Antidiarrheal Research Articles

Symptomatic Overlap Between Microscopic Colitis and Irritable Bowel Syndrome

Microscopic colitis and irritable bowel syndrome (IBS) are the common causes of watery diarrhea, abdominal discomfort, and other gastrointestinal symptoms. Previous retrospective data and post hoc analysis of information from a randomized controlled trial have suggested that there is considerable overlap between the symptoms seen in patients with microscopic colitis and the symptom-based criteria for IBS. We sought to study this overlap in a prospective cohort. A random cohort of patients with biopsy-proven microscopic colitis seen at our institution were administered a symptom questionnaire. Based on their responses, the proportion of patients who met various definitions for IBS was determined. Clinical characteristics of those meeting IBS criteria were compared with those who did not. In the 120 patients who were included, 38% to 58% met the diagnostic criteria for IBS. These patients tended to be younger and more likely female than those who did not meet IBS criteria. Patients with microscopic colitis frequently meet the diagnostic criteria for IBS. Therefore, these criteria are not specific enough to exclude the presence of microscopic colitis. In patients with watery diarrhea, colonoscopy with mucosal biopsies should be performed if symptoms are not controlled by antidiarrheal medications.

Acute toxicity investigation and anti-diarrhoeal effect of the chloroform–methanol extract of the seeds of Persea americana in albino rats

Abstract Background and Aim Persea americana is a plant used by traditional medicine practitioners to treat ailments including diarrhoea and diabetes mellitus in Nigeria. Hence, the chloroform and the methanol fractions of the chloroform–methanol extract of the seeds of P. americana were evaluated for their acute toxicity as well as anti-diarrhoeal effects in Wistar rats to substantiate this claim. Methods The chloroform and methanol fractions [at graded doses of 100 and 200 mg/kg body weight (b.w) of each] were studied for their anti-diarrhoeal effects in terms of the reductions in the wetness of faeces and the frequency of defaecation of castor oil-induced diarrhoea. To understand the mechanism of their anti-diarrhoeal effects, their actions were further evaluated on castor oil-induced enteropooling (intestinal fluid accumulation). Results The median lethal dose (LD 50 ) of the chloroform and methanol fractions were each found to be less than 5000 mg/kg b.w. At the two doses, the chloroform and the methanol fractions showed dose-dependent significant ( p p p Conclusion Experimental findings show that the chloroform–methanol extract of the seeds of P. americana possesses significant anti-diarrhoeal effect and may be a potent source of anti-diarrhoeal drug(s) in future.

Ethnobotany and folk medicinal uses of major trees and shrubs in Northern Iran

This research was carried out to introduce important useful plants and their medicinal characteristics in Heyrat indigenous region. Approximately 16 medicinal species of trees and shrubs belonging to 12 families were recorded. It is found that all these plants are used by the rural people in traditional uses and food consumption, and that the main species of them included: Borago officinalis, Arctium lappa, Sambucus ebulus, Lamium album, Hyoscyamus niger, Mespilus germanica, Crataegus oxyacantha, Grossularia reclinata, Sorbus torminalis, Berberis vulgaris, Rosa canina, Ferula gummosa, Plantago major, Viscum album, Althaea officinalis, and Rosmarinus officinalis. The conventional ethnomedicinal plants were mostly used as antipyretic, anti diarrheal, anti inflammatory, laxative, blood purifiers and for toothache. The studies presented here could suggest new inputs for further photochemical, pharmacological and toxicological studies among Iranian folk pharmacopoeia. Key words: Ethnobotany, folk medicine, medicinal plants, Heyrat, Mazandaran province, Iran.

