Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator,VX-770

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P_o) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl⁻ secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by ≈10-fold, to ≈50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na⁺ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.     

Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension

Background

Renal sympathetic denervation (RDN) reduces sympathetic activity and blood pressure (BP) in patients with resistant hypertension. The present study aimed to investigate the effects of RDN on HR and other electrocardiographic parameters.

Methods

136 patients aged 62.2 ± 0.8 years (58% male, BP 177 ± 2 / 93 ± 1 mm Hg) with resistant hypertension underwent RDN. BP and a 12-lead electrocardiogram (ECG) were recorded before, 3 months (n = 127), and 6 months (n = 88) after RDN.

Results

After 3 months (3 M) and 6 months (6 M), systolic BP was reduced by 25.5 ± 2.4 mm Hg (p < 0.0001) and 28.1 ± 3 mm Hg (p < 0.0001). HR at baseline was 66.1 ± 1 beats per minute (bpm) and was reduced by 2.6 ± 0.8 bpm after 3 months (p = 0.001) and 2.1 ± 1.1 bpm after 6 months (p = 0.046). Patients with HR at baseline between 60–71 bpm and ≥ 71 bpm had a reduction of 2.9 ± 7.6 bpm (p = 0.008) and 9.0 ± 8.6 bpm (p < 0.0001), respectively, whereas in patients with baseline HR < 60 bpm HR slightly increased after 3 months (2.7 ± 8.4 bpm; p = 0.035). Neither baseline HR nor change of HR correlated with the reduction of systolic BP. The PR interval was prolonged by 11.3 ± 2.5 ms (p < 0.0001) and 10.3 ± 2.5 ms (p < 0.0001) at 3 and 6 months after RDN, respectively.

Conclusions

Renal sympathetic denervation reduced heart rate and the PR interval as indicators of cardiac autonomic activity.     

Telemedicine and health policy: is there life after the recissions?

Recent Congressional budget recissions are likely to reduce the development of telemedicine in the United States, yet federal support is considered essential for such development. Both the executive and the legislative branches continue to show interest in the field. Pressure is mounting for research data documenting the effects of telemedicine on health care cost, quality, and access. Other policy issues arise from the recent revolution in the telecommunications industry and changes in health care delivery.     

Seromucosal transport of intravenously administered carbamazepine is not enhanced by oral doses of activated charcoal in rats

The fate of carbamazepine after intravenous injection in rats (n = 24) and the influence of activated charcoal on the kinetics was investigated. After randomization to four groups (n = 6, each), plasma concentration and the quantities of carbamazepine and metabolites excreted into bile, urine and intestine were determined using an in situ perfusion model of the small intestine (Ringer's solution) with or without orally administered activated charcoal (AC+; AC-) and with or without bile duct cannulation (BD+; BD-). The cumulative amount of carbamazepine and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 15% in BD- animals and about 3% in BD+ animals. About 20% of the dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 159 min. to 194 min. within the four treatment groups without statistical significant difference (P = 0.751). Correspondingly, the area under the curve did not vary significantly and ranged between 1.13 and 1.41 g/min./l (P = 0.378). Excretion of carbamazepine and metabolites into urine varied between 3% and 6% of dose within all groups and showed close correlation with diuresis. In an identical experimental approach using a 2-fold intestinal perfusion rate (50 ml/hr; n = 8), no fundamental changes compared to the main experiment regarding pharmacokinetics of carbamazepine were observed. The lack of effect of activated charcoal on the elimination of carbamazepine and metabolites must be contributed to the small amount of the drug being exsorbed into the intestine and may be further influenced by reduced intestinal permeability of carbamazepine and metabolites or inadequate luminal stirring.