1: World J Gastroenterol. 2003 Aug;9(8):1804-7.

Contractile effects and intracellular Ca2+ signalling induced by emodin in circular smooth muscle cells of rat colon.

Ma T, Qi QH, Yang WX, Xu J, Dong ZL.
Department of Surgery, General Hospital of Tianjin Medical University, Tianjin , China .

AIM: To investigate whether emodin has any effects on circular smooth muscle cells of rat colon and to examine the mechanism underlying its effect. METHODS: Smooth muscle cells were isolated from the circular muscle layer of Wistar rat colon and the cell length was measured by computerized image micrometry. Intracellular Ca(2+) ([Ca(2+)]i) signalling was studied in smooth muscle cells using Ca(2+) indicator Fluo-3 AM on a laser-scanning confocal microscope. RESULTS: Emodin dose-dependently induced smooth muscle cells contraction. The contractile responses induced by emodin were inhibited by preincubation of the cells with ML-7 (an inhibitor of MLCK). Emodin caused a large, transient increase in [Ca(2+)]i followed by a sustained elevation in [Ca(2+)]i. The emodin -induced increase in [Ca(2+)]i was unaffected by nifedipine, a voltage-gated Ca(2+)-channel antagonist, and the sustained phase of the rising of [Ca(2+)]i was attenuated by extracellular Ca(2+) removal with EGTA solution. Inhibiting Ca(2+) release from ryanodine-sensitive intracellular stores by ryanodine reduced the peak increase in [Ca(2+)]i. Using heparin, an antagonist of IP(3)R, almost abolished the peak increase in [Ca(2+)]i. CONCLUSION: Emodin has a direct excitatory effect on circular smooth muscle cells in rat colon mediated via Ca(2+)/CaM dependent pathways. Furthermore, emodin-induced peak [Ca(2+)]i increase may be attributable to the Ca(2+) release from IP(3) sensitive stores, which further promote Ca(2+) release from ryanodine-sensitive stores through CICR mechanism. Additionally, Ca(2+) influx from extracellular medium contributes to the sustained increase in [Ca(2+)]i.

2: Biol Pharm Bull. 2002 Dec;25(12):1608-13.

Permeation-enhancing effect of aloe-emodin anthrone on water-soluble and poorly permeable compounds in rat colonic mucosa.

Kai M, Hayashi K, Kaida I, Aki H, Yamamoto M.
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University , Japan .

The aims of this study were to examine the enhancing effects of aloe-emodin anthrone (AEA) on the colonic membrane permeability of water-soluble and poorly permeable compounds and to clarify the mechanism of the permeation-enhancing activity of AEA. The permeation-enhancing activity of AEA was estimated from changes in the permeability coefficient of 5(6)-carboxyfluorescein (CF) in rat colonic mucosa using a Ussing-type chamber. Various inhibitors were used to investigate the mechanism of action of AEA. The structural change in the membrane and the cytotoxicity of AEA in the intestinal mucosa were evaluated by measuring the electrical resistance of the membrane (R(m)) and lactate dehydrogenase (LDH) activity, respectively. AEA significantly increased the permeation of CF in a dose-dependent manner. The enhanced permeability was significantly suppressed by a histamine H(1) receptor antagonist, pyrilamine, and a mast cell stabilizer, ketotifen, but not by a histamine H(2) receptor antagonist, cimetidine. The enhancing effect was also inhibited by an inhibitor of protein kinase C (PKC). Potential difference and short-circuit current values decreased, while R(m) values remained constant throughout the experiment. The addition of AEA to the mucosal solution decreased R(m) to 30%, but then remained constant. LDH activity with AEA was not significantly different from that of the control. In conclusion, AEA is a candidate for effective absorption enhancers without damage of the membrane and cytotoxicity. We propose that AEA stimulates mast cells within the colonic mucosa to release histamine, which probably bind to the H(1) receptor. The intracellular PKC route activated by H(1) receptor activation enhances the permeability of water-soluble and poorly permeable drugs via opening of tight junctions in rat colonic membrane.

3: Yao Xue Xue Bao. 1998 May;33(5):321-5.

4: Life Sci. 2001 Sep 7;69(16):1871-7.