Increased Intestinal Absorption in the Era of Teduglutide and Its Impact on Management Strategies in Patients With Short Bowel Syndrome–Associated Intestinal Failure

Short bowel syndrome-associated intestinal failure (SBS-IF) as a consequence of extensive surgical resection of the gastrointestinal (GI) tract results in a chronic reduction in intestinal absorption. The ensuing malabsorption of a conventional diet with associated diarrhea and weight loss results in a dependency on parenteral nutrition and/or intravenous fluids (PN/IV). A natural compensatory process of intestinal adaptation occurs in the years after bowel resection as the body responds to a lack of sufficient functional nutrient-processing intestinal surface area. The adaptive process improves bowel function but is a highly variable process, yielding different levels of symptom control and PN/IV independence among patients. Intestinal rehabilitation is the strategy of maximizing the absorptive capacity of the remnant GI tract. The approaches for achieving this goal have been limited to dietary intervention, antidiarrheal and antisecretory medications, and surgical bowel reconstruction. A targeted pharmacotherapy has now been developed that improves intestinal absorption. Teduglutide is a human recombinant analogue of glucagon-like peptide 2 that promotes the expansion of the intestinal surface area and increases the intestinal absorptive capacity. Enhanced absorption has been shown in clinical trials by a reduction in PN/IV requirements in patients with SBS-IF. This article details the clinical considerations and best-practice recommendations for intestinal rehabilitation, including optimization of fluids, electrolytes, and nutrients; the integration of teduglutide therapy; and approaches to PN/IV weaning.

Bosutinib in the management of chronic myelogenous leukemia

Bosutinib (SKI-606) is an orally available, once-daily dual Src and Abl kinase inhibitor, approved by the US Food and Drug Administration for the treatment of adults with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia who are intolerant of or resistant to first- or second-generation tyrosine kinase inhibitors. Bosutinib effectively overcomes the majority of imatinib-resistance-conferring BCR-ABL mutations except V299L and T315I. In the Bosutinib Efficacy and Safety in chronic myeloid LeukemiA (BELA) trial, bosutinib attained a faster and deeper molecular response than imatinib in newly diagnosed chronic-phase chronic myelogenous leukemia patients. Treatment-emergent adverse events are usually very manageable. Low grade, mostly self-limiting diarrhea represents the most frequently observed toxicity of bosutinib. Anti-diarrheal drugs, antiemetic agents, and/or fluid replacement should be used to treat these patients. The improved hematological toxicity of bosutinib compared with other tyrosine kinase inhibitors has been ascribed to its minimal activity against platelet-derived growth factor receptor and KIT. In this review, we give an overview on the profile of bosutinib, the clinical potential and treatment-emergent adverse events.

Hospital management of children with acute gastroenteritis

Acute gastroenteritis (AGE) is a major cause of ED visits, hospitalizations, and prescription of investigations, drugs, and changes in diet. Several guidelines on management have been produced. There is new information on different rehydration protocols, use of antiemetics, and antidiarrheal drugs that could reduce the burden of AGE. The need of intravenous (i.v.) rehydration is the main cause of hospital admission yet a standardized rehydration scheme is not available. Rehydration therapy through nasogastric tube is better than i.v. rehydration, in children with moderate-severe dehydration. Ultrarapid rehydration has been proposed by enteric or i.v. route to reduce the time in hospital and costs. However, reduced rehydration times are associated with high readmission rates and side effects. Antiemetics may reduce the need of i.v. rehydration because of vomiting and the number of hospital admissions. However, the main antiemetic, ondansetron, has been loaded with a warning for potentially severe side effects. Selected antidiarrheal drugs could reduce the length of stay, but data on their use in inpatients are still not conclusive. Inappropriate medical interventions are still common in the hospital setting and have a high impact on costs. A validated management is still needed in inpatients.

