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The laxation induced by senna is not modified in rats either maintained on a diet deficient in essential fatty acids (EFAD) or exposed to cold (6 degrees C) or with yeast-induced fever. In light of our findings it appears conceivable that non-PG-mediated mechanism(s) play a relevant role in laxation induced by senna.
The metabolism of sennosides is discussed in view of the results obtained during the last years. Rhein anthrone is to be considered as the ultimate active form produced by microorganisms in the colon. Several contributions of this senna symposium bring complementary information of utmost interest.
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.
During the course of studies on the metabolism of sennosides by human intestinal bacteria, an enzyme which takes part in the reduction of sennosides and sennidins was originally isolated from Peptostreptococcus intermedius. This enzyme catalyzed the electron transfer from NADH to FAD, FMN or benzyl viologen, which reduced nonenzymatically sennosides and sennidins to 8-glucosyl-rhein anthrone and rhein anthrone, respectively.
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.
After gastric administration of daily 100 mg sennosides/kg body weight, no morphological differences could be found between the colon of treated rats and the controls. In particular, no damage to the intramural nerve tissue could be seen under the electron microscope.
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.
The effects of sennosides on uterine motility were evaluated by electromyography in healthy adult ewes between day 70 and 120 of pregnancy to assess possible disturbances of the physiological pattern of contractility and eventual risks in pregnancy maintenance. At this stage of pregnancy, the ovine genital tract presented motility episodes of 6-8 min duration occurring at approximately hourly intervals. A dose-range study (10-160 mg/kg intracolonically) in 2 ewes showed that diarrhea was systematically obtained with doses greater than 20 mg/kg and was connected with a marked depression of both ileum and spiral colon motility. A standard dose of 60 mg/kg administered intracolonically 1-3 times at 7- to 10-day intervals to 12 ewes was used in the uterus studies. The experiments showed that sennosides did not stimulate uterine motility in the pregnant ewe, but slightly depressed it in some ewes. Cervix motility was never influenced. Intolerance of the drug was observed in half of the animals resulting mainly in anorexia or weakness and confirming a specific toxicity of senna in ruminants which is not known from other species. These effects were not related to uterine motility and pregnancy maintenance was normal in all ewes.
The excretion of rhein, a laxatively active metabolite of sennosides, was investigated in 100 breast milk samples of 20 post-partum women after intake of a standardized senna laxative (Agiolax), which also contains seeds of Plantago ovata as bulk substances. After daily doses of 5 g of the senna laxative containing 15 mg sennosides for 3 days, the rhein concentration in milk samples from every lactation during 24 h post-dose varied between 0 and 27 ng/ml with values below 10 ng/ml in 94%. Based on median values, 0.007% of the sennoside intake (calculated as rhein) was excreted in breast milk. None of the breast-fed infants had an abnormal stool consistency. Assuming a (theoretical) complete metabolism of sennosides to rhein in the mother, the amount of rhein delivered to the infant (ng/kg b.w.) is by the factor 10(-3) below the rhein intake of the mother.
A HPLC method was developed to measure rhein, a laxatively active metabolite of sennosides A + B, in milk and plasma. Samples from 2 lactating rhesus monkeys were taken over 48 h after oral administration of sennosides (1 mg kg-1). Detectable rhein levels were found in plasma between 2 and 12 h and in milk between 4 and 12 h after administration, but rhein excretion in milk seems to be far below the dose necessary to elicit a laxative effect in the suckling offspring.
Laxatives are classified according to their actions on the gut, and the special role and use of senna in the treatment of constipation are discussed. Standardised senna is the most physiological of all the non-fibre laxatives and is safe when used in appropriate dosage avoiding loose stools. Additional advice on bulk supplement should be given.
Oral and intracecal administration of bisacodyl or sennosides A + B (10-100 mg/kg each) to rats induced a similar quantity of soft feces within 24 h and a similar acceleration of large intestinal transit time, but in each case bisacodyl had a prolonged action. Net fluid absorption in the perfused rat colon was reduced to a comparable extent by local bisacodyl in 1/10 of the molar concentration of rhein, an active metabolite of sennosides; recovery was delayed after bisacodyl. These results show that the time course of the laxative action of both drugs is different, probably attributable to their different pharmacokinetics. Both drugs influence colon motility as well as colonic secretion, but fluid secretion may contribute more to the laxative effect of bisacodyl than to that of sennosides.
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