Sennoside Research Articles

Ninth Pharmacologic-Historical Forum, 2024, Munich, Germany: the development of experimental pharmacology in Munich at the Walther Straub Institute.

In 1887, Hermann Tappeiner (1847-1927) was appointed as professor for medicinal chemistry and pharmacology. He studied the role of intestinal bacteria and contributed to better understanding of digestion. In 1923, Walther Straub (1874-1944) succeeded. He was at the zenith of his scientific career, gained habilitation in Leipzig already in 1900, accepted the direction of the Institute of Pharmacology at Marburg in 1905, of Würzburg in 1906, before he moved to Freiburg in 1907. Straub preferred quantitative studies with various alkaloids, cardiac glycosides, and Senna glycosides on isolated organs. One important legacy is his contribution "Die Digitalisgruppe" in Hefters Handb. Exp. Pharmakol. 1924. Walther Straub was editor of Naunyn-Schmiedeberg's Archives of Pharmacology and founded the Deutsche Pharmakologische Gesellschaft in 1920. In 1944 when most of the institute was destroyed by air raids, Walther Straub retired and succumbed in Bad Tölz. In 1946, August Wilhelm Forst (1890-1981), a pupil of Straub, was appointed to head the institute ruins. We owe to him the provisional reconstruction of the old building, institution of an Insulin Control Laboratory, and the development of a vibratory cage that allowed the registration of psychomotor activity in rodents. Forst published the first comprehensive review on "Detoxication." In 1961, Manfred Kiese (1910-1983), a pupil of W. Heubner, came from Tübingen and accompanied the erection of a new building. Kiese made important contributions to the understanding of the biotransformation of foreign compounds and was the first to describe the biological N-oxygenation. His studies on ferrihemoglobin formation resulted in the development of an effective cyanide antidote, 4-dimethylaminophenol. "Methemoglobinemia, a Comprehensive Treatise" is part of his scientific legacy. In 1980, Wolfgang Forth (1932-2009) from Bochum headed the institute and convinced the medical faculty of LMU to rename the building into Walther Straub Institute. His scientific interests were centered on interactions between essential and toxic metals during intestinal absorption. He was co-editor of the German Textbook on Pharmacology and Toxicology founded in 1975, which is presently in its 13th edition. In 2000, Peter Eyer (1942) was commissioned to lead the institute until Thomas Gudermann (1960) was appointed to direct the chair in 2008.

МАРКЕТИНГОВИЙ АНАЛІЗ СЕГМЕНТА РИНКУ ЛІКАРСЬКИХ ЗАСОБІВ – ПОХІДНИХ 9,10-АНТРАХІНОНУ В УКРАЇНІ

A marketing analysis of the pharmaceutical market for drugs - derivatives of 9,10-anthraquinone was carried out. It is shown that in the Ukrainian market, the vast majority of the assortment of these drugs is formed by foreign-made drugs, the leaders of which are the manufacturing countries Austria, Italy, Germany and India. It has been determi ned that the majority of anthraquinone drugs are represented by agents for the treatment of diseases of various types of cancer and strengthening of the intestinal reticulum. It has been established that “Sinbias Pharma” LLC is engaged in the production of four anticancer substances in Ukraine. For preparations based on anthraquinone-containing medicinal herbal raw materials, domestic manufacturers are PJSC “Liktravy” and PJSC Pharmaceutical Factory “Viola”, and the producers of senna glycosides are JSC “Lubnypharm”, “Ternopharm” LLC and Pharmaceutical company “Zdorovye”. Injection solutions, lyophilisates, tablets and hard capsules are the main dosage forms of drugs – derivatives of 9,10-anthraquinone.

Frailty and Co-Prescribing of Potentially Interacting Drugs in New Users of Warfarin.

BackgroundWarfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known.ObjectiveThe objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients.MethodsWe conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation.ResultsIn total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively.ConclusionsThe overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.Electronic supplementary materialThe online version of this article (10.1007/s40266-020-00755-0) contains supplementary material, which is available to authorized users.

Aquaporins Alteration Profiles Revealed Different Actions of Senna, Sennosides, and Sennoside A in Diarrhea-Rats.