Crofelemer, a novel antisecretory agent approved for the treatment of HIV-associated diarrhea

Secretory diarrhea has a significant impact on morbidity and mortality worldwide and may be a predominant or minor component of pathogenesis in diarrhea of various etiologies. Crofelemer is a first-in-class antidiarrheal medication with unique inhibitory mechanisms at both the cystic fibrosis transmembrane conductance regulator and the calcium-activated chloride channels which are responsible for chloride secretion and subsequent luminal hydration. The efficacy of crofelemer has been investigated in patients with HIV-associated diarrhea, diarrhea of various infectious etiologies, as well as diarrhea-predominant irritable bowel syndrome. Crofelemer was approved by the FDA in December 2012 to treat diarrhea in HIV/AIDS patients on antiretroviral therapy. Crofelemer is not absorbed in the body and well-tolerated in small trials performed to date although long-term safety data is lacking. Crofelemer may be an important addition to the currently available drugs for the management of secretory diarrhea.

Role of antidiarrhoeal drugs as adjunctive therapies for acute diarrhoea in children.

Acute diarrhoea is a leading cause of child mortality in developing countries. Principal pathogens include Escherichia coli, rotaviruses, and noroviruses. 90% of diarrhoeal deaths are attributable to inadequate sanitation. Acute diarrhoea is the second leading cause of overall childhood mortality and accounts for 18% of deaths among children under five. In 2004 an estimated 1.5 million children died from diarrhoea, with 80% of deaths occurring before the age of two. Treatment goals are to prevent dehydration and nutritional damage and to reduce duration and severity of diarrhoeal episodes. The recommended therapeutic regimen is to provide oral rehydration solutions (ORS) and to continue feeding. Although ORS effectively mitigates dehydration, it has no effect on the duration, severity, or frequency of diarrhoeal episodes. Adjuvant therapy with micronutrients, probiotics, or antidiarrhoeal agents may thus be useful. The WHO recommends the use of zinc tablets in association with ORS. The ESPGHAN/ESPID treatment guidelines consider the use of racecadotril, diosmectite, or probiotics as possible adjunctive therapy to ORS. Only racecadotril and diosmectite reduce stool output, but no treatment has yet been shown to reduce hospitalisation rate or mortality. Appropriate management with validated treatments may help reduce the health and economic burden of acute diarrhoea in children worldwide.

The Acute Gastrointestinal Subsyndrome of the Acute Radiation Syndrome

The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15-d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of antibiotics and blood transfusions. The model defines the dose response relationship and time course of acute gastrointestinal syndrome-induced morbidity and mortality in the rhesus macaque.

Collagenous Gastritis in a Patient Treated with Venlaflaxine

Purpose: Collagenous colitis, subtype of microscopic colitis, is a diagnosis made via assessment of typically normal appearing colonic mucosa biopsies. Collagen deposition is seen in the sub-epithelial layer. Symptoms include loose, watery diarrhea; abdominal pain; weight loss; and dehydration. Although collagenous colitis is a well-known entity, etiology is still unknown with medications as possible triggers. Successful treatment and symptom resolution has been shown with corticosteroids, specifically budesonide. Case reports have documented the spread of collagenous colitis to the small bowel, however, extent to gastric mucosa is extremely rare. A 62-year-old Caucasian female presented to clinic for chronic diarrhea and moderate epigastric cramping for the past 3 months. Patient's medical history included anxiety and depression treated with venlafaxine that was started 7 months prior to presentation. Patient described the diarrhea as watery with mucus, non-bloody and occurring up to 30 times per day with intermittent epigastric discomfort. No other symptoms were reported and weight loss was not experienced. Patient denied any recent illness, antibiotic use, sick contacts or travel. Treatment with over the counter anti-diarrheal medications and prescribed oral ciprofloxacin were unsuccessful. An extensive investigation that included routine blood tests, serologic markers, stool studies, urine collection were within normal limits. An EGD and colonoscopy were performed with biopsies taken from normal appearing stomach, small and large intestine, and rectal mucosa. Samples taken from the ascending, transverse and sigmoid colon along with the rectum showed collagen deposition compatible with collagenous colitis. Surprisingly, gastric antrum samples also showed collagen deposition. The patient was treated with an oral course of budesonide, which resolved symptoms 2 weeks after initiation. Although collagenous colitis symptoms, complications and treatment options are widely reported, collagenous gastritis appears to be a rare entity. To our knowledge, few cases of collagenous gastritis have been reported in adults and children with young women being the major group associated with the disease. Even less data is available on treatment with few reported successes with corticosteroid therapy. Possible trippers include anti-depressants such as venlafaxine in our patient. Clinicians should be cognizant of collagenous gastritis to be a cause of symptoms in patients with epigastric pain or discomfort with diffuse watery diarrhea. A thorough colonoscopy and EGD with multiple biopsies of normal appearing mucosa is justified in these patients and close follow-up is mandatory as relapse of the disease state may recur.

