母乳營養的最新進展 - tyhma.org.tw

母乳營養的最新進展 - tyhma.org.tw

Racecadotril Racecadotril

Distribution of causes of death among children aged below 5 years and within the neonatal period, 2004 Noncommunic Injuries able Diseases (Postneonatal), (Postneonatal), 4% 4% Other Infectious and Parasitic Diseases, 9% Neonatal Deaths, 37% HIV/AIDS, 2% Measles, 4% Malaria, 7% Diarrhoeal Diseases

(Postneonatal), 16% Acute Respiratory Infections (Postneonatal) , 17% 5. WHO Web site. http://www.who.int/mediacentre/factsheets/fs330/en/index.html. Accessed 3 March 2012. 11. The World Health Organization. The Global Burden of Disease: 2004 update. 2008. About 1.7 to 5 billion cases of diarrhea occur per year*** 2 It is most common in developing countries were young children get diarrhea on average three times a year. Worldwide, as of 2012, it is the second most common cause of death in children less than five (0.76 million or 11%)..sup. 3 Frequent episodes of diarrhea are also a common cause of malnutrition and the most common cause in those less than five years of age. Other long term problems that can result include poor physical and intellectual development. 2 See Diarrhoea: why children are still dying and what can be done, The United Nations Children's Fund, World Health Organization, 2009.3 See Diarrhoeal Disease

Fact Sheet N.sup.o 330, World Health Organization, April 2013. Segment Prevalence/Burdena Developing world 2.5 million deaths/ year In USA 200 to 300 million new cases in US annually with a heath expenditure of 23 million dollars/year Infants / children (<5 years) ~1.5 billion episodes and 3 million deaths /year In Europe (in children <3 years) 0.5 to 1.9 episodes/child/year

Elderly Associated with significant morbidity and quality of life 9.1 % prevalence rate (according to Rome criteria) Viral aetiology >70% of infectious diarrhoea: 600,000 to 800,000 deaths annually(Rota virus) Bacterial aetiology 1.5%-5.6% of cases Amoebic aetiology 50 million people resulting in 40 000 deaths per year (Entamoeba histolytica ) Travellers diarrhoea 30% to 40% of travellers visiting developing countries Drug-related

7% of drugs adverse effects manifest as diarrhoea The true prevalence is underestimated due to misdiagnosis and lack of medical or hospital attention sought by patients. a 1. 2. 3. 4. 5. 6. Baldi F. World J Gastroenterol. 2009;15(27):3341-3348. The global burden of disease 2004 update. The World Health Organization. 2008. Gottlieb T. BMJ. 2011;02:901. Mackell S. CID. 2005;41(8):s547-552. Guarino A. J Pediatr Gastroenterol Nutr. 2008;46 (2):S81-122. Steffen.CID. 2005;41:S53640. Viral AGE with Evidence Based Diarrhea Disease Severity Chen SY et al, 2007

TABLE 1. Etiology and clinical manifestations of 257 pediatric patients with AGE Clinical data Age (months old) Symptoms Frequency of vomiting Duration of vomiting (days) Frequency of diarrhea Duration of diarrhea (days) Fever severity score Disease severity score Complications (n) Laboratory findings

Leukocyte count> 10,000/mm3 (n) CRPb (mg/l) Hospitalization days Rotavirus Norovirus Astrovirus Adenovirus Mixed infections Undetermined etiology (n=78) (n=21)

(n=7) (n=51) (n=53) (n=47) 24 (9-35) 24 (10.5-48) 21(12-33) 14 (12-24) 24 (12-36.25) 24 (9-38.75 3 (2-5) 2 (1-3)

0 (0-1) 2 (1-3) 3 (2-3.25) 2 (0-3) 2 (2-3) 2 (1-2) 0 (0-1.75) 2 (0-2) 3 (2-4) 2 (0-3) 4 (3-8) 4 (3-5)

3 (2.75-5.25) 3 (2-6.5) 4 (3.25-7.25) 6 (3-6) 4 (3-5) 4 (3-6) 4 (3-6) 4 (3-6) 3 (2-6) 4 (2-6) 1 (1-2) 11 (9-14) 0 (0-1) 8 (6-10) 1 (0.25-2.75)

