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The action of sennosides and related compounds on human colon and rectum 1
Abstract
The direct action of intraluminal senna and related compounds on the human colon and rectum has been investigated. Motility was recorded by balloon kymography with recording units inserted into well established transverse colostomies or into the rectum.The motility of the colon was not changed by intraluminal senna glycosides but the introduction of senna previously incubated with faeces or Esch. coli stimulated the colon to peristalt. The peristalsis was similar to that stimulated by rheinanthrone, an oxanthrone produced by chemical hydrolysis and reduction of senna.Both activated senna and rheinanthrone appeared to act in the colon by contact stimulation. No peristaltic response was stimulated in the rectum, either with activated senna or with rheinanthrone.
... Rhei Rhizoma (Rhubarb in English and Daio in Japanese) is one of the most frequently used herbs for constipation throughout the world. Rhei Rhizoma contains dianthrone glucosides (sennosides A to F) and anthraquinones (e.g., rhein, aloe-emodin, emodin, physcion, chrysophanol; Hardcastle and Wilkins, 1970;Dreessen et al., 1981;Ngoc et al., 2008). Among these components, sennosides (i.e., stimulative laxatives), have been well documented for their pharmacological action on constipation (de Witte, 1993). ...
... Among these components, sennosides (i.e., stimulative laxatives), have been well documented for their pharmacological action on constipation (de Witte, 1993). Sennosides A and B play a central role in the motility of the alimentary tract as prodrugs that are converted to an active principle, rheinanthrone, by intestinal microbiota (Hardcastle and Wilkins, 1970;Dreessen et al., 1981). A recent study showed that sennoside A may exert a laxative effect by inhibiting water transfer from the intestinal tract to the vascular side via decreasing aquaporin-3 expression in the colon (Kon et al., 2014). ...
Constipation is characterized by a variety of bowel symptoms such as difficulty passing stool, hard stool, and a feeling of incomplete evacuation. The multifactorial causes of constipation limit the clinical efficacy of current conventional treatments that use a single drug that acts through only one pathway. To complement the shortcomings of the current Western medical model and provide a complete holistic approach, herbal medicines capable of targeting multiple organs and cellular sites may be used. In Japan, many herbs and herbal combinations have traditionally been used as foods and medicines. Currently, Japanese physicians use standardized herbal combinations that provide consistent and essential quality and quantity. This review highlights representative Japanese herbal medicines (JHMs), Rhei rhizoma-based JHMs including Daiokanzoto and Mashiningan, and Kenchuto-based JHMs including Keishikashakuyakuto and Daikenchuto, which coordinate the motility of the alimentary tract. This review provides a framework to better understand the clinical and pharmacological efficacies of JHMs on constipation according to the unique theory of Japanese traditional medicine, known as Kampo medicine.
... Since ancient times, Kampo medicine daio (Rhei rhizoma or Sennae folium) has been employed as a purgative crude drug because of its purgative properties. Sennoside A and B, the main laxative constituent of daio, are prodrugs that are converted to an active principle, rheinanthrone , by intestinal microbiota891011. Therefore, there is a considerable difference in the efficacy of this drug among individuals. ...
... In contrast, certain patients experience diarrhoea as a side effect of daio medicine. Since 1970, several studies have been performed to investigate the relationship between sennosides and intestinal microbiota and the metabolism of sennosides [8,12,13]. The bacterial strains that can hydrolyse sennosides were isolated from intestines [14– 16], and these microbiota have been found to employ several pathways to metabolize sennosides [13]. ...
While there are a variety of identifiable causes of constipation, even idiopathic constipation has different possible mechanisms. Sennosides, the main laxative constituents of Daio, an ancient Kampo medicine, are prodrugs that are converted to an active principle, rheinanthrone, by intestinal microbiota. In this study, we aimed to determine the sennoside hydrolysis ability of lactic acid bacterial strains and bifidobacteria in the intestine and to investigate their effect on intestinal peristalsis in mice.
A total of 88 lactic acid bacterial strains and 47 bifidobacterial strains were evaluated for their ability to hydrolyze sennosides. Our results revealed that 4 strains, all belonging to the genus Bifidobacterium, had strong sennoside hydrolysis ability, exhibiting a decrease of >70% of sennoside content. By thin-layer chromatography analysis, rheinanthrone was detected in the medium cultured with B. pseudocatenulatum LKM10070 and B. animalis subsp. lactis LKM512. The fecal sennoside contents significantly (P<0.001) decreased upon oral administration of these strains as compared with the control. Intestinal peristalsis activity was measured by the moved distance of the charcoal powder administered orally. The distance travelled by the charcoal powder in LKM512-treated mice was significantly longer than that of control (P<0.05). Intestinal microbiota were analysed by real-time PCR and terminal-restriction fragment length polymorphism. The diversity of the intestinal microbiota was reduced by kanamycin treatment and the diversity was not recovered by LKM512 treatment.
We demonstrated that intestinal peristalsis was promoted by rheinanthrone produced by hydrolysis of sennoside by strain LKM512 and LKM10070.
... It contains anthracene derivatives, such as sennosides, which on hydrolysis by bacterial enzymes in the gut, release aglycones of three types; namely anthraquinones, anthranols and oxanthrones. 13 These aglycones are the active part of sennosides, and cause the laxative action by influencing the transport of water and electrolytes. 14 ...
The outbreak of the novel coronavirus (SARS-CoV-2) since December 2019 has created an unprecedented state. As it is a new variant of a virus treatment options are not only limited but require painstaking trials to confirm their effectiveness. Due to the lack of awareness in many developing countries people have started using herbal medications, used for various other diseases, to combat COVID-19. Misleading information on social media regarding “Senna Makki” has gone viral in Pakistan. However, consumption of Senna Makki is not advised as a treatment option for COVID-19 due to its many harmful associated side-effects. Although its use in other diseases is evident, trials to confirm its effectiveness against COVID-19 need to be prioritized as the public has started consuming Senna Makki in high doses and without monitored prescription.
