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A Two-Year Follow-up of Young Students with Bronchial Hyperresponsiveness To determine the possibility that asymptomatic bronchial hyperresponsiveness (BHR) develops into symptomatic asthma, a two-year follow-up study was conducted in 81 [...]

XueShuanTong, a lyophilized extract of Panax notoginsengroots (Sanqi) for intravenous administration, is extensively used as add-on therapy in the treatment of ischemic heart and cerebrovascular diseases and comprises therapeutically active ginsenosides. Potential for XueShuanTong–drug interactions was determined; the investigation focused on cytochrome P450 (CYP)3A induction and organic anion-transporting polypeptide (OATP)1B inhibition. Ginsenosides considerably bioavailable for drug interactions were identified by dosing XueShuanTong in human subjects and their interaction-related pharmacokinetics were determined. The CYP3A induction potential was determined by repeatedly dosing XueShuanTong for 15 days in human subjects and by treating cryopreserved human hepatocytes with circulating ginsenosides; midazolam served as a probe substrate. Joint inhibition of OATP1B by XueShuanTong ginsenosides was assessed in vitro, and the data were processed using the Chou–Talalay method. Samples were analyzed by liquid chromatography/mass spectrometry. Ginsenosides Rb1, Rd, and Rg1and notoginsenoside R1were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb1and Rd, long terminal half-lives (32‒57 and 58‒307 h, respectively) and low unbound fractions in plasma (0.8%‒2.9% and 0.4%‒3.0%, respectively). Dosing XueShuanTong did not induce CYP3A. Based on the pharmacokinetics and inhibitory potency of the ginsenosides, XueShuanTong was predicted to have high potential for OATP1B3-mediated drug interactions (attributed chiefly to ginsenoside Rb1) suggesting the need for further model-based determination of the interaction potential for XueShuanTong and, if necessary, a clinical drug interaction study. Increased awareness of ginsenosides’ pharmacokinetics and XueShuanTong–drug interaction potential will help ensure the safe use of XueShuanTong and coadministered synthetic drugs.

The Nav1.7 channel represents a promising target for pain relief. In the recent decades, a number of Nav1.7 channel inhibitors have been developed. According to the effects on channel kinetics, these inhibitors could be divided into two major classes: reducing activation or enhancing inactivation. To date, however, only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy, thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state. In the present study, we investigated the action mechanisms of a recently clinically confirmed inhibitor CNV1014802 using both electrophysiology and site-directed mutagenesis. We found that CNV1014802 inhibited Nav1.7 channels through stabilizing a nonconductive inactivated state. When the cells expressing Nav1.7 channels were hold at 70 mV or 120 mV, the half maximal inhibitory concentration (IC50) values (with 95% confidence limits) were 1.77 (1.20–2.33) and 71.66 (46.85–96.48) μmol/L, respectively. This drug caused dramatic hyperpolarizing shift of channel inactivation but did not affect activation. Moreover, CNV1014802 accelerated the onset of inactivation and delayed the recovery from inactivation. Notably, application of CNV1014802 (30 μmol/L) could rescue the Nav1.7 mutations expressed in CHO cells that cause paroxysmal extreme pain disorder (PEPD), thereby restoring the impaired inactivation to those of the wild-type channel. Our study demonstrates that CNV1014802 enhances the inactivation but does not reduce the activation of Nav1.7 channels, suggesting that identifying inhibitors that preferentially affect inactivation is a promising approach for developing drugs targeting Nav1.7.