Acute Infectious Diarrhoea in Children – The Role of Drug Treatment
European Gastroenterology & Hepatology Review, 2011;7(1):31-36
Abstract
Acute infectious diarrhoea is a common problem with a wide spectrum of clinical severity in children. Replacing the fluid and electrolytes lost, preferably by using an oral rehydration solution, and continuing to feed the child with age-appropriate foods is the basis for the treatment of this disease. This article reviews the role of antimicrobials and non-antimicrobial antidiarrhoeal drugs in the treatment of children with acute infectious diarrhoea. With the exception of cholera, routine use of antimicrobials to treat watery diarrhoea cases is neither necessary nor appropriate. Antimicrobials are indicated in invasive diarrhoeas when Shigella infection is suspected. Among the non-antimicrobial antidiarrhoeal agents, cholestyramine, loperamide and bismuth subsalicylate do not have a worthwhile additive effect over the clinical course of the disease and are not free from potentially serious side effects when used in children. Racecadotril and diosmectite are two effective and safe antidiarrhoeal agents that can be used in children, in addition to oral rehydration, to shorten diarrhoea duration and to reduce its volume – two clinical outcomes that physicians and parents expect in the treatment of this disease. New antidiarrhoeal agents are in development, pending testing in clinical trials.
Keywords
Diarrhoea, oral rehydration, antidiarrhoeals, ciprofloxacin, cholestyramine, loperamide, bismuth subsalicylate, diosmectite, racecadotril, cholera, shigella, rotavirus
Diarrhoea, oral rehydration, antidiarrhoeals, ciprofloxacin, cholestyramine, loperamide, bismuth subsalicylate, diosmectite, racecadotril, cholera, shigella, rotavirus
Disclosure
The author has no conflicts of interest to declare.
Received:
October 09, 2010 Accepted
October 20, 2010
Correspondence:
Eduardo Salazar-Lindo, Av. El Polo 740, Of. C-410, Surco, Lima 33, Peru. E: esalazar@gastrolabperu.com
Acute infectious diarrhoea is a very common disorder in children, and has a wide spectrum of clinical severity. Sometimes it takes the form of a mild episode that recedes after a few hours; however, at other times it may quickly lead to dehydration, acidosis and potassium depletion or to sepsis, or it may persist for several days, causing nutritional wasting. Because of its abrupt onset and frequent association with alarming symptoms such as fever and vomiting, an episode of diarrhoea carries great concern among family members, even in mild cases. For instance, it has been estimated that in North America and Europe, 4–8% of all emergency room visits among children under five years of age are for a case of acute diarrhoea.1,2 In developing countries, the disease burden is further increased by a high rate of hospital admissions and deaths from early or late complications of the disease.3,4 Consequently, prompt, effective and safe treatment of children with acute diarrhoea is essential to their wellbeing. This article aims to discuss the role of both antimicrobial and non-antimicrobial drugs in the treatment of children with acute infectious diarrhoea within the context of using oral rehydration as the mainstay of appropriate clinical management.
Clinical Syndromes
Diarrhoea is usually recognised as the passage of stools that are looser and more frequent than normal. Clinically, diarrhoeic stools can appear with or without mucus and blood. The term ‘watery diarrhoea’ is generally used when no blood or mucus is present in the stools; ‘dysentery’ or ‘bloody diarrhoea’ is used otherwise. Acute diarrhoea is generally a self-limiting disease lasting from one to two tofive to seven days. However, occasionally diarrhoea may continue regardless of the treatment provided; the term ‘persistent diarrhoea’ is used to refer to an episode of diarrhoea that lasts for 14 days or more. In some cases diarrhoea persists because the infectious agent has the ability to stay in the gut for a long time; in other cases it is because the host is too young or malnourished and unable to mount a rapid and effective healing response to the initial infectious insult.5
References:
1. Parashar UD, Holman RC, Bresee JS, et al., Epidemiology of
diarrheal disease among children enrolled in four West
Coast health maintenance organizations, Pediatr Infect Dis J,
1998;17:605–11.