Optimization of total flavonoids content extracted from Flos Populi using response surface methodology

Flos Populi is an excellent source of total flavonoids used as an antidiarrheal drug. For better utilization of the resource, Box–Behnken design was used to optimize the extraction conditions of total flavonoids from Flos Populi. The effects of four independent variables in terms of extraction time, temperature, ethanol concentration, and the ratio of liquid to material on the flavonoids yield were determined and the optimal conditions for flavonoids were evaluated by means of response surface methodology. Correlation analysis of the mathematical regression model indicated that a quadratic polynomial model could be employed to characterize extraction process for the total flavonoids. Response surface plots showed that these independent variables significantly influenced the extraction yield of total flavonoids. The optimal extraction parameters to obtain the highest total flavonoids yield were temperature of 94.66°C, ethanol concentration of 45.92%, the ratio of liquid to material of 18.55:1 (mL/g), and time duration of 2.27h. The average experimental total flavonoids yield under the optimum conditions was found to be 53.08±0.43mg/g, which agreed with the predicted value of 52.04mg/g. The extraction method was applied successfully to extract total flavonoids from Flos Populi.

Health Challenges of Young Travelers Visiting Friends and Relatives Compared With Those Traveling for Other Purposes

The study objective was to assess differences in demographics and travel health challenges between youths ≤18 years old traveling internationally to visit friends and relatives (VFRs) compared with those traveling for other purposes (non-VFR). The Boston Area Travel Medicine Network consists of 5 clinics collecting anonymous data from international pretravel consultations. Data on all travelers ≤18 years of age seen between January 2008 and July 2010 were used. VFRs were compared with non-VFRs on demographics, primary language, trip characteristics, travel vaccinations administered, malaria prophylaxis and antidiarrheal medications prescribed. Thirty-five percent (610/1731) listed VFR as their purpose of travel. Almost half of VFRs were <5 (46%) years old compared with <5% of non-VFRs. Thirty percent of US-born VFRs with foreign-born parents were ≤2 years compared with 4% of foreign-born VFR children and 3% of US-born VFRs with US-born parents. More VFRs than non-VFRs planned travel to countries that were yellow fever holoendemic, had malaria risk and were high-risk for typhoid (44% versus 20%, 39% versus 12%, 25% versus 15%, P < 0.01). VFRs were less likely than non-VFRs to be prescribed atovaquone-proguanil (adjusted prevalence ratio = 0.57, confidence interval = 0.44-0.72) and to have had an antidiarrheal medication prescribed (adjusted prevalence ratio = 0.68, confidence interval = 0.60-0.75). To reduce travel-related morbidity, healthcare providers should be prepared to give travel advice to parents of VFR infants and children, particularly those US-born VFRs with foreign-born parents, regarding antimalarial and antidiarrheal medications and preventing yellow fever, malaria and typhoid.

Irritable bowel syndrome: treatment options

SUMMARY Irritable bowel syndrome is a common gastrointestinal disorder that considerably reduces the patient’s quality of life and represents an economic burden to society due to the high consumption of healthcare resources and the nonproductivity of irritable bowel syndrome patients. The options for the treatment of irritable bowel syndrome are nonpharmacological and pharmacological. The nonpharmacological approach includes: information and reassurance, dietary guidance, regular exercise, probiotic intake, hypnotherapy and cognitive therapy, psychodynamic interpersonal therapies and relaxation training. There is still some uncertainty regarding the role of cognitive behavior, psychodynamic interpersonal therapies and relaxation training in managing irritable bowel syndrome. This is due to significant challenges in terms of study design, patient selection and the interpretation of results. Pharmacological treatment mainly includes laxatives, antidiarrheal drugs, antispasmodic drugs, antidepressants and an...