... A growing body of evidence shows that glycosides are capable of acting as prodrugs and have direct therapeutic effects. One example of a class of glycoside pharmaceutical prodrugs is senna glycosides (Senokot, Ex-Lax), which are administered orally, followed by decoupling of the sugars in the large intestine by β-glucosidases secreted from intestinal microbiota (Hardcastle 1970). Site-specific delivery of steroid glycosides to the colon has also been demonstrated (Friend 1985, Friend 1984 tissue-specific drug delivery, which would release simple glucose sugars upon prodrug decoupling. ...
The cannabinoid signaling system has recently garnered attention as a therapeutic target for numerous indications, and cannabinoids are now being pursued as new treatment options in diverse medical fields such as neurology, gastroenterology, pain management, and oncology. Cannabinoids are extremely hydrophobic and relatively unstable compounds, and as a result, formulation and delivery options are severely limited. Enzymatic glycosylation is a strategy to alter the physicochemical properties of small molecules, often improving their stability and aqueous solubility, as well as enabling site-specific drug targeting strategies. To determine if cannabinoids are a candidate for glycosylation, a library of glucosyltransferase (UGT) enzymes was screened for glycosylation activity towards various cannabinoids. The UGT76G1 enzyme from Stevia rebaudiana has been identified as having glucosyltransferase activity towards a broad range of cannabinoids. Compounds that were successfully glycosylated by UGT76G1 include the phytocannabinoids cannabidiol (CBD), Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), cannabidivarin (CBDV), and cannabinol (CBN), and the human endocannabinoids anandamide (AEA), 2-arachidonoyl-glycerol (2AG), 1-arachidonoyl-glycerol (1AG), and synaptamide (DHEA). Interestingly, UGT76G1 is able to transfer primary, secondary, and tertiary glycosylations at each acceptor of most of the cannabinoids tested. Additionally, Os03g0702000p, a glycosyltransferase from Oryza sativa , was able to transfer secondary glucose residues onto cannabinoid monoglycosides previously established by UGT76G1. This new class of cannabinoid-glycosides has been termed cannabosides. The compounds have greatly improved solubility in aqueous solutions. This increased aqueous solubility may enable new oral pharmaceutical delivery options for cannabinoids, as well as targeted delivery and release of cannabinoids within the intestines through glycoside prodrug metabolism.
... Many studies have been conducted to examine the laxative action of sennoside A. Elke Leng-Peschlow and Staumont et al. showed that sennoside A notably accelerates colon transit in animals [1][2][3][4]. Dreessen et al. found that rhein anthrone was generated when sennoside A was incubated with cecal contents and reported that peristaltic movements in the colon were accelerated when either the culture solution or the rhein anthrone were given to animals [5,6]. The laxative action of sennoside A or daiokanzoto has been reported to be reduced when they are given to mice treated with an antibiotic [7]. ...
Aim
The laxative action of daiokanzoto (a compound containing rhubarb and glycyrrhiza) is thought to be due to sennoside A, an ingredient in rhubarb. Glycyrrhizin, which has anti‐inflammatory effects, is the main ingredient in glycyrrhiza, and it alleviates adverse reactions, such as abdominal pain and painful defecation, due to rhubarb. No consensus has been reached, however, on why daiokanzoto contains glycyrrhiza. We found that sennoside A exerts a laxative action by decreasing aquaporin‐3 (AQP3) expression through the activation of macrophages in the colon. This study analyzed the effect of glycyrrhizin on the laxative action of sennoside A focusing on AQP3 expression.
Methods
Sennoside A, glycyrrhizin, or a combination of both were given orally to rats, and diarrhea severity was assessed. The expression of AQP3, inflammatory cytokines, and cyclo‐oxygenase (COX) was analyzed.
Results
Although diarrhea occurred when sennoside A and glycyrrhizin were given together orally, it was less severe than when sennoside A was used alone, and, correspondingly, only sennoside A inhibited AQP3 expression to a greater extent than the combination of both drugs. When glycyrrhizin was given concomitantly, the sennoside A‐induced increased expression of pro‐inflammatory cytokines and COX‐2 was suppressed.
Conclusions
The laxative action of sennoside A and the decreased expression of AQP3 were suppressed when sennoside A and glycyrrhizin were given concomitantly, likely due to the anti‐inflammatory effects of glycyrrhizin. This indicates that glycyrrhizin both attenuates the adverse reactions caused by sennoside A and plays a role in its laxative action.
... The Choice of a Laxative to Treat OIC/OIBD Depends on the Perceived Efficacy and the Preference of the Patient; Indirect Evidence Favors Bisacodyl, Sodium Picosulfate, Macrogol (Polyethelene Glycol), and Sennosides as First Choice Comment: Both bisacodyl (and its derivative sodium picosulfate) and sennosides stimulate secretion and are very potent prokinetics in the colon. Their prokinetic action may potentially also be active in the more oral segments of the gut [137][138][139]. Bisacodyl is used as the rescue laxative in most of the therapeutic trials for OIC, and the amount taken is considered a sensitive variable for the efficacy of the drug under investigation [32][33][34]43,[140][141][142]. ...
Objective:
To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction.
Setting:
Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term "opioid-induced bowel dysfunction."
Methods:
A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system.
Results:
From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction.
Conclusions:
In recent years, more insight has been gained in the pathophysiology of this "entity"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present.
... The laxative propriety of anthrone rhein is well known, which is obtained as sennosides primarily from Cassia acutifolia and C. angustifolia and is metabolized by bacteria from the intestinal tract of humans. 9 n-Hexane and methanol extracts of the leaves of S. macranthera have strong laxative activity, comparable with that of the positive control bisacodyl, and anti-inflammatory activity, similar to that of diclofenac sodium. 10 The dimeric indole alkaloid cassiaindoline in the leaves of S. alata has significant analgesic and anti-inflammatory activities, and the anthraquinones in the leaves of this species has effective antifungal and bactericidal activities. ...
Methanolic, diethyl ether and n-hexane extracts of leaves of four species of Senna (S. gardneri, S. macranthera, S. splendida and S. trachypus) were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Using linear retention indices and mass spectral data, 34 compounds were identified, including fatty acids, flavonoids, terpenoids and steroids that were not reported previously for these species. Additionally, the cytotoxicity of the extracts against different tumor cell lines was determined. The cytotoxicity was then correlated with the chemical composition of the extracts by partial least squares-discriminant analysis (PLS-DA). The n-hexane extract of S. gardneri and the ethyl ether extract of S. splendida were the most active against human colon (59.75 and 31.37%, respectively) and human glioblastoma (52.85 and 48.28%, respectively) cell lines.
