Laxatives: an update on mechanism of action.
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An assay (enteropooling assay) to test the diarrheogenic property of prostaglandins is described. Fasted rats are given a prostaglandins either orally or subcutaneously, and are killed 30 min later. The entire small intestine is removed and its contents collected into a test tube. The greater the volume of this intestinal fluid, the more diarrheogenic is the prostaglandin. The assay is simple, rapid, quantitative, and predictive of diarrhea. It can be used to grade the relative diarrhoegenic activity of prostaglandins as well as to test agents that may block this effect. The accumulation of fluid into the small intestine is called "enteropooling". It is the sum of (a) the fluid being excreted from the blood into the lumen, and (b) to a lesser extent, the portion of fluid already into the lumen but whose absorption is inhibited by the prostaglandin. The degree of enteropooling depends also on how much fluid flows from the small to the large intestine. Our results support the hypothesis that the diarrhea observed after administration of high doses of prostaglandins is due to accumulation of abundant fluid into the small intestine, and not intestinal hypermotility. This fluid is then carried into the large intestine and eventually expelled as diarrhea. Agents other than prostaglandins were tested for enteropooling activity. Laxatives such as castor oil, hypertonic solutions and bile salts caused enteropooling.
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.
Primary faecal incontinence (encopresis) in children is usually treated with laxative medication and a behaviour modification programme aimed at promoting regular toileting, but the effectiveness of laxatives has never been adequately investigated. 169 children with encopresis and evidence of stool on plain abdominal radiograph were randomly allocated to receive multimodal (MM) therapy (laxatives plus behaviour modification; n = 83) or behaviour modification alone (BM; n = 86). Mean (SD) follow-up was 55.1 (27.0) weeks and 56.7 (32.0) weeks, respectively. By 12 months' follow-up 42 (51%) of the MM group and 31 (36%) of the BM group (p = 0.079) had achieved remission (at least one 4 week period with no soiling episodes) and 52 (63%) vs 37 (43%) (p = 0.016) had achieved at least partial remission (soiling no more than once a week). MM subjects achieved remission significantly sooner than BM subjects, and the difference in the Kaplan-Meier remission curves was most striking in the first 30 weeks of follow-up (p = 0.012). The patterns of compliance with toileting in the treatment groups were almost identical, although about 1 in 8 children overall did not comply with the sitting programme. After exclusion of the 24 poor compliers, there was no significant difference between BM and MM groups. This study shows a clear advantage overall for the use of laxative medication, although the benefit may not be as great for children who are able to maintain regular toileting.
The present in vitro and in vivo experiments were undertaken to clarify the genotoxic potential of the hydroxyanthrachinone aloeemodin which can be found in different plant derived products for therapy of constipation. The results demonstrate that aloeemodin is able to induce mutagenic effects in vitro. Positive results were obtained in the chromosomal aberration assay with CHO cells, as well as in the Salmonella reverse mutation assay (frameshift mutations in strains TA 1537, TA 1538 and TA 98). No mutagenic potential of aloeemodin, however, was observed in the gene mutation assay with mammalian cells in vitro (HPRT assay in V79 cells). Each assay was performed in the presence and absence of an extrinsic metabolic activation system (S9-mix). In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot text [DBA/2JxNMRI]) no indication of a mutagenic activity of aloeemodin was found. Information about a possible reaction of aloeemodin with DNA was derived from an in vivo UDS assay. Hepatocytes of aloeemodin-treated male Wistar rats did not show DNA damage via repair synthesis. All these data suggest that aloeemodin is able to interact with DNA under certain in vitro conditions. However, in vivo the results that were negative did not indicate a genotoxic potential. Therefore, it may be assumed that a genotoxic risk for man might be unlikely.
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We measured plasma levels of 6-keto-prostaglandin F1 alpha by radioimmunoassay in patients with hypokalemia due to various disorders. Plasma 6-keto-PGF1 alpha in patients with disorders involving hypokalemia was not different from that of normal controls. Treatment with inhibitors of prostaglandin synthesis for 5-7 days in three patients with Bartter's syndrome decreased 6-keto-PGF1 alpha plasma levels by about 25%. It is suggested that, plasma 6-keto-PGF1 alpha may, on occasions, be a poor index of circulating prostacyclin.
