Pharmacokinetic and pharmacodynamic considerations for the current chronic constipation treatments

Expert Opinion on Drug Metabolism and Toxicology

Volumn 9, Issue 4, 2013, Pages 391-401

  Müller Lissner, Stefan ^a  

^a Park Klinik Weissensee   (Germany)

Author keywords

5 HT; Cisapride; Constipation; Defecation; Gastrointestinal motility; Gastrointestinal transit; Hypomotility; Laxatives; Prokinetics; Prucalopride; Quality of life; Serotonin; Stools

Indexed keywords

ANTHRAQUINONE DERIVATIVE; AQUAPORIN 3; BISACODYL; DIPHENYLMETHANE DERIVATIVE; DOCUSATE SODIUM; ELOBIXIBAT; ENEMA; GLYCEROL; LACTOSE; LACTULOSE; LAXATIVE; LINACLOTIDE; LIQUID PARAFFIN; LUBIPROSTONE; MACROGOL; MAGNESIUM HYDROXIDE; MAGNESIUM SULFATE; OSMOTIC AGENT; PHOSPHATE; PICOSULFATE SODIUM; PROKINETIC AGENT; PROSTAGLANDIN E2; PRUCALOPRIDE; RHEIN ANTHRONE; SENNOSIDE; SENNOSIDE A; SENNOSIDE B; SORBITOL; TEGASEROD; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABDOMINAL CRAMP; ABDOMINAL DISTENSION; ABDOMINAL PAIN; ABORTION; ASPIRATION PNEUMONIA; BLOATING; CARDIOVASCULAR DISEASE; CHEMICAL COMPOSITION; CHRONIC CONSTIPATION; CONSTIPATION; DIARRHEA; DRUG BIOAVAILABILITY; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; ELECTROLYTE DISTURBANCE; FETOTOXICITY; HEADACHE; HUMAN; HYPERMAGNESEMIA; HYPERPHOSPHATEMIA; IRRITABLE COLON; LACTATION DISORDER; MALABSORPTION; NAUSEA; NONHUMAN; PHARMACODYNAMICS; PHARMACOKINETICS; QT PROLONGATION; REVIEW; SUPPOSITORY; SYSTEMATIC REVIEW; TERATOGENICITY; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT;

ALPROSTADIL; ANTHRAQUINONES; BENZOFURANS; BISACODYL; CHRONIC DISEASE; CONSTIPATION; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; LAXATIVES; PEPTIDES; POLYETHYLENE GLYCOLS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; TREATMENT OUTCOME;

EID: 84875162338     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2013.773972     Document Type: Review

References (111)