... The glucoside cathartics senna and cascara are hydrolysed to release their active agents. It has been demonstrated (Hardcastle and Wilkins, 1970) that whereas cascara sagrada has no effect on the colon the aglycone increases colic motility of rabbits. If the free aglycone is fed to the animals it has no cathartic action, indicating that it is sensitive to either gastric or small intestinal secretions. ...
Colonic bacteria can be studied by identifying and enumerating the major groups or by studying their biochemical activities. The recto sigmoid flora is similar to the faeces but differs from that found in the region of the ileocaecal junction. The major species is Bacteroides fragilis. E coli and Strep. viridans also are common. Lack of good selective media makes the less frequent organisms difficult to count. Luminal flora are easily counted but the mucosal flora may be quite different and difficult to identify. Diet is known to affect faecal flora but the changes take place slowly. Colonic flora cause hydrolysis of glycosides followed by fermentation of the monosaccharide. This reaction may produce either toxic or therapeutic effects. The enterohepatic circulation plays an important role in this. It is also important in the production of ammonia from amino acids and urea, acting through bacterial urease. Control of nitrogen metabolism in hepatic coma is achieved by either reducing nitrogen intake, getting rid of ammonia producing organisms, shortening the time available for organisms to produce ammonia by giving purgatives and enemas, or retaining the ammonia in the gut by using lactulose to lower the pH. Gut bacteria deconjugate bile acids mainly in the ileum, by dehydroxylation occurring in the large bowel, and contribute to the total faecal loss of bile acids. Colon carcinogens may be unsaturated bile acids produced by anaerobic gut organisms commonly found in human faeces in areas of high colon cancer incidence and rarely found where the incidence of colon cancer is low. In a recent trial, concentrations of faecal bile acids and nuclear dehydrogenating clostridia were much higher in patients with colon cancer than in a control group. It may be possible to use these tests in the future to predict colon cancer. (Hennessy - Dublin)
Objectives:
Low-volume polyethylene glycol plus ascorbic acid (PEG-Asc) reduces the dosage of colonoscopic bowel preparation (BP) solution, but is still poorly tolerated. Adding laxatives to the BP solution reduces the volume of fluid required, without affecting quality. This study aimed to compare 1-L PEG-Asc plus 24 mg senna (1L-PEG/AS) and conventional 2-L PEG-Asc (2L-PEG/A) regimens on BP quality and patient tolerability.
Methods:
A single-center, randomized, investigator-blinded, non-inferiority trial was performed between June and August 2022. Outpatients scheduled for colonoscopy were randomized (1:1) to the 1L-PEG/AS or 2L-PEG/A group. The Boston Bowel Preparation Scale (BBPS) was used to evaluate BP quality. Adverse events and tolerability were surveyed using questionnaires.
Results:
Overall, 344 patients received 1L-PEG/AS or 2L-PEG/A regimens. The baseline characteristics and adverse events of the two groups were comparable. The 1L-PEG/AS group showed non-inferior adequate BP rates compared with the 2L-PEG/A group (88% vs. 89%, P=1.00); overall BBPS was 7.1±1.5 and 7.2±1.5, respectively (P=0.39). Higher willingness to repeat the BP was observed in the 1L-PEG/AS group (85% vs. 62%, P<0.01).
Conclusions:
The 1L-PEG/AS regimen was comparable to the 2L-PEG/A regimen in terms of BP adequacy, requiring lesser BP solution volumes, with better patient tolerance. Thus, it may be a suitable alternative to the conventional BP solution for colonoscopy.
Unter „irritablem Kolon“ (i.K.) versteht man einen Symptomenkomplex abdomineller Beschwerden ohne faßbare organische Ursache, deren Ursprung vorwiegend im Dickdarm zu suchen ist. Die in ihrer Intensität wechselnden Beschwerden beeinträchtigen das Wohlbefinden des Betroffenen oft erheblich. Quo ad sanationem ist die Prognose dubiös, quo ad vitam gut.
Constipation is unsatisfactory defecation characterized by a variety of bowel symptoms such as difficulty passing stool, hard stool, and a feeling of incomplete evacuation. The multifactorial causes of constipation might limit the clinical efficacy of current conventional treatments that use a single drug that acts through only one pathway. Herbal medicines capable of targeting multiple organs and cellular sites are great fascinating from the standpoint of a holistic approach, making it possible to complement the shortcomings of the current Western medical system. In Japan, herbal medicines have been used throughout history as foods and medicines and currently Japanese physicians can use a standardized form of herbal combination with high quality.
This review provides an overview of the clinical application and pharmacological action of two types of Japanese herbal medicines (JHMs), Rhei rhizoma-based JHMs including Daiokanzoto and Mashiningan, and Kenchuto-based JHMs including Daikenchuto and Keishikashakuyakuto, in the treatment of constipated patient by combining the molecular basis of action drawn from many literatures and the unique theory of Japanese traditional medicine, known as Kampo medicine.
Drugs can cause impairment in nutritional status when they produce one or more of the following effects:
1
Anorexia with depression of food intake
2
Malabsorption
3
Vitamin antagonism
4
Mineral depletion
5
Catabolic stress with loss of lean body mass.
The main function of the large bowel is to store and absorb water, electrolytes, volatile fatty acids, nitrogenous substances, and some vitamins, but at the same time it must be able to propel its contents when they have reached the proper consistency and to interact with the central nervous system in order to provide continence and a socially acceptable pattern of defecation. The complex nature of the motility of the colon, rectum, and anus is not surprising in view of the need for the combination of retention and excretion properties over barely 100 cm of bowel.