2. Forster J, Guarino A, Parez N, et al., Hospital-based
surveillance to estimate the burden of rotavirus
gastroenteritis among European children younger than 5
years of age, Pediatrics, 2009;123:e393–400.
3. Ehrenkranz P, Lanata CF, Penny ME, et al., Rotavirus
diarrhea disease burden in Peru: the need for a rotavirus
vaccine and its potential cost savings, Rev Panam Salud Publica,
2001;10:240–8.
4. Nguyen VM, Nguyen VT, Huynh PL, et al., The epidemiology
and disease burden of rotavirus in Vietnam: sentinel
surveillance at 6 hospitals, J Infect Dis, 2001;183:1707–12.
5. Ochoa TJ, Salazar-Lindo E, Cleary TG, Management of
children with infection-associated persistent diarrhea,
Semin Pediatr Infect Dis, 2004;15:229–36.
6. Field M, Intestinal ion transport and the pathophysiology of
diarrhea, J Clin Invest, 2003;111:931–43.
7. Davidson GP, Gall DG, Petric M, et al., Human rotavirus
enteritis induced in conventional piglets. Intestinal structure
and transport, J Clin Invest, 1977;60:1402–9.
8. Jourdan N, Brunet JP, Sapin C, et al., Rotavirus infection
reduces sucrase-isomaltase expression in human intestinal
epithelial cells by perturbing protein targeting and
organization of microvillar cytoskeleton, J Virol, 1998;72:
7228–36.
9. Halaihel N, Lievin V, Alvarado F, Vasseur M, Rotavirus
infection impairs intestinal brush-border membrane Na(+)-
solute cotransport activities in young rabbits, Am J Physiol
Gastrointest Liver Physiol, 2000;279:G587–96.
10. Barrett KE, New insights into the pathogenesis of intestinal
dysfunction: secretory diarrhea and cystic fibrosis, World J
Gastroenterol, 2000;6:470–4.
11. Jentsch TJ, Stein V, Weinreich F, Zdebik AA, Molecular
structure and physiological function of chloride channels,
Physiol Rev, 2002;82:503–8.
12. Giannella RA, Escherichia coli heat-stable enterotoxins,
guanylins, and their receptors: what are they and what do
they do?, J Lab Clin Med, 1995;125:173–81.
13. Ménard LP, Dubreuil JD, Enteroaggregative Escherichia coli
heat-stable enterotoxin 1 (EAST1): a new toxin with an old
twist, Crit Rev Microbiol, 2002;28:43–60.
14. Estes MK, Morris AP, A viral enterotoxin. A new mechanism
of virus-induced pathogenesis, Adv Exp Med Biol, 1999;473:
73–82.
15. Lundgren O, Svensson L, Pathogenesis of rotavirus diarrhea,
Microbes Infect, 2001;3:1145–56.
16. Takahashi A, Kenjyo N, Imura K, et al., Cl-secretion in
colonic epithelial cells induced by the Vibrio
parahaemolyticus hemolytic toxin related to thermostable
direct hemolysin, Infect Immun, 2000;68:5435–8.
17. Sansonetti P, Microbes and microbial toxins: paradigms for
microbial-mucosal interactions III. Shigellosis: from
symptoms to molecular pathogenesis, Am J Physiol Gastrointest
Liver Physiol, 2001;280:G319–23.
18. Schroeder GN, Hilbi H, Molecular pathogenesis of Shigella
spp.: controlling host cell signaling, invasion, and death by
type III secretion, Clin Microbiol Rev, 2008;21:134–56.
19. Khuroo MS, Mahajan R, Zargar SA, et al., The colon in
shigellosis: serial colonoscopic appearances in Shigella
dysenteriae I, Endoscopy, 1990;22:35–8.
20. Huffman SL, Combest C, Role of breast-feeding in the
prevention and treatment of diarrhea, J Diarrhoeal Dis Res,
1990;8:68–81.
21. King CK, Glass RI, Bresee JS, Duggan C; Centers for Disease
Control and Prevention, Managing acute gastroenteritis
among children: oral rehydration, maintenance, and
nutritional therapy, MMWR Recomm Rep, 2003;52(RR-16):1–16.