Induction of cell proliferation by laxatives and related compounds in rat intestines was analysed by BrdU-labelling and compared with histopathological changes in the mucosa and findings for feces. Male F344 rats were fed a diet containing danthron, sennosid A, bisacodyl, 1-hydroxyanthraquinone (1-HAQ), magnesium sulfate (MgSO4), dextran sulfate sodium (DSS), pectin, carboxymethylcellulose sodium (CMC-Na) or sodium chloride (NaCl) for 7 days. The stimulant laxatives, danthron, sennosid A and bisacodyl, significantly induced cell proliferation in almost the entire intestinal epithelia in a clear dose-dependent manner. DSS also induced cell proliferation in some portions at high doses. Increase in BrdU-labelling indices was correlated well with the severity of inflammatory changes in the intestinal mucosa as well as with purging effects of stimulant laxatives and DSS. In contrast, the bulk-forming laxative CMC-Na did not consistently enhance cell proliferation nor cause apparent cytotoxicity in the intestine despite exerting remarkable purging effects. 1-HAQ and MgSO4 slightly induced cell proliferation in the cecum and the colorectum, although there was little or no intestinal cytotoxicity. Pectin and NaCl did not influence cell kinetics of the epithelia, nor cause any inflammatory changes in the mucosa. Our results thus indicate that diarrhea caused by laxatives is not necessarily correlated with induction of cell proliferation, as in the intestinal mucosa, and that inflammatory changes followed by regenerative process could be responsible for enhancing cell kinetics. Although the precise significance of cell proliferation in carcinogenesis remains unclear, it is crucial for setting doses of carcinogenicity testings that charges in cell kinetics caused by chemicals be taken into account.
Anthraquinone glycosides of Senna and Cascara were investigated for their ability to induce aberrant crypt foci (ACF) in the rat colon mucosa, which are considered putative preneoplastic lesions. Dietary exposure to high doses of these glycosides for 56 successive days did not cause the appearance of ACF or increase in incidence of ACF induced by 1,2-dimethyl-hydrazine (DMH). However, in rats treated with both DMH and the highest dose of glycosides, the average number of aberrant crypts per focus, considered a consistent predictor of tumor outcome, was higher than in rats given DMH alone. These findings suggest that Senna and Cascara glycoside might behave as weak promoters in rat colon carcinogenesis.
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The tumor-promoting activity of the anthraquinone laxative danthron was studied by giving 3 groups of male rats a single subcutaneous injection of the colon tumor-inducing agent 1,2-dimethylhydrazine (DMH). After 1 week, the animals were fed diets containing 0, 600 or 2400 ppm of danthron for 26 weeks. Two other groups of rats were included in the study; one received no treatment while the other was given danthron only. Altogether 9 tumors were observed among animals given DMA with or without danthron. The incidence of colon tumors was higher in animals receiving DMH and danthron than in those given DMH only (5/60 vs. 0/30), but this difference was not statistically significant. The kidneys and lymph nodes of mesocolon were enlarged and showed a yellowish-red and brown discoloration, respectively. The pigment mostly displayed a PAS-positive reaction but contained no lipid as determined by several staining procedures. The available evidence suggests that the pigment is drug-derived.
Herbalists in Nigeria use a variety of herbal remedies to treat various types of illness. Thirteen commonly used herbal plants in the Anambra State of Nigeria were identified and collected. Extracts were prepared and studied pharmacologically on various isolated and intact preparations. Toxicological and phytochemical studies were also conducted on most of these plants.
This paper deals with an interdisciplinary study covering historic, botanical, phytochemical, pharmacological and clinical aspects of rhubarb and related species, to lay stress on the correlation between plant phylogeny, chemical constituents and purgative activity. It was found that the official rhubarbs were exclusively restricted in the Sect. Palmata, e.g. Rheum palmatum, R. palmatum var. tanguticum, R. officinale; the following criteria may serve as their standard, viz., the presence of sennoside derivatives and rhein, the occurrence of the reduced form of rhein and aloe-emodin, the leaves with any kind of palmate incision. Comprehensive multivariate analyses showed that there is a very close relationship between the leaf incision, existence of sennosides or rhein and purgative activity.
A large amount of ethnobotanical data of almost 200 botanical species used for medicinal purposes in the Canary Islands is presented. We are endeavouring to avoid the definitive loss of the islands' phytotherapeutic heritage, in view of the rapid social changes taking place over the last few years and hope that this work may serve to promote further pharmacological research that may confirm, scientifically and experimentally, the information presented here. A brief description of the geographical, botanical and historical circumstances is included. The species listed have been classified according to a basically therapeutical criterion.