IntroductionAnatomical and Physiological Consideration Relevant to Colonic Delivery of DrugsThe Evolution of Colon-Specific Drug Delivery: From Laxative Drugs to 5-ASA [62]Design Considerations in Colonic Drug Delivery SystemsSlow Release and Enteric-Coated BarriersPolymers with Enzyme-Driven Degradation PropertiesAZO PolymersNatural Polysaccharides and Related Design OutlinesSynthetic Saccharidic PolymersColon-Specific Prodrugs: Glycosidic and Glucuronic Acid Prodrugs of SteroidsPolymeric ProdrugsDextran ProdrugsConclusion and ProspectsReferences
Introduction The majority of cancer patients (approximately 80%) develop pain before they die. Pain in cancer patients is often underdiagnosed, and inadequate treatment with opioid analgesics is well documented. Many factors influence pain management in this patient group. Inappropriate and suboptimal education of physicians and other health care professionals has been identified as the major barrier to adequate opiate use. In developing countries, a further issue is reduced availability of opioids due to financial limitations and government regulations. As a result of a major educational effort by a number of organizations, including the World Health Organization, the International Association for the Study of Pain, and the American Society of Clinical Oncology, opioid use has improved very significantly in developed countries during the past two decades. The results of such efforts have been quite variable. However, in many regions of the world, progress has been made, with opioids being used in higher doses and at earlier stages in palliative care. Cancer patients, who now have earlier exposure to opioids and generally have treatment with higher dosages, are better managed than in the past. This highly desirable increase in the use of opioids, combined with increased vigilance, has resulted in increased detection of several side effects, most notably neurotoxicity. With this increase in opioid use and the improvement in identification of adverse effects, management strategies for dealing with these unwanted effects have been developed and augmented.
Proprietary laxatives represent a multimillion dollar industry and are widely used by the apparently well population. They are traditionally classified into bulk laxatives, lubricants, stimulants, stool softeners, and osmotic laxatives. The latter 3 probably act mainly by favouring accumulation of fluids and electrolytes in the lumen of the gut. Magnesium-containing saline laxatives are believed to act by releasing cholecystokinin which, in turn, favours intraluminal fluid accumulation. Bran is not a proprietary laxative. It is a bulking agent with capacity to hold water in the stool, thereby improving bowel function. The lubricant, mineral oil (liquid paraffin), is obsolete.
In constipation associated with the spastic colon, bran will transform the difficult-to-pass scybala into softer, bulkier and more easily passed stools. Atonic constipation, in which defaecation fails to be triggered by a full rectum, is less satisfactorily treated with bran. In these individuals, chronic laxative use often compounds the problem. Bowel retraining with occasional (and decreasing) use of laxatives such as bisacodyl or ‘Senokot’ (standardised senna) are often effective. Occasionally, a glycerin suppository will trigger the defaecation reflex.
Patients with an acute illness, undergoing surgery or suffering from perianal disease benefit from the early institution of bran to encourage the easy passage of soft stool. Bisacodyl or ‘Senokot’ should be kept in reserve. In patients who become impacted, particularly following a barium enema, an oil retention enema followed by a tap water enema may be successful, but manual disimpaction should not be unduly delayed. Laxatives may alter the appearance of the colon mucosa and so should be avoided before sigmoidoscopy. Preparation for an air contrast barium enema or colonoscopy necessitates a 2 day program of taxation including a fluid diet.
Laxatives are probably more important to modern medicine for the harm they do than for their benefit. Use of the stimulant cathartics can lead to an atonic colon in which the neuromuscular apparatus is permanently damaged. Vigorous purgation may produce a paradoxical diarrhoea complicated by electrolyte derangement, malabsorption, and protein-losing enteropathy. Other than bran, most clinicians will have little need for laxatives and their use by patients should also be discouraged.
The motility of the colon is modulated by the enteric nervous system. It is very complex, governing backward and forward movements of the feces. Primary megacolon and megarectum are clinically diverse. Megacolon refractory to laxative treatment may be subject to colectomy, while megarectum should be treated by consistent laxation. Acute colonic pseudo-obstruction may occur with severe systemic diseases and electrolyte disturbances or it may be postoperatively and/or medically induced. A small proportion of chronically constipated patients suffer from slow transit constipation, others from disordered defecation. In the remaining patients no objective cause of the complaints may be found. In slow transit constipation, propulsive colonic motility is disturbed, dietary fiber is ineffective, and the response to bisacodyl is blunted. Pelvic floor dyssynergia is characterized by a voluntary (although unconscious) contraction of the anal sphincter simultaneously with the abdominal muscles. It can be treated by avoiding straining and by sphincter training.
Die chronische Obstipation tritt häufig auf und verlangt oft eine pharmakologische Behandlung. Auf dem Markt sind diverse Abführmittel erhältlich, die sehr unterschiedlichen pharmakologischen Gruppen angehören. Deren wichtigste Vertreter sind unter den älteren Laxanzien die osmotischen Salze, Zucker und Zuckeralkohole, Macrogol, Anthrachinone und die diphenolischen Laxanzien (Bisacodyl und Natriumpicosulfat), unter den neueren Laxanzien Prucaloprid und Linaclotid. Die Wirksamkeit aller genannten Substanzen wurde in klinischen Studien belegt. Bei korrekter Dosierung kommt es nicht wie oft befürchtet zu Elektrolytstörungen (mit seltenen Ausnahmen bei salinischen Laxanzien). Die älteren Substanzen sind auch hinsichtlich Schwangerschaft und Stillzeit sicher; für die neueren Präparate fehlen noch entsprechende Daten. Unklar ist, ob die neueren Substanzen gegenüber den älteren Vorteile bieten. Vergleichsstudien gibt es nicht. Bei opiatinduzierter Obstipation kommen neben Laxanzien auch bestimmte Opiatantagonisten infrage.
The ability to deliver drugs to the human colon in a specific manner has become feasible in the last decade. A variety of means, including protective coats and pH-dependent polymers, are currently in use. Utilization of the metabolic activity of the colon is an attractive implement to improve the drug carriers' specificity. Biodegradable polymers, which are cleaved by colonic enzymes, can be used for that purpose. The mechanism of choice is azo-reduction and glycosidic-bond hydrolysis. In this review, some of the most common approaches to target drugs to the colon are reviewed and special attention is paid to modified polysaccharides as potential drug carriers to the human colon. Drug Dev. Res. 50:435–439, 2000. © 2000 Wiley-Liss, Inc.