1. Müller-Lissner SA. What has happened to the cathartic colon? Gut 1996;39:486-8
2. Attar A, Lémann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999;44:226-30
3. Kamm MA, Mueller-Lissner SA, Wald A, et al. Stimulant laxatives are effective in chronic constipation: multi-center, 4-week, double-blind, randomized, placebo-controlled trial of bisacodyl. Clin Gastroenterol Hepatol 2011;9:577-83
4. Ruidisch MH, Hutt H-J, Konig E. Laxanzien-Langzeittherapie mit Bisacodyl. Wirksamkeit und Verträglichkeit bei Patienten mit Rü ckenmarkverletzungen. A ̈ rztliche Forschung 1994;41:3-8
5. Müller-Lissner S, Kamm MA, Wald A, et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of sodium picosulfate in patients with chronic constipation. Am J Gastroenterol 2010;105:897-903
6. Heiny BM. Langzeitbehandlung mit einem pflanzlichen Laxativum. Serumelektrolyte und Säurenbasenhaushalt. A ̈ rztliche Praxis 1976;28:563-4
7. Rosprich G. Dauerbehandlung mit Laxantien. Therapiewoche 1980;30:5836-7
8. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther 2007;25:1351-61
9. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008;103:170-7
10. Lembo AJ, Johanson JF, Parkman HP, et al. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci 2011;56:2639-45
11. Lee N, Wald A. The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide. Expert Opin Drug Metab Toxicol 2011;7:651-9
12. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358:2344-54
13. Quigley EM, Vandeplassche L, Kerstens R, Ausma J. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation-a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009;29:315-28
14. Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009;58:357-65
15. Kinnunen O, Salokannel J. Constipation in the elderly long-stay patients: its treatment by magnesium hydroxide and bulk laxative. Ann Clin Res 1987;19:321-3
16. Aydogan T, Kanbay M, Uz B, et al. Fatal hyperphosphatemia secondary to a phospho-soda bowel preparation in a geriatric patient with normal renal function. J Clin Gastroenterol 2006;40:177
17. Bengtsson M, Ohlsson B. Retrospective study of long-term treatment with sodium picosulfate. Eur J Gastroenterol Hepatol 2004;16:433-4
18. Preston DM, Lennard-Jones JE. Severe chronic constipation of young women: 'idiopathic slow transit constipation'. Gut 1986;27:41-8
19. Kinnunen O, Salokannel J. Comparison of the effects of magnesium hydroxide and a bulk laxative on lipids, carbohydrates, vitamins A and E, and minerals in geriatric hospital patients in the treatment of constipation. J Int Med Res 1989;17:442-54
20. Tatsuki M, Miyazawa R, Tomomasa T, et al. Serum magnesium concentration in children with functional constipation treated with magnesium oxide. World J Gastroenterol 2011;17:779-83
21. Tatsumi H, Masuda Y, Imaizumi H, et al. A case of cardiopulmonary arrest caused by laxatives-induced hypermagnesemia in a patient with anorexia nervosa and chronic renal failure. J Anesth 2011;25:935-8
22. Chen H, Li X, Ge Z. Comparative study on two colonic bowel preparations for patients with chronic constipation. Scand J Gastroenterol 2009;44:375-9
23. Medoff J, Katz S, Malik P, et al. Openlabel, dose-ranging pilot study of 4 weeks of low-dose therapy with sodium phosphate tablets in chronically constipated adults. Clin Ther 2004;26:1479-91
24. Kinnunen O, Winblad I, Koistinen P, Solokannel J. Safety and efficacy of a bulk-laxative containing senna versus lactulose in the treatment of chronic constipation in geriatric patients. Pharmacology 1993;47(Suppl 1):253-5
25. Wesselius-De Casparis A, Braadbaart S, et al. Treatment of chronic constipation with lactulose syrup: results of a double-blind study. Gut 1968;9:84-6
26. Lederle FA, Busch DL, Mattox KM, et al. Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose. Am J Med 1990;89:597-601
27. Kleessen B, Sykura B, Zunft HJ, Blaut M. Effects of inulin and lactose on fecal microflora, microbial activity, and bowel habit in elderly constipated persons. Am J Clin Nutr 1997;65(5):1397-402
