Wednesday, 29 March 2017

Combination agents

Sodium picosulfate/magnesium citrate. Sodium picosulfate/magnesium citrate preparations have recently become available in the United States. This preparation acts locally in the colon as a combination of a stimulant laxative to increase the frequency and force of peristalsis (sodium picosulfate component) and an osmotic laxative to retain fluid in the colon (magnesium citrate component).102 Sodium picosulfate is a prodrug that is hydrolyzed by bacteria in the colon to its active metabolite 4,40 -dihydroxy-diphenyl-(2-pyridyl) methane. Two phase 3 clinical trials were conducted in the United States before FDA approval of this preparation. One of these trials compared a split-dose sodium picosulfate/magnesium citrate regimen with a day-before low-volume 2-L PEG-ELS with 10 mg bisacodyl regimen and found improved bowel cleansing and patient acceptance with sodium picosulfate/ magnesium citrate. It should be noted, however, that the split-dose regimen likely favored the sodium picosulfate/magnesium citrate arm, constipated patients were excluded from the trial, and the rate of adequate preparation observed with sodium picosulfate/magnesium citrate was only 84.2%. The other phase 3 trial compared sodium picosulfate/magnesium citrate with low-volume 2-L PEGELS with 10 mg bisacodyl, both administered the day before the colonoscopy and found sodium picosulfate/magnesium citrate to be noninferior to PEG-ELS with 10 mg bisacodyl.104 In this trial, sodium picosulfate/magnesium citrate resulted in adequate cleansing in only 83%.

Adverse events associated with this preparation are generally GI in nature and mild to moderate in severity.Subjects receiving the entire preparation in 1 day reported increased abdominal cramps/pain and higher nausea/vomiting scores; however, these symptoms were better tolerated in a split-dose regimen. There are rare reports of hyponatremia and other electrolyte disturbances that have caused significant clinical symptoms with this preparation

Sodium sulfate and SF-PEG-ELS. Recently, a preparation consisting of a combination of OSS with 2 L of SFPEG-ELS has become commercially available. The results of two randomized, controlled trials involving 737 outpatients undergoing colonoscopy with this preparation compared with 2 other low-volume PEG-ELS preparations were recently reported.106 In the first trial, 186 patients received OSSþSF-PEG-ELS, and 185 patients received a low-volume 2-L PEG-ELS with ascorbic acid preparation, both administered in a split-dose fashion. Both preparations resulted in successful (excellent or good) bowel preparation scores in 93.5%. In this trial, OSSþSF-PEG-ELS was associated with twice the rate of vomiting compared with the PEG-ELS with ascorbic acid (13.5% vs 6.7%, P Z .042). In the second trial, OSSþSF-PEG-ELS (n Z 196) was compared with PEG-ELS þ 10 mg bisacodyl, both administered the evening before the colonoscopy. OSSþSF-PEG-ELS resulted in successful preparation in 89.8% of patients compared with 83.5% with PEG-ELS þ bisacodyl (P ! .001 for noninferiority). In this trial, overall discomfort was rated worse with OSSþSF-PEG-ELS (mean score, 2.1 vs 1.8; P Z .032). There were no serious adverse events considered related to the preparations in either trial.

Laxatives such as bisacodyl and/or magnesium citrate are administered in some regimens to reduce the volume of lavage solution required and hence volume-related symptoms, such as abdominal bloating and cramping. Bisacodyl is a diphenylmethane derivative that is poorly absorbed in the small intestine and is hydrolyzed by endogenous esterases. Its active metabolites stimulate colonic peristalsis.107 One study of bisacodyl as a preparation adjunct found that the laxative shortened the duration of whole-gut irrigation, although no significant difference in colonic cleansing was identified.108 When used as an adjunct to PEG-ELS, bisacodyl did allow for less volume of PEG-ELS required for adequate colonic cleansing.109,110 Bisacodyl can cause abdominal cramping and has been associated with ischemic colitis.111 Accordingly, when used as an adjunctive agent for bowel preparations, 5- and 10-mg doses are recommended. The only FDAapproved regimen of low-volume 2-L PEG-ELS combined with bisacodyl was discontinued by the manufacturer in 2013.

Two studies found that magnesium citrate used as an adjunct to PEG-ELS allowed less PEG-ELS solution (2 L)to be used to achieve adequate cleansing. The use of magnesium citrate as an adjunct to other colonic preparations may also be helpful in patients who have previously had inadequate preparation by using a standard bowel preparation or those with a long-standing history of constipation. Studies of full-volume (4 L) PEG-ELS compared with low-volume (2 L) SF-PEG-ELS combined with magnesium citrate or bisacodyl demonstrate equal ef- ficacy of colonic cleansing, with improved overall patient tolerance.Because of the renal excretion of magnesium, magnesium citrate should be avoided in patients with renal insufficiency or renal failure. 

Senna is a stimulant laxative that contains anthraquinone derivatives (glycosides and sennosides) that are activated by colonic bacteria. The activated derivatives have a direct effect on intestinal mucosa, increasing the rate of colonic motility, enhancing colonic transit, and inhibiting water and electrolyte secretion.Senna has been used as an adjunct to PEG-ELS regimens in a manner similar to that of bisacodyl. No differences were found between senna and bisacodyl when used as an adjunct in combination with PEG-ELS. The adjunctive use of senna with PEGELS solutions has been demonstrated to improve the quality of bowel preparation116 and to reduce the amount of PEG-ELS required for effective bowel preparation.

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