Chronic constipation is a frequent condition often requiring pharmacological treatment. A number of laxatives that belong to very different pharmacological groups are available. Most relevant are the older representatives osmotic salts, sugars and sugar alcohols, macrogol, anthraquinones, diphenolic laxatives (bisacodyl and sodium picosulphate), and the newer compounds prucalopride and linaclotide. For all of these laxatives, efficacy has been shown in controlled trials. Electrolyte problems do not occur when laxatives are given in therapeutic doses (rare exceptions with salinic laxatives). The older laxatives are also safe regarding teratogenicity, abortion, and lactation; for the newer compounds no respective data are available as yet. It is questionable whether the newer laxatives offer advantages over the older ones. Unfortunately, comparative trials are lacking. Opiate-induced constipation may also be treated with laxatives or certain opiate antagonists.
Introduction:
Chronic constipation is a frequent condition often treated pharmacologically. The laxatives available belong to very different pharmacologic groups.
Areas covered:
This is a short but comprehensive review of the pharmacology, efficacy and safety of currently available laxatives for chronic constipation. Pertinent publications were retrieved from reference lists of publications and by literature searches via PubMed, lastly performed in November 2012.
Expert opinion:
The most relevant laxative groups are the older representatives osmotic salts, sugars and sugar alcohols, macrogol, anthraquinones, diphenolic laxatives or diphenyl methanes (bisacodyl and sodium picosulfate) and the newer compounds prucalopride, lubiprostone and linaclotide. For all of these laxatives efficacy has been shown in controlled trials. Electrolyte losses do not occur when laxatives are given in therapeutic doses (rare exceptions with phosphate salts and salinic laxatives). The older laxatives are also safe regarding teratogenicity, abortion and lactation. For the newer compounds no respective data are available as yet. It is questionable whether the newer compounds offer advantages over the older ones. Unfortunately, comparative trials are lacking.
The human gastrointestinal tract consists of a highly complex ecosystem of aerobic and anaerobic microorganisms that plays a significant role in the metabolism of nutrients as well as drugs. In the colon, bacteria ferment various types of substrates that are not susceptible to digestion in the small intestine. This arouses interest in specific drugs, drug delivery systems, and prodrugs that escape small bowel digestion, arrive intact, and are absorbed or degraded in the large bowel. For the past forty years, experience has been gained with the azo prodrug of 5-amino salicylic acid, salazopyrine, which is cleaved by colonic bacteria to its parent drug. Some laxative drugs were also reported to degrade into active metabolites in the colon. Lately equally interesting and more sophisticated microbial controlled delivery systems, have been developed based on similar principles.
Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side effects limit chronic glucocorticoid therapy. The dose, and consequently the side effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid–dextran conjugates in which dexamethasone and methylprednisolone were attached to dextran (weight-average molecular weight = 72 600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, the hydrolysis kinetics of the hemiesters (hemiester = glucocorticoid + linker) and dextran conjugates were determined after incubation at 37 °C in diluted luminal contents of the gastrointestinal (GI) trace of male Sprague–Dawley rats. The hemiesters were rapidly hydrolyzed in the proximal small intestine (e.g., dexamethasone–hemiglutarate t1/2 = 0.5 h). This rate decreased progressively down the GI tract (t1/2 = 4.8, 54, and 68 h in distal small intestine, cecum, and colon, respectively). The enzyme responsible for hemiester hydrolysis, apparently a type-A alkaline carboxylesterase, is probably of host origin because its activity is highest in the small intestine where bacterial count is low. The dextran conjugates resisted hydrolysis in upper GI tract contents but were rapidly degraded in cecal and colonic contents where the bacterial count is high. The dextran conjugate tested, methylprednisolone–succinate–dextran, was easily hydrolyzed by an endodextranase, indicating that substrate specificity is not lost upon the attachment of glucocorticoid. The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the large intestine for the treatment of colitis.
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
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.
The delivery of drugs to the colon has a number of important implications in the field of pharmacotherapy. Several diseases, including IBD, can be treated more effectively by local delivery of antiinflammatory agents to the large intestine. SASP is the classic prodrug used to deliver 5-ASA for localized chemotherapy of IBD. Due to adverse side-effects of SASP, a number of newer 5-ASA prodrugs are under development. The use of azo-reductase activity of colonic microflora has also been used to liberate 5-ASA from polymeric prodrugs and more recently to catalyze the partial degradation of hydrogels in the colon. These hydrogels may be useful in the delivery of peptides and proteins to the colon. The colonic bacteria also produce a wide array of glycosidases capable of hydrolyzing simple glycosides as well as polysaccharides. These enzymes have been exploited to release drugs in the large intestine. A number of studies have indicated that corticosteroids released from glycoside prodrugs are absorbed from the lumen of the large intestine and lead to much higher colonic tissue levels than are possible when the parent corticosteroid is administered systemically. The colon is also a potential site for absorption of peptides and proteins. Some potential limitations involved in oral peptide and protein delivery from the colon are discussed. In addition, the use of specific receptors and lectins on colonic mucosal cells offer the potential to deliver drugs to the colonic mucosa in a selective way. Interestingly, certain lectins have significantly increased binding to colonic mucin in several disease states: IBD and large bowel carcinoma. Exploiting these differences could lead to new, biologically oriented colonic drug delivery systems that deliver drugs selectively to the target cells, thereby reducing systemic exposure.
Dexamethasone-β-d-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent dexamethasone. To deliver dexamethasone selectively to the colon, the glycoside prodrug must be slowly absorbed from the alimentary canal and it must be chemically and enzymatically stable in the stomach and small intestine. Once the prodrug reaches the large intestine, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-β-d-glucoside for colon-specific delivery of dexamethasone was first assessed in the rat, and more recently in the guinea pig, an animal in which an inflammatory bowel disease (IBD) model had been developed. The hydrolytic activity of both the tissues and contents of the guinea pig stomach, proximal and distal portions of the small intestine, cecum, and colon were measured. For the tissues, β-d-glucosidase activity was greatest in the proximal small intestine while the contents of the cecum and colon showed the greatest β-d-glucosidase activity. The luminal contents retained their activity even after repeated centrifugation and resuspension in a buffer; the activity was also unaffected by homogenization. Movement and hydrolysis of dexamethasone-β-d-glucoside down the gastrointestinal tract (GIT) in the guinea pig was also examined. About 20 to 30% of an oral dose appeared to reach the guinea pig cecum. Here the prodrug was rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-β-d-glucoside is poorly absorbed in the GIT (bioavailability < 1%). There is a selective advantage for delivery of dexamethasone in cecal tissues of about 9 in the guinea pig under conditions of this experiment. In another study, degraded carrageenan was used to develop experimental IBD in the guinea pig. Following oral dosing of dexamethasone-β-d-glucoside (1.3 μmol/kg or 0.65 μmol/kg), dexamethasone (1.3 μmol/kg), or the dosing vehicle (H2O/EtOH, 0.95:0.05, v/v), the total number of ulcers in each group of animals was counted. Relative to control animals (dosing vehicle only), the drug and prodrug treatments significantly (P < 0.05) reduced the total number of ulcers. While there was no difference statistically between the drug and prodrug treatments, the results indicate that a lower dose of dexamethasone, administered as its glucoside prodrug, can be equally efficacious relative to higher dose of dexamethasone. This conclusion is consistent with the pharmacokinetic data obtained in normal guinea pigs and suggests there is a potential to decrease the usual dose of corticosteroids with a concomitant reduction in the systemic exposure.
