Factitious diarrhea induced by stimulant laxatives: accuracy of diagnosis by a clinical reference laboratory using thin layer chromatography.

BACKGROUND: Surreptitious ingestion of laxatives can lead to serious factitious diseases that are difficult to diagnose. Most cases involve ingestion of bisacodyl or senna. Thin layer chromatography (TLC) of urine or stool is the only commercially available test for these laxatives. Such testing is considered highly reliable, but its accuracy in clinical practice is unknown. Our aim was to evaluate the reliability of TLC laxative testing by a clinical reference laboratory in the United States. METHODS: Diarrhea was induced in healthy volunteers by ingestion of bisacodyl, senna, or a control laxative (n = 11 for each laxative group). Samples of urine and diarrheal stool were sent in blinded fashion to the clinical reference laboratory for bisacodyl and senna analysis. RESULTS: TLC testing for bisacodyl-induced diarrhea revealed a sensitivity of 73% and specificity of 91% when urine was tested and sensitivity and specificity of 91% and 96%, respectively, when stool was analyzed. When diarrhea was induced by senna, the TLC assay for senna failed to identify even a single urine or stool specimen as positive (zero% sensitivity). CONCLUSIONS: Considering the expected prevalence of surreptitious laxative abuse in patients with chronic idiopathic diarrhea (2.4%-25%, depending on the clinical setting), TLC of urine or stool for bisacodyl by this reference laboratory would often produce misleading results, and testing for senna would have no clinical value. The major problems are false-positive tests for bisacodyl and false-negative tests for senna.

Screening procedure for detection of stimulant laxatives and/or their metabolites in human urine using gas chromatography-mass spectrometry after enzymatic cleavage of conjugates and extractive methylation.

A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of stimulant laxatives and/or their metabolites in human urine after enzymatic cleavage of conjugates followed by extractive methylation. The part of the phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by capillary GC and identified by computerized MS in the full scan mode. By use of mass chromatography with the ions m/z 305, 290, 335, 320, 365, 350, 311, 326, 271, and 346, the possible presence of stimulant laxatives and/or their metabolites could be indicated. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with the reference spectra. This method allowed the detection of the diphenol laxatives bisacodyl, picosulfate, and phenolphthalein and of the anthraquinone laxatives contained in plant extracts and/or their metabolites in human urine samples. The overall recoveries of the stimulant laxatives and/or their metabolites ranged between 33% and 89% with a coefficient of variation of less than 15%, and the limits of detection ranged between 10 and 25 ng/mL (S/N 3) in the full scan mode. After ingestion of the lowest therapeutic dose of sodium picosulfate, its main metabolite, bisacodyl diphenol, was detectable in urine samples for 72 hours. After ingestion of the lowest therapeutic dose of a senna extract, the main metabolite of sennosides, rhein, was detectable in urine samples for 24 hours. This procedure is part of a systematic toxicological analysis procedure for acidic drugs and poisons with the modification of enzymatic cleavage of conjugates.

Is bisacodyl absorbed at all from suppositories in man?

A HPLC procedure was developed to determine free BHPM in human plasma and urine after prior deconjugation of its glucuronides with glucuronidase. A single dose administration of a 10 mg bisacodyl suppository from Glaxo Wellcome, Poznan (Poland) to 16 volunteers each resulted in its low active metabolite (BHPM) plasma levels (10-55 microgram l(-1)) according to general assumptions. Its prompt laxative effect appeared within 56.6+/-10.8 min. The calculated serum half-life time of BHPM glucuronide excretion in urine was approximately 7.32+/-0.99 h. BHPM was excreted in urine in only 3. 36+/-0.52% if compared with the above bisacodyl rectal dose administered. Any relationship between BHPM plasma and/or urine levels and its laxative action does not occur. These results confirm the thesis that the laxative action of bisacodyl suppositories is initiated through a direct interaction of the drug in the rectum.

A rapid high-performance thin-layer chromatographic urine screen for laxative abuse.

Laxative abuse, if unrecognized, can lead to unnecessary and costly investigations. The stimulants and cathartics are the most commonly abused laxatives and have the potential for causing the most long-term damage. We have optimized a solid-phase extraction coupled with high-performance thin-layer chromatography (HPTLC) to provide rapid, simple, and sensitive detection of phenolphthalein, danthron, rhein, aloin, and bisacodyl and its metabolites in urine. Positive screens have revealed laxative abuse in 3 of 42 samples from patients presenting with diarrhea of unknown origin.