22. Boschi-Pinto C, Velebit L, Shibuya K, Estimating child
mortality due to diarrhoea in developing countries, Bull World
Health Organ, 2008;86:710–7.
23. Bhattacharya MK, Manna B, Dutta D, et al., Risk factors for
development of dehydration in young children with acute
watery diarrhoea: a case-control study, Acta Paediatr,
1995;84:160–4.
24. Lima AA, Moore SR, Barboza MS Jr, et al., Persistent
diarrhea signals a critical period of increased diarrhea
burdens and nutritional shortfalls: a prospective cohort
study among children in northeastern Brazil, J Infect Dis,
2000;181:1643-51.
25. Checkley W, Epstein LD, Gilman RH, et al., Effects of acute
diarrhea on linear growth in Peruvian children, Am J Epidemiol,
2003;157:166–75.
26. Assis AMO, Barreto ML, Santos LMP, et al., Growth faltering
in childhood related to diarrhea: a longitudinal community
based study, Eur J Clin Nutr, 2005;59:1317–23.
27. El-Mougi M, El-Akkad N, Hendawi A, et al., Is a lowosmolarity
ORS solution more efficacious than standard
WHO ORS solution?, J Pediatr Gastroenterol Nutr, 1994;19:83–6.
28. Multicentre evaluation of reduced-osmolarity oral
rehydration salts solution, International Study Group on
Reduced-osmolarity ORS solutions, Lancet, 1995;345:282–5.
29. CHOICE Study Group, Multicenter, randomized, double-blind
clinical trial to evaluate the efficacy and safety of a reduced
osmolarity oral rehydration salts solution in children with
acute watery diarrhea, Pediatrics, 2001;107:613–8.
30. Desjeux D, Favre I, Simongiovanni J, et al., Why is oral
therapy associated with drugs in the treatment of diarrhea?,
J Pediatr Gastroenterol Nutr, 1996;22:112–4.
31. Nizami SQ, Khan IA, Bhutta ZA, Self-reported concepts
about oral rehydration solution, drug prescribing and
reasons for prescribing antidiarrhoeals for acute watery
diarrhoea in children, Trop Doct, 1996;26:180–3.
32. Bojalil R, Calva JJ, Antibiotic misuse in diarrhea. A household
survey in a Mexican community, J Clin Epidemiol,
1994;47:147–56.
33. Jousilahti P, Madkour SM, Lambrechts T, Sherwin E,
Diarrhoeal disease morbidity and home treatment practices
in Egypt, Public Health, 1997;111:5–10.
34. Nizami SQ, Khan IA, Bhutta ZA, Drug prescribing practices of
general practitioners and paediatricians for childhood
diarrhoea in Karachi, Pakistan, Soc Sci Med, 1996;42:1133–9.
35. Szajewska H, Hoekstra JH, Sandhu B, The Working Group on
Acute Diarrhoea of the European Society for Paediatric
Gastroenterology, Hepatology and Nutrition, Management of
acute gastroenteritis in Europe and the impact of the new
recommendations: a multicenter study, J Pediatr Gastroenterol
Nutr, 2000;30:522–7.
36. Salazar-Lindo E, Chea-Woo E, Kohatsu J, Miranda PR,
Evaluation of clinical management training programme for
diarrhea, J Diarrhoeal Dis Res, 1991;9:227–34.
37. Bhattacharya R, Kaur P, Reddy DC, Impact of education in
the knowledge and practices of rural mothers and key
family members on diarrhoea and its treatment at home,
J Diarrhoeal Dis Res, 1988;6:15–20.
38. Hudelson PM, ORS and the treatment of childhood diarrhea
in Managua, Nicaragua, Soc Sci Med, 1993;37:97–103.
39. Centers for Disease Control and Prevention (CDC), Rotavirus
surveillance-worldwide, 2001–2008, MMWR Morb Mortal Wkly
Rep, 2008;57:1255–7.
40. Atmar RL, Estes MK, The epidemiologic and clinical
importance of norovirus infection, Gastroenterol Clin N Am,
2006;35:275–90.