Fifteen years of research in the area of colon-specific drug delivery has left us with a slim choice of viable techniques, not because of the lack of proofs of concept but because of the ambiguity regarding the therapeutic necessity of targeting the colon with drugs. Critical analysis of existing technologies as well as medically based novel ideas could lead to interesting prospects.Section editors:Daan J.A. Crommelin – Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The NetherlandsGerrit Borchard – Enzon Pharmaceuticals, Piscataway, NJ, USA
An evidence-based systematic review, including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.
To prospectively investigate the effectiveness and patient's tolerance of two low-cost bowel cleansing preparation protocols based on magnesium citrate only or the combination of magnesium citrate and senna.
A total of 342 patients who were referred for colonoscopy underwent a colon cleansing protocol with magnesium citrate alone (n = 160) or magnesium citrate and senna granules (n = 182). The colonoscopist rated the overall efficacy of colon cleansing using an established score on a 4-point scale. Patients were questioned before undergoing colonoscopy for side effects and symptoms during bowel preparation.
The percentage of procedures rescheduled because of insufficient colon cleansing was 7% in the magnesium citrate group and 4% in the magnesium citrate/senna group (P = 0.44). Adequate visualization of the colonic mucosa was rated superior under the citramag/senna regimen (P = 0.004). Both regimens were well tolerated, and did not significantly differ in the occurrence of nausea, bloating or headache. However, abdominal cramps were observed more often under the senna protocol (29.2%) compared to the magnesium citrate only protocol (9.9%, P < 0.0003).
The addition of senna to the bowel preparation protocol with magnesium citrate significantly improves the cleansing outcome.
Fifty patients who had undergone proctologic operations were given a combination of standardized senna concentrate and dioctyl sodium sulfosuccinate for prevention or treatment of postoperative constipation. Two Senokot S tablets were given on the evening of the first postoperative day. Patients who had bowel movements after receiving this dose and remained in the hospital received two tablets on each of the following two days. Otherwise, dosage was increased gradually to a maximum of four tablets twice daily until defecation occurred or until the four-day treatment period was over. All patients achieved bowel movements, and in no case was it necessary to administer an enema. No hard stools were passed on the day patients were discharged from the hospital. Overall results were excellent or good in 94 per cent of cases; these results were not affected by age. Ninety-two per cent had bowel movements after the first or second dose was administered. On the day of discharge from the hospital, fecal consistency was satisfactory in 88 per cent of cases and loose in 12 per cent. Except for a single instance of diarrhea after administration of one dose, which involved a patient with a history of loose stools, no side effect occurred during the trial. In view of these responses and the virtual absence of side effects in this study group, Senokot S tablets are judged to be of demonstrated value in the postoperative management of patients undergoing proctologic operations.
A 12-week program for 42 chronically constipated patients in a nursing home involved a graduated dosage regimen of standardized senna concentrate with dioctyl sodium sulfosuccinate (Senokot-S Tablets), a high-fiber diet, and an increased fluid intake. The program achieved a satisfactory pattern of bowel evacuation in 36 (86 percent) of these patients. This pattern, as observed during a 4-week follow-up period while therapy was continued, was characterized by absence of fecal impactions, regular comfortable bowel movements of appropriate consistency, minimal or no straining at stool, and minimal or no resort to enemas. In the initial 2-week control period, none of the 42 patients had responded adequately to only dietary modification and increased hydration. Six additional patients whose response to the control regimen was equivocal, also appeared to benefit from the medication program. Two of these were able to discontinue the laxative tablets completely by the end of the 12-week test period. None of the 48 patients who completed the course experienced any adverse effects related to this rehabilitative program.
Recognition that altered intestinal electrolyte transport (decreased absorption and/or increased secretion) is a primary factor in many types of diarrhoea is shaping the search for new types of antidiarrhoeal agents; it also supports continuing interest in the time-honoured but still largely unproved adsorbents. Recognition that altered intestinal electrolyte transport is also a primary effect of certain of the laxatives is of less immediate practical significance, because of the appropriate emphasis on dietary fibre and other nonpharmacological measures for prevention and correction of functional constipation. However, interest in the laxatives and their mechanisms of action will probably be directed to unanswered problems in bowel motility and the pathogenesis of constipation, which could subsequently modify use of the laxatives.
X-Prep Liquid, used as a radiologic bowel evacuant, was found to be more effective, better tolerated, and more readily accepted than castor oil. The efficacy of a single full dose of this peristaltic stimulant was confirmed, and a divided dose of X-Prep Liquid was practically as effective and produced less griping and cramping. This less intensive divided-dose approach appears to be appropriate, especially in aged or debilitated patients.
After the use of a number of varied purgation regimens for precolonoscopy preparation of the bowel and use of X-Prep liquid for the purgation phase in 500 patients with a very high success rate and low side-effects, we have found that this preparation provides the best results, both for the patient and the endoscopist.
Constipation is endemic in the Western world. Stool consistence and associated symptoms are more important than stool frequency. The patient's attitude towards his bowel habit is also important. Exclusion of "organic" disease, reassurance and discussion of normal variations of bowel habit are necessary first steps in treatment. Adquate bulk in the stool must be ensured, either through diet or bulking agnets, and bowel retraining attempted. Laxatives should be reserved for episodes of constipation following enforced bedrest, or as a preparation for diagnostic procedures. Long-term use should be avoided.
