A STUDY ON RACECADOTRIL FOR ITS EFFICACY SAFETY AND COMPARISON WITH LOPERAMIDE

A STUDY ON RACECADOTRIL FOR ITS EFFICACY SAFETY AND COMPARISON WITH LOPERAMIDEM. V. NoushadHH, Sijo Pattam

National College of Pharmacy, Manassery, Calicut

Cite this: M. V. Noushad, Sijo Pattam "A STUDY ON RACECADOTRIL FOR ITS EFFICACY SAFETY AND COMPARISON WITH LOPERAMIDE", B. Pharm Projects and Review Articles, Vol. 1, pp. 1024-1066, 2006. (http://farmacists.blogspot.in/)

 

INTRODUCTION

    Infections of the gastro intestinal tract, especially infectious diarrhea, are among the most common debilitating infectious diseases, afflicting people of all ages around the world. Diarrhoea can be defined as the passage of loose or watery stools, usually at least three times in a 24 hr period it may be accompanied by anorexia, nausea vomiting, abdominal cramps. It is not a disease but sign of some infections or gastro intestinal disorders. Some times diarrhoea may occur in association with ulcerative colitis chrons disease and irritable bowed syndrome etc. Traveller's diarrhoea is another common cause of diarrhoea occurring in 8-50% of travelers depending on destination. ¹

 

    Racecadotril is being proposed as a new 'wonder' drug for the treatment of acute diarrhea in children and adult. It is a synthetic enkephalinase inhibitor and its antidiarrheal effects are attributed to its anti secretory properties mediated by inactivating endogenous opioid peptides, enkiphalins, secreted by myentric and sub mucosal plexes in the digestive tract.²

 

    Rotavirus and small round structured virus (SRSV) are the most common identified causes of gastro enteritis in children. In adults campylobacter followed by rotavirus are the most common causes of diarrhoea. Other causes include E coli, Salmonella, Shigella, Clostridium perfingens enterotoxins. This pathogens produce diarrhoea by producing enterotoxins that affect gut function with secretion and loss of fluids. Traveller's diarrhoea frequently affecting traveling people mainly associated with contaminated food ingestion. Many drugs particularly broad spectrum antibiotics such as ampicillin, erythromycin and neomycin induce diarrhoea secondary to therapy.

 

    Acute onset diarrhoea is associated with loose or watery stools that will probably be accompanied by anorexia, nausea, vomiting, abdominal cramps flatulence or bloating symptoms become more prominent in moderate dehydration and include thirst along with tiredness, apathy and dizziness, dry mucous membranes absence of tears on crying and postural hypotension are common additional finding of diarrhoea.

 

General treatment of Diarrhoea

    Oral rehydration therapy is the main stay of treatment for infants children and also elder patients. However oral rehydration therapy does not offer rapid relief of diarrehoeal symptoms which can lead to the inappropriate use antimicrobial agents with the consequent risk of developing antimicrobial resistance. Further more, antimotility agents such as loperamide which are effective in adults, are not indicated for use in very young children general measure like, patients should be advised on hand washing and other hygene related issues to prevent transmission to other persons. Dehydration and electrolyte disturbance can be readily treated but may, if severe, progress to acidosis and circulatory failure with hypoperfusion of vital organs, renal failure and death. ¹

 

1. Dehydration treatment:

    It is important to ensure the maintaining of fluid and electrolyte imbalance. Most patients can be advised to increase their intake of foods particularly. Fruit juices with their glucose and potassium content and soups because their sodium chloride content. High carbohydrate food can also recommended. The WHO recommends the oral rehydration solution for use in the treatment of diarrhoea. ORS contains following ingredients in one litre of water. Glucose (20 g) sodium (3.5 g – Nacl); potassium (1.5 g – Kcl) bicarbonate 2.5 g – NaH co₃. The volume of ORS to be taken in treating mild to moderate diarrhoea is dependant on age. An adults 2 litre of ORS should be given in the 1^st 24 hrs followed by un restricted normal fluid with 200 ml of ORS solution per loose stool or vomit. For children 30 – 50 ml/kg ORS should be given over 3-4 hrs. The solution is best sipped every 5 – 10 min rather than drink in large quantities less frequently.
¹³

 

 

 

2. Therapy with antidiarrhoal compounds

• Alteration of intestinal motility:

    Loperamide – may decrease transit velocity and increase the ability of the gut to retain fluid. It can reduce stools and shorten the course of diarrhea in infants and children with gastro enteritis. Loperamide also has a high incidence of severe side effects besides fluid loss in the ileus, including lethargy, respiratory depression and coma.