Chronic diarrhea due to surreptitious use of bisacodyl: case reports and methods for detection.

Surreptitious abuse of laxatives is a common cause of severe chronic diarrhea. Standard laboratory screening studies of urine and stool specimens may identify phenolphthalein, diuretics, and magnesium-containing agents. An assay for bisacodyl, a commonly used over-the-counter laxative, however, is not included in routine screening tests. Herein we describe two patients with chronic watery diarrhea of large volume; analysis of stool and urine samples revealed that surreptitious use of bisacodyl was the cause. In one patient, nonspecific inflammatory changes of the colonic mucosa were noted on biopsy, and fecal leukocytes were detected in both patients. In a prospective study of eight patients who received bisacodyl as part of a preparation for colonoscopy, we analyzed serial urine samples for bisacodyl diphenol during a 48-hour period. This metabolite was found in seven of eight hydrolyzed urine samples obtained 12 hours after oral administration of bisacodyl but not in samples obtained 24 and 48 hours after ingestion of the laxative. We recommend that urinalysis and, in some cases, stool analysis for bisacodyl should be considered in the diagnostic assessment for surreptitious use of laxatives.

A screening method for establishing laxative abuse.

Abuse of laxatives, most of them belonging to the group of colonic stimulants or cathartics, can cause various disorders. Extensive diagnostic work can be avoided by early toxicological screening of the suspected patients with respect to laxatives. Because no screening method of this kind was available, we developed a procedure with which all phenolic and anthraquinone laxatives--except sodium picosulfate--can be detected in urine. This method is based on high-performance thin-layer chromatography in two systems after pretreatment of a 20-mL urine sample with beta-glucuronidase and subsequent column extraction. The procedure is very sensitive: at least 32 h after a single dose of bisacodyl, danthron, phenolphthalein, or sennoside, the drug can be detected in the urine. Bisoxatin and oxyphenisatin are still detectable in the urine 18 h after intake. The method is also highly specific; none of 73 other drugs interfered in either of the two chromatographic systems. This procedure can be helpful for the early diagnosis of laxative abuse.

Qualitative and quantitative analysis of some synthetic, chemically acting laxatives in urine by gas chromatography-mass spectrometry.

A method for the qualitative and quantitative simultaneous analysis of dioxyanthraquinone, desacetyl-Bisacodyl, phenolphthalein and Oxyphenisatin in human urine using gas chromatography-mass spectrometry (GC-MS) has been developed. The compounds were extracted from urine at pH 7.5 with diethyl ether using Extrelut extraction columns, followed by evaporation and trimethylsilylation. The method used electron beam ionization GC-MS employing a computer-controlled multiple-ion detector (mass fragmentography). The recovery from urine for the various compounds was between 80% and 100%. The detection limit for these compounds was in the range 0.01--0.05 micrograms/ml of urine. The method proved to be suitable for measuring urine concentrations for at least four days after administration of a single oral low therapeutic dose of the laxatives to sixteen healthy volunteers.

Quantitation of a bisacodyl metabolite in urine for the diagnosis of laxative abuse.

A 2 year history of severe diarrhea, tiredness, and weight loss in a female patient could not be diagnosed satisfactorily despite repeated and extensive clinical investigations of various kinds. The final diagnosis of laxative abuse was arrived at after identification and quantitation of a bisacodyl metabolite in the urine from the patient. The metabolite was bisacodyl disphenol. The analytical method developed was based on liquid chromatographic determination after hydrolysis of the conjugated metabolite of bisacodyl and selective isolation from the urine. The precision of the method was 5% at the 2.3 microgram/ml level (n = 9) of bisacodyl diphenol, and the absolute recovery was estimated at 80%. The method allowed detection of 0.5 migrogram/ml of the metabolite in urine. After a single dose (10 mg) of bisacodyl to volunteers, urinary concentrations of the metabolite in the range of 1--5 microgram/ml were found. The bisacodyl diphenol recovered in the urine corresponded to 20--30% of the original dose. The urinary concentration of the diphenol derivative in the patient was estimated at 17 microgram/ml.