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PubMed2004

Priorities for treatment research from different professional perspectives.

The consensus conference "Advancing the Treatment of Fecal and Urinary Incontinence Through Research" had as one of its goals the development of a comprehensive list of research priorities. Experts from all disciplines that treat incontinence-gastroenterology, pediatric gastroenterology, urology, urogynecology, colorectal surgery, geriatrics, neurology, nursing, and psychology-and patient advocates were asked to identify their highest priorities for treatment-related research. Meeting participants were shown the aggregated list and invited to propose additional priorities. Treatments for fecal incontinence (biofeedback, sphincteroplasty, antidiarrheal and laxative medications, and sacral nerve stimulation) require validation by randomized, controlled trials. For urinary incontinence, the greatest need is to compare pharmacological, behavioral, and surgical treatments. Trials assessing combined treatments (e.g., biofeedback plus surgery vs. surgery alone or biofeedback alone) are also needed. New drugs are needed that target anal canal resting pressure in fecal incontinence and hypersensitivity to distention in urge urinary incontinence. It may be possible to substantially reduce the incidence of incontinence through modification of obstetric practices (e.g., avoiding episiotomies or offering elective cesarean delivery to high-risk patients), providing pelvic floor exercises before childbirth, and educating patients to avoid straining during defecation. For the elderly, practical behavioral and pharmacological treatments are needed that can postpone or avoid institutionalization. Social science research may identify ways to counteract the social stigma of fecal incontinence and assist physicians in providing patients with more comprehensive and understandable information on the risks associated with different treatment options.

Clinical Trials as Topic↗
PubMed2006

Zinc in the treatment of acute diarrhea: current status and assessment.

The improved treatment of acute diarrhea in children during the past 35 years has reduced its morbidity and mortality substantially. However, better therapy still is required. This article reviews the role of oral rehydration solution in the treatment of acute diarrhea with particular attention to recent efforts to develop improved oral rehydration solution formulations. One promising approach is the administration of Zinc (Zn). Based on its beneficial effects in infections, including pneumonia, Zn has been shown to be effective in the treatment of acute diarrhea in several randomized controlled trials including subsequent meta-analyses. Thus, an emerging body of clinical data indicates that Zn can be useful for treating acute diarrhea. However, only limited information is known about the mechanism(s) by which Zn reduces diarrhea. Recent studies have indicated that Zn acts as a K channel blocker of adenosine 3',5'-cyclic monophosphate-mediated chlorine secretion, but may not affect either Ca2+- or guanosine 3',5'-cyclic monophosphate-mediated chlorine secretion. These data provide a strong rationale for further trials testing its efficacy in specific clinical settings and for more detailed physiologic studies examining how Zn exerts its antidiarrheal effect.

Acute Disease↗
PubMed1980

Analgesic activity of the naturally occurring heptapeptide [Met]enkephalin-Arg6-Phe7.

[Met]Enkephalin-Arg6-Phe7 is an opiate-like peptide normally found in the the adrenal gland and brain that has analgesic (antinociceptive) activity when administered directly into the cerebral ventricles of mice. On a molar basis, [Met]-enkephalin-Arg6-Phe7, with a median effective dose (ED50) of 38.5 nmol/mouse, is 8 times more potent than [Met]enkephalin. As with [Met]enkephalin, analgesic activity is blocked by naloxone and intravenous administration does not produce characteristic opiate effects in tests for analgesic, antidiuretic, or antidiarrheal activity. These findings suggest that [Met]enkephalin-Arg6-Phe7 may be at least as important as the enkephalins in the postulated enkephalin system mediating pain and analgesia.

Analgesics↗
PubMed1988

Update on traveler's diarrhea.

Traveler's diarrhea affects a substantial number of travelers to high-risk areas of the world. The key to controlling this troublesome disease is prevention. The most important preventive measures depend on educating patients to consume only safe foods and pure water. Physicians cannot overemphasize the importance of avoiding high-risk foods and of boiling water if a safe water supply is not available. Prophylactic medications are a secondary consideration and should be prescribed with discretion. In most cases, diarrhea is mild and self-limited, requiring only fluid and electrolyte replacement and perhaps an antidiarrheal agent. In moderate to severe cases, the addition of an antimicrobial agent may be of benefit. Until an efficacious polyvalent vaccine is developed, caution and common sense, together with discretionary dietary and hygienic practices, are the best defenses against traveler's diarrhea. The ultimate solution is greatly improved sanitation and personal hygiene, especially in high-risk countries. However, only dreamers will consider waiting for this transformation to occur.

