Chemotherapy-induced diarrhoea (CID) is a common side-effect experienced by patients being treated with a variety of antineoplastic agents. Approximately 80% of patients undergoing chemotherapeutic treatment for colorectal and other gastrointestinal cancers present with CID; moreover, about 5% of early deaths associated with combination anti-cancer chemotherapy are due to CID. Chronic post-treatment diarrhoea amongst cancer survivors can persist for more than 10 years greatly effecting long-term quality of life. Gastrointestinal toxicities such as diarrhoea and vomiting are amongst the primary contributors to dose reductions and delays throughout anti-cancer treatment, presenting a significant hurdle in clinical management of anti-cancer regimes and often result in sub-optimum treatment. However, little is known about pathophysiological mechanisms underlying CID. This work provides a review of chemotherapy-induced diarrhoea, current management guidelines, and shortcomings of current treatments as well as emerging and already existing anti-diarrhoeal treatments potentially suitable for CID.
Arndt, V., Merx, H., Stegmaier, C., Ziegler, H. and Brenner, H. (2004) Quality of Life in Patients with Colorectal Cancer 1 Year after Diagnosis Compared with the General Population: A Population-Based Study. Journal of Clinical Oncology, 22, 4829-4836. http://dx.doi.org/10.1200/JCO.2004.02.018
Lochhead, P. and El-Omar, E.M. (2008) Gastric Cancer. British Medical Bulletin, 85, 87-100. http://dx.doi.org/10.1093/bmb/ldn007
World Health Organisation (2011) CancerStats Cancer Worldwide. International Agency for Research on Cancer, World Health Organisation. http://publications.cancer researchuk.org/downloads/Product/CS_CS_WORLD.pdf
Economists Intelligence Unit (2009) Breakaway: The Global Burden of Cancer-Challenges and Opportunities, a Report from the Economist Intelligence Unit. The Economist. https://assets-livestrong-org.s3.amazonaws.com/media/site_proxy/data/c49ced3068f7205319cb1edf653dd91e0baee3ba.pdf
Isomoto, H. (2010) Global Dissemination of Endoscopic Submucosal Dissection for Early Gastric Cancer. Internal Medicine, 49, 251-252. http://dx.doi.org/10.2169/internalmedicine.49.3074
Saidi, H., Nyaim, E.O., Githaiga, J.W. and Karuri, D. (2008) Surgery Trends in Kenya, 1993-2005. World Journal of Surgery, 32, 217-223. http://dx.doi.org/10.1007/s00268-007-9301-2
Gao, F.H., Hu, X.H., Li, W., Liu, H., Zhang, Y.J., Gou, Z.Y., Xu, M.H., Wang, S.T., Jiang, B., Liu, F., Zhao, Y.Z., Fang, Y., Chen, F.Y. and Wu, Y.L. (2010) Oridonin Induces Apoptosis and Senescence in Colorectal Cancer Cells by Increasing Histone Hyperacetylation and Regulation of p16, p21, p27 and c-myc. BMC Cancer, 10, 610-621. http://dx.doi.org/10.1186/1471-2407-10-610
Yao, Y., Zhao, H., Sun, Y., Lin, F., Tang, L. and Chen, P. (2008) Combined Chemotherapy of Hydroxycampothecin with Oxaliplatin as an Adjuvant Treatment for Human Colorectal Cancer. Tohoku Journal of Experimental Medicine, 215, 267-278. http://dx.doi.org/10.1620/tjem.215.267
Jeon, H.J., Woo, J.H., Lee, H.Y., Park, K.J. and Choi, H.J. (2011) Adjuvant Chemotherapy Using the FOLFOX Regimen in Colon Cancer. Journal of the Korean Society of Coloproctology, 27, 140-146. http://dx.doi.org/10.3393/jksc.2011.27.3.140
Karaca-Mandic, P., McCullough, J.S., Siddiqui, M.A., Van Houten, H. and Shah, N.D. (2011) Impact of New Drugs and Biologics on Colorectal Cancer Treatment and Costs. Journal of Oncology Practice, 7, 30-37. http://dx.doi.org/10.1200/JOP.2011.000302
Takashima, A., Yamada, Y., Nakajima, T.E., Kato, K., Hamaguchi, T. and Shimada, Y. (2009) Standard First-Line Chemotherapy for Metastatic Gastric Cancer in Japan Has Met the Global Standard: Evidence From Recent Phase III Trials. Gastrointestinal Cancer Research, 3, 239-244.
