Background — Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen ( AGT ) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies. Methods and Results — Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng · kg −1 · min −1 ) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular ( P =0.0002) and adrenal ( P =0.002) responses to infused exogenous Ang II were associated with the AGT −6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT −6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT −6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT −6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the −6AA genotype was present in only 17.8% ( P =0.001). Conclusions — A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT −6A genotype results in increased tissue expression of angiotensinogen and Ang II.

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SoluMatrix® meloxicam has been developed using SoluMatrix Fine Particle Technology™ to produce a meloxicam drug product with enhanced absorption properties to enable treatment at lower doses than available oral meloxicam drug products. This follows recognition of serious dose-dependent adverse events (AEs) associated with nonsteroidal anti-inflammatory drugs, including meloxicam. This study investigated the pharmacokinetic (PK) properties of SoluMatrix meloxicam 5-mg (fasting conditions) and 10-mg capsules (fasting and fed conditions) and compared SoluMatrix meloxicam 10-mg capsules with meloxicam 15-mg tablets under fasting conditions. This four-period crossover study randomized 28 healthy adult participants to receive single doses of SoluMatrix meloxicam 5-mg capsules (fasting) and 10-mg capsules (fasting or fed) and meloxicam tablets 15 mg (fasting). Meloxicam plasma concentrations were assessed through 96 h postdose. Safety was assessed. Twenty-five participants (89.3 %) completed the study. Under fasting conditions, SoluMatrix meloxicam 10 mg [1252.8 (254.22) ng/mL] produced similar meloxicam mean (standard deviation (SD)) maximum plasma concentrations vs meloxicam 15-mg tablets [1288.8 (424.40) ng/mL]. The overall mean (SD) systemic meloxicam exposure was 33 % lower for SoluMatrix meloxicam 10 mg [29,173.01 (11,042.09) ng*h/mL] vs meloxicam 15-mg tablets [40,875.6 (11,733.47) ng*h/mL]. The median time to maximum plasma meloxicam levels occurred earlier following SoluMatrix meloxicam 5 mg (2.0 h) and 10 mg (2.0 h) administration vs meloxicam 15-mg tablets (4.0 h). Few study-medication-related AEs were reported. SoluMatrix meloxicam 10 mg was more rapidly absorbed and associated with a lower overall exposure compared with meloxicam 15-mg tablets in this study in healthy adults under fasting conditions.

Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.