41. Rodriguez WJ, Kim HW, Arrobio JO, et al., Clinical features of
acute gastroenteritis associated with human reovirus-like
agent in infants and young children, J Pediatr, 1977;91:
188–93.
42. Staat MA, Azimi PH, Berke T, et al., Clinical presentations of
rotavirus infection among hospitalized children, Pediatr Infect Dis J, 2002;21:221–7.
43. Phavichitr N, Catto-Smith AG, Acute gastroenteritis in
children. What role for antibacterials?, Pediatr Drugs,
2003;5:279–90.
44. Pierce NF, Banwell JG, Mitra RC, et al., Controlled
comparison of tetracycline and furazolidone in cholera,
Br Med J, 1968;3(5613):277–80.
45. Rabbani GH, Islam MR, Butler T, et al., Single-dose treatment
of cholera with furazolidone or tetracycline in a doubleblind
randomized trial, Antimicrob Agents Chemother,
1989;33:1447–50.
46. Hoge CW, Gambel JM, Srijan A, et al., Trends in antibiotic
resistance among diarrheal pathogens isolated in Thailand
over 15 years, Clin Infect Dis, 1998;26:341–5.
47. Sack DA, Sack RB, Nair GB, Siddique AK, Cholera, Lancet,
2004;363:223–33.
48. Struelens MJ, Patte D, Kabir I, et al., Shigella septicemia:
prevalence, presentation, risk factors and outcome, J Infect
Dis, 1985;152:784–90.
49. Saraswathi K, De A, Jog A, Gogate A, Shigella septicemia,
Indian Pediatr, 2002;39:777–9.
50. Haltalin KC, Nelson JD, Coliform septicemia complicating
shigellosis in children, JAMA, 1965;192:441–3.
51. Neglia TG, Marr TJ, Davis AT, Shigella dysentery with
secondary Klebsiella sepsis, J Pediatr, 1976;89:253–4.
52. Wilson AP, Ridgway GL, Sarner M, et al., Toxic dilatation of
the colon in shigellosis, BMJ, 1990;301:1325–6.
53. Koster F, Levin J, Walker L, et al., Hemolytic-uremic
syndrome after shigellosis. Relation to endotoxemia and
circulating immune complexes, N Engl J Med, 1978;298:
927–33.
54. Bhimma R, Rollins NC, Coovadia HM, Adhikari M,
Post-dysenteric hemolytic uremic syndrome in children
during an epidemic of Shigella dysentery in Kwazulu/Natal,
Pediatr Nephrol, 1997;11:560–4.
55. Houdouin V, Doit C, Mariani P, et al., A pediatric cluster of
Shigella dysenteriae serotype 1 diarrhea with hemolytic
uremic syndrome in 2 families from France, Clin Infect Dis,
2004;38:e96–9.
56. Ashkenazi S, Dinari G, Zevulunov A, Nitzan M, Convulsions
in childhood shigellosis. Clinical and laboratory features in
153 children, Am J Dis Child, 1987;141:208–10.
57. Khan WA, Dhar U, Salam MA, et al., Central nervous system
manifestations of childhood shigellosis: prevalence, risk
factors, and outcome, Pediatrics, 1999;103:e18.
58. Bennish ML, Salam MA, Wahed MA, Enteric protein loss
during shigellosis, Am J Gastroenterol, 1993;88:53–7.
59. Black RE, Brown KH, Becker S, Effects of diarrhea associated
with specific enteropathogens on the growth of children in
rural Bangladesh, Pediatrics, 1984;73:799–805.
60. Wang LH, Fang XC, Pan GZ, Bacillary dysentery as a
causative factor of irritable bowel syndrome and its
pathogenesis, Gut, 2004;53:1096–101.
61. Ji S, Park H, Lee D, et al., Post-infectious irritable bowel
syndrome in patients with Shigella infection, J Gastroenterol
Hepatol, 2005;20:381–6.