Herszenyi, L. and Tulassay, Z. (2010) Epidemiology of Gastrointestinal and Liver Tumors. European Review for medical and Pharmalogical Sciences, 14, 249-258.
Jemel, A., Center, M.M., DeSantis, C. and Ward, E.M. (2010) Global Patterns of Cancer Incidence and Mortality Rates and Trends. Cancer Epidemiology Biomarkers & Prevention, 19, 1893-1907. http://dx.doi.org/10.1158/1055-9965.EPI-10-0437
Muss, H.B. and Bynum, D.L. (2012) Adjuvent Chemotherapy in Older Patients with Stage III Colon Cancer: An Underused Lifesaving Treatment. Journal Clinical Oncology, 30, 2576-2578. http://dx.doi.org/10.1200/JCO.2012.42.3780
Baek, K.L., Lee, J., Park, S.H., Park, J.O., Park, Y.S., Lim, H.Y., Kiang, W.K., Cho, Y.B., Yun, S.H., Kim, H.C., Lee, Y.W. and Chun, H.K. (2010) Oxaliplatin-Induced Chronic Peripheral Neurotocixity: A Prospective Analysis in Patients with Colorectal Cancer. Cancer Research and Treatment, 45, 185-190. http://dx.doi.org/10.4143/crt.2010.42.4.185
Cathomas, R., Koberle, D., Ruhstaller, T., Mayer, G., Rass, A., Mey, U. and Moos, R.V. (2010) Heated (37℃) Oxaliplatin Infusion in Combination with Capecitabine for Metastatic Colorectal Carcinoma: Can It Reduce Neuropathy? Support Care Cancer, 18, 1263-1270. http://dx.doi.org/10.1007/s00520-009-0740-1
McWhinney, S.R., Goldberg, R.M. and McLoeod, H.L. (2009) Platinum Neurotoxicity Pharmacogenetics. Molecular Cancer Theories, 8, 10-16. http://dx.doi.org/10.1158/1535-7163.MCT-08-0840
Quasthoff, S. and Hartung, H.S. (2002) Chemotherapy-Induced Peripheral Neuropathy. Journal of Neurology, 249, 9-17. http://dx.doi.org/10.1007/PL00007853
Verstappen, C.C.P., Heimans, J.J., Hoekman, K. and Postma, T.J. (2003) Nuerotoxic Complocations of Chemotherapy in Patients with Cancer, Clinical Signs and Optimal Management. Therapy in Practice, 63, 1549-1563.
Leonard, G.D., Wright, M.A., Quinn, M.C., Fioravanti, S., Harold, N., Schuler, B., Thomas, R.R. and Grem, J.L. (2005) Survey of Oxaliplatin-Associated Neurotoxicity Using an Interview-Based Questionnaire in Patients with Metastatic Colorectal Cancer. BMC Cancer, 5, 116.
Benson III, A.B., Ajani, J.A., Catalano, R.B., Engelking, C., Kornlau, S.M., Martenson Jr., J.A., McCallum, R., Mitchell, E.P., O’Dorsio, T.M., Vokes, E.E. and Wadler, S. (2004) Recommended Guidelines for the Treatment of Cancer Treatment-Induced Diarrhea. Journal of Clinical Oncology, 22, 2918-2926. http://dx.doi.org/10.1200/JCO.2004.04.132
Rothenberg, M.L., Meropol, N.J., Poplin, E.A., Van Cutsem, E. and Wadler, S. (2001) Mortality Associated with Irinotecan Plus Bolus Fluorouracil/Leucovorin: Summary Findings of an Independent Panel. Journals of Clinical Oncology, 19, 3801-3807.
