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Senna and damage of the nerve plexus of the intestinal wall.
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Senna and pseudomelanosis coli.
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2nd International Symposium on Senna. Proceedings. Konstanz, April 23-34, 1993.
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The senna drug and its chemistry.
Senna consists of the dried leaflets or fruits of Cassia senna (C. acutifolia) known in commerce as Alexandrian senna and of Cassia angustifolia commonly known as Tinnevelly senna. The senna plants are small shrubs of Leguminosae cultivated either in Somalia, the Arabian peninsula and near the Nile river. Tinnevelly senna is obtained from cultivated plants mainly in South India and Pakistan. Owing to the careful way in which the plant is harvested, the leaflets of the drug are usually little broken. Damaged leaves and lower quality products are often used for making galenicals. The senna pods (fruits) are collected during the same period as the leaves, then dried and separated into various qualities. The active principle of Senna was first isolated and characterized by Stoll in 1941. The first two glycosides were identified and attributed to the anthraquinone family. These were found to be dimeric products of aloe emodin and/or rhein which were named sennoside A and sennoside B. They both hydrolyze to give the aglycones sennidin A and B and two molecules of glucose. Later work confirmed these findings and further demonstrated the presence of sennosides C and D. Small quantities of monomeric glycosides and free anthraquinones seem to be present as well. The active constituents of the pods are similar to those of the leaves but present in larger quantities. Two naphthalene glycosides isolated from senna leaves and pods are 6-hydroxymusicin glucoside and tinnevellin glucoside. Both compounds can be utilized to distinguish between the Alexandrian senna and the India senna, since tinnevellin glucoside is only found in the latter and the first only in the C. senna.(ABSTRACT TRUNCATED AT 250 WORDS)
Sennoside-induced secretion and its relevance for the laxative effect.
The effect of oral treatment with sennosides (50 mg/kg) on the time-course of net H2O and electrolyte transport rates was studied in 1-hour incubation experiments in the rat colon in vivo. Net H2O, Na+ and Cl- absorption rates did not change during the first 4 h after treatment, but were reversed to net secretion after 6 h and partly recovered during the next 18 h. K+ and Ca2+ were secreted in controls, and net secretion increased from 6 to 24 h after treatment. Paracellular permeability of [14C]erythritol was 3-fold 6 h after treatment but unchanged at other times after treatment (2, 4, 12 or 24 h). LDH leakage into the lumen was not enhanced by treatment. Neither mucosal Na+, K(+)-ATPase activity nor cAMP or phosphodiesterase activity was affected by sennosides. As stool consistency and acceleration of transit by sennosides has entirely normalized 24 h after treatment but not net absorption of H2O and electrolytes, it is concluded that there may be regional differences in the absorptive behavior of the colon induced by sennosides. Slow transit and increased absorption in some parts of the colon may overcome secretion in other parts.
Suppression of the purgative action of rhein anthrone, the active metabolite of sennosides A and B, by calcium channel blockers, calmodulin antagonists and indomethacin.
The involvement of Ca2+ in the mechanism of the purgative action of rhein anthrone was studied. Among individual or combination pretreatments with calcium channel blockers, calmodulin antagonists and prostaglandin biosynthesis inhibitors, the combination of indomethacin and nifedipine completely blocked the diarrhoea induced by rhein anthrone and also inhibited its effects on colonic fluid and electrolyte transport, and large intestinal motility. Calmodulin antagonists were less active regarding suppression of the effects of rhein anthrone. We concluded that, in addition to prostaglandins, diarrhoea induced by rhein anthrone must also involve the calcium channel which can be blocked by nifedipine, but not verapamil.
Anthranoids and the mucosal immune system of the colon.
The mechanism of action of anthranoids in general and of sennosides at the cellular level is not precisely known. Pseudomelanosis or pseudolipofuscinosis, a condition characterized by the accumulation of pigmented macrophages in the lamina propria, is one of the well-known effects of these products. It is most probably the result of an interaction between apoptotic epithelial cells and the lamina propria cellular infiltrate. Treatment of cell suspensions of intestinal epithelial cells and of human intestinal epithelial cells in culture with rhein anthrone, the active compound of sennosides, demonstrates a direct influence of the drug on these epithelial cells. Low doses induce alterations in cellular shape and organelles consistent with increased metabolism. High doses induce apoptotic changes. The interaction between the epithelial cells and cells of the monocyte/macrophage lineages induces also the release of prostaglandins of the E series as shown by experiments on cell cultures of epithelial cells and peripheral blood cells. An increase of PGE2 release to about 140% of the control value is noted following administration of low doses of rhein anthrone to a combination of human intestinal epithelial cells and human peripheral blood mononuclear cells. This finding indicates that rhein anthrone is activating cellular components of the intestinal immune system and may by this pathway induce secretion and motility.