62. Guidelines for the control of shigellosis, including epidemics
due to Shigella dysenteriae type 1, World Health
Organization, 2005. Available at: www.who.int/child_
adolescent_health/documents/9241592330/en/index.html
63. Martin LJ, Flint J, Ravel A, et al., Antimicrobial resistance
among Salmonella and Shigella isolates in five Canadian
provinces (1997 to 2000), Can J Infect Dis Med Microbiol,
2006;17:243–50.
64. Sivapalasingam S, Nelson JM, Joyce K, Het al., High
prevalence of antimicrobial resistance among Shigella
isolates in the United States tested by the National
Antimicrobial Resistance Monitoring System from 1999 to
2002, Antimicrob Agents Chemother, 2006;50:49–54.
65. Kuo CY, Su LH, Perera J, et al., Antimicrobial susceptibility of
Shigella isolates in eight Asian countries, 2001–2004,
J Microbiol Immunol Infect, 2008;41:107–11.
66. Kosek M, Yori PP, Pan WK, et al., Epidemiology of highly
endemic multiply antibiotic-resistant shigellosis in children
in the Peruvian Amazon, Pediatrics, 2008;122:e541–9.
67. Fedorak RN, Field M, Antidiarrheal therapy. Prospects for
new agents, Dig Dis Sci, 1987;32:195–205.
68. Schiller R, Review article: anti-diarrhoea1 pharmacology and
therapeutics, Aliment Pharmacol Ther, 1995;9:87–106.
69. Farthing MJ, Antisecretory drugs for diarrheal disease,
Dig Dis, 2006;24:47–58.
70. Costello AM, Bhutta TI, Antidiarrhoeal drugs for acute
diarrhoea in children, BMJ, 1992;304:1–2.
71. Farthing MJ, Novel agents for the control of secretory
diarrhoea, Expert Opin Investig Drugs, 2004;13:777–85.
72. Schiller LR, Santa Ana CA, Morawski SG, Fordtran JS,
Mechanism of the antidiarrheal effect of loperamide,
Gastroenterology, 1984;86:1475–80.
73. Harford WV, Krejs GJ, Santa Ana CA, Fordtran JS, Acute
effect of diphenoxylate with atropine (Lomotil) in patients
with chronic diarrhea and fecal incontinence,
Gastroenterology, 1980;78:440–3.
74. Hughes S, Higgs NB, Turnberg LA, Loperamide has
antisecretory activity in the human jejunum in vivo, Gut,
1984;25:931–5.
75. Burleigh DE, Loperamide but not morphine has antisecretory
effects in human colon, in vitro, Eur J Pharmacol,
1991;202:277–80.
76. Li ST, Grossman DC, Cummings P, Loperamide therapy for
acute diarrhea in children: systematic review and metaanalysis,
PLoS Med, 2007;4:e98.
77. Chow CB, Li SH, Leung NK, Loperamide associated
necrotising enterocolitis, Acta Paediatr Scand, 1986;75:1034–6.
78. Bhutta TI, Tahir KI, Loperamide poisoning in children, Lancet,
1990;335:363.
79. Olm M, Gonzalez FJ, GarcÃa-Valdecasas, et al., Necrotising
colitis with perforation in diarrhoeic patients treated with
loperamide, Eur J Clin Pharmacol, 1991;40:415–6.
80. Gussin RZ, Withdrawal of loperamide drops, Lancet,
1990;335:1603–4.
81. DuPont HL, Hornick RB, Adverse effect of lomotil therapy in
shigellosis, JAMA, 1973;226:1525–8.
82. Portnoy BL, DuPont HL, Pruitt D, et al., Antidiarrheal agents
in the treatment of acute diarrhea in children, JAMA,
1976;236:844–6.
83. Thompson WG, Cholestyramine, Can Med Assoc J,
1971;104:305–9.
84. Mullan NA, Burgess MN, Bywater RJ, Newsome PM, The
ability of cholestyramine resin and other adsorbents to bind
Escherichia coli enterotoxins, J Med Microbiol, 1979;12:487–96.
85. Brouillard MY, Rateau JG, Cholestyramine adsorbs
Escherichia coli and Vibrio cholerae toxins by way of ion
exchange mechanism, Ann Gastroenterol Hepatol (Paris),
1990;26:27–30.