Senna and its main components sennosides are well-known effective laxative drugs and are used in the treatment of intestinal constipation in the world. Their potential side effects have attracted more attention in clinics but have little scientific justification. In this study, senna extract (SE), sennosides (SS), and sennoside A (SA) were prepared and used to generate diarrhea rats. The diarrhea rats were investigated with behaviors, clinical signs, organ index, pathological examination, and gene expression on multiple aquaporins (Aqps) including Aqp1, Aqp2, Aqp3, Aqp4, Aqp5, Aqp6, Aqp7, Aqp8, Aqp9, and Aqp11. Using qRT-PCR, the Aqp expression profiles were constructed for six organs including colon, kidney, liver, spleen, lung, and stomach. The Aqp alteration profiles were characterized and was performed with Principle Component Analysis (PCA). The SE treatments on the rats resulted in a significant body weight loss (p < 0.001), significant increases (p < 0.001) on the kidney index (27.72%) and liver index (42.55%), and distinguished changes with up-regulation on Aqps expressions in the kidneys and livers. The SS treatments showed prominent laxative actions and down regulation on Aqps expression in the colons. The study results indicated that the SE had more influence/toxicity on the kidneys and livers. The SS showed more powerful actions on the colons. We suggest that the caution should be particularly exercised in the patients with kidney and liver diseases when chronic using senna-based products.

Are Senna based laxatives safe when used as long term treatment for constipation in children?

Senna is a stimulant laxative commonly used by pediatricians, pediatric gastroenterologists, and pediatric surgeons. Many clinicians avoid Senna for reasons such as tolerance or side effects but this has little scientific justification. We recently found several patients we were caring for developed perineal blistering during the course of Senna treatment. Because of this we chose to review the literature to identify side effects in children taking this medication as well as to analyze our Center's experience with Senna's secondary effects. We performed a literature review (MEDLINE, PUBMED) using the keywords of Senna, sen, sennosides and children, and pediatric and functional (idiopathic) constipation. We looked for articles with information regarding perineal blisters related to Senna as well as other secondary effects of Senna laxatives in children when used on a long-term basis. We also reviewed the charts of our patients who had previously taken Senna or are currently taking Senna, looking for adverse reactions. Eight articles in the literature reported perineal blisters after administration of Senna laxatives in 28 patients. Of those occurrences, 18 patients (64%) had accidental administration of Senna and 10 (36%) had Senna prescribed as a long term treatment. All of the blistering episodes were related to high dose, night-time accidents, or intense diarrhea with a long period of stool to skin contact. At our institution, from 2014 to 2017, we prescribed Senna and have recorded data to 640 patients. During the study period, 17 patients (2.2%) developed blisters during their treatment. Patients who developed blisters had higher doses 60mg/day; 60 [12-100] vs. 17.5 [1.7-150] (p<0.001). All of the blistering episodes were related to night-time accidents, with a long period of stool to skin contact. 83 (13%) patients presented minor side effects such as abdominal cramping, vomiting or diarrhea which resolved once the type of laxatives were changed or enemas were started. The doses of Senna was not significantly different in these patients 15mg/day [4.4-150] vs. 17.5mg/day [1.5-150]. There were no other long-term side effects from Senna found in the pediatric literature for long-term treatment besides abdominal cramping or diarrhea during the first weeks of administration. We found no evidence of tolerance to Senna in our review. There is a paucity of information in the literature regarding side effects of sennosides as a long-term therapy, and to our knowledge, this is the first review of Senna side effects in children. Senna induced dermatitis is rare, but may occur when patients need a higher dose. All of the cases described had a long period of exposure of the skin to stool. Besides the perineal rash with blisters, we could find no other described major side effect with Senna administration in the pediatric population or evidence of the frequently mentioned concern of the development of tolerance to Senna. Pediatric caregivers should advise families of the rare side effect of skin blistering and educate them to change the diaper frequently in children who are not toilet- trained to reduce stool to skin exposure. We can conclude from this review that Senna is a safe treatment option for constipation in children. IV.