A meta analysis of the efficacy of Saccharomyces boulardii in children with acute diarrhea

This study was performed to evaluate the efficacy of Saccharomyces boulardii in treating children with acute diarrhoea. Medicinal databases and review articles were screened with prespecified criteria for randomized controlled trials that reported the effects of S. boulardiiand other antidiarrhoeal drugs in treating children with acute diarrhoea. The quality of the study was critically evaluated. A total of 678 articles were found and 8 articles were finally included. Heterogeneity test: Diarrhoea duration analysis (Qstatistic=33.58, p<0.0001, I2=79%), stool frequency on day 3 analysis (Qstatistic=4.53, p=0.10, I2 = 56%), stool frequency on day 4 analysis (Qstatistic=0, p=1.00, I2=0%) and stool frequency on day 7 analysis (Q statistic=0.18, p=0.68, I2=0%). The results of meta-analysis showed that when compared with the control group, S. boulardii was more effective in diarrhoea duration (MD=-0.92, 95% CI: -1.32 to -0.52), stool frequency on day 3 (MD=-1.92, 95% CI: -1.63 to -0.95), day 4 (MD=-0.51, 95% CI: -0.89 to -0.33) and day 7 (MD=-0.44, 95% CI: -0.72 to -0.16), respectively. The evidence currently available shows that S. boulardii treatment is used for children with acute diarrhoea. Key words: Saccharomyces boulardii, acute diarrhoea, meta-analysis.

Preoperative MRI sphincter morphology and anal manometry: can they be markers of functional outcome following anterior resection for rectal cancer?

Good functional outcome following anterior resection (AR) for rectal cancer is an important clinical goal, but its prediction has proven difficult. Assessments such as anal manometry have been advocated as a potential tool but functional anatomy as depicted on MRI has not been investigated. This study looked at whether sphincter complex measurements recorded from preoperative staging MRIs and preoperative anal manometry have any correlation with functional outcome. Consecutive patients with rectal adenocarcinoma underwent preoperative manometric assessment and MRI staging. MRIs were assessed with regard to anorectal angle, puborectalis thickness, canal length and external and internal anal sphincter thickness. Functional outcome was categorized into three groups according to the number of adverse postoperative symptoms (frequency, urgency, leakage, diarrhoea, use of pads, use of antidiarrhoeal medication): 0, 1 and ≥ 2. This was evaluated 1 year following surgery and 6 months following stoma reversal where applicable. Univariate analysis of an ordinal regression model was performed with significance at the 5% level. Thirty patients were assessed. No single preoperative manometric parameter proved significant (P > 0.05). Only puborectalis thickness showed a significant (P = 0.01) relationship with the number of adverse symptoms suffered postoperatively. On receiver operating characteristics analysis, a cut-off value of 3.5 mm gave an optimal sensitivity of 0.5 (95% CI, 0.17-0.83) and specificity of 0.86 (95% CI, 0.64-0.96). Measurements of the puborectalis thickness on preoperative staging MRIs for rectal cancer may help predict functional outcome following AR. Prospective assessment of larger numbers with a fully validated continence score are required to evaluate these findings further.