86. Duffau G, Emilfork M, Prenzel I, et al., Cholestyramine in the
treatment of acute bacterial diarrhea in infants, Bol Med Hosp
Infant Mex, 1979;36:735–42.
87. Vesikari T, Isolauri E, Maki M, Efficacy of cholestyramine in
acute infantile diarrhoea: placebo-controlled double-blind
trial in hospitalized children and in outpatients, J Diarrhoeal
Dis Res, 1984:151–8.
88. Vesikari T, Isolauri E, A comparative trial of cholestyramine
and loperamide for acute diarrhoea in infants treated as
outpatients, Acta Paediatr Scand, 1985;74:650–4.
89. Isolauri E, Vesikari T, Oral rehydration, rapid feeding, and
cholestyramine for treatment of acute diarrhea, J Pediatr
Gastroenterol Nutr, 1985;4:366–7.
90. Isolauri E, Vähäsarja V, Vesikari T, Effect of cholestyramine
on acute diarrhoea in children receiving rapid oral
rehydration and full feedings, Ann Clin Res, 1986;18:99–102.
91. Scheel PJ Jr, Whelton A, Rossiter K, Watson A,
Cholestyramine-induced hyperchloremic metabolic acidosis,
J Clin Pharmacol, 1992;32:536–8.
92. Fan FS, Chow KM, Szeto CC, Li PK, Hyperchloraemic
metabolic acidosis, Emerg Med J, 2008;25:613.
93. Dupont C, Vernisse B, Anti-diarrheal effects of diosmectite
in the treatment of acute diarrhea in children: a review,
Pediatr Drugs, 2009;11:89–99.
94. Clark KJ, Sarr AB, Grant PG, et al., In vitro studies on the use
of clay, clay minerals and charcoal to adsorb bovine
rotavirus and bovine coronavirus, Vet Microbiol,
1998;63:137–46.
95. Fioramonti J, Droy-Lefaix MT, Bueno L, Changes in gastrointestinal
motility induced by cholera toxin and experimental
osmotic diarrhoea in dogs: effects of treatment with an
argillaceous compound, Digestion, 1987;36:230–7.
96. Weese JS, Cote NM, deGannes RV, Evaluation of in vitro
properties of di-tri-octahedral smectite on clostridial toxins
and growth, Equine Vet J, 2003;35:638–41.
97. Mahraoui L, Heyman M, Plique O, et al., Apical effect of
diosmectite on damage to the intestinal barrier induced by
basal tumour necrosis factor-a, Gut, 1997;40:339–43.
98. Guarino A, Bisceglia M, Castellucci G, et al., Smectite in the
treatment of acute diarrhea: a nationwide randomized
controlled study of the Italian Society of Pediatric
Gastroenterology and Hepatology (SIGEP) in collaboration
with primary care pediatricians. SIGEP Study Group for
Smectite in Acute Diarrhea, J Pediatr Gastroenterol Nutr,
2001;32:71–5.
99. Narkeviciute I, Rudzeviciene O, Leviniene G, et al.,
Management of Lithuanian children’s acute diarrhoea
with Gastrolit solution and dioctahedral smectite, Eur J
Gastroenterol Hepatol, 2002;14:419–24.
100. Yen ZS, Lai MS, Best evidence topic report. Smectite for
acute diarrhoea in children, Emerg Med J, 2006;23:65–6.
101. Szajewska H, Dziechciarz P, Mrukowicz J, Meta-analysis:
Smectite in the treatment of acute infectious diarrhoea in
children, Aliment Pharmacol Ther, 2006;23:217–27.
102. Dupont C, Foo JL, Garnier P, et al., Oral diosmectite reduces
stool output and diarrhea duration in children with acute
watery diarrhea, Clin Gastroenterol Hepatol, 2009;7:456–62.
103. DuPont HL, Ericsson CD, Mathewson JJ, et al., Zaldaride
maleate, an intestinal calmodulin inhibitor, in the therapy of
travelers’ diarrhea, Gastroenterology, 1993;104:709–15.