 

Opiates and opiate - antispasmodic combinations: - These drugs are contra indicated in children because of potentially severe side effects. ⁵

 

• Alteration of secretion:

    Bismuth subsalicylate has been used effectively for many years for the prophylaxis and treatment of travellers diarrhoea. These drugs decrease secretion from the gut, are safe for infants and children and are effective in decreasing both the quantity of stools and the duration of diarrhea. The administration of salicylate should be avoided in children with chickenpox or influenza because of the possible risk of Reye's syndrome. Bismuth is also contra indicated with patient with renal impairment.
¹⁰

 

• Racecadotril:

    Racecadotril (acetorphan) an enkephalinase inhibitor represents a promising new approach to the treatment of diarrhea. It enhances the antisecretory role of the neuro transmitter enkephalin and is a safe and effective treatment for acute diarrhea in adults and children.

 

• Adsorption of toxins or fluid:

    Kaolin, pectin, fibre and activated charcoal have no place in the treatment of diarrhea and dehydration in infants and children. Although non toxic, disadvantages may include adsorption of nutrients, enzymes and antibiotics in the intestine as well as making the severity of fluid loss in to the intestine .

 

• Alteration of intestinal microflora:

    Lactobacillus – Early administration of lactobacillus casei species rhamnosis (lactobacillus GG) associated with the administration of ORS significantly decreases the amount and duration of diarrhea and increases weight gain compared with ORS plus placebo.

 

• Immunization:

    Active: – Rotavirus immunization was found to be as effective as natural infection in preventing subsequent rotavirus diarrhoea.

    Passive: – Oral ingestion of immunoglobulins extracted from immunized bovine colostrums is effective in the management of children with acute rotavirus diarrhea.

 

• Other adjuncts:    

    Folic acid administration has also been found to be of little use in treating diarrhea and there is little evidence for routine administration of vitamin A to influence the course of diarrhoea. On the other hand zinc therapy decreases the duration and severity of diarrhea when given during the course of gastroenteritis in children.

 

• Antibiotics:

    Routine empirical use of antibiotics for infectious diarrhea should be avoided because of the self-limited nature of most cases. The cost of antibiotics and the potential of worsening the already significant problem of antibiotic resistance of enteric pathogens. For patients with severe invasine or prolonged diarrhea or who are at high risk of complications, empirical treatment with a quinolone antibiotic for three to give days can be considered. Antibiotic treatment can be highly effective for Shigella, Ecoli, and vibrio cholerae infections and metronidazole is indicated for clostridium difficile colitis. The impact of antibiotics for other specific pathogens is modest, and antibiotic therapy in these case should be reserved for the same group of patient who would be considered for empirical treatment.¹⁰

EFFECT OF RACECADOTRIL IN INFANTS AND YOUNG CHILDREN

 

    In infants the dose of Racecadotril (1.5mg/kg) corresponds to an average 100 mg dose in adults but would result in longer sustained levels of its active metabolites. In babies and infants (ages 3-48 months, average 13 months). This dose given every 8 hr. was significantly effective in reducing stool out put, diarrhoea duration and recovery within the first 24 and 48 hr, when compared to placebo. WHO recommendations in infants and small children: only ORS an essential treatment. The Enkephalin plasma concentration in infants are more than 10 fold higher than in adults and the half life of Racecadotril is longer in infants compared with adults.
³

 

• Fewer Adverse effects of Racecadotril

    Constipation in infants and children

    Incidence of vomiting

• Prescribing and formulary considerations

    Oral racecadotril has been shown to reduce the duration and frequency of acute diarrhea in adults and children as young as 2 months of age. It is significantly more effective than placebo and shows similar or slightly reduced efficacy compared with loperamide. However, it is appears to be better tolerated than loperamide resulting in lower instances of post-treatment constipation and abdominal distension. The good tolerability profile in children </ = 4 years of age is particularly important since loperamide is not recommended for use in infants and young children. Rececadotril appears to be as effective in children with rotavirus infection as it is in those negative for this infection. However it was not effective in HIV-positive patients infected with protozon, cryptosporidium.

 

EFFECT OF RECECADOTRIL IN ADULTS

    Rececadotril has been shown to reduce both the frequency and duration of acute diarrhoea of presumed infection origin in randomized, placebo controlled studies in both adults and children. The drug significantly reduced the incidence and duration of diarrhea and the number of diarrhoea related symptoms compared with placebo in a double-blind trial in adult patients with acute diarrhoea of infectious origin.
¹²

 

RACECADOTRIL

Identification Of The Substance

    Racecadotril is an oral encephalinase inhibitor used in the treatment of acute diarrhoea. It has an empirical formula C₂₁H₂₃NO₄S and molecular weight of 385.48.

