Antidiarrheal and antispasmodic activities of Trillium govanianum rhizomes extract: involvement of calcium channel blockade.

The antidiarrheal effect of methanolic extract of Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae) was studied at doses of 12.5, 25, and 50 mg/kg in different animal models of diarrhea including castor oil (6 mL/kg), magnesium sulfate (2 gm/kg), sodium picosulfate (2 mL/kg) and lactitol (0.25 mL/kg). The antispasmodic effect of T. govanianum was studied on isolated rabbit's jejunum, using acetylcholine as tissue stabiliser and verapamil as calcium channel blocker. T. govanianum attenuated the diarrhea by producing a significant decrease in the number and weight of stool, and an increase in stool latency time. T. govanianum completely inhibited both spontaneous as well as high potassium induced contractions of isolated rabbit's jejunum, which was analogous to verapamil. Moreover, T. govanianum produced a right shift in calcium concentration response curve, confirming its calcium channel blocking activity. These findings provide scientific ground to its medicinal use in diarrhea and gut spasms.

Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes.

Changrolin (2, 6-bis[pyrrolidin-1-ylmethyl]-4-[quinazolin-4-ylamino] phenol) is an anti-arrhythmic drug derived from ß-dichroine, an active component of the Chinese medicinal herb, Dichroa febrifuga Lour. To elucidate the mechanism underlying the anti-arrhythmic effect of changrolin, we used the whole-cell patch-clamp technique to characterize the electrophysiological actions of changrolin in isolated rat cardiomyocytes. In this study, changrolin inhibited delayed rectified K(+) currents (I(K)) in a concentration-dependent manner with inhibiting the current by 11.9%±4.7%, 27.8%±3.4%, 31.5%±3.6% and 40.8%±3.7% at 10, 30, 100 and 300 µM, respectively (n=7-8). Changrolin was less effective against transient outward K(+) currents (I(to)), and only showed significantly inhibitory effect at the highest concentration (300 µM). Changrolin also induced a concentration-dependent inhibition of sodium currents (I(Na)) with an IC(50) of 10.19 µM (Hill coefficient=-1.727, n=6-7). In addition, changrolin exerted a holding potential-dependent block on Na(+) channels, produced a hyperpolarizing shift in the steady-state inactivation curve, as well as exhibited a marked frequency-dependent component to the blockade of Na(+) channels. Finally, calcium currents (I(Ca)) was decreased by changrolin in a concentration-dependent manner with an estimated IC(50) of 74.73 µM (Hill coefficient=-0.9082, n=6). In conclusion, changrolin blocks Na(+) and Ca(2+) channels, and also blocks K(+) channels (I(to) and I(K)) to some extent. Notably, changrolin preferentially blocks the inactivated state of Na(+) channels. These effects lead to a modification of electromechanical function and likely contribute to the termination of arrhythmia.

Safety Pharmacology Society: 8th annual meeting.

Of the numerous topics discussed during the eighth annual meeting of the Safety Pharmacology (SP) Society the author identified the following key topics: i) the impact of hERG (human ether-à-go-go related gene) channel data on drug development, ii) safety evaluation of biological products, iii) opportunities and expectations from SP, iv) human stem cell derived cardiomyocytes for safety assessment, v) role of cellular calcium pathways in drug-induced arrhythmias, vi) collaboration initiatives for finding solutions to cardiac repolarisation and other recognised SP risks, vii) Pharma and FDA perspectives on ICH S7B guideline, viii) joint PhRMA-FDA dialogue on drug abuse potential assessment, ix) frontloading SP strategies for mitigating non-clinical and clinical attrition; and x) approaches to measure non-clinical assay predictability for human outcome. The establishment of consortia to accelerate the solution of critical SP issues and the implementation of Frontloading SP or Exploratory SP strategies for an early selection of safe clinical candidates are promising avenues for consolidating SP as an indispensable drug development discipline and for transforming established regulatory SP investigations into a risk-known exercise.