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Home , Loperamide, Racecadotril, Thiorphan

Drug Therapy

Racecadotril bond developed from research into the structure-activity relationships of the molecule. is Jitender Nagpal rapidly converted to which Sidhartha Gogia interacts specifically with the active site of (endogenous enkephalinase to produce potent blockade of ) act as neurotransmitters along the the enzyme preventing inactivation of entire digestive tract where they mediate endogenous peptides (enkephalins) intestinal absorption without affecting released by submucosal and myenteric intestinal transit time or motility(1). They are neurons. The encephalins in turn mediate short-lived peptides rapidly cleaved by their effect through delta receptor activa- 2 membrane peptidases: an enkephalinase tion that induces a selective increase in and a carboxypeptidase. Enkephalinase is chloride absorption by inhibiting adenylate abundant in the and cyclase(1). accounts for over 85% hydrolysis of Pharmacodynamics methionine and leucine enkephalins provid- ing a potentially novel target for the treatment Inhibition of encephalinase activity of acute watery . Racecadotril or Preclinical studies have documented acetorphan (derived from thiorphan) through selective inhibition of enkephalinase activity inhibition of enkephalinase reinforces the by racecadotril in various animal models. physiological activity of endogenous Intravenous administration of 1 mg/kg enkephalins and therefore shows intestinal racecadotril in mice significantly reduced antisecretory activity. The Drug Controller enkephalinase activity in striatal membrane General of India approved it as an anti- fractions for approximately 8 hrs(3). Also, diarrheal in October 2001(2). The drug has enkephalinase activity in hypothalamic not yet been approved by the FDA (Food and membranes was reduced by 55, 68 and 70% Drug Administration). one hour after intraperitoneal administration Structure and mechanism of action of racecadotril 10, 25 and 50 mg/kg(4). Similarly, in a double blind placebo- Racecadotril [acetorphan: N-[(R,S)-3- controlled cross-over trial on 8 human volun- acetylmercapto-2benzylpropanoyl]-, teers enkephalinase activity was reduced by benzyl ester, is a lipophilic derivative of up to 89 % using a 300 mg dose(5). Thiorphan. It is a dipeptide with a single amide Efficacy in experimental models of diarrhea From the Department of Pediatrics, Maulana Azad In a randomized double-blind study on 6 Medical College, New Delhi 110 002, India. adult volunteers with castor oil-induced Correspondence to Dr. Jitender Nagpal, diarrhea, racecadotril significantly reduced Department of Pediatrics, Maulana Azad Medical College and associated Lok Nayak stool weight during the following 24 h period Hospital, New Delhi 110 002, India. by 37% and stool number by 49% (p = 0.009 E-mail: [email protected] and p < 0.002, respectively) compared with

INDIAN PEDIATRICS 1218 VOLUME 41__ D ECEMBER 17, 2004 DRUG THERAPY placebo(6). Similarly in a model employing In children segmental perfusion of the human proximal jejunum, cholera toxin was used to induce In a well designed double blind intestinal secretion through an intestinal randomized control trial in Peru on 3 to 35 perfusion technique. Acetorphan had no months old children, racecadotril and influence on basal water and rehydration were compared with rehydration absorption (133 vs. 140 mL/30 cm × h). In a alone in 166 boys with acute non-bloody control group with cholera toxin alone, diarrhea without severe dehydration or significant water secretion was induced serious concomitant illness(9). Significant (131 mL/30 cm × h). Acetorphan completely reductions were documented in 48 h stool prevented this secretion by leaving an output (92 ± 12g/kg vs. 170 ± 15g/kg; absorption rate of 27 mL/30 cm × h. Intestinal p <0.001), mean total stool output (157 ± 27 electrolyte transport was also significantly g/kg vs. 331 ± 37 g/kg; p <0.001) and median changed towards absorption by acetorphan duration of diarrhea (28 vs. 52 h; p <0.001). (7). Further, in a study evaluating the oro- The overall five-day cure rates were 84 caecal and colonic transit times there was no percent in the racecadotril group and 66% in significant modification in transit time linked the placebo group. Seventy three (44%) to acetorphan treatment(8). children tested positive for while bacterial pathogens were identified in 53 (32%) children. The results on stratified After oral administration, racecadotril is analysis showed the drug to be equally rapidly absorbed and quickly metabolized to efficacious for rotavirus positive and negative its thiorphan, which in turn children excepting that the mean stool output mediates all further actions. The activity on were higher in general for the rotavirus group plasmatic enkephalinase appears 30 min after and the diarrhea tended to last longer (72 h vs. the administration. The peak plasma 52 h). Cezard, et al.(11) documented similar concentration of thiorphan is reached 60 min results with the 24 hour stool output in the after administration of a single oral dose of racecadotril group being 65% of that of racecadotril. The biological half-life of placebo. The drug was equally efficacious in + + enkephalinase activity is 3 h. The pharmaco- rotaviral diarrhea. Also, a Na /K ratio of less kinetic parameters of repeated doses of than 1 in the urine was found in 24.1% of racecadotril are similar on days 1 and 7 as patients receiving racecadotril and 53.3% of those observed for a single oral dose. those receiving placebo (P = 0.01), suggesting greater re-hydration with raceca-dotril. Therapeutic trials Cojocaru, et al(9) also documented similar The clinical efficacy of racecadotril in findings using number of stools and recovery diarrhea in humans has been under time as outcome parameters. investigation since 1992 when first such In adults reports appeared(6). The drug has since been evaluated in children(9,11,12), adults The results of efficacy trials conducted in (6,10,13), cholera(7,18), chronic diarrhea in adults are essentially similar to those in HIV patients(19) and in chemotherapy children with a study from Brazil docu- induced diarrhea(20) in developing and menting a 24 h difference in recovery time developed countries (Table I). using racecadotril(10).