The study of the Ukrainian pharmaceutical market of laxatives

Constipation is one of the most common reasons for visiting a doctor in the world. In different countries every third or fourth adult has constipation continuously or periodically. Laxatives (L) are OTC-drugs. Therefore, to simplify the choice of a laxative by patients, pharmacists and doctors the study of the pharmaceutical market of L is of current interest. Aim . To analyze the pharmaceutical market of laxatives in Ukraine. Material and methods . Data of ATC/DDD-indexes of the WHO Center on methodology of statistical studies of drugs, doses for L recommended by the manufacturer, data on the average retail price of medicines in Ukraine in August 2016 were used in the study. The methods of research were frequency analysis and ATC/DDD-methodology. Results and discussion . As the result of the structural analysis of the ATC classification and the presence of L at the pharmaceutical market of Ukraine it was found that the following drugs of group A06A were available to treat constipation: softeners (emollients), contact L, bulk-forming L, osmotically acting L, L in enemas and other drugs. The frequency analysis showed that there were 18 INN and 76 TN of L at the pharmaceutical market of Ukraine in 2016; among them domestic drugs were 55 %, and foreign – 45 %. Laxatives were supplied in Ukraine by such manufacturing countries as Portugal, Italy, Spain, Poland, France, Germany, India, Netherlands, Bulgaria, Latvia, Russian Federation and United Kingdom. The cost of the defined daily dose (DDD) for softeners (Vaseline oil) ranged from 2.94 to 3.39 UAH. The cost of DDD for contact L was from 0.60 to 3.90 UAH: for bisacodyl – from 0.60 to 2.82 UAH, for castor oil – 2.50-5.13 UAH, for senna glycosides – 0.84-3.20 UAH, for sodium picosulfate – 1.35-3.90 UAH, for combination of sodium picosulfate with a dry extract of senna leaves – 1.34-1.55 UAH. The cost of DDD of bulk-forming L ranged from 1.75 to 129.03 UAH: for L with Plantago ovata seeds ranged from 3.58 to 28.92 UAH, for laminaria – 1.75-1.97 UAH. The cost of DDD for osmotically acting L varied from 2.51 to 112.59 UAH: for magnesium sulfate – 2.15-2.51 UAH., and the cost for combination of inorganic salts – 112.59 UAH, for macrogol – 51.01 UAH, for lactulose – 3.75-18.74 UAH, for combinations with macrogol – 54,88-127,32 UAH. The cost of DDD for L in enemas varied from 33.39 to 129.03 UAH. The cost of DDD for other drugs for treatment of constipation was from 1.37 to 48.15 UAH: for glycerol – 3.44-36.49 UAH, for pruсalopride – 31.72-48.15 UAH, for others – 1.37-1.49 UAH. Conclusions . In 2016 there were 18 INN and 76 TN of laxatives at the pharmaceutical market of Ukraine; drugs of domestic manufacture prevailed, the ratio between domestic and foreign drugs was 1.2 : 1. The cost of DDD for L in the context of the minimum and maximum cost of generics ranged from 0.60 to 129.03 UAH.

Influence of Repeated Senna Laxative Use on Skin Barrier Function in Mice.

BackgroundSenna, one of the major stimulant laxatives, is widely used for treating constipation. Chronic senna use has been reported to be associated with colonic disorders such as melanosis coli and/or epithelial hyperplasia. However, there is no obvious information on the influence of chronic senna use on organs except for the intestine.ObjectiveTo clarify the influence of senna laxative use on skin barrier function by repeated senna administration.MethodsEight-week-old male hairless mice received senna (10 mg/kg/day) for 21 days. After administration, we evaluated transepidermal water loss (TEWL), and investigated the biomarkers in plasma and skin using protein analysis methods.ResultsFecal water content on day seven was significantly increased; however, on day 21, it was significantly decreased after repeated senna administration. In the senna-administered group, TEWL was significantly higher compared to the control on days seven and 21. Plasma acetylcholine concentration and NO2 −/NO3 − were increased on days seven and 21, respectively. In skin, tryptase-positive mast cells and inducible nitric oxide synthase (iNOS)-positive cells were increased on days seven and 21, respectively. The increase of TEWL on days seven and 21 was suppressed by the administration of atropine and N(G)-nitro-L-arginine methyl ester, respectively.ConclusionIt was suggested that diarrhea or constipation induced by repeated senna administration caused the impairment of skin barrier function. There is a possibility that this impaired skin barrier function occurred due to degranulation of mast cells via cholinergic signals or oxidative stress derived from iNOS.