10 (7.25-12.75) 1 (0-1) 11 (9-12) 1 (0-2) 12 (10-14) 1 (0-2) 10 (8-12) 28 7 2 18 23 12

8 3 25 23 18 2 (0-6.5) 6 (4-8) 2 (0.5-22.5) 4 (3.25-7.5) 6 (2-17.75) 5 (4-7) 2 (1-18) 5 (4-6.25) a

30 4.5 (1-22) 5 (4-6) 27 (2-60.25) 5 (4-7) a Median values and 25% (Q1) and 75% (Q3) quartiles are given as median (Q1-Q3). b CRP, C-reactive protein. Averagely, 10-30 times Diarrhea in an AGE Racecadotril

Passage of abnormally liquid or unformed stools at an increased frequency Stool weight >200 g/day Diarrhea is not: Frequent passage of formed stools Passage of loose, "pasty stools by breastfed babies 1. 2. 3. Camilleri M, et al. Harrison's Principles of Internal Medicine. 18th ed. USA: McGraw-Hill; 2012. 2008:308-319. Diarrhoeal disease. WHO Web site: http://www.who.int/mediacentre/factsheets/fs330/en/index.html. 2009. Hodges K, et al. Gut Microbes. 2010;1(1):4-21. Viral gastroenteritis Bacterial enteritis Extraintestinal infections Antibiotic-associated diarrhea Functional diarrhea

Lactase deficiency Osmotic diarrhea Secretory diarrhea Motility-related diarrhea Inflammatory diarrhea Secretory diarrhoea: mechanisms and emerging therapies 446457 published:(2015) a | Luminal and basolateral membrane transporters and intracellular signalling mechanisms are involved in intestinal fluid absorption and secretion by enterocytes Enkephalins

Delta Receptor c-AMP ATP Secretio n Absorption VIP ( ) Prostaglandins Enkephalins Enkephalinase Secretion 1. Schwartz JC. Int J Antimicrob Agents. 2000;14(1):75-79. Absorption

Toxic peptides from virus / bacteria Delta Receptor c-AMP ATP Enkephalins Absorption Enkephalinase Hypersecretion Diarrhea 1. 2.

Farthing MJ. J Gastroenterol Hepatol. 2000;15 Suppl:G38-G45. WHO Web site. http://whqlibdoc.who.int/publications/2005/9241593180.pdf. Accessed 3 March 2012. Racecadotril assess the degree of dehydration start rehydration using hypo-osmolar ORS continue breast feeding continue enteral feeding limit antibiotics to selected cases consider active medical treatment use zinc Scoring Systems- sinking in the fontan elle in infants

sudden tearles s eyes dry mouth little or no urine; the urine is dark yellow sudden weight loss fast, week pulse loss of elasticity or stretch iness of the skin Antimotility / Antiperistaltic drugs Adsorbents Probiotics Anti-Infective therapy Antiseretory agents Antimotility / Antiperistaltic drugs Adsorbents

Probiotics Anti-Infective therapy Antiseretory agents Loperamide: Overview Loperamide FDA warning Jun16 Current Pharmacological Therapy Antimotility / Antiperistaltic drugs Adsorbents Probiotics Anti-Infective therapy Antiseretory agents Adsorbents: Diosmectite (Smecta)a Smecta is a pharmaceutical clay Mode of Action Therapeutic Indications Possess mucosal coating property on

GIT Symptomatic treatment of acute diarrhoea along with ORS in infants, children . Interacts with mucosal glycoproteins Symptomatic treatment of acute diarrhoea in adults Increases resistance of mucosal gel Method of Administration Posology For diarrhoea Symptomatic treatment of chronic diarrhoea b

<1 years: 2 sachets/day for 3 days and then 1 packet per day After 1 year: 4 sachets/day for 3 days then 2 sachets per day. Adults: 3 sachet/day Orally with water or along with food either between or after meals based on indication Adsorbents have no proven practical value for the routine treatment of acute diarrhoea. (WHO guidelines) a In practice the daily dosage is recommended to be doubled at the beginning of treatment b