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TABLE I– Clinical Efficacy of Racecadotril

Author Design; Evidence Subjects Study Groups Outcome Variables Results and Conclusions Year, Country Funding gradeΨ Cojocaru B et al RCT 166 children aged Alternate child rehydration + Number of medical examinations in 7 days Racecadotril group had a significant lower number of stools (p < 0.001), faster recovery 2002, France(9) NA - three mo to three y drug or racecadotril alone Number of stools during the first 48 h, (p < 10(-9)), needed less additional ED visits for the same episode (p < 0.05) with no Duration of diarrhea and weight on day 7 difference for the weight-gain on day 7 Cezard JP et al RCT 172 children aged 3 Two groups- Racecadotril Stool output in 24 h, Recovery time, During the first 48 hours of treatment, patients receiving racecadotril had a significantly 1- 2001,France(11) IC* mo to 4 y (n=89) vs. placebo (n=83) ORS use and Na/K ratio in urine lower stool output Salazar-Lindo E RCT 135 boys aged 3 to Two groups- study (n=68) 48 h stool output, The mean (+/-SE) 48-hour stool output was 46% less in racecadotril group (P<0.001), et al FD# 1- 35 mo with watery Placebo (n=67) Total stool output, Duration of diarrhea, Total The total stool output, duration of diarrhea & intake of ORS was significantly less) in 2000, Peru(12) diarrhea intake of ORS the racecadotril group (P<0.001) Moraes E et al RCT-double 336 adults Two groups-racecadotril Recovery time In mild cases a 24-hour difference (76 hours for racecadotril vs. 52 hours) between the 2001, Brazil(10) blind-NS? (n=175) vs. Saccharomyces Associated symtoms like abdominal pain, two groups (p=0.017) and in severe cases the difference between the groups was 17 1+ Multicentre boulardi (161) *3 days distention, nausea and anorexia hours (p=0.016). No difference in associated symtoms was observed in the in the two groups Hamza H et al RCT-double 70 adults Two groups- Racecadotril vs. Stool weight and number Significant (P = 0.025) decrease in stool weight during the first day of treatment, - 1999,Tunisia(13) blind/ NA placebo significantly fewer stools after 1 day of treatment (p = 0.027). Baumer P et al RCT- double 194 with sev. Ac. Two groups- Racecadotril Duration of diarrhea & treatment, Frequency The duration of diarrhea and treatment were diminished; (ii) withdrawal from study 0 vs. 1992, France(6) blind / IC* 1- diarrhea (>5 stools (n=96) vs. placebo(n=98) of other symptoms, Withdrawal from study 5 (iii) the frequency of symptoms with diarrhea after two weeks was nearly halved; /d) Baumer P et al Experimental- 6 human volunteers Racecadotril and placebo one Mean stool weight Mean stool weight 672 ± 76 g/kg vs. 426 ± 83 g/kg(racecadotril)(p<0.01). 1992, France (6) double 2+ week apart in cross over Total number of stools Number of stools = 3.7 ± 0.3 vs 1.8 ± 0.2 (racecadotrial) (p=0.002) blind/IC* format Racecadotril vs. Prado D et al RCT-single 945 adults Two groups- Racecadotril Duration of diarrhea, occurrence and duration Racecadotril produced greater reduction in abdominal pain and distension than blind (n=473) vs. loperamide of abdominal pain, distension, other associated loperamide (P = 0.024 and 0.03, respectively). Duration of was 2002 # 1- Guatemala(14) FD (n=472) signs and symptoms shorter with racecadotril (P = 0.0001) was less frequent (P = 0.001). Multicentre 52 children aged 2 to Two groups- Racecadotril vs. Number of stools Both the groups passed a similar number of stools before recovery,duration of diarrhea Turck D et al RCT 10 y loperamide Duration of diarrhea similar in both groups. Incidence of adverse events was lower with racecadotril (11.5% 1999 - NA vs. 22%), and more patients on loperamide had constipation (58% vs. 36.5%; P = 0.03) France(15) Vetel JM et al Multicentre 157 adults with acute Two groups- Racecadotril vs. Number of stools and duration of diarrhea Both groups passed similar numbers of stools before recovery and the duration of 1999 RCT-double - diarrhea loperamide diarrhea was similar in both groups. However, more patients on loperamide reported d France(16) blind/ NA constipation during treatment (18.7% vs. 9.8%) Roge J et al RCT-double- 69 adults with acute Two groups- Racecadotril Recovery Time Diarrhea resolved in both groups in nearly 2 days. With racecadotril abdominal 1993 blind 1- diarrhea of infectious (n=37) vs. loperamide (n=32) Associated symptoms like distention, distension vanished significantly more rapidly, and reactive constipation was less (8% France(17) IC* origin abdominal pain and copnstipation versus 31% with loperamide Racecadotril in Cholera Alam NH et al RCT-double 110 male adult Two groups –placebo (n=56) Stool output, ORS intake, Unscheduled Racecadotril safe but no additional benefit in severe cholera in adults 2003 blind 1- cholera patients Study group (n=54) intravenous fluid requirements, Duration of Bangladesh(18) FD# diarrhea Hinterleitner TA Experimental Ten human Two groups-Control group- Intestinal secretion rate by jejunal perfusion In a control group with cholera toxin alone, significant water secretion was induced (131 et al, 1987 Case-control volunteers cholera toxin alone technique mL/30 cm × h). Racecadotril completely prevented this secretion by leaving an 2+ Austria(7) NA Study group-toxin +acetorphan absorption rate of 27 mL/30 cm × h. Intestinal electrolyte transport was also Cholera toxin intra-jejunal significantly changed towards absorption by acetorphan. HIV associated chronic diarrhea Beaugerie L et al Open RCT- 13 AIDS in- 13 patients were given both Response was defined as a reduction by at Mean daily stool number was reduced to 4.6 +/- 1.1 with racecadotril (P less than or 1996 crossover patients with drugs in random order during least one-third of both daily stool number and equal to 0.05) but was 5.6 +/- 1.2 with (NS). Daily lipid output in faeces was - France(19) NA refractory diarrhea two 1-week periods weight. reduced non-significantly with racecadotril (11.5 +/- 2.3 g) but was nearly doubled with fro 35 ± 8 w octreotide (33.7 +/- 12.0 g). * IC-conflict of interest (probably at least one of the authors was directly working under a pharmaceutical company manufacturing the drug # FD-funded by pharmaceutical company manufacturing the drug y Evidence grade (26) 1++ high quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias; 1+ well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias; 1- meta-analyses, systematic reviews, or RCTs with a high risk of bias; 2++ high quality systematic reviews of case control or cohort studies, high quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal; 2+ well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal; 2- case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal; 3 Non-analytical studies; 4 Expert opinion, NA- Not available; ß-NS-not specified in article