Chau, I. and Cunningham, D. (2002) Chemotherapy in Colorectal Cancer: New Options and New Challenges. British Medical Bulletin, 64, 159-180. http://dx.doi.org/10.1093/bmb/64.1.159
Pietrangeli, A., Leandri, M., Terzoli, E., Jandolo, B. and Garufi, C. (2006) Persistence of High-Dose Oxaliplatin-Induced Neuropathy at Long-Term Follow-Up. European Neurology, 56, 13-16. http://dx.doi.org/10.1159/000094376
Conroy, T., Paillot, B., Franois, E., Bugat, R., Jacob, J.H., Stein, U., Nasca, S., Metges, J.P., Rixe, O., Michel, P., Magherini, E., Hua, A. and Deplanque, G. (2005) Irinotecan Plus Oxaliplatin and Leucovorin-Modulated Fluorouracil in Advanved Pancreatic Cancer-A Groupe Tumeurs Digestives of the Federation National des Centres de Lutte Contre le Cancer Study. Journal of Clinical Oncology, 23, 1228-1236. http://dx.doi.org/10.1200/JCO.2005.06.050
Garcia, I.S., Rueda, A. and Alba, E. (1999) Irinotecan-Induced Central Nervous System Toxicity: A Case Report. Journal of the National Cancer Institute, 91, 647. http://dx.doi.org/10.1093/jnci/91.7.647
Gholam, D., Giacchetti, S., Brezault-Bonnet, C., Bouchahda, M., Hauteville, D., Adam, R., Ducot, B., Ghemard, A., Kustlinger, F., Jasmin, C. and Levi, F. (2006) Chronomodulated Irinotecan, Oxaliplatin and Leucovorin-Modulated 5-Fluoruoracil as Ambulatory Salvage Therapy in Patients with Irinotecanand Oxaliplatin-Resistant Metatastic Colorectal Cancer. The Oncologist, 11, 1072-1080.
Dvorak, A.M., Onderdonk, A.B., McLeod, R.S., Monahan-Earley, R.A., Cullen, J., Antonioli, D.A., Blair, J.E., Morgan, E.S., Cisneros, R.L., Estrellla, P., Cohen, Z. and Silen, W. (1993) Axonal Necrosis of Enteric Automatic Nerves in Continent Heal Pouches Implications for Pathogenesis of Crohn’s Disease. Annals of Surgery, 217, 260-271. http://dx.doi.org/10.1097/00000658-199303000-00008
Stringer, A.M., Gibson, R.J., Logan, R.M., Bowen, J.M. and Yeoh, A.S. (2007) Chemotherapy-Induced Diarrhoea Is Associated with Changes in the Luminal Environment in the DA Rat. Experimental Biology & Medicine, 232, 96-106.
Stringer, A.M., Gibson, R.J., Bowen, J.M., Logan, R.M., Ashton, K., Yeoh, A.S.J., Al-Dasooqi, N. and Keefe, D.M.K. (2009) Irinotecan-Induced Mucositis Manifesting as Diarrhoea Corresponds with Amended Intestinal Flora and Mucin Profile. International Journal of Experimental Pathology, 90, 489-499. http://dx.doi.org/10.1111/j.1365-2613.2009.00671.x
Stein, A., Voigt, W. and Jordan, K. (2010) Review: Chemotherapy-Induced Diarrhea: Pathophysiology, Frequency and Guideline Based Management. Therapeutic Advances in Medical Oncology, 2, 51-63. http://dx.doi.org/10.1177/1758834009355164
Keefe, D.M., Schubert, M.M., Elting, L.S., Sonis, S.T., Epstein, J.B., Raber-Durlacher, J.E., Migliorati, C.A., McQuire, D.B., Hutchins, R.D. and Peterson, D.E. (2007) Updates Clinical Practice Guidelines for the Prevention and Treatment of Mucositis. Cancer, 109, 820-832. http://dx.doi.org/10.1002/cncr.22484
Richardson, G.G. and Dobish, R.R. (2007) Chemotherapy Induced Diarrhea. Journal of Oncology Pharmacy Practice, 13, 181-198. http://dx.doi.org/10.1177/1078155207077335
Maroun, J.A., Anthony, L.B., Blais, N., Burkes, R., Dowden, S.D., Dranitsaris, G., Samson, B., Shah, A., Thirlwell, M.P., Vincent, M.D. and Wong, R. (2007) Prevention and Management of Chemotherapy-Induced Diarrhoea in Patients with Colorectal Cancer: A Consensus Statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Current Oncology, 14, 14-20. http://dx.doi.org/10.3747/co.2007.96
National Cancer Institute (2009) Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. US Department of Health and Human Services, National Institutes of Health. http://evs.nci.nih.gov/ftp1 /CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Stringer, A.M., Gibson, R.J., Bowen, J.M., Logan, R.M., Yeoh, A.S.J. and Keefe, M.K. (2007) Chemotherapy-Induced Mucositis: The Role of Gastrointestinal Microflora and Mucins in the Luminal Environment. The Journal of Supportive Oncology, 5, 259-267.