Efficacy and side-effect profiles of lactulose, docusate sodium, and sennosides compared to PEG in opioid-induced constipation: A systematic review

La constipation induite par les opioides (CIO) est un effet secondaire du traitement aux opioides qui peut avoir une incidence sur la qualite de vie, la fidelite au traitement, la morbidite, voire la mortalite. Objectifs : Mener des recherches afin de savoir si le docusate sodique, les sennosides et le lactulose ont une efficacite et des profils d’effets secondaires equivalents a ceux du polyethylene glycol (PEG) dans la prise en charge de la CIO chez les adultes. Methodologie : Un examen systematique a ete realise. Des essais cliniques aleatoires aupres d’adultes prenant des opioides pour leur douleur d’origine cancereuse et non cancereuse etaient pris en consideration s’ils satisfaisaient aux criteres d’inclusion. Conclusions : L’agregation statistique etait impossible puisqu’aucune etude ne satisfaisait aux criteres d’inclusion. Des essais cliniques aleatoires de grande envergure et dotes de beaucoup de ressources sont faisables. Des definitions normalisees de la CIO faciliteraient la realisation de ces etudes et en rehausseraient la validite interne et externe. De nouvelles recherches sont vivement encouragees.

Identification of compounds in hexane extracts of Elephantorrhiza elephantina and their comparison with selected over the counter products

The purpose of this study was to analyze hexane extracts of Elephantorrhiza elephantina(Ee) roots and to compare their chemical composition with some selected over the counter (OTC) products. Selection of the OTC products was based on their usage in treating stomach ailments, similar to the usage of E. elephantina in some regions of Southern Africa. A gas chromatography/mass spectrometer (GC/MS) and a Fourier transform infrared/attenuated total reflection (FTIR/ATR) spectrometer were used for data acquisition. OTC products included dulcolax, fish oil, imodium, senokot, stool softener, castor oil, and triphala. GC/MS results indicated that E. elephantina roots contained hexadecanoic, 9,12-octadecadienoic, 9-octadecenoic, and octadecanoic acids as major components, making up about 3 mg fatty acids/g E. elephantina roots. The OTC products contained at least two fatty acids in common with E. elephantina, namely, hexadecanoic and octadecanoic acids. Principal component analysis of the FTIR/ATR data indicated high similarities between E. elephantina roots and senokot or triphala, and the least similarities between E. elephantinaand fish oil, castor oil, and stool softener. Key words: Fourier transform infrared/attenuated total reflection (FTIR/ATR) spectrometry,Elephantorrhiza elephantina, gas chromatography/mass spectrometry (GC/MS), hexane extracts, fatty acids, over the counter (OTC) products.

Low-volume bowel preparation is inferior to standard 4 l polyethylene glycol

Four liters or more of orally taken polyethylene glycol solution (PEG) has proved to be an effective large-bowel cleansing method prior to colonoscopy. The problem has been the large volume of fluid and its taste, which is unacceptable to some examinees. We aimed to investigate the effectiveness of 2l PEG combined with senna compared with 4l PEG for bowel preparation. The design was a single-center, prospective, randomized, investigator-blinded study with parallel assignment, in the setting of the Endoscopy Unit of Umeå University Hospital. Outpatients (n=490) scheduled for colonoscopy were enrolled. The standard-volume arm received 4l PEG, and the low-volume arm received 36mg senna glycosides in tablets and 2l PEG. The cleansing result (primary endpoint) was assessed by the endoscopist using the Ottawa score. The patients rated the subjective grade of ease of taking the bowel preparation. Analysis was on an intention-to-treat basis. There were significantly more cases with poor or inadequate bowel cleansing after the low-volume alternative with senna and 2l PEG (22/203) compared with after 4l PEG (8/196, p=0.027). The low-volume alternative was better tolerated by the examinees: 119/231 rated the treatment as easy to take compared with 88/238 in the 4l PEG arm (p=0.001). 4l PEG treatment is better than 36mg senna and 2l PEG as routine colonic cleansing before colonoscopy because of fewer failures.

Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity?

Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular remedy for constipation and are frequently used abusively. Therefore, it is important to characterize its harmful and/or toxic effects. The sennosides, main active metabolites of senna, exhibit a very low toxicity in rats, and its genotoxic activity in bacterial strains as well as mammal cells was classified as weak in those cases where it was shown to be significant. The toxicological and mutagenic status of the crude extract of senna, however, is not as well characterized, and it is necessary to do so since it is frequently, and at the same time incorrectly, believed that the chronic use of anthranoid laxatives is a risk factor for the development of colorectal cancer. The objective of this article was to review the information that arises in various scientific medical databases using key words such as senna, sen, Senna alexandrina, Cassia angustifolia, sennosides, laxative toxicity, mainly ISI and non-ISI articles of journals with an editorial committee. Web pages of products or companies that publicize or commercialize this type of laxative were not included. This analysis establishes that (1) there is no convincing evidence that the chronic use of senna has, as a consequence, a structural and/or functional alteration of the enteric nerves or the smooth intestinal muscle, (2) there is no relation between long-term administration of a senna extract and the appearance of gastrointestinal tumors or any other type in rats, (3) senna is not carcinogenic in rats even after a two-year daily dose of up to 300 mg/kg/day, and (4) the current evidence does not show that there is a genotoxic risk for patients who take laxatives containing senna extracts or sennosides.

Expression of severe acute respiratory syndrome coronavirus receptors, ACE2 and CD209L in different organ derived microvascular endothelial cells

To investigate the expression of the 2 severe acute respiratory syndrome coronavirus (SARS-CoV) receptors, angiotensin-converting enzyme 2 (ACE2) and CD209L in different human organ/tissue derived microvascular endothelial cells. Endothelial cells from the microvessels in human brain, lung, hepatic sennoside, fat adipose tissue, adrenal gland, esophagus, lymph nodes, and bone were culture. RT-PCR, Western blotting and immunocytochemistry were used to detect the expression of ACE2 and CD209L receptors. Both SARS-CoV receptors of ACE2 and CD209L were expressed in the 8 organ/tissue-derived endothelial cells. The expression of ACE2 receptor was the highest in the human lung microvascular endothelial cells, and lowest in the lymphatic endothelial cells. The expression of CD209L was relatively higher in the human lymphatic endothelial cells. The organ derived microvascular endothelial cells are the important target of SARS-CoV. The pathological injury of lung and lymph system induced by SARS-CoV may be mediated respectively by different receptors of SARS-CoV.

Acute Liver Failure with Renal Impairment Related to the Abuse of Senna Anthraquinone Glycosides

To report a case of chronic ingestion of very large amounts of senna fruits as an herbal tea, possibly leading to severe hepatotoxicity. A 52-year-old woman who had ingested, for >3 years, one liter of an herbal tea each day made from a bag containing 70 g of dry senna fruits, developed acute hepatic failure and renal impairment requiring intensive care therapy. The severity of the hepatic failure was reflected by the increase in prothrombin time (international normalized ratio >7) and the development of encephalopathy. Liver transplantation was discussed, but the patient ultimately recovered with supportive therapy. Renal impairment was consistent with proximal tubular acidosis, also with marked polyuria refractory to vasopressin administration. Suprisingly, large amounts of cadmium were transiently recovered in the urine. Cassia acutifolia and angustifolia plants are widely used as laxatives. Their chronic abuse may be associated with serious manifestations, including fluid and electrolyte loss, with chronic diarrhea. Severe hepatotoxicity is unusual, but could be explained by the exposure of the liver to unusual amounts of toxic metabolites of anthraquinone glycosides (sennosides). An objective causality assessment suggests that hepatotoxicity was possibly related to senna laxative abuse. Regarding nephrotoxicity, there are no available human data on sennosides, while experimental models suggest that anthraquinone derivatives may also accumulate in the kidneys. The finding of high urinary concentrations of cadmium would suggest contamination of the herbal tea by metals, but this hypothesis could not be verified. Ingestion of large doses of senna laxatives may expose people to the risk of hepatotoxicity.