Gastrointestinal Disease Outbreak Detection Using Multiple Data Streams from Electronic Medical Records

Passive reporting and laboratory testing delays may limit gastrointestinal (GI) disease outbreak detection. Healthcare systems routinely collect clinical data in electronic medical records (EMRs) that could be used for surveillance. This study's primary objective was to identify data streams from EMRs that may perform well for GI outbreak detection. Zip code-specific daily episode counts in 2009 were generated for 22 syndromic and laboratory-based data streams from Kaiser Permanente Northern California EMRs, covering 3.3 million members. Data streams included outpatient and inpatient diagnosis codes, antidiarrheal medication dispensings, stool culture orders, and positive microbiology tests for six GI pathogens. Prospective daily surveillance was mimicked using the space-time permutation scan statistic in single and multi-stream analyses, and space-time clusters were identified. Serotype relatedness was assessed for isolates in two Salmonella clusters. Potential outbreaks included a cluster of 18 stool cultures ordered over 5 days in one zip code and a Salmonella cluster in three zip codes over 9 days, in which at least five of six cases had the same rare serotype. In all, 28 potential outbreaks were identified using single stream analyses, with signals in outpatient diagnosis codes most common. Multi-stream analyses identified additional potential outbreaks and in one example, improved the timeliness of detection. GI disease-related data streams can be used to identify potential outbreaks when generated from EMRs with extensive regional coverage. This process can supplement traditional GI outbreak reports to health departments, which frequently consist of outbreaks in well-defined settings (e.g., day care centers and restaurants) with no laboratory-confirmed pathogen. Data streams most promising for surveillance included microbiology test results, stool culture orders, and outpatient diagnoses. In particular, clusters of microbiology tests positive for specific pathogens could be identified in EMRs and used to prioritize further testing at state health departments, potentially improving outbreak detection.

In vivo evaluation of anti-diarrheal activity of the rhizome of Nymphaea alba (Nymphaeaceae)

Ethanol extract of the of rhizome of Nymphaea alba, at graded doses was investigated for anti-diarrhoeal activity in term of reduction in the rate of defecation in castor oil induced diarrhoea and anti-inflammatory activity in term of reduction in inflammation of rat paw. To understand the mechanism of its anti-diarrhoeal activity, its effect was further evaluated on intestinal transit and castor oil induced intestinal fluid accumulation (enteropooling). At various doses (100 & 200 mg/kg body weight) the extract showed a remarkable anti-diarrhoeal activity evidenced by the reduction in the rate of defecation. Results are comparable to that of standard drug diphenoxylate (5 mg/kg body weight). A single oral dose of N. alba extract of 100 mg/kg body weight produced a significant decrease in the severity of diarrhoea. Extract produced profound decrease in intestinal transit (25.73 and 37.29%) also significantly inhibited castor oil induced enteropooling comparable to that of intraperitoneal injection of standard drug atropine sulphate at doses of 0.1 mg/kg body weight and loperamide at 5 mg/kg body weight respectively. Results indicate N. alba possess significant anti-diarrhoeal activity and may be a potent source of anti-diarrhoeal drug in future. But the extract did not show anti-inflammatory activity.

Management of faecal incontinence in graft-versus-host disease

Graft-versus-host disease (GvHD), a common yet serious complication of allogeneic haemopoietic stem cell transplantation, can cause significant morbidity and negatively impact on patients' quality of life. The gastrointestinal tract is frequently affected resulting in nausea and vomiting, abdominal pain and profuse diarrhoea (Washington and Jagasia, 2009) which can be both distressing and humiliating for patients. The volume of watery, green diarrhoea produced can be greater than 2 litres per day (Ferrara et al, 2009) and is one indicator of the severity of GvHD. It may, in some cases, lead to faecal incontinence. Management of GvHD-associated diarrhoea involves the use of high-dose steroids to control the exaggerated immune response, anti-diarrhoeal medication, management of fluid and electrolytes, and nutritional management. It may also require management of faecal incontinence and prevention of incontinence-associated dermatitis. This paper describes the pathology of GvHD, the management of GvHD-associated diarrhoea and faecal incontinence and discusses the potential use of a faecal management system inappropriately selected individuals with uncontrolled diarrhoea and limited mobility.