Effect of senna is not mediated by platelet-activating factor.
The effect of in vivo treatment with senna was examined on the ex vivo formation of platelet-activating factor (PAF) by small and large intestine of rat, mouse and guinea pig. A single or a prolonged oral administration of senna (60-240 mg/kg) to animals did not increase intestinal PAF content. Nor did senna increase the intraluminal release of acid phosphatase. A similar result was obtained in the colonic tissue of rat perfused in vitro with rhein (1-500 micrograms/ml) or rhein anthrone (1-500 micrograms/ml). In contrast, a single oral administration of phenolphthalein (20 mg/kg), bile salts (20 mg/kg) or magnesium sulfate (30 mg/kg) to rats increased intestinal PAF content. Magnesium sulfate also increased the intraluminal release of acid phosphatase. Colonic tissue of rats perfused in vitro with calcium ionophore A23187 (10 micrograms/ml) formed large amounts of PAF and acid phosphatase. PAF stimulates intestinal motility and secretion and mediates gut damage while acid phosphatase is a marker of cellular damage. Therefore, our data suggest that senna is well tolerated in animals and PAF does not mediate senna-induced laxation.
Serotonin antagonists inhibit sennoside-induced fluid secretion and diarrhea.
The aim of this study was to investigate whether 5-hydroxytryptamine (serotonin, 5-HT) is involved in the mediation of sennoside-induced colonic fluid secretion and diarrhea. Oral administration of purified sennosides (25, 40 and 64 mg/kg) dose-dependently reversed net fluid absorption to net fluid secretion, enhanced the incidence of diarrhea and stimulated the release of 5-HT into the colonic lumen from 7.1 to 17.3 ng/g wet weight. The 5-HT2 antagonist ketanserin and the 5-HT3 antagonist tropisetron dose-dependently but only partially reduced sennoside (40 mg/kg)-induced fluid secretion whereas the 5-HT3 antagonist granisetron dose-dependently reduced and at 300 micrograms/kg totally abolished sennoside-induced secretion. Granisetron, but not ketanserin and tropisetron, reduced the incidence of diarrhea in sennoside-treated rats, indicating the involvement of 5-HT also in acceleration of large intestinal transit. It is concluded that 5-HT is an important mediator both of sennoside-induced fluid secretion in the rat colon and of diarrhea.
Metabolism and pharmacokinetics of anthranoids.
Anthranoid derivatives are used all over the world as a treatment for constipation. These compounds are present in several drugs of plant origin, especially as O- or C-glycosides. Besides featuring different substituents, the aglycone might consist of an anthraquinone, an anthrone or a dianthrone. So far, detailed information concerning their metabolism and pharmacokinetic characteristics is available only in a few cases. The best characterized compounds are sennoside, a dianthrone O-glycoside present in senna leaves and senna pods, and its aglycone (rhein anthrone). After oral administration, sennoside is degraded only in the lower parts of the gastrointestinal tract, releasing its active metabolite rhein anthrone. Nowadays, this process is understood at the molecular level. A study with 14C-labelled rhein anthrone administered intracecally to rats, revealed that the compound is scarcely absorbed. Since on the contrary its anthraquinone equivalent is absorbed to a much larger extent, it is inferred that dianthrone- or anthrone-glycosides exhibit a lower systemic availability than anthraquinone O-glycosides.
Analytics of senna drugs with regard to the toxicological discussion of anthranoids.
Toxicological studies indicate that two hydroxyanthraquinones (HAs), aloe-emodin and emodin, present as minor components in senna, might represent a genotoxic or cancerogenetic risk for man. Since aloe-emodin and emodin occur in senna in the free form as well as their glucosides and dianthrone glucosides, a HPLC method was established to allow the quantification of all free and glycosidic 1,8-dihydroxy anthranoids. The sum of the free HAs and their calculated content in each of their prodrug forms is defined as the potential HA content. For the comparison of different senna drugs in respect to the genotoxic risk arising from their potential aloe-emodin or emodin contents, a risk index has been established.
