Potentiating effect of sennoside C on purgative activity of sennoside A in mice.
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Animals↗
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[Quantitative chromatographic determination of the active principles of senna (sennoside A, sennoside B)].
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Chromatography, Thin Layer↗
New aspects on the metabolism of the sennosides.
Pure sennoside B was administered to rats. On appearance of the first wet faeces, sennoside B and its metabolites were determined in different parts of the alimentary tract, in faeces and in the urine. The total recovery of unchanged sennoside B and its metabolites was determined by alkali fusion followed by colorimetry and high-pressure liquid chromatography (HPLC). Alkali fusion in 1 N sodium hydroxide solution formed red solutions with sennosides and sennoside derivatives. The molar absorbance of sennosides A and B, sennidin B monoglucoside, sennidins, rhein, danthron, dithranol, rhein-8-glucoside and rhein anthrone at wavelengths of 505-530 nm related approximately to the number of ionizable hydroxy groups in the molecule. Brown polymerized products were isolated from the senna drug. The colour intensity of these products was approximately the same by weight as that of the sennosides themselves, although sennidins could no longer be freed from these by acid hydrolysis. After administration of sennoside B, the average sum of unchanged glucoside and known metabolites in different parts of the gastrointestinal tract and faeces of rats was 61.6% according to HPLC and 92.8% according to the alkali fusion procedure. This difference is indicative of the presence of substances which are no longer identifiable as sennoside derivatives, either by HPLC or by other classical chromatographic methods. Sennosides seem to be partly present in the alimentary tract in polymerized or bound form. The alkali fusion method may be useful in connection with the isolation of as yet unknown metabolites of the sennosides in the gastrointestinal tract.
Alkalies↗
A sennoside-hydrolyzing beta-glucosidase from Bifidobacterium sp. strain SEN is inducible.
Bifidobacterium sp. strain SEN was isolated and characterized by hydrolytic conversion of sennosides to sennidins (Akao et al., Appl. Environ. Microbiol., 60, 1041 (1994)). The sennoside-hydrolyzing capacity of the strain SEN was disappeared following the addition of glucose to the media in spite of good bacterial growth and potent activity hydrolyzing p-nitrophenyl beta-D-glucopyranoside (pNPG). In a fructose-containing medium, no such suppressing effect was shown. Following a 10 h incubation in 50 mM potassium phosphate buffer (pH 7.4), the sennoside-hydrolyzing activity of the bacterium increased, dose-dependently, with the addition of sennoside B. Inhibition of the substrate-induced increase in sennoside-hydrolyzing activity was observed following the addition of some antibiotics (chloramphenicol, streptomycin, and rifampicin). In particular, chloramphenicol completely inhibited the increase of sennoside-hydrolyzing activity while 38% pNPG-hydrolyzing activity remained. It is suggested that the strain SEN produces two different beta-glucosidases of which the sennoside-hydrolyzing enzyme is inducible. In addition, the glucosides pNPG, esculin, salicin, or amygdalin stimulated the induction of the sennoside beta-glucosidase, but less markedly than sennoside. Sennidin A or sugars (glucose, fructose, cellobiose, or maltose) did not induce the enzyme.
Anthraquinones↗
Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandin mediation.
The effects of sennosides on colonic motility were investigated in eight conscious dogs chronically fitted with two strain gauge transducers in the proximal colon, an intracolonic silicone catheter and a polyethylene catheter implanted in a branch of the right colonic artery. Oral sennosides (30 mg/kg) inhibited colonic motility for 12 to 18 h after a three to six hours delay, and associated with giant contractions and diarrhoea. The minimal oral dose of sennosides to produce such changes varied from 5 to 15 mg/kg. Intracolonic sennosides at the minimal effective dose and at 30 mg/kg reproduced the effects of oral sennosides, but with a shorter latency (0.5-1.5 h). Intracolonic PGE2 (100 micrograms/kg) in viscous gel medium or intra-arterial PGE2 (10 micrograms/h) inhibited colonic motility and induced giant contractions often associated with defecation. The colonic motor changes induced by intracolonic sennosides at the minimal effective dose, but not those induced by intracolonic PGE2, were blocked by intra-arterial indomethacin (10 micrograms/h) or piroxicam (5 micrograms/h). These results suggest that colonic motor actions of sennosides are mediated through a local prostaglandins synthesis, as they were blocked by cyclooxygenase inhibitor and reproduced by PGE2.
Animals↗
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.
Animals↗
Acceleration of large intestine transit time in rats by sennosides and related compounds.
