Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

UNLABELLED: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. INTRODUCTION: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. METHODS: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. RESULTS: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. CONCLUSION: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Protective effect of 17beta-estradiol on ischemic acute renal failure through the PI3K/Akt/eNOS pathway.

Estrogens attenuate renal injury induced by ischemia/reperfusion (I/R), an effect that is related to nitric oxide production in the post-ischemic kidney. The compound 17beta-estradiol (E(2)-beta) acting via estrogen receptors (ERs) is known to activate endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. We determined if this pathway contributes to the renoprotective effect of E(2)-beta in the uninephrectomized ischemia reperfusion rat model of acute renal injury. Treatment with E(2)-beta suppressed the I/R-induced increases in blood urea nitrogen, plasma creatinine, urine flow, and fractional excretion of sodium while augmenting creatinine clearance, renal blood flow, and urine osmolality, indicating attenuation of renal injury. Phosphorylation of Akt and eNOS protein was significantly increased 30-60 min after reperfusion in estradiol-treated compared to vehicle-treated rats. The protective effects of E(2)-beta and protein phosphorylation were reversed by the PI3K inhibitor wortmannin or the ER antagonist tamoxifen. Furthermore, the E(2)-beta-induced renoprotective effects were not seen in eNOS knockout mice with renal injury. We conclude that the E(2)-beta-induced renoprotective effect is due to activation of the PI3K/Akt pathway followed by increased eNOS phosphorylation in the post-ischemic kidney.

Effects of alpha-lipoic acid on deoxycorticosterone acetate-salt-induced hypertension in rats.

We investigated the potential of natural occurring antioxidant alpha-lipoic acid to prevent hypertension and hypertensive tissue injury induced by deoxycorticosterone acetate (DOCA) and salt in rats. Two weeks after the start of DOCA-salt treatment, the rats were given alpha-lipoic acid (10 or 100 mg/kg/day, s.c.) or its vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as sham-operated controls. In vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3-4 weeks. Daily administration of 100 mg/kg alpha-lipoic acid for 2 weeks suppressed the increase in systolic blood pressure, whereas 10 mg/kg alpha-lipoic acid did not affect the progression of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was morphometrically evaluated at 4 weeks, there were significant increases in media cross-sectional area in vehicle-treated DOCA-salt rats compared with sham-operated rats. The development of vascular hypertrophy was markedly suppressed by alpha-lipoic acid at 100 mg/kg but not at 10 mg/kg. Histopathological examination of the kidney in vehicle-treated DOCA-salt rats revealed fibrinoid-like necrosis in glomeruli and thickening of small arteries. In these animals, creatinine clearance decreased, and fractional excretion of Na(+), urinary excretion of protein and N-acetyl-beta-glucosaminidase increased. Such renal lesions and dysfunctions were ameliorated in DOCA-salt rats given alpha-lipoic acid. In addition, a marked increase in endothelin-1 content in both the aorta and kidney was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. Significant attenuation of this increase occurred in alpha-lipoic acid-treated DOCA-salt rats. These results suggest that administration of alpha-lipoic acid to DOCA-salt hypertensive rats lessens the increased blood pressure and protects against renal and vascular injuries, possibly through the suppression of renal and vascular endothelin-1 overproduction.

Dependence of power Doppler image on a high pass filter instrumented in ultrasound machine.

The aim of this study was to examine the influence of flow velocity, beam incident angle and a wall motion filter on the intensity of power Doppler image of steady flow in vitro. Power Doppler images of flow were recorded using a 7.5-MHz linear transducer with the fixed repetition frequency, gain and frame rate settings at the velocity levels of 15, 20, 35 and 65 cm/s with the beam incident angles of 30 degrees and 60 degrees. The power (P) of received Doppler signal was digitized to 25 gray values (G) for imaging using a wall motion filter with the transfer function: G = a x log P + b (a, b = constant values). Image intensity was measured at the center of the flow image off-line and compared with the flow velocity measured by conventional pulsed wave Doppler. Below the Nyquist limit, G increased as velocity increased, and G with the incident angle 30 degrees was lower than those with 60 degrees. Overall relationship between the Doppler shift frequency and the image intensity exhibited an excellent correlation when fit to the theoretical curve derived from the filter property (r = 0.97). The signal intensity of power Doppler image of flow depends upon the mean Doppler frequency shift or the flow velocity and was clearly affected by the wall motion filter.

Effects of short-term administration of sublingual nifedipine on coronary arterial wall elastic properties: evaluation by intravascular ultrasound.

Intravascular ultrasound is suited to measure coronary cross-sectional anatomy. Therefore the regional coronary wall elasticity was evaluated by examining the response to nifedipine. In 20 patients, coronary ostial pressure (P) and intravascular ultrasound images were simultaneously recorded before and after sublingual administration of 10 mg nifedipine. We identified the perimeter of the vessel wall, with normal or atherosclerotic plaque, on ultrasound image. At the atherosclerotic site, we measured segmental perimeter (S) for each normal or plaque segment. The ratio of the individual segment length (delta S/delta P) and cyclic variation of cross-sectional area (delta A/delta P) per mm Hg increase in P were calculated. Nifedipine decreased pressure (133/79-120/73 mm Hg) and increased heart rate (79-82 beats/min). After nifedipine, delta A/delta P increased from 8.5 +/- 10.2 x 10(-3) to 16.5 +/- 14.4 x 10(-3) mm2/mm Hg at 20 normal sites (p = 0.005) but was unchanged at 17 atherosclerotic sites (6.6 +/- 7.0 x 10(-3) to 6.7 +/- 7.1 x 10(-3) mm2/mm Hg). Nifedipine increased delta S/delta P in normal segments (4.5 +/- 8.7 x 10(-3) to 9.9 +/- 10.9 x 10(-3) mm/mm Hg; p = 0.02) but produced no change in segments with calcified or soft plaque (-1.1 +/- 0.3 x 10(-3) to 1.4 +/- 1.6 x 10(-3) mm/mm Hg and 5.0 +/- 3.6 x 10(-3) to 6.1 +/- 4.8 x 10(-3) mm/mm Hg, respectively). This study demonstrated that nifedipine increases regional coronary arterial elasticity at normal segments but not at that containing mildly atherosclerotic segment, and likely that the arterial wall function indicated by the response to nifedipine was impaired at an early stage of atherosclerosis.

A case of subclavian steal syndrome with a specific form of obstruction of the right proximal subclavian artery.

We experienced a case of subclavian steal syndrome (SSS) with a specific form of obstruction of the right proximal subclavian artery. The patient was a 44-year-old man who complained of numbness of the right hand. Right carotid-subclavian artery anastomosis was performed under general anesthesia. The obstructed segment was a fibrous cord, 3.5 cm in length and 2.0 mm in diameter. Postoperatively, the patient was free from the symptom. In the Japanese literature, 73 cases of SSS were reported from 1965 to 1986, and the etiology was mentioned in 64 cases. In 28 cases the cause was aortitis syndrome (43.8%), in 22 cases arteriosclerosis (34.4%), in 13 cases congenital malformation (20.3%), and in 1 case iatrogenic lesion (1.6%). These data indicated that SSS caused by congenital malformation was not so rare as previously believed. Of 13 cases with congenital malformation, our case and 3 other cases had similar aspect in clinical features. All 4 patients were middle-aged men (aged 34, 26, 45 and 44 years) with a fibrous cord at the proximal portion of the right subclavian artery. None had any other cardiovascular anomalies.