Our current lifestyle has led to an important increase in the demand for laxatives, medicinal products that induce or contribute to defecation. Their high demand is clearly established: in 1995, it was estimated that 25% of women and 10% of men in Germany considered they had difficulty to defecate and suffered constipation [1
Along with analgesics, laxatives are the most commonly obtained medicines by patients without consulting a doctor. Therefore, they could be easily used inadequately and abusively. In Germany sales figures of around 39 million units per year, with a value of DM 400 million [1
], and in the United States around USD 600 million of laxatives are sold every year [2
The commercialization of laxatives is greater every year and covers broad sectors of modern society, where its use is observed in different economic strata and different age groups. This is a cause for concern and leads to a permanent analysis of risks which could be associated to the massive use of these types of medicines.
Among the most used laxatives being self-administed or prescribed by a physician, we find that senna infusions, bisacodyl, sodium picosulphate, sodium docusate, stimulating laxatives, and lactulose are considered osmotic-type laxatives.
From its introduction by the Arabs in the XIX century, the anthranoid laxatives have been widely used around the world. Among the plants that contain anthranoid laxatives, Senna (Senna alexandrina or Cassia angustifolia) is the most used. Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular medicament for constipation, frequently used abusively.
There is an important need, therefore, to characterize the potential harmful and/or toxic effects of the anthranoid laxatives. The derivatives are obtained from leaves and/or dried pods of Senna alexandrina, or from the direct use of the plant parts, separately or mixed.
The anthranoid compounds are classified in anthrones (rhein anthrone), anthraquinones (aloe-emodin, chrysophanol rhein) and dianthrones (sennosides), and are present in plants mainly as sugar derivatives. Since the β
-glycosidic bond is resistant to acid digestion and to α
-glycosidase activity in the small intestine, the anthranoid glycosides are not absorbed in the small intestine. Instead, they are maintained as prodrugs until they reach the large intestine where they are metabolized to the active drug, the aglicone rhein anthrone for the β
-glycosidase and reductase activity of the intestinal flora [4
Senna contains various anthranoids, where the most important are sennosides A and B; followed by aloe-emodin, emodin, and chrysophanol [6
]. The sennosides, main active metabolite of senna, show a very low toxicity in rats [7
] and their genotoxic activity in bacterial strains as well as mammal cells, in the cases where it was significant, was classified as weak [8
The toxicological and mutagenic status of the senna crude extract, however, is less characterized. In a study by Hietala et al. [7
], the laxative effect and the acute toxicity of certain fractions of senna extracts in rats were investigated. The same tests were carried out with various pure anthraquinone derivatives in senna pods. Results showed that the laxative and toxic components could be separated from pods and senna extracts. The most powerful laxative components, sennosides A + B and the V
fraction (with relative potentials of 1 and 0.9, resp.) have the lowest toxicity (intravenous toxicity relative to 1 and less than 1) while the fractions with very low laxative activity (rhein-8-glucoside and fraction IV
with relative potentials of 0.56 and 0.05) have the highest acute toxicity (relative toxicities of 10 and 32, resp.). This suggests that there are other active molecules in the senna extract that could be responsible for its toxicity. Anthranoids such as chrysantine, hidroxyanthraquinones, presenting in trace concentrations in the extract, show a different and highly controversial toxicological status to the sennosides. The hydroxyanthraquinones emodin and aloe-emodin gave positive results in genotoxic assays in Salmonella typhimurium
, V79-HGPRT, rat hepatocytes, and mouse fibroblasts [12
], however, in another study, such genotoxicity was not observed [10
]. In a study by Mori, the induction of neoplasms in the intestine, stomach, and rat liver, subjected to a diet containing 1% hidroxyanthraquinones for 480 days, was induced [13
]. It is worth mentioning that these effects were only observed at extremely high doses and prolonged treatments. Other studies have not found mutagenic effects for these compounds. However, it is necessary to precisely pinpoint the possible harmful effects of the anthranoid laxatives, since recently and from results by Siegers, it has been suggested that the chronic use of laxatives such as aloe (Aloe spp
.), frangula (Rhamnus frangula
), and cascara sagrada (Rhamnus purshiana
DC) could constitute a risk factor for the development of colorectal cancer [14
The objective of this article was to review scientific-medical publications found in different databases (Toxnet, Ovid, IBIDS, ScienceDirect, Scirus, PubMed) with keywords such as senna, sen, Senna alexandrina, Cassia angustifolia, sennosides, and laxative toxicity. Web pages of products and companies that publicize or commercialize these types of laxatives were not included.