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In cholera mucosa for a longer time aiding reabsorption. However, µ receptor agonism can lead to The anti-secretory efficacy of racecadotril decreased peristalsis, dilatation of small in cholera was earlier demonstrated in bowel and colon and increased tone of the experimental studies conducted in rats(3), anal sphincter. The intestinal stasis induced dogs(21) and human volunteers(7) using by loperamide can promote bacterial cholera toxin induced diarrhea. However, overgrowth, paralytic , recently in a study on 110 adult patients with and blind loop syndrome; hence it is not severe cholera (stool output >5 mL/kg/hr in recommended for use in children below 2 last 4-6 hours) and severe dehydration, years of age. In contrast, racecadotril has been the patients were randomized to receive shown neither to affect the intestinal transit racecadotril or placebo based on an expected time(8) nor does it cause bacterial over- reduction of 33% in stool output(19). Both growth in (23). the groups were administered doxycycline with rehydration resulting in rapid resolution The efficacy of racecadotril has been within 24 h in a substantial proportion of compared with loperamide in children(15) cases. There was no significant difference in and adults(14,16,17). Both drugs have been total stool output (mean ± SD) (racecadotril found to have equivalent impact on the 315 ± 228 g/kg vs. placebo 280 ± 156 g/kg), duration of diarrhea in three studies from total ORS intake 390 ± 264 mL/kg vs. 369 ± France (15-17) one of which was conducted 240 mL/kg, or duration of diarrhea 35 ± 15 h in children(15). Also, racecadotril caused vs. 32 ± 13 h between the groups. It was earlier relief in abdominal pain and hypothesized by the authors that the failure distention. Moreover, the incidence of of racecadotril therapy was due to (a) adverse effects like constipation was higher inadequate absorption of the drug with with loperamide. This may imply that the lower than required tissue and/or serum drug is potentially as effective as loperamide concentrations of racecadotril due to short with the advantage of being free from the intestinal transit time; or (b) inadequate adverse effects that preclude the use of therapeutic effect to offset the impact of a loperamide as an anti-diarrheal agent in marked secretory process in severe cholera. children. Thus the role of racecadotril in cases of severe watery diarrhea entails further investigation. Investigational uses In chronic diarrhea The drug was shown to ameliorate -precipitated Racecadotril has not been evaluated in symptoms by peripheral administration of the chronic diarrhea except in cases of HIV in rats(24). associated diarrhea(19) and irinocetam(20) induced diarrhea where it has shown some Dosage, Route and Mode of Administration promise. In adults, adequate plasmatic levels are Racecadotril versus loperamide maintained with the administration of 100 mg of racecadotril every 8 h, and are not affected Loperamide is a µ , by repeated administration or in aged which increases the transit time of intestine. patients. The recommended dose in children Thus the fluid remains in contact with the is 1.5 mg/kg of racecadotril every 8 hourly.