Gibson, R.J. and Keefe, D.M.K. (2006) Cancer Chemotherapy-Induced Diarrhoea and Constipation: Mechanisms of Damage and Prevention Strategies. Supportive Care in Cancer, 14, 890-900. http://dx.doi.org/10.1007/s00520-006-0040-y
Baldi, F., Bianco, M., Nardone, G., Pilotto, A. and Zamparo, E. (2009) Focus on Acute Diarrhoeal Disease. World Journal of Gastroenterology, 15, 3341-3348.
Ferrell, B.R. and Coyle, N. (2005) Textbook of Palliative Nursing. Oxford University Press, Oxford.
Castro-Rodriguez, J.A., Salazar-Lindo, E. and Leon-Barua, R. (1997) Differentiation of Osmotic and Secretory Diarrhoea by Stool Carbohydrate and Osmolar Gap Measurements. Archives of Disease in Childhood, 77, 201-205. http://dx.doi.org/10.1136/adc.77.3.201
Vera, G., Castillo, M., Cabezos, P.A., Chairlone, A., Martin, M.I., Gori, A., Paquinelli, G., Barbara, G., Staghelleni, V., Corinaldesi, R., De Giorgio, R. and Abalo, R. (2011) Enteric Neuropathy Evoked by Repeated Cisplatin in the Rat. Neurogastroenterology & Motility, 23, 370-e162. http://dx.doi.org/10.1111/j.1365-2982.2011.01674.x
Wafai, L., Taher, M., Jovanovska, V., Bornstein, J.C., Dass, C.R. and Nurgali, K. (2013) Effects of Oxaliplatin on Mouse Myenteric Neurons and Colonic Motility. Frontiers in Neuroscience, 7, 1-8. http://dx.doi.org/10.3389/fnins.2013.00030
Devila, M. and Bresalier, R.S. (2008) Gastrointestinal Complication of Oncologic Therapy. Nature Reviews Gastroenterology and Hepatology, 5, 682-696. http://dx.doi.org/10.1038/ncpgasthep1277
Wadler, S., Benson III, A.B. and Engelking, C. (1998) Recommended Guidelines for the Treatment of Chemotherapy-Induced Diarrhea. Journal of Clinical Oncology, 16, 3169-3178.
Yang, X., Hu, Z. and Chan, S.Y. (2005) Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea. Current Medicinal Chemistry, 12, 1343-1358. http://dx.doi.org/10.2174/0929867054020972
Saltz, L.B. (2003) Understanding and Managing Chemotherapy Induced Diarrhea. Journal of Supportive Oncology, 1, 35-46.
Dranitsaris, G., Maroun, J. and Shah, A. (2005) Estimating the Cost of Illness in Colorectal Cancer Patients Who Were Hospitalized for Severe Chemotherapy-Induced Diarrhea. Canadian Journal of Gastroenterology, 19, 83-87.