Diarrhea↗
PubMed1989

Acute diarrhea in children. What to do and what not to do.

Acute diarrhea is a leading cause of childhood morbidity and mortality. Primary care physicians and pediatricians should be familiar with its clinical features and management. Rehydration and maintenance of proper fluid and electrolyte balance are the most important aspects of treatment. While intravenous rehydration is the best form of treatment for children who are in shock or unable to drink, oral rehydration is the treatment of choice for the majority of children who have mild to moderate dehydration. Oral rehydration therapy is simple, practical, inexpensive, effective, and safe for children in developing as well as developed countries. We recommend the use of commercially available rather than homemade solutions. Antibiotic and antidiarrheal agents are usually not indicated. Early reintroduction of milk, formula, or solid food is important, as is instruction of parents in measures to minimize transmission of infectious agents.

Acute Disease↗
PubMed1990

Hemolytic-uremic syndrome in children. A serious hazard of undercooked beef.

Hemolytic-uremic syndrome is the leading cause of acute renal failure in childhood. Its incidence in North America is increasing. Escherichia coli O157:H7 is the most common infectious trigger and is spread by contaminated beef products as well as from person to person. Antibiotics or antidiarrheal medications should not be used in the treatment of E coli hemorrhagic colitis or hemolytic-uremic syndrome. Mortality in children with the syndrome has fallen to less than 10% in North America, largely because of careful attention to nutrition, maintenance of a normal fluid and electrolyte balance, and careful monitoring. Education and emotional support of the family are important aspects of the treatment program.

Child↗
PubMed1992

Cultural and medical perspectives on geophagia.

Geophagia, the eating of dirt, usually clay, has been recorded in every region of the world both as idiosyncratic behavior of isolated individuals and as culturally prescribed behavior of particular societies. The behavior has long been viewed as pathological by the medical profession, and it has been claimed to be both a cause and a consequence of anemia. While there is now reason to believe that the consumption of some clays may interfere with the absorption of elemental iron, zinc, and potassium, there is little evidence for the position that geophagia, especially its culturally prescribed form, is caused by anemia. These and other maladaptive consequences of clay consumption may be offset by the adaptive value of its antidiarrheal, detoxification, and mineral supplementation potentials.

Adaptation, Biological↗
PubMed2004

Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy.

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated epithelial Cl- channel that, when defective, causes cystic fibrosis. Screening of a collection of 100,000 diverse small molecules revealed four novel chemical classes of CFTR inhibitors with Ki < 10 microM, one of which (glycine hydrazides) had many active structural analogues. Analysis of a series of synthesized glycine hydrazide analogues revealed maximal inhibitory potency for N-(2-naphthalenyl) and 3,5-dibromo-2,4-dihydroxyphenyl substituents. The compound N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH-101) reversibly inhibited CFTR Cl- conductance in <1 min. Whole-cell current measurements revealed voltage-dependent CFTR block by GlyH-101 with strong inward rectification, producing an increase in apparent inhibitory constant Ki from 1.4 microM at +60 mV to 5.6 microM at -60 mV. Apparent potency was reduced by lowering extracellular Cl- concentration. Patch-clamp experiments indicated fast channel closures within bursts of channel openings, reducing mean channel open time from 264 to 13 ms (-60 mV holding potential, 5 microM GlyH-101). GlyH-101 inhibitory potency was independent of pH from 6.5-8.0, where it exists predominantly as a monovalent anion with solubility approximately 1 mM in water. Topical GlyH-101 (10 microM) in mice rapidly and reversibly inhibited forskolin-induced hyperpolarization in nasal potential differences. In a closed-loop model of cholera, intraluminal GlyH-101 (2.5 microg) reduced by approximately 80% cholera toxin-induced intestinal fluid secretion. Compared with the thiazolidinone CFTR inhibitor CFTR(inh)-172, GlyH-101 has substantially greater water solubility and rapidity of action, and a novel inhibition mechanism involving occlusion near the external pore entrance. Glycine hydrazides may be useful as probes of CFTR pore structure, in creating animal models of CF, and as antidiarrheals in enterotoxic-mediated secretory diarrheas.