Trace Element Content of Senna Study Material and Selected Senna-Based Dietary Supplements as Determined by Inductively Coupled Plasma-Optical Emission Spectrometry and Inductively Coupled Plasma-Mass Spectrometry

The efficacy of senna laxative products and the worldwide trend towards self-medication with dietary supplements of a natural origin have fueled several investigations into the potential health effects associated with their use. The goal of this work was to determine the trace element content [aluminum (Al), arsenic (As), barium (Ba), calcium (Ca), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), sodium (Na), lead (Pb), strontium (Sr), vanadium (V), and zinc (Zn)] of a bulk senna sample that was procured for use as a study material in one such investigation. In addition, seven commercially available senna-based dietary supplements were purchased and analyzed along with the study material. Samples were digested using high-purity acids and oxidants and were analyzed by inductively coupled plasma-optical emission spectrometry (ICP-OES) and inductively coupled plasma-mass spectrometry (ICP-MS). Differences between the trace element content of the analyzed products were observed. Lead was detected in three of the tested samples (ranging from 0.686 to 1.12 μg g−1), and arsenic was detected in seven samples (ranging from 0.063 to 0.280 μg g−1). Recovery data for fortified control samples and standard reference materials (NIST 1573a Tomato Leaves, NIST 1547 Peach Leaves) indicated accurate and precise method performance.

Senna Laxatives

Senna Laxatives

Senna Laxatives: Skin Breakdown, Blisters

Senna Laxatives: Skin Breakdown, Blisters

Combination use of kampo-medicines and drugs affecting intestinal bacterial flora

The intestinal bacteria, Eubacterium sp. and Bifidobacterium sp., participate in the metabolism of active kampo-ingredients, glycyrrhizin (GL), sennoside (SEN) and baicalin (BL). Since antibiotics and bacterial preparations, Bifidobacterium longum (LAC-B), Clostridium butyricum (MIYA-BM), and Streptococcus faecalis (BIOFERMIN), affect the bacterial population in intestinal bacterial flora, metabolism of the active kampo-ingredients in the bacterial flora may be altered by their combined administration. We investigated 1199 prescriptions including kampo-medicines for 308 patients. Combination use of kampo-medicines with antibiotics and bacterial preparations occurred with 7% and 10% of the kampo-prescription, respectively. Most antibiotics have activity against intestinal bacteria, except that cephems and macrolides are not active against to E. coli. This means that antibiotics may lower the metabolism of GL, SEN and BL when administered in combination. On the other hand, it is also highly possible that bacterial preparations increase the number of Eubacterium sp. and Bifidobacterium sp., resulting in enhanced metabolism of GL and SEN when they are used concomitantly with kampo-medicines. The present results suggested that the drug interactions of kampo-medicines with antibiotics and bacterial preparations should be confirmed in clinical studies.

Reactive nitrogen species modulate the effects of rhein, an active component of senna laxatives, on human epithelium in vitro.

Senna laxatives are used worldwide. However, their misuse can lead to chronic mucosal inflammation with the accumulation of pigment-laden leukocytes and may cause colon cells to undergo apoptosis. This study explores the mechanisms by which rhein, an active component of senna, acts on a human intestinal cell line to induce ion secretion, apoptosis, and indirect chemotaxis of polymorphonuclear leukocytes. Human colonic adenocarcinoma (CaCo-2) monolayer cells, in the presence or in the absence of rhein, were used to monitor the production of reactive nitrogen species using the Griess reaction. Modified Ussing chambers were used to study electrolyte secretion. The capacity to recruit human polymorphonuclear leukocytes was evaluated using masked well chemotaxis chambers. Rhein-induced apoptosis was investigated by counting apoptotic nuclei stained with Hoechst 33258 dye. Rhein caused a dose-dependent increase in short-circuit current that was abolished in chloride-free bathing buffer or by preincubating with 100 micromol/L NG-nitro-L-arginine (L-NAME) methyl ester. The concentration that maximally stimulated intestinal secretion, 50 micromol/L rhein, induced nitrate production. Supernatants obtained from CaCo-2 cultures after incubation with 50 micromol/L rhein stimulated a time-dependent polymorphonuclear leukocytes chemotaxis that was significantly decreased with 100 micromol/L L-NAME, whereas rhein per se was not active. Neutralizing antibodies anti-interleukin-8 (IL-8) and anti-ENA78 also inhibited chemotaxis. Overnight rhein incubation produced an increased number of apoptotic cells in the culture supernatant that was significantly decreased by preincubation with 100 micromol/L L-NAME. Light-degraded rhein had no effects on CaCo-2 monolayers. The integrity of rhein is crucial to generating nitric oxide, which mediates, with different time courses, ion secretion, chemotaxis, and apoptosis of human-derived cells.