Mitchell, E.P. (2006) Gastrointestinal Toxicity of Chemotherapeutic Agents. Seminars in Oncology, 33, 106-120. http://dx.doi.org/10.1053/j.seminoncol.2005.12.001
Shafi, M.A. and Bresalier, R.S. (2010) The Gastrointestinal Complications of Oncologic Therapy. Gastroenterology Clinics of North America, 39, 629-647. http://dx.doi.org/10.1016/j.gtc.2010.08.004
Kuebler, J.P., Colengalo, L., O’Connell, M.J., Smith, R.E., Yothers, G., Begovic, M., Robinson, B., Seay, T.E. and Wolmark, N. (2007) Severe Enteropathy among Patients with Stage II/III Colon Cancer Treated on a Randomized Trial of Bolus 5-FU/Leucovorin Plus or Minus Oxaliplatin. Cancer, 110, 1945-1950. http://dx.doi.org/10.1002/cncr.23013
Arbuckle, R.B., Huber, S.L. and Zacker, C. (2000) The Consequences of Diarrhea Occurring during Chemotherapy for Colorectal Cancer: A Retrospective Study. The Oncologist, 5, 250-259. http://dx.doi.org/10.1634/theoncologist.5-3-250
Janinis, J., Papakostas, P., Samelis, G., Skarlos, D., Papagianopoulos, P. and Fountzilas, G. (2000) Second-Line Chemotherapy with Weekly Oxaliplatin and High-Dose 5-Fluorouracil with Folinc Acid in Metastatic Colorectal Carcinoma: A Hellenic Cooperative Oncology Group (HeCOG) Phase II Feasibility Study. Annals of Oncology, 11, 163-167. http://dx.doi.org/10.1023/A:1008397109048
Denlinger, C.S. and Barsevick, A.M. (2009) The Challenges of Colorectal Cancer Survivorship. Journal of the National Comprehensive Cancer Network, 7, 883-894.
Viele, C.S. (2003) Overview of Chemotherapy-Induced Diarrhoea. Seminars in Oncology Nursing, 19, 2-5. http://dx.doi.org/10.1053/j.soncn.2003.09.007
Lenfers, B.H.M., Loeffler, T.M., Droege, C.M. and Hausmen, T.U. (1999) Substantial Activity of Budesonide in Patients with Irinotecan (CPT-11) and 5-Fluorouracil Induced Diarrhea and Failure of Loperamide Treatment. Annals of Oncology, 10, 1251-1251. http://dx.doi.org/10.1023/A:1008390308416
Sharma, R., Tobin, P. and Clarke, S.J. (2005) Management of Chemotherapy-Induced Nausea, Vomiting, Oral Mucositis and Diarrhoea. The Lancet Oncology, 6, 93-102. http://dx.doi.org/10.1016/S1470-2045(05)01735-3
Hogenauer, C., Aichnichler, S., Sanat Ana, C., Prter, J. and Fordtran, J. (2002) Effect of Octreotide on Fluid Absorption and Secretion by the Normal Human Jejunum and Ileum in Vivo. Alimentary Pharmacology & Therapeutics, 16, 769-777. http://dx.doi.org/10.1046/j.1365-2036.2002.01228.x
Hovind, P., Simonsen, L. and Bulow, J. (2010) Decreased Leg Glucose Uptake during Exercise Contributes to the Hyperglyceamic Effects of Octreotide. Clinical Physiology and Functional Imaging, 30, 141-145. http://dx.doi.org/10.1111/j.1475-097X.2009.00917.x
Yumuk, P.F., Aydin, S.Z. and Dane, F. (2004) The Absence of Early Diarrhea with Atropine Premedication during Irinotecan Therapy in Metastatic Colorectal Patients. International Journal of Colorectal Disease, 19, 609-610. http://dx.doi.org/10.1007/s00384-004-0613-5
Jansman, F.G.A., Sleijfer, D.T., de Graaf, J.C., Coenen, J.L.L.M. and Brouwers, J.R.B.J. (2001) Management of Chemotherapy-Induced Adverse Effects in the Treatment of Colorectal Cancer. Drug Safety, 24, 353-367. http://dx.doi.org/10.2165/00002018-200124050-00002
Bengt, G. (2005) Benefit-Risk Assessment of Irinotecan in Advanced Colorectal Cancer. Drug Safety, 28, 417-433. http://dx.doi.org/10.2165/00002018-200528050-00005
Karthaus, M., Ballo, H. and Abenhardt, W. (2005) Prospective, Double Blind, Placebo Controlled, Multicenter, Randomized Phase III Study with Orally Administered Budesonide for Prevention of Irinotecan (CPT-11)-Induced Diarrhea in Patients with Advanced Colorectal Cancer. Oncology, 68, 326-332. http://dx.doi.org/10.1159/000086971
Chowbay, B., Sharma, A., Zhou, Q., Cheung, Y.B. and Lee, E.J.D. (2003) The Modulation of Irinotecan-Induced Diarrhoea and Pharmacokinetics by Three Different Classes of Pharmacological Agents. Oncology Reports, 10, 745-751.