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The drug is available as 10 mg, 30 mg sachet profile of the drug is limited. Thus, it may be and 100 mg capsule for oral administration. premature to recommend the drug for general use in acute diarrheas of children. Side effects and tolerability Contributors : SG was involved with the review of The frequency and type of adverse events literature and drafting of the manusript. JN reviewed showed no significant differences from those the literature, finalized the draft and will act as occurring in placebo-treated patients in most guarantor for the paper of the efficacy trials(6,12). Headache and Funding: None. hypokalemia have been observed as probable Competing interests: None stated. side effects of racecadotril administration in one study each, warranting observation in REFERENCES future. Experiments have shown that 1. M J G Farthing. Novel targets for the control racecadotril does not promote bacterial of secretory diarrhoea. Gut 2002; 50: 315- overgrowth in the small intestine(23). The 318. drug lacks any potential for neurotoxicity, 2. List of Drugs approved during 1994-2004. and radiolabelled studies have demonstrated Available from URL http://cdsco.nic.in/ that the drug does not enter the brain after oral html/DRUGSAPRVD.htm. Accessed on 5/ administration(22). No potential for abuse or 10/2004. has been seen. 3. Lecomte JM, Costentin J, Vlaiculescu A, Chaillet P, Marcais-Collado H, Llorens- However, in a study conducted on mouse Cortes C, Leboyer M, Schwartz JC. bone marrow a decrease in macrophagic Pharmacological properties of acetorphan, differentiation with an increase in granu- a parenterally active “enkephalinase” locytic differentiation was documented(25). inhibitor. J Pharmacol Exp Ther 1986; 237: The implications of this if any in humans have 937-944. not been evaluated. No studies were found on 4. Lecomte JM, Costentin J, Vlaiculescu A, et Medline search specifically directed towards al. Pharmacological properties of acetor- the uncommon and unsolicited adverse phan, a parenterally active “enkepha-linase” inhibitor. J Pharmacol Exp Ther 1986; 237: effects. 937-944. To conclude the drug is an antisecretory 5. Matheson AJ, Nobel S. Racecadotril. Drugs agent based on the principle of enkephalinase 2000; 59: 829-835. inhibition. Clinical trials on the role of 6. Baumer P, Danquechin Dorval E, Bertrand J, racecadotril in diarrrhea published to date Vetel JM, Schwartz JC, Lecomte JM. Effects suggest that the drug has efficacy in reducing of acetorphan, an enkephalinase inhibitor, the recovery time and total stool output. on experimental and acute diarrhoea. Gut However many of the trials quoted have been 1992; 33: 753-758. funded by companies manufacturing the 7. Hinterleitner TA, Petritsch W, Dimsity G, drug enhancing the possibility of bias. The Berard H, Lecomte JM, Krejs GJ. Acetorphan prevents cholera-toxin-induced water and efficacy of the drug remains to be ascertained electrolyte secretion in the human jejunum. in South Asian countries where the etiological Eur J Gastroenterol Hepatol 1997; 9: 887- spectrum as well as the underlying nutritional 891. status (including that of micronutrients like 8. Bergmann JF, Chaussade S, Couturier D, Zn) of the children may differ from elsewhere. Baumer P, Schwartz JC, Lecomte JM. Information related to the adverse effect Effects of acetorphan, an

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nase inhibitor acetorphan. Psychopharma- culture of mouse bone marrow. Biomed cology (Berl) 1988; 94: 540-544. Pharmacother 1995; 49: 375-380. 25. Krizanac-Bengez L, Boranic M. Enke- 26. Harbour R and Miller J. A new system for phalinase-blocking agent thiorphan affects grading recommendations in evidence cell growth and differentiation in long term based guidelines. BMJ 2001; 323; 334-336.

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