Sennosides A + B and their natural metabolites, sennidins A + B, rheinanthrone and rhein, as well as the synthetic laxative danthron, were investigated for their influence on small and large intestine transit time in rats. Carmine red, as a marker, was administered through a gastric tube for small intestine transit or intracaecally by a chronically implanted catheter for colon transit. High doses of sennosides (250-500 mg kg-1) given orally from 20 min or up to 6 h before marker administration had no effect on small intestine transit time. The metabolites and danthron (10-100 mg kg-1 p.o.) also did not accelerate upper gastrointestinal passage. Intracaecal administration at the same time as carmine red, however, reduced the time for the appearance of the first coloured faeces from more than 8 h in the controls to 46 +/- 9 min after sennosides, 34 +/- 11 min after sennidins, 53 +/- 83 min after rhein and 16 +/- 4 min after rheinanthrone (50 mg kg-1 of each). Danthron was ineffective. Thus, sennosides and their natural metabolites specifically influence large intestinal motility. Acceleration of colonic transport seems to be a major component of the laxative action whereas for danthron motility changes are not responsible for its laxative action. Indomethacin partly inhibited the acceleration of large intestine transit induced by sennosides. An involvement of endogenous prostaglandins may therefore be possible, although a local bolus administration of PGF2 alpha or PGE2 into the caecal lumen neither influenced transit time nor induced diarrhoea.
Animals↗
Sennoside-induced secretion is not caused by changes in mucosal permeability or Na+,K(+)-ATPase activity.
The effect of sennosides (50 mg kg-1) on the rat colon in-situ was studied 6 h after oral treatment when the laxative effect was maximal. In a second experiment, rhein (4 x 10(-3) M), an active sennoside metabolite, was administered into the lumen of the colon for 1 h. Both sennosides and rhein reduced net H2O and Na+ absorption or reversed it to net secretion. Paracellular permeability, as measured using erythritol as a small marker molecule, was increased 2- to 3-fold; permeability to a large molecule, PEG 1000, was unchanged. The activity of Na+,K(+)-ATPase in the colon mucosa was not affected. There was no damage of the epithelial cells as determined by lactic acid dehydrogenase release. These results indicate that neither inhibition of Na+,K(+)-ATPase nor damage of the colon epithelium are involved in the secretory effect of sennosides or rhein. The increased paracellular permeability of small molecules fits into the concept of stimulation of active chloride secretion by sennosides, which is electrochemically and osmotically balanced by an increase in Na+ and H2O flow via the paracellular pathway.
Animals↗
Isolation of a human intestinal anaerobe, Bifidobacterium sp. strain SEN, capable of hydrolyzing sennosides to sennidins.
A strictly anaerobic bacterium capable of metabolizing sennosides was isolated from human feces and identified as Bifidobacterium sp., named strain SEN. The bacterium hydrolyzed sennosides A and B to sennidins A and B via sennidin A and B 8-monoglucosides, respectively. Among nine species of Bifidobacterium having beta-glucosidase activity, only Bifidobacterium dentium and B. adolescentis metabolized sennoside B to sennidin B, suggesting that the sennoside-metabolizing bacteria produce a novel type of beta-glucosidase capable of hydrolyzing sennosides to sennidins.
Anthracenes↗
Effect of sennosides on colon motility in cats.
The actions of sennosides on colonic motility are incompletely understood. We therefore studied the effects of sennosides A + B on colonic myoelectric activity and transit of a radio-opaque meal in 7 conscious cats. Intraduodenal application of sennosides (2 mg/kg body weight) accelerated the half colon transit time from 60 +/- 10 (SEM) to 43 +/- 7 min. At the same time the ratio of long-spike bursts to short-spike bursts was changed from 0.22 to 10.1. Loperamide, an antidiarrheal agent, had the opposite effect. The overall spike activity was not altered by sennosides, but increased by loperamide. It is concluded that the propulsive action of sennosides in the colon is reflected by myoelectric patterns and not by the total number of spikes.
Animals↗
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.
Aldosterone↗
Metabolic activation of sennoside C in mice: synergistic action of anthrones.
Sennosides A and C directly injected into the caecum of mice showed equal purgative activity. Intracaecal administration reduced time to onset of diarrhoea induced by sennoside C from about 3 h after oral administration to about 24 min. At 2.3 h after oral administration of sennoside C, nearly equimolar amounts of aloe-emodin anthrone and rhein anthrone were detected in the large intestine of mice. The purgative effect of oral sennoside C could be reduced by pretreating mice with chloramphenicol. This was observed as a decreased formation of total anthrones in the large intestine. Both anthrones and an equimolar mixture of both anthrones directly injected into the caecum exerted a purgative effect, although the activity was lower for aloe-emodin anthrone. The intracaecal ED50 values were 54.5 (24.1-89.6), 11.4 (5.0-15.7) and 11.2 (6.1-14.6) mumol kg-1 for aloe-emodin anthrone, rhein anthrone and an equimolar mixture of both anthrones, respectively. We concluded that aloe-emodin anthrone and rhein anthrone, formed mainly by intraluminal bacterial action, are the true active metabolites of sennoside C in mice and that both anthrones synergistically exert their purgative effects on mice.