Kehrer, D.F., Sparreboom, A., Verweij, J., De Bruijn, P., Nierop, C.A., Van De Schraaf, J., Ruijgrok, E.J. and De Jonge, M.J. (2001) Modulation of Irinotecan-Induced Diarrhea by Cotreatment with Neomycin in Cancer Patients. Clinical Cancer Research, 7, 1136-1141.
Schmittel, A., Jahnke, K., Theil, E. and Keilholz, U. (2004) Neomycin as a Secondary Prophylaxis for Irinotecan-Induced Diarrhea. Annals of Oncology, 15, 1296. http://dx.doi.org/10.1093/annonc/mdh310
Flieger, D., Klassert, C., Hainke, S., Keller, R., Kleinschmidt, R. and Fischbach, W. (2007) Phase II Clinical Trial for Prevention of Delayed Diarrhea with Cholestyramine/Levofloxacin in the Second-Line Treatment with Irinotecan Biweekly in Patients with Metastatic Colorectal Carcinoma. Oncology, 72, 10-16. http://dx.doi.org/10.1159/000111083
De Jong, F.A., Scott-Horton, T.J., Kroetz, D.J., McLeod, H.L., Friberg, L.E., Mathijssen, R.H., Verweij, J., Marsh, S. and Sparreboom, A. (2007) Irinotecan-Induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein. Clinical Pharmacology and Therapeutics, 81, 42-49. http://dx.doi.org/10.1038/sj.clpt.6100019
Furnam, W.L., Crews, K.R., Billups, C., Wu, J., Gajjar, A.J., Daw, N.C., Patrick, C.C., Rodriguez-Galindo, C., Stewart, C.F., Dome, J.S., Panetta, J.C., Houghton, P.J. and Santana, V.M. (2006) Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients with Refractory Solid Tumours. Journal of Clinical Oncology, 24, 563-570. http://dx.doi.org/10.1200/JCO.2005.03.2847
De Pestel, D.D. and Aronoff, D.M. (2013) Epidemiology of Clostridium difficile Infection. Journal of Pharmacy Practices, 26, 464-475. http://dx.doi.org/10.1177/0897190013499521
Khanna, S. and Pardi, D.S. (2012) Clostridium difficile Infection: New Insights into Management. Mayo Clinic Proceedings, 87, 1106-1117. http://dx.doi.org/10.1016/j.mayocp.2012.07.016
Levine, S.A., Nath, S.K., Tse, C.M., Yun, C. and Donowitz, M. (1994) L-Glutamine in Intestinal Sodium Absorption: Lessons for Physiology, Pathobiology and Therapy for Diarrhea. Gastroenterology, 106, 1698-1702.
Fox, A.D., Kripke, S.A., De Paula, J., Berman, J.M., Settle, R.G. and Rombeau, J.L. (1988) Effects of a GlutamineSupplemented Enteral Diet on Methotrexate-Induced Enterocolitis. Journal of Parenteral and Enteral Nutrition, 12, 325-331. http://dx.doi.org/10.1177/0148607188012004325
Xue, H., Sawyer, M.B., Field, C.J., Dieleman, L.A., Murray, D. and Baracos, V.E. (2008) Bolus Oral-Glutamine Protects Rats against CPT-11-Induced Diarrhea and Differentially Activates Cytoprotective Mechanisms in the Host Intestine but Not Tumour. The Journal of Nutrition, 138, 740-746.