28. Lee-Robichaud H, Thomas K, Morgan J, Nelson RL. Lactulose versus polyethylene glycol for chronic constipation. Cochrane Database Syst Rev 2010(7):CD007570
29. van der Spoel JI, Oudemans-van Straaten HM, et al. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med 2007;35:2726-31
30. DiPiro JT, Michael KA, Clark BA, et al. Absorption of polyethylene glycol after administration of a PEG-electrolyte lavage solution. Clin Pharmacol 1986;5:153-5
31. Rothfuss KS, Bode JC, Stange EF, Parlesak A. Urinary excretion of polyethylene glycol 3350 during colonoscopy preparation. Z Gastroenterol 2006;44:167-72
32. Corazziari E, Badiali D, Bazzocchi G, et al. Long term efficacy, safety, and tolerability of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation. Gut 2000;46:522-6
33. Di Palma JA, Cleveland MV, McGowan J, et al. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007;102:1436-41
34. Di Palma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation. Am J Gastroenterol 2007;102:1964-71
35. Mamtani R, Cimino JA, Cooperman JM. Comparison of total costs of administering calcium polycarbophil and psyllium mucilloid in an institutional setting. Clin Ther 1990;12:22-4
36. Hamilton JW, Wagner J, Burdick BB, Bass P. Clinical evaluation of methylcellulose as a bulk laxative. Dig Dis Sci 1988;33:993-8
37. Szojda MM, Mulder CJ, Felt-Bersma RJ. Differences in taste between two polyethylene glycol preparations. J Gastrointest Liver Dis 2007;16:379-81
38. De Maeyer JH, Lefebvre RA, Schuurkes JA. 5-HT4 receptor agonists: similar but not the same. Neurogastroenterol Motil 2008;20:99-112
39. Briejer MR, Bosmans JP, Van Daele P, et al. The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol 2001;423:71-83
40. Briejer MR, Prins NH, Schuurkes JA. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil 2001;13:465-72
41. Müller-Lissner S, Rykx A, Kerstens R, Vandeplassche L. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil 2010;22:991-8
42. Potet F, Bouyssou T, Escande D, Baro I. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-a-gogo K(+) channel. J Pharmacol Exp Ther 2001;299:1007-12
43. Boyce M, Kerstens R, Beyens G, et al. Cardiovascular safety of prucalopride in healthy subjects: results from two randomized, double-blind, placebo-controlled, cross-over trials [abstract]. Gastroenterology 2009;136(Suppl 1):T1265
44. Camilleri M, Beyens G, Kerstens R, et al. Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study. Neurogastroenterol Motil 2009;21:1256-e117
45. Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointes Liver Physiol 2006;290:G942-7
46. Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. Am J Physiol Cell Physiol 2004;287:C1178-83
47. Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA. Physiological functions of ClC Cl-channels gleaned from human genetic disease and mouse models. Annu Rev Physiol 2005;67:779-807
48. Ueno R, Osama H, Habe T, et al. Oral spi-0211 increases intestinal fluid secretion and chloride concentration without altering serum electrolyte levels (abstract). Gastroenterology 2004;126:A-100
49. Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci 2010;55:1090-7
50. Castro J, Martin C, Hughes PA, et al. A novel role of cyclic GMP in colonic sensory neurotransmission in healthy and TNBS-treated mice. Gastroenterology 2011;140:S-538
51. Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 2010;8:19-20
52. Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil 2010;22:312-22
53. Johnston JM, Kurtz CB, Drossman DA, et al. Pilot study on the effect of linaclotide in patients with chronic constipation. Am J Gastroenterol 2009;104:125-32
54. Lembo AJ, Kurtz CB, Macdougall JE, et al. Efficacy of linaclotide for patients with chronic constipation. Gastroenterology 2010;138:886-95
55. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011;365:527-36
56. Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation- predominant irritable bowel syndrome. Gastroenterology 2007;133:761-8
57. Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010;139:1877-86
58. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107:1702-12
59. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107:1714-24
