A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion

Abstract

We have identified an agent (SP-303) that shows efficacy against in vivo cholera toxin-induced fluid secretion and in vitro cAMP-mediated Cl−secretion. Administration of cholera toxin to adult mice results in an increase in fluid accumulation (FA) in the small intestine (FA ratio = 0.63 vs. 1.86 in control vs. cholera toxin-treated animals, respectively). This elevation in FA induced by cholera toxin was significantly reduced (FA ratio = 0.70) in animals treated with a 100 mg/kg dose of SP-303 at the same time as the cholera treatment. Moreover, when SP-303 was administered 3 h after cholera toxin, a dose-dependent inhibition of FA levels was observed with a half-maximal inhibitory dose of 10 mg/kg. In Ussing chamber studies of Caco-2 or T84 monolayer preparations, SP-303 had a significant effect on both basal current and forskolin-stimulated Cl− current. SP-303 also induced an increase in resistance that paralleled the observed decrease in current. These data suggest that SP-303 has an inhibitory effect on cAMP-mediated Cl− and fluid secretion. Thus SP-303 may prove to be a useful broad-spectrum antidiarrheal agent.

Effect of Ethanol Extracts of Three Chinese Medicinal Plants With Anti-diarrheal Properties on Ion Transport of the Rat Intestinal Epithelia

“…TJ-14 was also shown to inhibit water secretion caused by cholera toxin (34,35). SP-303 derived from latex of the plant Croton lechleri, from South America, also has an effect on reducing the forskolin-stimulated Cl -current (36). The present study proves that ethanol extracts of Qinpi, Kushen, and Huanglian can reduce the short circuit current across the forskolin-activated rat ileal epithelia by affecting Na + , Cl -, or other ion movements in the rat intestinal epithelia.…”

Effect of Ethanol Extracts of Three Chinese Medicinal Plants with Laxative Properties on Ion Transport of the Rat Intestinal Epithelia

“…Fluctuation of the short-circuit current can be monitored and reflects changes of ion across the epithelia. 12,13) Using this method, our previous work revealed that the ethanol extracts of three Chinese medicinal plants had antidiarrheal properties, namely, Qinpi (Fraxini cortex), Kushen (Sophora flavescens, AITON), and Huanglian (Coptis teeta, WALLICH) affect Na ϩ or Cl Ϫ movement in the rat intestinal epithelia. 14) Since laxatives and antidiarrheal agents all act primarily on the intestinal tissue, the present study was aimed at discerning the effects of extracts from three Chinese medicinal plants with laxative characteristics on ion transport of the rat intestinal epithelia.…”

Profile of crofelemer for the symptomatic treatment of diarrhea in HIV-infected persons

“…When SP-303 was administered to the mice, the effectiveness of therapy was measured based on the amount of fluid accumulation in the small intestine after the mice were killed and dissected, and their intestines weighed (before and after excess fluid removal). 10 The investigators confirmed that the drug had significant effect on chloride channels, and, thus, fluid secretion, in vivo. 10 A subsequent trial in humans in India showed that crofelemer, compared to placebo, decreased stool volume in persons diagnosed with cholera.…”

“…10 The investigators confirmed that the drug had significant effect on chloride channels, and, thus, fluid secretion, in vivo. 10 A subsequent trial in humans in India showed that crofelemer, compared to placebo, decreased stool volume in persons diagnosed with cholera. 16 Another study published in the late 1990s was performed by Holodniy et al This time, humans were the subject of the double-blind randomized placebo-controlled Phase II study.…”

“…16 As a result, standard pharmacokinetic parameters have not been determined. 10 In addition, while crofelemer may have some in vitro effect on cytochrome P450 isozyme 3A4, the only documented in vivo effect to date is a 20% decreased exposure to lamivudine when crofelemer was dosed at 500 mg every 6 hours. 16 While in clinical trials, doses of crofelemer have ranged from 125 to 500 mg every 6-12 hours; the ADVENT trial determined the optimal dose of crofelemer to be 125 mg twice daily.…”