To assess the effects of unilateral nephrectomy, we evaluated renal function and hypertension in kidney donors who had had nephrectomies 10 years ago or more and siblings who had not had nephrectomies. No statistically significant difference was found between the prevalence of hypertension in donors and siblings. Serum creatinine concentrations were 20% higher in donors and creatinine clearances, 20% lower than corresponding values in siblings. Twenty-four-hour urinary protein excretion increased in all donors after nephrectomy and was more marked in men than women. Of the 38 donors, 12 excreted more than 150 mg/24 h of urinary protein, but only 2 excreted more than 300 mg/24 h. The presence of proteinuria did not correlate with the presence of hypertension, level of renal function, or time since nephrectomy. We conclude that, with the exception of mild proteinuria of unknown clinical significance, unilateral nephrectomy is not associated with adverse effects on kidney function.

Carvedilol is a relatively new drug with beta- and alpha 1-receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple-dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(-)-carvedilol, R(+)-carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice-daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose-proportional increases in steady-state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady-state plasma concentrations of the active metabolites also increased in a dose-proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25-50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.

Electrocardiographic (ECG) recordings from 3 placebo-controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls.

Nitrated oleic acid (NO2-OA) was first identified in 2003, and after the characterization of its formation and thiol reactivity, it was used as a prototypical molecule to investigate the physiological actions of endogenous nitrated fatty acids (NO2-FA). Based on in vitro observations showing significant activation of cytoprotective and anti-inflammatory signaling responses by NO2-FA, experiments were designed to determine their pharmacological potential. Supported by strong intellectual protection and favorable pharmacokinetic and pharmacodynamic data, 10-NO2-OA (CXA-10) underwent pharmaceutical development as a drug to treat fibrotic and inflammatory diseases. NO2-FA are at the intersection of three unconventional drug candidate classes that include 1) fatty acids, 2) metabolic intermediates and 3) electrophilic molecules. These three groups use different scaffolds for drug development, are characterized by broad activities and are individually gaining traction as alternatives to mono-target drug therapies. In particular, NO2-FA share key characteristics with currently approved pharmacological agents regarding reactivity, distribution, and mechanism of action. This review first presents the characteristics, liabilities, and opportunities that these different drug candidate classes display, and then discusses these issues in the context of current progress in the preclinical and clinical development of NO2-FA as drugs. Lessons learned from the novel approaches presented herein were considered early on during development to structurally define and improve NO2-FA and their disease targets.