60. Hardcastle JD, Mann CV. Study of large bowel peristalsis. Gut 1968;9:512-20
61. Hardcastle JD, Wilkins JL. The action of sennosides and related compounds on human colon and rectum. Gut 1970;11:1038-42
62. Materia E, Corraziari E, Bausano G, et al. Effect of bisacodyl on motor activity of sigmoid colon. Ital J Gastroenterol 1988;20:246-9
63. Rodriguez L, Siddiqui A, Nurko S. Internal anal sphincter relaxation associated with bisacodyl-induced colonic high amplitude propagating contractions in children with constipation: a colo-anal reflex? Neurogastroenterol Motil 2012;24:1023-e545
64. Binder HJ, Donowitz M. A new look at laxative action. Gastroenterology 1975;69:1001-5
65. Ewe K, Holker B. The effect of a diphenolic laxative (Bisacodyl) on waterand electrolyte transport in the human colon. Klin Wochenschr 1974;52:827-33
66. Ikarashi N, Baba K, Ushiki T, et al. The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE2 secretion from macrophages. Am J Physiol Gastrointest Liver Physiol 2011;301:G887-95
67. Lemli M. Metabolism of sennosides-an overview. Pharmacology 1988;36(Suppl 1):126-8
68. Marlett JA, Li BUK, Patrow CJ, Bass P. Comparative laxation of psyllium with and without senna in an ambulatory constipated population. Am J Gastroenterol 1987;82:333-7
69. Passmore AP, Wilson-Davies K, Stoker C, Scott ME. Chronic constipation in long-stay elderly patients: a comparison of lactulose and a senna-fibre combination. BMJ 1993;307:769-71
70. Kinnunen O, Salokannel J. The carry-over effect on the bowel habit in elderly long-term patients of long-term bulk-forming products containing stimulant laxative. Acta Med Scand 1987;222:477-9
71. Maclennan WJ, Pooler AF. A comparison of sodium picosulphate with standardized senna in geriatric patients. Curr Med Res 1975;2:641-7
72. Willems M, van Buuren HR, de Krijger R. Anthranoid self-medication causing rapid development of melanosis coli. Neth J Med 2003;61:22-4
73. Speare GS. Melanosis coli. Experimental observations on its production and elimination in twenty-tree cases. Am J Surg 1951;82:631-7
74. Ghadially FN, Parry EW. An electron-microscope and histochemical study of melanosis coli. J Path Bact 1966;92:313-17
75. Scott RS. Management of constipation in obstetrics: a clinical report on 592 cases. Western Med 1965;6:342-4
76. Wager HP, Melosh WD. The management of constipation in pregnancy. Quart Rev Surg 1958;15:30-4
77. Heidemann A, Miltenburger HG, Mengs U. The genotoxicity status of senna. Pharmacology 1993;47(Suppl 1):178-86
78. Cameron BD, Phillips MWA, Fenerty CA. Milk transfer of rhein in the rhesus monkey. Pharmacology 1988;36:221-5
79. Faber P, Strenge-Hesse A. Relevance of rhein excretion into breast milk. Pharmacology 1988;36(Suppl 1):212-20
80. Werthmann MW Jr, Krees S. Quantitative excretion of senokot in human breast milk. Med Am Dist Columbia 1973;42:4-5
81. Roth W. Pharmakokinetik und laxierende Wirkung von Bisacodyl nach Gabe verschiedener Zubereitungsformen. Arzneim Forsch Drug Res 1988;38:570-4
82. Kienzle-Horn S, Vix JM, Schuijt C, et al. Efficacy and safety of bisacodyl in the acute treatment of constipation: a double-blind, randomized, placebo-controlled study. Aliment Pharmacol Ther 2006;23:1479-88
83. Kienzle-Horn S, Vix JM, Schuijt C, et al. Comparison of bisacodyl and sodium picosulfate in the treatment of chronic constipation. Curr Med Res Opin 2007;23:891-9
84. Wulkow R, Vix JM, Schuijt C, et al. Randomised, placebo-controlled, double-blind study to investigate the efficacy and safety of the acute use of sodium picosulphate in patients with chronic constipation. Int J Clin Pract 2007;61:944-50
85. Nishimura M, Kast A, Tsunenari Y. Reproduction studies of sodium picosulphate. Pharmacometrics 1976;12:67-78
86. Friedrich C, Richter E, Trommeshauser D, et al. Lack of excretion of the active moiety of bisacodyl and sodium picosulfate into human breast milk: an open-label, parallel group, multiple dose study in healthy lactating women. Drug Metab Pharmacokinet 2011;26:458-64