104. Okhuysen PC, DuPont HL, Ericsson CD, et al., Zaldaride
maleate (a new calmodulin antagonist) versus loperamide in
the treatment of traveler’s diarrhea: randomized, placebocontrolled
trial, Clin Infect Dis, 1995;21:341–4.
105. Silberschmidt G, Schick MT, Steffen R, et al., Treatment of
travellers’ diarrhoea: zaldaride compared with loperamide
and placebo, Eur J Gastroenterol Hepatol, 1995;7:871–5.
106. Verkman AS, Lukacs GL, Galietta LJ, CFTR chloride channel
drug discovery—inhibitors as antidiarrheals and activators
for therapy of cystic fibrosis, Curr Pharm Des, 2006;12:
2235–47.
107. DuPont HL, Bismuth subsalicylate in the treatment and
prevention of diarrheal disease, Drug Intell Clin Pharm, 1987;21:
687–93.
108. Gorbach SL, Bismuth therapy in gastrointestinal diseases,
Gastroenterology, 1990;99:863–75.
109. Soriano-Brücher H, Avendano P, O’Ryan M, et al., Bismuth
subsalicylate in the treatment of acute diarrhea in children:
a clinical study, Pediatrics, 1991;87:18–27.
110. Figueroa-Quintanilla D, Salazar-Lindo E, Sack RB, et al., A
controlled trial of bismuth subsalicylate in infants with acute
watery diarrheal disease, N Engl J Med, 1993;328:1653–8.
111. Chowdhury HR, Yunus M, Zaman K, et al., The efficacy of
bismuth subsalicylate in the treatment of acute diarrhoea
and the prevention of persistent diarrhoea, Acta Paediatr,
2001;90:605–10.
112. Food and Drug Administration, HSS, Labeling for oral and
rectal over-the-counter drug products containing aspirin
and nonaspirin salicylates; Reye’s Syndrome warning. Final
rule, Fed Regist, 2003;68:18861–9.
113. Marçais-Collado H, Uchida G, Costentin J, et al., Naloxonereversible
antidiarrheal effects of enkephalinase inhibitors,
Eur J Pharmacol, 1987;144:125–32.
114. Baumer P, Danquechin-Dorval E, Bertrand J, et al., Effects of
acetorphan, an enkephalinase inhibitor, on experimental
and acute diarrhea, Gut, 1992;33:753–8.
115. Bergmann JF, Chaussade S, Couturier D, et al., Effects of
acetorphan, an antidiarrhoeal enkephalinase inhibitor, on
oro-caecal and colonic transit times in healthy volunteers,
Aliment Pharmacol Ther, 1992;6:305–13.
116. Duval-Iflah Y, Berard H, Baumer P, et al., Effects of
racecadotril and loperamide on bacterial proliferation and
on the central nervous system of the newborn gnotobiotic
piglet, Aliment Pharmacol Ther, 1999;13(Suppl. 6):9–14.
117. Rachmilewitz D, Karmeli F, ChorevM, Selinger Z, Effect of
opiates on human colonic adenylate cyclase activity,
Eur J Pharmacol, 1983;93:169–73.
118. Kachur JF, Miller RJ, Filed M, Control of guinea pig
intestinal electrolyte secretion by a delta-opiate
receptor, Proc Natl Acad Sci U S A, 1980;77:2753–6.
119. Primi MP, Bueno L, Baumer P, et al., Racecadotril
demonstrates intestinal antisecretory activity in vivo,
Aliment Pharmacol Ther, 1999;13(Suppl. 6):3–7.
120. Turvill J, Farthing M, Enkephalins and enkephalinase
inhibitors in intestinal fluid and electrolyte transport,
Eur J Gastroenterol Hepatol, 1997;9:877–80.
121. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez
M, Racecadotril in the treatment of acute watery diarrhoea
in children, N Engl J Med, 2000;343:463–77.
122. Cézard JP, Duhamel JF, Meyer M, et al., Efficacy and
tolerability of racecadotril in acute diarrhea in children,
Gastroenterology, 2001;120:799–805.
123. Edelman R, Prevention and treatment of infectious
diarrhea. Speculations on the next 10 years, Am J Med,
1985;78:99–106.