 

 

Chemical formula

(RS) – 2 – [[2 – [2 – (acetyl sulfanyl) methyl] – 3 – phenyl – propanoyl] amino] acetate of benzyl

 

Pharmacology:

Mechanism of action:

    Racecadotril is a prodrug, which is rapidly absorbed after by-oral income and hydrolyzed to Thiorphan as active metabolites. This is an inhibitor of the Enkephalinase, a cell membrane peptidase, which is located in different fabrics, above all however in the small intestine epithelium. This enzyme diminishes exogenous and endogenous peptide like Enkephaline. Therefore Racecadotril protects selectively endogenous Enkephaline, which is physiologically active in the digestive tract. This leads to an extension of the antisekretorischen effect. The substance works exclusively in the intestine antisekretorich. It does not reduce the intestinal hypersecretion of water and electrolytes, due to choleratoxine or inflammations, and has an effect to the basal secretion. ⁴

 

 

 

Physiology of enkephalins:

    Natural enkephalins are pentpeptides of L-amino acids. These opioid peptides and their synthetic (mainly D) analogs, have a wide range of pharmacological actions. They play a role in analgesia, gastro intestinal motility, fluid absorption, oflaction, respiration, cognitive function and mood. Although enkephalins are often proposed to act selectively on d opiate receptors in the gut. Thereby reducing the mucosal cyclic AMP levels and decreasing the hyper secretion of water and electrolytes. It is recognized that they also bind m opiate receptors and influence the motor function and trasit of the gut. Their complex array of motility-inhibiting. Proabsorptive and antisecretory actions can be effectuated at different levels from mucosa to brain. For instance, in intestinal preparations, enkephalins inhibit the peristaltic reflex and cholinergic-mediated peristaltic contractions. They modulate motor activity (stimulatory or inhibitory) in a similar way as opiate-receptor agonists, depending on the gut segment studied and they delay duodenal and rectal transit. Centrally acting selective opioid receptor agonists result in potent colonic antipropulsive effects and inhibition of gastrointestinal transit. ⁸

 

    Antisecretory action of enkephalins also has been documented, both peripherally and centrally. Exposed to human colonic mucosa, they inhibit the PEG₂ induced increase in cyclic AMP, an effect similar to that of morphine and blocked by the m-opiate receptor antagonist naloxone. In addition in brain and plasma, their concentrations are much higher in the new born than in the adult and they decrease with age.

 

Effect Of Drug On Gi Motility And Transit

    Experimentally, it has been shown that racecadotril or thiorphan affects the post prandial colonic motor response after central, but not after IV administration, increases the motor activity of colonic long spike bursts during feeding and fasting and reduces the duration of feeding motor activity, while delaying the return of an MMC after a meal.
⁸

 

    In humans, Racecadotril 100mg three times a day had no significant effect on orocecal transit and excretion of colonic markers. Considering the fact that enkephalin inhibit the gut motility and transit, it is surprising that such effects have not been demonstrated so far with racecadotril, especially if one assumes that the drug acts peripherally in the gut circumstances that can explain the lack of observations in isolated experimental models of diarrhoea include:

1. Absent or very slow conversion of the prodrug racecadotril to active thiorphan. The invitro inhibitory potency of racecadotril is 1000 times lower than that of thiorphan
2. In vitro test condition, inhibiting the expression of enkephalinase

 

Antisecretory Action

    Antisecretory effects of racecadotril have been documented in vivo against cholera and E coli toxins. They were antagonized by naloxone. Reduction of mucosal cyclic AMP, proposed to result from its indirect selective d-opioid receptor interaction was not documented. The studies used high oral doses administered prior to the induction of secretion or systemic administration. In the human jejunum, a single dose of 300 mg racecadotril, administered 2.5 hr before induction of secretion by cholera toxin, prevented jejunal water and electrolyte secretion. The effect of a therapeutic 100mg dose or of a dose given after induction of the secretion, was not documented.
⁸

 

Selectivity of peripheral action:

    So far there appears to be no documentation of selective peripheral antiseretory or motility inhibiting antidiarrhoeal properties of Racecadotril (or its active compound thiorphan) in isolated gut segments. The selectivity of its action in the gut has been proposed based on the observation of intensive radio labeling of the gut after administration of 14_C labeled racecadotril in the rat and based on its failure to inhibit enkephalnase in human cerebrospinal fluid. The sensitivity of these tests to exclude CNS activity has not been published. In the auto radiographic study 10 mg/kg of ¹⁴C labeled rececadotril was orally administered: This dose corresponds to the lowest orally effective ED₅₀ in this model and needs to be administered intra peritoneally in order to result in an antidiarrhoeal effect comparable to oral loperamide in that species. ⁸

 

    In humans, enkephalinase inhibition was lacking in the cerebrospinal fluid after an oral dose of 20 mg/kg but not after intravenous influsion of 26 mg/kg/min for 60 min. The maximal velocity of enkephalinase in the human cerebrospinal fluid is, however, 10 times lower than in the plasma and 1000 times lower than in the plasma and 1000 times lower than in brain homogenates. Furthermore, an acute oral dose of the enkephalinase inhibiting the drug captopril does not significantly inhibit the enkephalinase in human cerebrospinal fluid, despite crossing the Blood Brain Barrier.