87. Hofmann AF, Poley JR. Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection. I. Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology 1972;62:918-34
88. Mekjian HS, Phillips SF, Hofmann AF. Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man. J Clin Invest 1971;50:1569-77
89. Coremans G, Tack J, Vantrappen G, et al. Is the irritable bowel really irritable? Ital J Gastroenterol 1991;23(8 Suppl 1):39-40
90. Chey WD, Camilleri M, Chang L, et al. A randomized placebo-controlled phase IIb trial of A3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am J Gastroenterol 2011;106:1803-12
91. Simren M, Bajor A, Gillberg PG, et al. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation. Aliment Pharmacol Ther 2011;34:41-50
92. Wong BS, Camilleri M, McKinzie S, et al. Effects of A3309, an ileal bile acid transporter inhibitor, on colonic transit and symptoms in females with functional constipation. Am J Gastroenterol 2011;106:2154-64
93. Rafati M, Karami H, Salehifar E, Karimzadeh A. Clinical efficacy and safety of polyethylene glycol 3350 versus liquid paraffin in the treatment of pediatric functional constipation. Daru 2011;19:154-8
94. Urganci N, Akyildiz B, Polat TB. A comparative study: the efficacy of liquid paraffin and lactulose in management of chronic functional constipation. Pediatr Int 2005;47:15-19
95. Gondouin A, Manzoni P, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J 1996;9:1463-9
96. Hawley PH, Byeon JJ. A comparison of sennosides-based bowel protocols with and without docusate in hospitalized patients with cancer. J Palliat Med 2008;11:575-81
97. McRorie JW, Daggy BP, Morel JG, et al. Psyllium is superior to docusate sodium for treatment of chronic constipation. Aliment Pharmacol Ther 1998;12:491-7
98. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013;45(1):2-13
99. McRorie J, Pepple S, Rudolph C. Effects of fiber laxatives and calcium docusate on regional water content and viscosity of digesta in the large intestine of the pig. Dig Dis Sci 1998;43:738-45
100. Ashton MR, Sutton D, Nielsen M. Severe magnesium toxicity after magnesium sulphate enema in a chronically constipated child. BMJ 1990;300(6723):541
101. Hsu HJ, Wu MS. Extreme hyperphosphatemia and hypocalcemic coma associated with phosphate enema. Intern Med 2008;47:643-6
102. Mendoza J, Legido J, Rubio S, Gisbert JP. Systematic review: the adverse effects of sodium phosphate enema. Aliment Pharmacol Ther 2007;26:9-20
103. Farahmand F, Eftekhari K, Modarresi V, et al. Comparing oral route paraffin oil versus rectal route for disimpaction in children with chronic constipation; a randomized control trial. Iran J Pediatr 2010;20:291-6
104. Flig E, Hermann TW, Zabel M. Is bisacodyl absorbed at all from suppositories in man? Int J Pharm 2000;196:11-20
105. Shafe ACE, Lee S, Dalrymple JSO, Whorwell PJ. The LUCK study: laxative usage in patients with GP-diagnosed constipation in the UK, within the general population and in pregnancy. An epidemiological study using the General Practice Research Database (GPRD). Therap Adv Gastroenterol 2011;4:343-63
106. Underwood D, Makar RR, Gidwani AL, et al. A prospective randomized single blind trial of Fleet phosphate enema versus glycerin suppositories as preparation for flexible sigmoidoscopy. Ir J Med Sci 2010;179:113-18
107. Müller-Lissner SA, Kamm MA, Scarpignato C, Wald A. Myths and misconceptions about chronic constipation. Am J Gastroenterol 2005;100:232-42
108. Müller-Lissner S, Pehl C. Laxantiengebrauch und Zufriedenheit chronisch obstipierter Frauen-eine Umfrage bei Patientinnen und Gastroenterologen in Deutschland. Z Gastroenterol 2012;50:573-7
109. Müller-Lissner S, Tack J, Feng Y, et al. Levels of satisfaction with current chronic constipation treatment options in Europe-an internet survey. Aliment Pharmacol Ther 2012;doi: 10.1111/apt.12124; Epub ahead of print
110. Tytgat GN, Heading RC, Müller-Lissner S, et al. Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. Aliment Pharmacol Ther 2003;18:291-301
111. Anonymous. Prucalopride. In chronic constipation: poorly documented risks. Prescrire Int 2011;20:117-20