Animals↗
PubMed2000

Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trial Group.

To evaluate the efficacy of paromomycin for the treatment of symptomatic cryptosporidial enteritis in human immunodeficiency virus-infected adults, we conducted a prospective, randomized, double-blind, placebo-controlled trial before the widespread introduction of highly active antiretroviral therapy (HAART). Seven units under the auspices of the AIDS Clinical Trials Group enrolled 35 adults with CD4 cell counts of < or = 150/mm(3). Initially, 17 patients received paromomycin (500 mg 4 times daily) and 18 received matching placebo for 21 days. Then all patients received paromomycin (500 mg q.i.d.) for an additional 21 days. Clinical definitions of response were measured by an average number of bowel movements per day in association with concurrent need for antidiarrheal agents that was lower than that before study entry. There was no treatment response during the placebo-controlled phase of the study according to protocol-defined criteria (P=.88). Three paromomycin recipients (17.6%) versus 2 placebo recipients (14.3%) responded completely. Rates of combined partial and complete responses in the paromomycin arm (8 out of 17, 47.1%) and the placebo arm (5 out of 14, 35.7%) of the study were also similar (P=.72). The clinical course of cryptosporidiosis was quite variable. Paromomycin was not shown to be more effective than placebo for the treatment of symptomatic cryptosporidial enteritis. However, inadequate statistical power prevents definitive rejection of the usefulness of paromomycin as therapy for this infection.

AIDS-Related Opportunistic Infections↗
PubMed1999

Prevalence of enteric pathogens in HIV-related diarrhea in the midwest.

HIV disease is often associated with the condition of diarrhea, which may be accompanied by enteric infection or gastrointestinal tumor. This study prospectively investigated 27 episodes of chronic diarrhea in 24 patients with HIV infection. Upper endoscopy and sigmoidoscopy with biopsies at three sites (distal duodenum, sigmoid colon, and rectum) and viral and mycobacterial blood cultures were performed. Stool specimens were sent for standard tests. A primary infectious diagnosis was found in 10 (37%) of 27 episodes: cytomegalovirus (CMV) colitis (n = 4), 3 microsporidiosis (n = 3), cryptosporidiosis (n = 2), and colonic histoplasmosis (n = 1). Patients with CD4 counts of less than 50 cells/mm3 and with lower albumin levels were more likely to have a primary infectious diagnosis. Adenovirus was found in 7 cases but was often associated with another organism; these were not considered to be primary diagnoses. Blood cultures for viruses were not useful, and all mycobacterial cultures were negative. A flexible sigmoidoscopy with histologic examination and culture of biopsy samples were the diagnostic tools that yielded most infectious diagnoses. Follow-up showed that two thirds of patients improved with nonspecific antidiarrheal medications regardless of diagnosis. The study supports a minimalistic approach to the problem of diarrhea in patients with HIV infection. Upper and lower endoscopy lead to a precise diagnosis in a minority of cases, and the outcome was similar in patients with or without a primary infectious diagnosis.

Adult↗
PubMed1989

Rapid detection of giardia antigen in stool with the use of enzyme immunoassays.

Enzyme-linked immunosorbent assays (ELISAs) using sera from rabbits and goats immunized with Giardia trophozoites were compared for detection of Giardia antigen in 300 stool specimens, 80 of which had positive results for Giardia by microscopic examination. The diagnostic accuracy of the two assays was similar, with sensitivities of 92% and 87% and specificities of 87% and 91% with the use of rabbit and goat antisera, respectively. Both ELISAs detected Giardia antigen in stool samples from asymptomatic as well as symptomatic excretors and from treated patients after organisms were no longer visualized by microscopic examination. The specificity of the assays was confirmed by consistently negative results on stool specimens from 10 neonates and 27 patients with enteric parasitic infections other than Giardia. Negative results also occurred when stool specimens containing 21 bacterial enteropathogens were tested. Potential confounding variables including multiple freezing and thawing episodes, prolonged storage, and stool filtration did not affect test results from clinical specimens. Antidiarrheal compounds did not interfere with assay results. Preservation of specimens in formalin did interfere with the assay, even if formalinized stool specimens were dialyzed before testing. For diagnosis of giardiasis, the ELISA is a sensitive and specific test that is not influenced by many environmental factors or by other enteropathogens. This test provides a practical and reliable method for evaluating large numbers of specimens in a variety of clinical and epidemiologic settings.