Laxatives abuse has been associated with an increased risk for colon cancer. However, little is known about laxatives long-term carcinogenic potential in experimental studies. The present study was designed to investigate the effects of bisacodyl (4.3 and 43 mg/kg) and cascara (140 and 420 mg/kg) on azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors. Animals, divided in 10 groups were treated with AOM and laxatives (alone or in combination) for 13 weeks. At the end of treatment animals were killed and the colon removed and analysed for the determination of ACF and tumors. Bisacodyl (4.3 and 43 mg/kg), given alone, did not induce the development of colonic ACF and tumors. Bisacodyl (4.3 mg/kg) coupled with AOM increased the number of crypt per focus, but not the number of tumors. Bisacodyl (43 mg/kg) significantly increased the number of crypt per focus and tumors. Cascara (140 and 420 mg/kg) did not induce the development of colonic ACF and tumors and did not modify the number of AOM-induced ACF and tumors. The results of the present study indicate a possible promoting effect of bisacodyl on rat colon carcinogenesis (especially at higher doses) and absence of any promoting or initiating activity of a laxative and diarrhoeal dose of cascara.

5: J Pharm Pharmacol. 1999 Jan;51(1):93-5.

This study was performed to determine whether intracaecally administered rhein anthrone and anthraquinones such as aloe-emodin, chrysophanol, emodin or rhein synergistically enhance the purgative action as has been observed for rhein anthrone and aloe-emodin anthrone. These anthraquinones were less potent than rhein anthrone. An equimolar mixture of aloe-emodin and rhein anthrone had synergistic potentiating effects because the ED50 value (50% purgative dose) of the combination was smaller than that calculated additively from the ED50 values of aloe-emodin and rhein anthrone. An equimolar mixture of other anthraquinones and rhein anthrone tended to potentiate the purgative action. These results confirmed that rhein anthrone and aloe-emodin synergistically exert a purgative action as has been observed for rhein anthrone and aloe-emodin anthrone.

6: Eur J Pharmacol. 1997 Mar 26;323(1):93-7.

The role of constitutive and inducible nitric oxide (NO) synthase in rats treated with senna and cascara was studied. Senna (60 mg/kg p.o.) and cascara (800 mg/kg p.o.) ex vivo significantly increased Ca(2+)-dependent constitutive NO synthase activity in the rat colon. Induction of NO synthase (12% of the total NO synthase) was associated with cascara, but not senna, administration. Dexamethasone (0.03-0.3 mg/kg i.p.), which inhibits the expression of inducible NO synthase, significantly and dose-dependently reduced cascara-(but not senna-) induced diarrhoea and colonic fluid secretion. These findings suggest that senna probably exerts its laxative effect through stimulation of the constitutive isoform of NO synthase, while the inducible isoform of NO synthase also seems to be involved in the laxative effect of cascara.

7: J Pharm Pharmacol. 1997 Jan;49(1):22-5.

This study aimed to explore the mechanism involved in the synergistic purgative action of aloe-emodin anthrone and rhein anthrone, the active metabolites of sennoside C. Aloe-emodin anthrone and rhein anthrone, and their equimolar mixture, induced excretion of an approximately equal number of faeces by intracaecal administration at a dose of 23.2 mumol kg- 1 in mice (= 1.0 standard dose). The number of wet faeces induced by aloe-emodin anthrone was less than those of rhein anthrone and the mixture. At the same dose, rhein anthrone and the mixture significantly stimulated large intestinal propulsion, though aloe-emodin anthrone had little stimulatory effect. Aloe-emodin anthrone and rhein anthrone decreased net water absorption but could not reverse it to the net secretion at 1/2 dose. The mixture significantly decreased net water absorption and reversed it to the net secretion at this dose. These anthrones did not stimulate mucus secretion in the colon at 1/2 dose. We concluded that the synergistic purgative effect of aloe-emodin anthrone and rhein anthrone in mice results from synergistic stimulation of large intestinal transit and large intestinal water secretion.

8: Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994 Jul;14(7):429-31.

[Study on effect of emodin on the isolated intestinal smooth muscle of guinea-pigs]

Jin ZH, Ma DL, Lin XZ.
Dept. of Pharmacology, Tianjin Medical College .

Emodin is an active principle of Rheum palmatum. It is reported that emodin possesses antibiotic and antineoplastic functions. The effect of emodin action on the isolated intestinal smooth muscle of guinea-pigs were dose dependent. When the dose of emodin was less than 29.6 mumol/L, the contraction effect enhanced obviously with increasing dosage; but whenever the dose increased to more than 29.6 mumol/L, on the contrary, the effect decreased gradually and ceased finally. Emodin with appropriate concentration (14.8 mumol/L) strengthened the effect of acetylcholine (Ach) on the isolated ileum and large intestine of guinea-pigs (P < 0.05 and P < 0.01). But high concentration of emodin could reduce even completely antagonize the effect of Ach. Under such condition, CaCl2 could restore the effect of Ach on the smooth muscle. It is suggested that emodin has biphasic regulatory effect on the intestinal smooth muscle, and its effect is related to calcium ion.

