Pharmacokinetics, Safety Profile, and Efficacy of Aliskiren in Pediatric Patients With Hypertension.
Pharmacokinetics, Safety Profile, and Efficacy of Aliskiren in Pediatric Patients With Hypertension.
Clin Pediatr (Phila). 2013 Apr 22;
Sullivan JE, Keefe D, Zhou Y, Satlin L, Fang H, Yan JH
Objective. To assess the pharmacokinetics (PK) and safety profile of aliskiren in pediatric patients (6-17 years old) with hypertension. Methods. Patients were randomized to a single weight-based dose of either 2 mg/kg (n = 19) or 6 mg/kg (n = 20) of aliskiren daily for 8 days. The PK, pharmacodynamics, safety profile, and efficacy of aliskiren were assessed. Results. Of the 39 randomized patients, 37 (94.9%) completed the study. Aliskiren plasma concentration (maximum plasma concentration and area under the plasma concentration-time curve) increased dose dependently, achieving peak concentrations in 1 to 2 hours, and tmax was comparable across the dose and age groups. Treatment-emergent adverse events (AEs) were reported in 18 (46.2%) patients, with headache, abdominal pain, and nausea being the most frequent. Conclusions. Aliskiren 2 mg/kg and 6 mg/kg daily showed dose-dependent increases in the plasma concentration. The drug was well tolerated in hypertensive children aged 6 to 17 years. AEs were generally mild and not related to either the drug or the dose. HubMed – drug
Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in an Ultra-Short-Term Skin Carcinogenesis Bioassay Using rasH2 Mice.
Vet Pathol. 2013 Apr 22;
Kawabe M, Urano K, Suguro M, Numano T, Taguchi F, Tsutsumi H, Furukawa F
Assessment of the skin tumor-promoting potential of 12-O-tetradecanoylphorbol-13-acetate (TPA) after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) was conducted using rasH2 transgenic (Tg) mice and their nontransgenic (non-Tg) littermates. Mice were treated with DMBA (50 ?g/100 ?L acetone) on clipped back skin at the commencement of the study, and 1 week thereafter, TPA was applied at 8 ?g/200 ?L or 4 ?g/200 ?L acetone, once or twice weekly, for 7 weeks. Skin nodules were observed in the rasH2 Tg mice from week 4, and the incidence reached 100% at weeks 5 and 6. The number of skin nodules (multiplicity) in the 8-?g twice-weekly, 8-?g once-weekly, 4-?g twice-weekly, and 4-?g once-weekly groups was 62.4, 46.2, 62.6, and 36.9, respectively. The non-Tg mice also developed skin nodules, but the sensitivity to induction in the rasH2 Tg mice was higher. No nodules were observed in the acetone groups, but single nodules were apparent in the no-treatment rasH2 Tg and non-Tg groups. In conclusion, skin promotion effects could be detected within only 8 weeks in the rasH2 mice, and the concentration of 4 ?g TPA once weekly was sufficient as a positive control. This short-term skin carcinogenesis bioassay using rasH2 mice could represent a useful tool for the assessment of drug and chemical safety with cutaneous treatment. HubMed – drug
The effect of long-term left ventricular assist device support on myocardial sympathetic activity in patients with non-ischaemic dilated cardiomyopathy.
Eur J Heart Fail. 2013 Apr 21;
George RS, Birks EJ, Cheetham A, Webb C, Smolenski RT, Khaghani A, Yacoub MH, Kelion A
AIMS: Dilated cardiomyopathy (DCM) patients have abundant levels of norepinephrine secondary to failure of the norepinephrine transporter uptake mechanism. Little is known about the effects of an LV assist device (LVAD) on cardiac sympathetic innervations and norepinephrine transporter dysfunction. This study examines the effects of continuous-flow HeartMate II LVAD on cardiac sympathetic innervations using [(123)I]metaiodobenzylguanidine ([(123)I]MIBG) nuclear imaging. METHODS AND RESULTS: After injecting 431 ± 21 MBq of [(123)I]MIBG, planar scintigraphy was performed at 15 min and 4 h in 14 consecutive non-diabetic non-ischaemic DCM patients. Scans were executed early post-LVAD implantation (T1) and prior to either device explantation for myocardial recovery or transplant listing (T2). [(123)I]MIBG measured parameters included early and delayed heart-mediastinum (H/M) ratios and washout rate (W/O). Catecholamine levels were measured using liquid chromatography-mass spectrometry. Following 208.4 ± 85.5 days of LVAD support, both early and delayed H/M ratios increased by 42.1% (P < 0.001) and 54.7% (P < 0.001), respectively. The W/O rate decreased by 46% (P = 0.003). Plasma norepinephrine, epinephrine, and dopamine decreased significantly in correlation with [(123)I]MIBG parameters. Ten patients had recovered and had their device explanted as they had demonstrated a higher percentage change in delayed H/M ratio, W/O rate, and norepinephrine levels. Linear regression analysis revealed a strong correlation between percentage changes in both norepinephrine and epinephrine and myocardial recovery. CONCLUSION: Combination therapy with LVAD and drug resulted in enhancement of [(123)I]MIBG uptake in DCM patients. HubMed – drug