Translational Approaches for Pharmacotherapy Development for Acute Diarrhea

Areport is presented of a National Institute of Diabetes and Digestive and Kidney Diseases–sponsored single topic conference designed to determine scientific advances needed to encourage development of pharmacotherapy for diarrheal diseases. Acute diarrheal diseases are a global public health problem in developing and developed countries. They are a leading cause of mortality and morbidity for children under the age of 5 worldwide and have a major economic impact in developed countries. Although oral rehydration solution (ORS) along with oral zinc therapy has reduced mortality owing to acute diarrheal diseases, there are essentially no other approved, safe, and effective drugs to decrease stool volume and prevent fluid loss. On September 25–27, 2011, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on Translational Approaches for Pharmacotherapy Development for Acute Diarrhea to assess current treatments for acute diarrhea, to identify common host pathways targeted by infectious agents associated with acute diarrhea, to evaluate which pathophysiologic mechanisms are most clinically relevant as potential targets, and to identify promising areas for translational research.

P1-17-08: A Phase II Trial of Ganetespib: Efficacy and Safety in Patients (pts) with Metastatic Breast Cancer (MBC).

Abstract Background: Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains the stability of a number of key cellular oncoproteins (client proteins). When Hsp90 is inhibited, its client proteins undergo ubiquitination and degradation. HER2 is one of the most sensitive client proteins of Hsp90 and we have previously shown that tanespimycin, a geldanamycin-based Hsp90 inhibitor, is active in trastuzumab-refractory HER2+ MBC, with a RR of 22% and clinical benefit rate of 59%. Ganetespib is a synthetic, small molecule, IV administered, non-geldanamycin Hsp90 inhibitor which has broader inhibitory effects on oncoproteins with pre-clinical antitumor activity in more breast cancer (BC) subtypes, including triple negative breast cancer (TNBC). We therefore tested ganetespib in an unselected cohort of patients with advanced BC. Methods: Pts with locally advanced or MBC were treated with single agent ganetespib at 200mg/m2 once weekly for 3 weeks, on a 28 day cycle. The primary endpoint of the trial was overall response rate using RECIST 1.1. Pts with HER2+ BC were required to have received prior therapy with trastuzumab. No more than 3 lines of chemotherapy in the metastatic setting were permitted and there was no limit on prior lines of hormone therapy. Pts were evaluated for response after 2 cycles. The trial used a Simon two-stage design requiring at least 3 responses among the first 22 pts, to allow expansion to a total of 40 pts. Results: A total of 14 pts have been treated thus far with a median age of 45.3 years (36.6 to 59.1) and the following subtypes: 8 ER+/HER2+, 3 ER-/HER2+, 1 ER+/HER2− and 2 TNBC. Pts received a median of 1.84 cycles (0.33 to 4). The most common treatment-related AEs were Grade 1/2 and included the following: diarrhea (64%), fatigue (50%), nausea (35%), vomiting (14%), insomnia (14%) and hypersensitivity reactions (35%). The diarrhea had an early onset (&amp;lt; 24 hrs) and lasted up to 48 hrs post-infusion and was managed with either Imodium or similar anti-diarrheal medication. Pts who developed a hypersensitivity reaction were successfully re-challenged following pre-medication using dexamethasone plus H1/H2 antagonists. Grade 3 AEs were limited to 2 pts: 1 with an asymptomatic and reversible elevation in serum amylase, and the other with abdominal pain and diarrhea requiring a dose reduction to 175mg/m2. Of the 10 pts evaluable for efficacy, there is 1 confirmed partial response (PR), 1 minor response (MR) and 2 pts with stable disease (14%). The pt with MR had TNBC and was taken off-study due to a complicated pneumonia requiring hospitalization (unrelated). The remaining 3 pts had HER2+ BC; 2 of these 3 pts (1 PR, 1 SD) are continuing on study and have completed 4 cycles thus far. Updated toxicity and efficacy data will be presented. Conclusions: These data show activity for single agent ganetespib in different subtypes of breast cancer. Ganetespib was well tolerated, with expected gastrointestinal toxicity that was mild in nature and manageable in all patients. Accrual continues and we will present updated data at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-08.