The relative anti-inflammatory effect of dexamethasone and a prodrug, dexamethasone-beta-D-glucoside, has been assessed in guinea-pigs with experimentally-induced inflammatory bowel disease (IBD). The glucoside prodrug is designed to reach the large intestine following oral administration. The active agent is liberated when the prodrug is hydrolysed by glycosidases of colonic bacteria. Guinea-pigs were administered degraded carrageenan in their drinking water to produce experimental IBD. Starting on day 15, dexamethasone (1.3 mumol kg-1) or dexamethasone-beta-D-glucoside (1.3 or 0.65 mumol kg-1) was administered by gastric intubation once daily for 5 days. Relative to control animals, the drug and prodrug treatments significantly (P less than 0.05) reduced the total number of caecal ulcers. While there was no difference statistically between the drug and prodrug treatments, the data suggest that a lower dose of dexamethasone, administered as its glucoside prodrug, could reduce side-effects without reduced efficacy. These results support the hypothesis that localized delivery of dexamethasone to the large bowel can improve pharmacotherapy of IBD by reducing the side-effects associated with corticosteroids.
Dexamethasone-β-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-β-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained β-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-β-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-β-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability
Attempts have been made to further improve the widely performed colonoscopy preparation with lavage. In a prospective study, 120 outpatients and inpatients scheduled for total colonoscopy were randomized to two preparatory regimens. The day before endoscopy either extractum sennae (N = 60) or a placebo solution (N = 60) was given. Just before examination all patients underwent whole gut irrigation with a polyethylene glycol electrolyte lavage solution (PEG-ELS). Adequacy of preparation, patient tolerance, and the necessary amount of PEG-ELS were assessed. Physician assessment of colon cleansing showed superiority in the group with additional laxative. The colon was free of solid debris in 66.7% of patients after PEG-ELS and in 90% after senna/PEG-ELS administration (p less than 0.01). Patient tolerance was similar in both groups with 86.7% vs. 83.3% of subjects rating the preparation as tolerable. Severe adverse events were not observed. In the senna/PEG-ELS group, significantly less (p less than 0.05) lavage fluid was needed. We conclude that the combination of senna and PEG-ELS is more effective than PEG-ELS in cleansing the colon for colonoscopy.
Effects of senna on the myenteric plexus of the colon were investigated in view of earlier reports that this anthraquinone cathartic depletes the plexus of its intrinsic neurons. Rats and mice were given purgative doses of sennosides in their drinking water for 4 and 5 months, respectively. Body growth was reduced, and the weight of the colon with its contents was increased relative to the weight of the whole body in the treated animals. The latter change was attributed to depressed propulsive motility of the large intestine. Total numbers of myenteric neurons were determined from whole-mount preparations stained with Cuprolinic Blue-magnesium chloride, which selectively coloured the neuronal somata. The number of neurons in the rat's colon was unaffected by treatment with senna, but the colons of the treated mice contained significantly more neurons than those of their controls. Staining with antisera to 10 putative neurotransmitters or their associated enzymes revealed immunoreactive somata and axons in the myenteric plexus. Treatment with senna was not associated with absence of neuronal somata or fibres stainable with any of the antisera in either species. Thus, there was no evidence of toxic destruction of any identifiable population of neurons that might have been too small to affect the total counts. We conclude that senna does not kill myenteric neurons in the colon of the rat or mouse.
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.
Rhein, an aglucone of a laxative-acting anthraquinone, which induces net secretion in the human jejunum and colon, does not induce net secretion under open circuit current in in vitro conditions but reduces net absorption of electrolytes and water. In the stripped rat descending colon at a concentration of 2.10(-4) mol/l, the Na+, K+-ATPase is almost completely inhibited resulting in a decreased net absorption of electrolytes and water. There are no changes of the diffusional resistance of the paracellular pathway. Results point to a cellular mechanism of rhein by which absorption is inhibited so that physiological cellular secretion dominates. This does not rule out an additional activation of cellular secretion but net secretion can be explained solely by inhibition of absorption without the assumption of any additional secretory mechanism.
High-fibre diet and laxatives are not always successful in the treatment of severe constipation. In a group of thirteen women with intractable constipation three experimental models of rectal evacuation showed that all had a disorder of defaecation. None could expel 120 ml barium paste as fast or as completely as could ten normal women; six could expel hardly any barium. Only three of the thirteen could expel a balloon containing 50 ml water from the rectum, whereas all of six normal subjects could do so easily. Four of the patients with repeated straining efforts could expel no more than 10% of a 500 ml saline enema, whereas six normal subjects rapidly passed 40-80%. It is postulated that dietary and drug treatment designed to soften and increase the bulk of the stools fails to help some patients because they find it difficult to expel even semi-solid or liquid stool. Electromyography showed that these patients tend to contract rather than relax the striated muscle of the pelvic floor on attempted defaecation. Their failure to defaecate is due to incoordination of the pelvic floor rather than an abnormality of the stool or a disorder of the colon.
Zusammenfassung 1.Die Resorption der wirksamen Bestandteile der Folia Sennae bei oraler Einverleibung erfolgt auf dem Blutwege vom Dünndarm aus.2.Die Sennasubstanzen sind auch parenteral, intramuskulär und intravenös wirksam.3.Zwischen Einverleibung und Wirkung am Dickdarm besteht je nach der Natur der Substanz eine Latenzzeit von 8 Stunden bis 30 Minuten.4.Während der Latenzzeit gehen chemische Veränderungen mit den Glykosiden vor sich, eine fermentative Abspaltung des Anthranols und eine Oxydation dieses zu Anthrachinon.5.Mit Wahrscheinlichkeit ist das Anthrachinon die eigentlich wirksame Substanz.6.Die genuine Glykosidform ist insofern von Bedeutung, als in Glykosidform das Anthrachinon leicht löslich, gleichmäßig, sicher und widerstandslos resorbierbar wird.7.Die reine Sennawirkung am Dickdarm ist eine Steigerung der Peristaltik, ohne Einfluß auf die Pendelbewegungen. Sie wird in sicherer Art durch das schwerspaltbare Glykosid erreicht.8.Während der Sennawirkung ist die Wasserresorption im Dickdarm etwas gehemmt, diese Wirkung scheint aber keine spezifische Sennawirkung zu sein.9.Das leichtspaltbare Glykosid und das Emodin bewirken neben der Peristaltikanregung Abschwächung bis Aufhebung der Pendelbewegungen und Steigerung des Tonus, bei Überdosierung Krämpfe und Erbrechen.10.Zur Erzielung einer Stuhlregelung mit langer Latenz ist das schwerspaltbare Glykosid allein geeignet.