21. Khediri F, Mrad A, Azzouz M. Efficacy of diosmectite (smecta) in the treatment of acute watery diarrhoea in adults: a multicentre, randomized, double-blind, placebocontrolled, parallel group study. Gastroenterol Res Pract. 2012;2011:1-8. 32. Smectite [PI]. Hong Kong: Beaufour Ipsen; 2011. 33. Diosmectite [Rsum Des Caractristiques]. Boulogne Billancourt: Ipsen Pharma; 2011. 34. The treatment of diarrhoea: A manual for physicians and other senior health workers. WHO Web site. http://whqlibdoc.who.int/hq/2003/WHO_FCH_CAH_03.7.pdf. Accessed March 3, 2012. Current Pharmacological Therapy Antimotility / Antiperistaltic drugs Adsorbents Probiotics Anti-Infective therapy Antiseretory agents With a positive recommendations With a negative recommendations ESPGHAN guideline 2014 Lack of recommendation

Current Pharmacological Therapy Antimotility / Antiperistaltic drugs Adsorbents Probiotics / Prebiotics / Synbiotics Anti-Infective therapy Antiseretory agents Anti-infective Agents in Acute Diarrhea Cholera 1st choice Doxycycline Adults: 300 mg once or Tetracycline Adults: 500 mg 4 times a day x 3 days Alternatives Azithromycin or

Ciprofloxacin Shigellosis 1st choice Ciprofloxacin Children: 15 mg/kg 2 times a day x 3 days Adults: 500 mg 2 times a day x 3 days Alternative Pivmecillinam Children: 20 mg/kg 4 times a day x 5 days Adults: 400 mg 4 times a day x 5 days Ceftriaxone Children: 50-100 mg/kg once a day IM

x 2 to 5 day Amoebiasis Giardiasis Metronidazole Children: 10 kg/kg 3 times a day x 5 days* Adults: 750 mg 3 times a day x 5 days* Metronidazole Children: 5 mg/kg 3 times a day x 5 days Adults: 250 mg 3 times a day x 5 days

*10 days for severe disease 27. World gastroenterology organisation practice guideline: Acute diarrhoea. WGO Web site. http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/01_acute_diarrhoea.pdf. Accessed March 3, 2012. Campylobacter Clarithromycin Azithromycin Current Pharmacological Therapy Antimotility / Antiperistaltic drugs Adsorbents Probiotics / Prebiotics / Synbiotics Anti-Infective therapy Antiseretory agents Racecadotril (Hidrasec) Pharmacology Racecadotril

Racecadotril (peptidase inhibitor) thiorphan Hidrasec (racecadotril) Thiorphan Racecadotril Toxic peptides from virus / bacteria Delta Receptor

c-AMP ATP Enkephalins Hypersecretion Enkephalinase DIARRHEA 1. 2. Farthing MJ. J Gastroenterol Hepatol. 2000;15 Suppl:G38-G45. WHO Web site. http://whqlibdoc.who.int/publications/2005/9241593180.pdf. Accessed 3 March 2012. Defective Absorption of Fluids, electrolyte nutrients

Racecadotril (Hidrasec): Overview 1 BASELINE STATE 2 HYPERSECRETION 3 NORMALISATION enkephalin-enkephalinase balance enkephalin enkephalinase Toxins, peptides HIDRASEC/

TIORFAN ENKEPHALINASE INHIBITOR receptor Small intestine Normal secretion Hypersection Normal secretion Selective inhibitor of enkephalinase that decreases intestinal hyper secretion 1. Drugs in focus. Wolters Kluwer Health. 2009.

Racecadotril Watery Diarrhoea in Children 2000 Salazar et al., STUDY OBJECTIVE To study the safety and efficacy profile of racecadotril as an adjunct to ORS vs. placebo in children with acute diarrhoea Patients 68 STUDY DESIGN Randomised, double-blind, placebocontrolled comparison INCLUSION CRITERIA

Boys aged between 3 to 35 months of age Acute diarrhoea requiring hospitalisation 67 Total: 135 1. 1.5 mg/kg Racecadotril + ORS Salazar-Lindo et al. E. N Eng J Med. 2000;343463-7 Placebo + ORS Efficacy Results: Cezard et al., 2001 48 (P = 0.02) 35

100 80 30 70 25 P = 0.001 P = 0.05 6.9 hrs vs 36 hrs 6090 50 20 40

15 30 10 0 Placebo 20 Racecadotril 10 5 RacecadotrilPlacebo (n = 24) (n = 31) RacecadotrilPlacebo (n = 29) (n = 32)