Animals↗
Effects of sennosides on colonic myoelectrical activity in man.
The effects of sennosides on colonic myoelectrical activity were investigated in man. Spiking activity of the left and sigmoid colons was continuously recorded in seven constipated patients during two sessions from 5:00 PM to 9:00 AM. Each patient received orally at 7:00 PM on two consecutive days 30 mg of sennosides one day (sequence S) and placebo on the other (sequence P) in a random fashion. A significant (P less than 0.05) increase of peristaltic activity (migrating long spike bursts or MLSBs) after sennosides was observed between 1:00 and 7:00 AM, and a corresponding decrease between 7:00 and 9:00 AM. No change was noted in total short spike burst (SSB) activity or in SSBs characteristic of the rectosigmoid area. This study indicates that the main modification of colonic motility induced by sennosides was a stimulation of propulsive activity (MLSBs), which occurred between 6-12 hr after oral administration, the delay required for orocecal transit and metabolism of the drug.
Action Potentials↗
Effect of sennosides on colon motility in dogs.
Oral administration of sennosides (20-30 mg/kg) to fasted dogs has been shown to induce a strong and long-lasting inhibition of myoelectric colon activity which was evident after a delay of 6-10 h corresponding to oro-cecal transit and colonic metabolism and was accompanied by abundant diarrhea. When sennosides were given 1 h before a meal, the postprandial increase in colon motility failed to appear. Recent studies with strain gage transducers confirm the inhibition of colonic motility after oral sennosides but, in addition, 3-10 'giant contractions' with a high amplitude appeared during the period of inhibition. Most of these single contractions were propagated over the second half of the colon at a velocity of 0.5-2 cm/min. Elimination of liquid feces was always associated with giant contractions. These giant contractions have also been described with other stimuli (i.v. guanethidine or neostigmine, oral castor oil, intraluminal hypertonic glucose) and are therefore not specific for sennosides.
Animals↗
Effect of sennosides and related compounds on intestinal transit in the rat.
The effect of pure sennosides A + B on large intestinal transit (LIT) was investigated in the rat. LIT was defined as the time from intracecal administration of a color marker through a chronically implanted catheter until first appearance of colored feces. Sennosides (50 mg/kg, administered orally 2-24 h before the marker) reduced LIT from greater than 6 h in controls to a minimum of 30-20 min after a 4- or 6-hour pretreatment. Longer pretreatment times increased LIT again reaching normal values after 24 h. Intracecal administration of sennosides and their natural metabolites (sennidins A + B, rhein-9-anthrone, rhein) simultaneously with the marker accelerated LIT to approximately 50-70 min. The laxative effect was less pronounced after rhein compared with the other compounds. Indometacin, loperamide, and calcium-channel antagonists (verapamil, nifedipine) partially antagonized the effect of intracecal sennosides on LIT and delayed, but did not suppress, appearance of soft feces.
Animals↗
Toxic effects of sennosides in laboratory animals and in vitro.
Sennosides were tested in a wide range of toxicity studies to evaluate risk assessment. From acute studies, sennosides could be classified as only slightly toxic in rats and mice after a single oral dose. The LD50 values were about 5,000 mg/kg in both species. The cause of death was probably due to an extensive loss of water and electrolytes following massive diarrhoea. In subacute studies with rats (max. 20 mg/kg) and dogs (max. 500 mg/kg), sennosides caused no specific local or systemic toxicity. Minor increase in kidney weight in rats was toxicologically not relevant. In a 6-month study with rats, sennosides were tolerated without specific toxic effects in doses up to 100 mg/kg. Effects on food consumption, body weight gain and some biochemical parameters as well as slight renal lesions can be interpreted as secondary effects following chronic diarrhoea. Mutagenicity tests and reproduction toxicity studies showed no abnormal results.
Animals↗
Long-term mucosal alterations by sennosides and related compounds.
Sennosides and related compounds are presumed to be severe cell poisons after prolonged ingestion. Some histological and ultrastructural studies in animals and man with such laxative misuse have revealed myenteric plexus and colonic epithelium injuries; but others have failed to point out identical data. In a first histological and ultrastructural study in mouse, we were unable to find any intestinal mucosa injury after long-term sennoside ingestion. In a second long-term experiment, we compared the effects of sennosides and 1,8-dihydroxyanthraquinone (synthetic anthracene derivative) on the mouse jejunum and colon. Electron microscopic observations showed nervous myenteric plexus abnormalities only in 1,8-dihydroxyanthraquinone-treated animals. These results suggest that sennosides have a good intestinal mucosa tolerance as opposed to aglycosidic-related compounds.
Animals↗
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.
Animals↗