Die Trockensubstanz des Sennaaufgusses bewirkt auch an Kaninchen bei Darreichung in genügend grossen Dosen per os regelmässig eine deutliche Kotabführung. Diese Erscheinung soil nach den Versuchen am Darm in situ sowie am herausgeschnittenen dadurch zustande kommen, dass die in der Substanz enthaltenen, an and für sich unwirksamen Anthrachinonglukoside erst im Dickdarm, gleichgultig, ob sie vom Dünn- direkt in den Dickdarm übergeführt werden, oder ob sie von dem ersteren aus resorbiert und dann wieder in den letzteren ausgeschieden werden, durch Einwirkung von den darin lebenden Mikroorganismen, wie Kolibazillen, in Oxyanthrachinone umgewandelt werden und als these unmittelbar den Auerbachschen Nervenplexus der Darmwaud erregen und dadurch die peristaltischen Bewegungen beschleunigen. Die Sennaabführung bei den anderen Tieren und Menschen findet höchst wahrscheinlich auf dieselbe Weise statt.
Anaerobic organisms are often overlooked in clinical and biologic laboratories because of the lack of a simple anaerobic medium which can be used just as any aerobic broth without the use of anaerobe jars or other special equipment or technics. It is well known that most clear liquid mediums when heated to drive out the air will be anaerobic for a short time. Whether this period is long enough to allow germination of the spores or growth of the anaerobes present depends on the composition of the medium, the amount of aeration while inoculating and several other factors. For most purposes the period of anaerobiosis obtainable in this manner is not sufficient. To avoid the use of mechanical devices such as the marble seal, special tubes or layers of oil or petrolatum, various substances have been added in attempts to prolong the anaerobiosis and still have a clear liquid medium
The effect of colonic distension and changes in intraluminal pH and osmolality have been investigated in patients with well established colostomies. Small volumes of acidic buffer (pH4) and hypertonic saline (4%) were found to be only a very weak peristaltic stimulus. Strong hypertonic solutions (glycerine BP) induced a poorly sustained peristaltic response in the majority of cases. Distension of the inactive colon did not stimulate peristalsis. Distension of a colon previously stimulated to peristaltic activity caused fresh waves of contraction. This study appears to show that by themselves physical factors play an unimportant role in initiating peristaltic activity in the colon.
Spontaneous colonic peristalsis inman occurs infrequently and,therefore, hasproved difficult to investigate; radiological studies havebeenlimited because ofthedangers ofirradiation, andobservations ofintraluminal pressure change havebeen mainly confined totherectumandlowersigmoid colon (Connell, 1961; Ritchie, Ardran, andTruelove, 1962). Progressive wavesofcontraction whichempty longsegments ofcolon can,however, bestimulated byanenema; suchactivity isusually called astrippingwaveandcanberegarded asaformofinduced peristalsis1 (Williams, 1967). Inthepresent study, bothspontaneous andinducedperistalsis ofthecolon havebeenstudied by balloon kymography andcomparisons havebeen madewithrectal activity. (Whenever possible, cineradiology hasbeenusedtoconfirm thefindings obtained withballoon kymography.) Thestudy was conducted intwoparts. balloons (5mm x 8mm),placed 5cmapart, connected byfinepolythene tubing totransducers, anda direct writing recorder, theunit being similar tothat described byAtkinson, Edwards, Honour, andRowlands (1957). Theunits wereintroduced into thecolon orrectum with asigmoidoscope withaslittle distension ofthebowel as possible. Access wasgained tothetransverse anddescending colon viawellestablished healthy colostomies, theunits being placed asfarfromthecolostomy opening aspossible. After introduction ofthepressure recording unit, thebowelwasleft undisturbed foratleast 30 minutes before astudy wasstarted. Thesensitivity ofthe recorder wasadjusted sothatachange ofpressure of 10cm ofwaterwasrepresented byadeflection ofapproximately 1cm.Incertain studies, thepressure changes werealsomonitored bywater-filled opentiptubes (internal diameter 1mm),inaddition totheballoon system. Bisacodyl wasusedeither assuppositories (10mg)or asasolution inethylene glycol. Oxyphenisatin wasdissolved inwater. Inseven patients, colonic peristalsis wasrecorded by simultaneous cineradiology andpressure recording. PARTI COLONICSTUDIES Spontaneous andstimulated peristalsis hasbeeninvestigated inpatients withwellestablished colostomies, accessbeing thereby gained totheright andleft colon. Bisacodyl andOxyphenisatin, drugs which areknownto increase thefrequency ofstripping waves(Schlegel, 1954; McLaren, King, andCopland, 1955, andWilliams, 1967), wereusedtostimulate colonic emptying. Afterestablishing thatthestripping waves excited bythese drugs wereperistaltic innatureandsimilar tothoseoccurring naturally, Bisacodyl wasused toinduce peristalsis, sothat further studies couldbe madeoftheunderlying mechanism. Theresults oftheseinvestigations are reported.
Colorimetric determination of the glycosides of senna
- W Kussmaul
- B Becker
Kussmaul, W., and Becker, B. (1947). Colorimetric determination of the glycosides of senna. Helv. chim. Acta, 41, 1, 2857- 2860
Wissenwertes fur die pharmazeutische Praxis
- H J Schmidt
Schmidt, H. J. (1960). Wissenwertes fur die pharmazeutische
Praxis. Die Chemie und Pharmakologie Slanzlicher
Laxartien. Mitt. dtsch. pharm. Ges., 30, 41-47.
Theoric der Abfuihrwirkung der Folia Sennae und ihrer wirksamen Inhaltsstoffe. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak
- W Straub
- E Triendl
Straub, W., and Triendl, E. (1937). Theoric der Abfuihrwirkung der Folia Sennae und ihrer wirksamen Inhaltsstoffe. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 185,
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