Animals↗
PubMedDate not supplied

In vitro antimicrobial activity of bismuth subsalicylate and other bismuth salts.

This report demonstrates that bismuth subsalicylate (BSS) effectively inhibits growth of a number of bacterial strains known to cause diarrhea, including Escherichia coli, Salmonella, Shigella, and Campylobacter. Other bismuth salts and sodium salicylate, a hydrolysis product of BSS in the gut, also were examined and were shown to have various degrees of activity. Growth of the organisms was monitored in vitro by inoculating culture fluid that contained one of the compounds to be tested and determining the concentration of viable organisms over a 24-hour period. Control cultures of each organism were grown in the absence of bismuth subsalicylate. BSS inhibited growth of all organisms examined in a dose-dependent fashion. Reductions of 2-6 logs, as compared with controls, were observed in cultures grown in the presence of 10-50 mM BSS. Other bismuth salts displayed various degrees of inhibition. These results suggest that the efficacy of BSS as an antidiarrheal agent may be related to an antimicrobial mechanism of action.

Bacteria↗
PubMed1986

Escherichia coli O157:H7 diarrhea in a nursing home: clinical, epidemiological, and pathological findings.

In September 1984, an outbreak of Escherichia coli O157:H7 infection occurred in a nursing home. It was the first recognized outbreak of this organism in the United States since 1982, when two outbreaks led to its recognition as a pathogen. Thirty-four of 101 residents developed a diarrheal illness; 14 were hospitalized with a severe illness characterized by crampy abdominal pain, marked abdominal distention, and grossly bloody diarrhea, and four died. The spectrum of illness associated with the infection was broad and included the following: asymptomatic infection, nonbloody diarrhea, hemorrhagic colitis, hemolytic uremic syndrome, and death. Clinical, radiographic, and postmortem pathological findings suggested involvement of the cecum and right colon. No evidence of response to antimicrobial agents could be documented, and antidiarrheal agents may have aggravated the disease. This investigation implicated hamburger as the vehicle transmission. Seventeen of 19 residents with hemorrhagic colitis, but only 28 of 67 healthy residents, had eaten hamburger on 13 September (P less than .001, Fisher's two-tailed exact test; relative risk [RR] = 7.7). Infection with E. coli O157:H7 can cause a wide range of manifestations. In the elderly these can be particularly severe and may resemble ischemic colitis.

Adult↗
PubMed1989

Investigation of an outbreak of listeriosis: new hypotheses for the etiology of epidemic Listeria monocytogenes infections.

From December 1986 to March 1987 an outbreak of Listeria monocytogenes infection occurred in the Philadelphia metropolitan area. A patient-control study showed patients were more likely than controls to have had an ill family member and to have used antidiarrheal medication during the month before their illness. Diet histories showed patients were significantly more likely to have eaten ice cream or salami than were controls, and to have shopped at one grocery store chain. Subtyping of L. monocytogenes isolates of patients showed no predominant strain, and cultures of food products eaten by patients were negative except for Brie cheese eaten by one patient. With no predominant strain of L. monocytogenes in the patients, a common source for this outbreak is unlikely. Thus, the identified risk factors may have been associated with carriage of L. monocytogenes and a coinfecting organism may have precipitated disseminated disease. Possible cofactors should be considered in investigations of future outbreaks of listeriosis.

Adolescent↗
PubMed1995

Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study.

BACKGROUND: CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks. RESULTS: Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%-25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade > or = 3) were diarrhea, leukocytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. These toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents. CONCLUSION: CPT-11 is an interesting moderately effective drug in pancreatic cancer.

Adult↗
PubMed1998

Phase II study assessing the feasibility of using elemental supplements to reduce acute enteritis in patients receiving radical pelvic radiotherapy.

