTZ (3.6 ± 0.2 mEq/L and 78.7 ± 2.5 kg), compared with amiloride (4.2 ± 0.1 mEq/L and 79.9 ± 2.4 kg) and placebo (4.0 ± 0.1 mEq/L and 80.2 ± 2.7 kg, P < .05). Oral clonidine (0.3 mg) produced a reduction in mean blood pressure by about 20%. Plasma norepinephrine levels were similar in patients receiving placebo, HCTZ, and amiloride (205 ± 18, 272 ± 40 and 277 ± 44 pg/mL, P > .20), and decreased significantly during CST. The maximal reduction for each subject averaged 72.7 ± 12.4%, 87.9 ± 3.8%, and 82.9 ± 5.7% for placebo, HCTZ, and amiloride. Clonidine also produced a four to seven‐fold increase in plasma growth hormone levels, reduced salivary flow by about 75%, and increased the level of sedation. There were no differences among the three pretreatment regimens in the effects of clonidine, indicating that diuretic therapy does not need to be systematically discontinued in patients undergoing CST.

PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B‐cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti‐inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole‐blood assays. The PD half‐life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B‐cell antigen receptor‐mediated B‐cell activation and 205 nM for inhibition of FcεRI‐mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti‐inflammatory activity of PRT062607 in the rat collagen‐induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once‐daily oral dosing.

ABSENCE OF QTC PROLONGATION WITH BETRIXABAN: A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND POSITIVE-CONTROLLED THOROUGH ECG STUDY

Betrixaban is an oral factor Xa inhibitor with a long half life, low renal clearance and is not metabolized by cytochrome P450 enzymes. Betrixaban is currently being studied for the prevention of venous thromboembolism in high risk acutely ill medical patients. The APEX trial is a randomized, double