Daniele, B., Perrone, F., Gallo, C., Pignata, S., De Martino, S., De Vivo, R., Barlettaa, E., Tambaroa, R., Abbiatie, R. and D’Agostino, L. (2001) Oral Glutamine in the Prevention of Fluorouracil Induced Intestinal Toxicity: A Double Blind, Placebo Controlled, Randomised Trial. Gut, 48, 28-33. http://dx.doi.org/10.1136/gut.48.1.28
Kozelsky, T.F., Meyers, G.E., Sloan, J.A., Shanahan, T.G., Dick, S.J., Moore, R.L., et al. (2003) Phase III Double-Blind Study of Glutamine versus Placebo for the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy. Journal of Clinical Oncology, 21, 1669-1674. http://dx.doi.org/10.1200/JCO.2003.05.060
Li, Y., Ping, X., Yu, B., Liu, F., Ni, X. and Li, J. (2009) Clinical Trial: Prophylactic Intravenous Alanyl-Glutamine Reduces the Severity of Gastrointestinal Toxicity Induced by Chemotherapy: A Randomized Crossover Trial. Alimentary Pharmacology & Therapeutics, 30, 452-458. http://dx.doi.org/10.1111/j.1365-2036.2009.04068.x
Sun, J., Wang, H. and Heping, H. (2012) Glutamine for Chemotherapy Induced Diarrhea: A Meta-Analysis. Asia Pacific Journal of Clinical Nutrition, 21, 380-385.
Pytlik, R., Benes, P., Patorkova, M., Chocenska, E., Gregora, E. and Prochazka, B. (2002) Standardized Parenteral Alanyl-Glutamine Dipeptide Supplementation Is Not Beneficial in Autologous Transplant Patients: A Randomized, Double-Blind, Placebo Controlled Study. Bone Marrow Transplantation, 30, 953-961. http://dx.doi.org/10.1038/sj.bmt.1703759
Kornblau, S., Benson III, A.B. and Catalano, R. (2000) Management of Cancer Treatment-Related Diarrhea: Issues and Therapeutic Strategies. Journal of Pain and Symptom Management, 19, 118-129. http://dx.doi.org/10.1016/S0885-3924(99)00149-9
Michael, M., Brittain, M. and Nagai, J. (2004) Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea. Journal of Clinical Oncology, 22, 4410-4417. http://dx.doi.org/10.1200/JCO.2004.11.125
Tack, J.F., Miner, P.B., Fischer, L. and Harris, M.S. (2011) Randomised Clinical Trial: The Safety and Efficacy of AST-120 in Non-Constipating Irritable Bowel Syndrome: A Double Blind, Placebo Controlled Study. Alimentary Pharmacology & Therapeutics, 34, 868-877. http://dx.doi.org/10.1111/j.1365-2036.2011.04818.x
Maeda, Y., Ohune, T., Nakamyra, M., Yamasaki, M., Kiribayashi, Y. and Murakami, T. (2004) Prevention of Irinotecan-Induced Diarrhoea by Oral Carbonaceous Adsorbens (Kremezin) in Cancer Patients. Oncology Reports, 12, 581-585.
Thiagarajah, J.R., Broadbent, T., Hsieh, E. and Verkman, A.S. (2004) Prevention of Toxin-Induced Intestinal Ion and Fluid Secretion by a Small-Molecule CFTR Inhibitor. Gastroenterology, 126, 511-519. http://dx.doi.org/10.1053/j.gastro.2003.11.005
Thiagarajah, J.R. and Verkman, A.S. (2012) CFTR Inhibitors for Treating Diarrheal Disease. Clinical Pharmacology and Therapeutics, 92, 287-290.
Ko, E.A., Jin, B.J., Namkung, W., Ma, T., Thiagarajah, J.R. and Verkman, A.S. (2013) Chloride Channel Inhibition by Red Wine Extract and a Synthetic Small Molecule Prevents Rotaviral Secretory Diarrhoea in Neonatal Mice. Gut, 1-10.