Rotavirus Positive Rotavirus Negative 1. Probability of Unresolved Diarrhoea (%) Stool Output (g/hour) 40 Cezard JP et al. Gastroenterology. 2001;120:799-805 0 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 Duration of Diarrhoea (min) Efficacy and Tolerability of Racecadotril in Acute Diarrhoea in Children Cezard et al., 2001

STUDY OBJECTIVE To study the efficacy and tolerability of racecadotril as an adjunct to ORS in the treatment of severe diarrhoea in infants and children Patients 89 Multi centered randomised double-blind placebocontrolled 83

Total: 172 1. 1.5 mg/kg Racecadotril Cezard JP et al. Gastroenterology. 2001;120:799-805 Placebo : Salazar et al., 2000 1. Criteria Racecadotril Placebo Occurrence of adverse events

10% 7% Vomiting 51% 52% Salazar-Lindo et al. E. N Eng J Med. 2000;343463-7 Racecadotril for Childhood Gastroenteritis: Patient Data Meta-analysis Lehert P et al., 2011 OBJECTIVE To study the efficacy of racecadotril in infants and children with acute gastroenteritis compared to placebo from Individual Patient Raw Data (IPD) Meta-analysis of 9 RCTs (1384 randomised patients) Individual Patient raw Data of RCTs were used for analysis At least racecadotril and placebo were randomised in RCTs

Male and female, infants and children from 1month to 15 years old Outcomes - 48 . - 1. 2. Hidrasec: monograph [Summary of the Product Characteristics]. Maidenhead, UK: Abbott Laboratories Limited; 2011. Lehert P. et al., Dig Liver Dis. 2011; S43(9):707-713. Meta-analysis Results: Lehert P et al., 2011 Results Placebo Racecadotril 2.81 1.75

Responders (patients with duration of diarrhoea <2 days) RR=1.98 25.8% 50.3% Need for i.v. rehydration (3 studies on out-patients) P<0.05 12/37 4/37 Diarrhoea duration after inclusion (Median days) P<0.001 Reference: Lehert P. et al., Dig Liver Dis. 2011; S43(9):707-713. NTD $18950

Hidrasec & WGO Guidelines ESPGHAN/ESPID 2014 guidelines: Recommendations on Racecadotril Updated 2014 Racecadotril can be considered in the management of AGE1 Compared to placebo, racecadotril significantly reduced: duration of diarrhea stool output number of diarrheic stools Racecadotril exhibited a favorable safety profile, with no difference in the incidence of adverse events compared with placebo AGE, acute gastroenteritis; ESPGHAN, European Society for Pediatric Gastroenterology, Hepatology and Nutrition; ESPID, European Society of Pediatric Infectious Diseases; ORS, oral rehydration solution 1. Guarino et al. 2014;

Take home message (smecta, Kaolin, Pectin)- (Lacteol, Infloran)- Paralytic ileus Take home message Racecadotril (Hidrasec): (New Weapon for Diarrhea Control in Taiwan) ?

Weight-Based Dosing in Infants and Children Age 3-9 months 9-30 months 30 months9 years + 9 years Dose (mg TID) 10 20 30

60 1 x 10 mg sachet 2 x 10 mg 1 x 30 mg 2 x 30 mg Sachets / sachet sachets sachets infants 1.5 mg/kg, TID, 1-year-old: pc TID children ; 3-5 y/o, 1pcchildren TID Dose infants TID TID TID TID

1. Hidrasec: 10 mgare granules [Summary of the Product Characteristics]. Hidrasec granules contraindicated in patients with fructoseMaidenhead, intolerance, UK: Abbott Laboratories Limited; 2011. glucose malabsorption syndrome and saccharase-isomaltase deficiency 2. Hidrasec: 30 mg granules [Summary of the Product Characteristics]. Maidenhead, UK: Abbott Laboratories Limited; 2011. 3. Proposal for the inclusion of racecadotril in the WHO model list of essential medicines. http://archives.who.int/eml/expcom/children/Applications/racecadotril/ Proposal_racecadotril.pdf. Accessed 12 March 2012.

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