Reactive Nitrogen Species Modulate the Effects of Rhein, an Active Component of Senna Laxatives, on Human Epithelium In Vitro

ABSTRACTBackgroundSenna laxatives are used worldwide. However, their misuse can lead to chronic mucosal inflammation with the accumulation of pigment‐laden leukocytes and may cause colon cells to undergo apoptosis. This study explores the mechanisms by which rhein, an active component of senna, acts on a human intestinal cell line to induce ion secretion, apoptosis, and indirect chemotaxis of polymorphonuclear leukocytes.MethodsHuman colonic adenocarcinoma (CaCo‐2) monolayer cells, in the presence or in the absence of rhein, were used to monitor the production of reactive nitrogen species using the Griess reaction. Modified Ussing chambers were used to study electrolyte secretion. The capacity to recruit human polymorphonuclear leukocytes was evaluated using masked well chemotaxis chambers. Rhein‐induced apoptosis was investigated by counting apoptotic nuclei stained with Hoechst 33258 dye.ResultsRhein caused a dose‐dependent increase in short‐circuit current that was abolished in chloride‐free bathing buffer or by preincubating with 100 μmol/L NG‐nitro‐L‐arginine (L‐NAME) methyl ester. The concentration that maximally stimulated intestinal secretion, 50 μmol/L rhein, induced nitrate production. Supernatants obtained from CaCo‐2 cultures after incubation with 50 μmol/L rhein stimulated a time‐dependent polymorphonuclear leukocytes chemotaxis that was significantly decreased with 100 μmol/L L‐NAME, whereas rhein per se was not active. Neutralizing antibodies anti–interleukin‐8 (IL‐8) and anti‐ENA78 also inhibited chemotaxis. Overnight rhein incubation produced an increased number of apoptotic cells in the culture supernatant that was significantly decreased by preincubation with 100 μmol/L L‐NAME. Light‐degraded rhein had no effects on CaCo‐2 monolayers.ConclusionsThe integrity of rhein is crucial to generating nitric oxide, which mediates, with different time courses, ion secretion, chemotaxis, and apoptosis of human‐derived cells.

No clastogenic activity of a senna extract in the mouse micronucleus assay

In previous studies, an analytically well-defined senna extract, commonly used as a laxative, gave positive responses in vitro in the Ames test and in the CHO assay. Therefore, the objective of this study was to investigate the genotoxic activity of the same senna extract in an in vivo genotoxicity assay by means of the generally acknowledged MNT. After administration of an oral dose of 2000 mg senna extract/kg to NMRI mice of both genders, which is equivalent to 119 mg potential 1 “Potential” indicates for each anthraquinone the sum of freely occurring substance and the amount of the same compound which can theoretically be formed by intestinal bacteria from anthranoid precursors such as sennosides. 1 rhein/kg, 5.74 mg potential aloeemodin/kg and 0.28 mg potential emodin/kg, there were no elevated levels of micronuclei in bone marrow cells. Kinetic studies were performed in parallel to demonstrate target organ availability. Highest concentrations in the plasma were reached after 1 h with 3.4 μg rhein/ml and 0.065 μg aloeemodin/ml. In all cases, emodin was below the limit of quantification. From the results, the in vitro clastogenic activity of the senna extract could not be confirmed in the mouse micronucleus assay. Together with further negative in vivo genotoxicity studies with anthranoids, the conclusion can be drawn that there is no indication so far demonstrating a genotoxic risk for patients taking senna laxatives.