Camilleri, M. (2008) Novel Pharmacology: Asimadoline, a К-Opioid Agonist, and Visceral Sensation. Neurogastroenterology and Motility, 20, 971-979.
Bender, H.M. and Dasenbrock, J. (1998) Brain Concentration of Asimadoline in Mice: The Influence of Coadministration of Various P-Glycoprotein Substrates. International Journal of Clinical Pharmacology and Therapeutics, 36, 76-79.
Mangel, A.W. and Hicks, G.A. (2012) Asimadoline and Its Potential for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome: A Review. Clinical and Experimental Gastroenterology, 5, 1-10. http://dx.doi.org/10.2147/CEG.S23274
Mangel, A.W., Bornstein, J.D., Hamm, L.R., Buda, J., Wang, J., Irish, W. and Urso, D. (2008) Clinical Trial: Asimadoline in the Treatment of Patients with Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics, 28, 239-249. http://dx.doi.org/10.1111/j.1365-2036.2008.03730.x
Turck, D., Berard, H. and Fretault, N. (1999) Comparison of Racecadotril and Loperamide in Children with Acute Diarrhoea. Alimentary Pharmacology & Therapeutics, 13, 27-32. http://dx.doi.org/10.1046/j.1365-2036.1999.00004.x-i1
Cezard, J.P., Duhamel, J.F. and Meyer, M. (2001) Efficacy and Tolerability of Racecadotril in Acute Diarrhea in Children. Gastroenterology, 120, 799-805. http://dx.doi.org/10.1053/gast.2001.22544
Baumer, P., Danquechin, D.E. and Bertrand, J. (1992) Effects of Acetorphan, an Enkephalinase Inhibitor, on Experimental and Acute Diarrhoea. Gut, 33, 753-758. http://dx.doi.org/10.1136/gut.33.6.753
Cezard, J.P., Duhamel, J.F. and Meyer, M. (1996) Efficacy and Tolerance of Acetorphan in Infant Actute Diarrhea. A Multicentric Double Blind Study. Gastroenterology, 110, A795.
Roge, J., Baumer, P. and Berard, H. (1993) The Enkephalinase Inhibitor Acetorphan, in Acute Diarrhoea. A Double-Blind, Controlled Clinical Trial versus Loperamide. Scandinavian Journal of Gastroenterology, 28, 352-354.
Vetel, J.M., Berard, H. and Frerault, N. (1995) Comparison of Racecadotril and Loperamide in Adults with Acute Diarhhoea. Alimentary Pharmacology & Therapeutics, 13, 21-26. http://dx.doi.org/10.1046/j.1365-2036.1999.00003.x-i1
Matheson, A.J. and Noble, S. (2000) Racecadotril. Drugs, 59, 829-835. http://dx.doi.org/10.2165/00003495-200059040-00010
Esfandyari, T., Camilleri, M., Ferber, I., Burton, D., Baxter, K. and Zinsmeister, A.R. (2006) Effect of a Cannabinoid Agonist on Gastrointestinal Transit and Postprandial Satiation in Healthy Human Subjects: A Randomized, Placebo-Controlled Study. Neurogastroenterology & Motility, 18, 831-838. http://dx.doi.org/10.1111/j.1365-2982.2006.00834.x
Esfandyari, T., Camilleri, M., Busciglio, I., Burton, D., Baxter, K. and Zinsmeister, A.R. (2007) Effects of a Cannabinoid Receptor Agonist on Colonic Motor and Sensory Functions in Humans: A Randomized, Placebo-Controlled Study. American Journal of Physiology. Gastrointestinal and Liver Physiology, 293, G137-G145.
Wong, B., Camilleri, M., Busciglio, I., Carlson, P., Szarka, L.A., Burton, D. and Zinsmeister, A.R. (2011) Pharmacogenetic Trial of a Cannabinoid Agonist Shows Reduced Fasting Colonic Motility in Patients with Nonconstipated Irritable Bowel Syndrome. Gastroenterology, 141, 1638-1647. http://dx.doi.org/10.1053/j.gastro.2011.07.036