Cleavages of the O- and C-glucosyl bonds of anthrone and 10,10'-bianthrone derivatives by human intestinal bacteria.
A strictly anaerobic bacterium, Bifidobacterium sp. SEN, capable of hydrolyzing the O-glucosyl of sennosides was isolated from human feces. The bacterium stepwisely hydrolyzed sennoside B to sennidin B through sennidin-8-monoglucoside in PYF medium but not in GAM broth. Addition of D-glucose to PYF medium resulted in loss of the hydrolyzing activity in culture but addition of D-fructose did not affect the activity. Coculture of this bacterium with Peptostreptococcus intermedius led to rapid accumulation of rhein anthrone in the medium. Similarly, a bacterium, Eubacterium sp. BAR, capable of cleaving the C-glucosyl of barbaloin was isolated from human feces. This bacterium grew in PYF medium containing barbaloin and produced enzyme(s) that cleave(s) the C-glucosyl. The induction of the enzymes was completely inhibited in the presence of D-glucose. Nojirimycin inhibited the enzyme activity induced by barbaloin but it did not inhibit the bacterial growth in the presence of D-glucose.
Effects of long-term sennoside treatment on in vitro motility of rat colon.
Colonic motility of rats chronically pretreated with either 10 or 40 mg sennosides/kg body weight daily, 30 mg sennosides/kg twice a week or 500 mg danthron/kg daily for 6 months has been evaluated in ex vivo preparations. Registration of colonic contractions 48 h after the last application of drugs or placebo revealed striking differences between the ascending, transverse and descending parts of the colon as well as between corresponding circularly or longitudinally orientated segments. Treatment did not influence motility in the various parts of the colon except some reduction in spontaneous motility in the descending colon. Response to electrical stimulation and acetylcholine was independent of treatment in most segments, but a decrease in maximal contraction was observed by the high daily sennoside dose and by danthron in the ascending colon and descending colon, respectively. Sensitivity to rhein, an active metabolite of sennosides, was similar in all groups. Thus, chronic treatment with anthranoids reveals no abnormal motility pattern but a residual pharmacological activity 48 h after the last administration of high doses.
In vivo motility of rat colon chronically pretreated with sennosides.
Ceco-colonic myoelectrical activity was investigated in rats pretreated for 23 weeks by sennosides (10 or 40 mg/kg/day), Na-picosulfate (2.5 or 10 mg/kg/day) or laxative vehicle (control). On the last week of treatment the animals were equipped with Nichrome electrodes on the cecum, the proximal and distal colon. In comparison with controls, sennoside or Na-picosulfate treatment did not induce any significant (p > 0.05) change in the duration of long spike bursts (LSB) which are associated with phasic contractions. On the last 2 days of treatment the frequency of LSB for 2 h before and 2 h after laxative administration, as well as for 30 min after a 3-gram meal was not significantly (p > 0.05) different in control and treated animals. Similarly, on the first 2 days, as well as on days 13 and 14, after the end of treatment, no significant (p > 0.05) difference in the LSB frequency appeared between control and treated animals, in the fasted state or after a 3-gram meal. It is concluded that long-term treatment with sennosides or Na-picosulfate does not induce chronic changes in colonic motility in rats.
Chronic sennoside treatment does not cause habituation and secondary hyperaldosteronism in rats.
Rats were treated with sennosides (6 x 10, 6 x 40 or 2 x 30 mg/kg weekly) or with danthron (6 x 500 mg/kg weekly) for 6 months. The laxative effect as measured by faecal wet weight during the first 10 h after treatment increased 3- to 4-fold by the higher sennoside doses (daily or intermittently) and 1- to 3-fold by danthron. The low sennoside dose had no measurable effect except on the 1st day (2 fold) compared with the control group. Mean faecal water content increased from 53% (controls) to 66-79% in rats treated with high sennoside doses and to 57 (1st day) -69% in danthron-treated rats. Serum aldosterone levels and mucosal Na(+)-K(+)-ATPase activities in the small intestine and colon did not change with treatment. There were no signs of habituation or secondary hyperaldosteronism due to sennosides or danthron in spite of chronic diarrhoea over 6 months.