9: Prostaglandins. 1983 Oct;26(4):557-62.

The effect of aloin and 1,8 dioxyanthraquinone on the release of prostaglandin-like material (PG) from rat isolated colon has been investigated. Orally administered aloin and 1,8 dioxyanthraquinone stimulates PG production by subsequently isolated segments of colon. Indomethacin was able to prevent this increased production of PG. These results suggest that the laxative properties of aloin and 1,8 dioxyanthraquinone may depend, at least in part, on increased prostaglandin synthesis by the intestinal tissue.

10: Prostaglandins Leukot Med. 1982 Apr;8(4):389-97.

The effect of cathartics on prostaglandin synthesis by rat gastro-intestinal tract.

Cohen MM.

Rats were dosed with the cathartics cascara, phenolphthalein, senna or ricinoleic acid with or without a 3 day pretreatment with indomethacin. Jejunum, proximal and distal ileum and colon were assayed for prostaglandin E (PGE) content by RIA. While indomethacin significantly reduced the PGE content of all tissue in all treatment groups it did not completely prevent the increase in PGE content induced by phenolphthalein, senna and ricinoleic acid. It is concluded that the contact cathartics increase PGE synthesis by the gastro-intestinal tract and this could in part explain their action. Ricinoleic acid did not appear to act as a PG precursor.

11: Gastrointest Radiol. 1982;7(4):383-9.

Colon cleansing regimens. A clinical study in 1200 patients.

Fork FT, Ekberg O, Nilsson G, Rerup C, Skinhoj A.

The purgative effect of bisacodyl, anthraquinone glycosides (Cascara), and sodium picosulfate, alone or in combination with a saline purge and a tap water enema, was studied in 1200 patients. The cleansing effect was scored with regard to retained fecal residue evident on double-contrast studies of the colon. The combination of a contact laxative and a saline purge produced good cleansing effect in 52%-80% of the patients. With an additional tap water enema given 1 hour before the colon examination, however, 96% of the colons were clean. The taste and the effects of the cleansing systems were tolerated favorably by more than 90% of the patients. However, 17% reported restriction in work capacity on the day of bowel cleansing.

Publication Types:

•  Clinical Trial

12: Wien Med Wochenschr. 1981 Mar 15;131(5):133-4.

[Bowel cleansing before irrigoscopy (author's transl)]

Wicke L.

The cleansing effect of Cascara and Salax on the colon was investigated as preparatory to barium enemas. The method showed very good results with very less side-effects.

13: Xenobiotica. 1981 Mar;11(3):217-25.

1. Absorption, excretion, tissue distribution and metabolism of the anthraquinone [14C]emodin was studied after a single oral administration (approx. 50 mg/kg) to rats. 2. Urinary excretion amounted to 18(+/- 5)% dose in 24 h and to 22(+/- 6)% in 72 h. 3. Metabolites found in pooled urine (0-72 h) were mostly free anthraquinones (emodin and emodic acid, 16% dose); 3% was conjugated and 3% was non-extractable radioactivity. 4. In 24 h, 48 +/- 11% and in 120 h, 68 +/- 8% dose was excreted in the faeces, mostly in the free anthraquinone form. 5. In two cannulated rats biliary excretion reached a maximum at approx. 6 h and amounted to 49% dose within 15 h; 70% of biliary activity was in the form of conjugated emodin. 6. The content of radioactivity in most organs decreased significantly between 3 and 5 days. In kidneys, however, the 14C activity was still equiv. to 4.33 p.p.m. emodin after five days. Mesenterium and fat tissue showed increasing 14C activity from 72 to 120 h.

14: J Pharm Sci. 1977 Sep;66(9):1300-3.

Electron-impact and field desorption mass spectrometry, together with NMR and circular dichroism spectroscopy, were used to confirm that cascarosides A and B are C-10 isomers of 8-O-(beta-D-glucopyranosyl)barbaloin. Several batches of cascarosides A and B were prepared and oxidatively hydrolyzed to aloe-emodin. The results are discussed in relation to the assay for cascara given in the European Pharmacopoeia, 1971.

15: Radiologe. 1975 Nov;15(11):421-6.

Cleansing of the colon without enemas.

Several methods have been used to cleanse the large bowel prior to roentgen examination and rectoscopy for more than ten years. A method with administration of a salt solution (SALAX) in combination with different oral laxatives (Cascara sagrada, Dantron, Bisacodyl) without cleansing enemas is described. Hospitalized patients should have an individual preparation while ambulatory patients are almost completely cleansed if they carefully follow the given instructions.