From June 1994 through September 1995, 17 patients with gynecologic cancer were entered into a feasibility study using elemental supplements (ES) during the course of pelvic radiotherapy. The level of compliance with the ES regimen was evaluated by assessing sachet counts and patients' weekly diaries. Diaries were also used to assess compliance with a modified diet program. Bowel function in 45 patients receiving radiotherapy outside this study was assessed concurrently. All patients were reviewed weekly to record bowel function, which was also recorded 1 year after radiotherapy. After treatment of all patients the grade, duration of enteritis, need for antidiarrheal agents, and the likelihood of resolution at 1 year after radiotherapy were analyzed. The study used compliance with the ES regimen as its primary endpoint. Compliance with the ES regimen was achieved in 76.5% of patients, and compliance with the modified diet was achieved regardless of whether the ES was tolerated. Patients not complying with the ES, or who did not receive ES, had higher grade diarrhea, which was longer in duration and was less likely to have resolved than patients in the compliant group. Elemental supplements are well tolerated when taken during a course of pelvic radiotherapy and cause a mild diarrhea, which resolves after treatment has been discontinued. The lack of enteritis 1 year later in patients who complied with ES suggests that reducing the grade of acute enteritis might influence the appearance of later bowel effects.

Acute Disease↗
PubMed1984

Restorative proctocolectomy with a three-loop ileal reservoir for ulcerative colitis and familial adenomatous polyposis. Clinical results in 66 patients followed for up to 6 years.

The results of restorative proctocolectomy with a three-loop ileal reservoir were reviewed. Of 66 patients treated between 1976 and 1982, 52 had ulcerative colitis and 14 had familial adenomatous polyposis. The temporary ileostomy was closed between 2 and 78 months previously in 63 cases. Of these, three patients had had the reservoir removed and two were lost to follow-up. One other patient was subsequently found to have Crohn's disease. Function was assessed in 55 patients who had undergone closure of the ileostomy more than 8 weeks previously. Mean frequency of defecation was 3.7 per 24 hours (range 1-9.5) and 11 patients (20%) were taking antidiarrheal medication. Spontaneous defecation occurred in 22 patients (40%) while 29 (52.7%) had to use a catheter passed per anum. Four patients defecated spontaneously but sometimes used a catheter. Continence was normal in 36 (65.4%) and minor leakage once every 2 to 3 days occurred at night in 16 (29.1%). Three patients (5.4%) had some soiling during day and night. Troublesome perianal soreness (five patients, 9.1%) necessitated a defunctioning ileostomy in one. Fifty-four of the 55 patients assessed preferred their quality of life to that with an ileostomy.

Adult↗
PubMed1994

The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function.

OBJECTIVE: The authors assessed the long-term effect of postoperative chemoradiotherapy on bowel function. SUMMARY BACKGROUND DATA: Adjuvant postoperative radiation therapy, often combined with chemotherapy, is being used increasingly often for rectal carcinoma. However, the long-term effect of this treatment on bowel function has not been investigated. METHODS: The records were reviewed of all patients undergoing anterior resection for rectal carcinoma 2 to 5 years previously. During this period, patients with Astler-Coller stage B2 or C tumors generally were given postoperative radiation therapy with chemotherapy, whereas those with earlier stage tumors were not. To minimize possible confounding factors that may have been more common in the group receiving chemoradiotherapy and that may affect bowel function, extensive exclusion criteria were used, such as invasion of contiguous organs, local or distant metastases, use of a dysfunctioning stoma, and anastomotic or pelvic complications. One hundred remaining patients were suitable for inclusion in the study and participated in a telephone questionnaire; 41 patients had postoperative chemoradiotherapy, and 59 did not. RESULTS: The two groups were well matched for sex, level of anastomosis, and length of follow-up, although the group receiving chemoradiotherapy was slightly younger. The group that had chemoradiotherapy had more bowel movements per day than the group that did not have radiation therapy (median 7 vs. median 2, p < 0.001); the former group had "clustering" of bowel movements more often (42% vs. 3%, p < 0.001), had nighttime movements more often (46% vs. 14%, p < 0.001), had occasional or frequent incontinence more often (39% and 17% vs. 7% and 0%, p < 0.001), wore a pad more often (41% vs. 10%, p < 0.001), and were unable to defer defecation for more than 15 minutes more often (78% vs. 19%, p < 0.001). The group that had chemoradiotherapy also had stool of liquid consistency, used antidiarrheal medications, had perianal skin irritation, were unable to differentiate stool from gas, and needed to defecate again within 30 minutes of a movement significantly more often than the group that did not receive chemoradiotherapy. CONCLUSION: Adjuvant postoperative chemoradiotherapy for rectal carcinoma has a major long-term detrimental effect on bowel function.

Adenocarcinoma↗