 

     In contrast to the idea of selective peripheral action in the gut, rececadotril may owe its antidiarrhoeal potential to its lipophylic nature, which allows it to easy penetrate in to the brain, where it is converted to active thiorphan. Thiorphan barely penetrates the Blood-brain barrier and is not effective orally in humans.

 

    Other arguments supporting a potential central action include (1) extensive binding and inhibition of cerebral enkephalinase after parenteral administration of 1-10 mg/kg racecadotril in mice and rats inhibition of the breakdown of synthetic inkephalins in the rat brain after peripherally administered rececadotril, exertion of various centrally mediated effects, some of which are naloxone reversible and opioid like, such as antinociceptive or analgesic effects and other naloxone intensitive such as the inhibition of gastric acid secretion.

 

    Analysis from different sources showed that after parenteral administration of racecadotril, published effective doses for central effects (<1 mg/kg) are lower than the minimally effective antidiarrhoeal doses ( ³ 5 mg/kg) reported elsewhere in the same species. Clear pharmacological differentiation between its antidiarrhoeal and central (analgesic) effect by dose with in one species, was not found.

 

    Experimental and clinical studies have shown that Racecadotril inhibits intestinal secretion induced by chemical or microbiological agents, without slowing gastro intestinal transit.

 

    In contrast to loperamide Racecadotril did not induce bacterial over growth and did not produce central neurotoxicity in new borngnotobiotic piglets. In human Racecadotril has no effects on the CNS and contrary to loperamide it can be administered in children of more than two years.

 

PHARMACOKINETICS

Pharmacokinetic Properties

 

Absorption:

    Racecadotril is quickly absorbed orally. The inhibiting activity of the plasmatic encephalinase appears in 30 minute. The amplitude and the duration of action of the racecadotril are related to the administered dose. The peak concentration is of 2.5 hrs approximately and corresponds to an inhibition of 90% of the enzymatic activity for the administered dose of 1.5 mg/kg. The duration of inhibiting activity on the plasma encephalinase is of approximately 3 hours. The half life is 3-4 hours. ⁶

 

 

    Quickly reabsorbed and hydrolyzed in a metabolite credit whose peak of activity appears one hour after a catch by oral way. This kinetics is not modified by the catch of Magnesium (Mg) and Aluminium hydroxide. The catch of a standard meal delays the peak but does not modify its height.

 

 

 

Distribution:    

    The tissue distribution is weak; it accounts for only approximately 1% of the administered dose. The racecadotril is fixed at 90% on plasma proteins (mainly albumin). The bioavailability of Racecadotril is not modified by food, but the peak of activity is delayed for 1.5 hours approximately. Duration of 4 hours action close. It does not cross the hemato-encephalic barrier.

 

Metabolism:

    Racecadotril is quickly hydrolyzed in LP 0.35 [(RS) – N – (1– oxo –2– (mercaptomethyl) –3– phenyl propyl ) glycine]; its metabolite. This is then tramformed in to active metabolite. Racecadotril is a prodrug, which is rapidly absorbed after by oral income and hydrolyzed to thiorphan as active metabolites.

 

Elimination:

    Racecadotril is eliminated in the urine. The repeated administration of racecadotril does not modify its pharmacokinetic properties and does not involve accumulation in the body.

Renal way: Elimination in form of metabolites

Fecal way: Elimination in the form of metabolite

 

Indications:

    In complement with the oral rehydration, symptomatic treatment of the acute diarrhoea. The importance of rehydration by solution of oral rehydration or intravenous way must be adapted according to the intensity of the diarrhoea, the age and the characteristics of the child.

Contraindications:

    If saccharose is present in the formulation, it is contra-indicated in the event of intolerance with fructose, malabsorption of glucose and galactose or of invert sugar-isomaltase deficit. It is contra-indicated in patients with known Hypersensitivity.

 

Routs of Administration – Orally

Warnings:

• The rehydration is the essential element of the treatment of the acute diarrhoea.
• In the child of more than 24 months, it will have to be systematically considered.
• The prevention or the treatment of dehydration will be done by solution of oral rehydration.
• It is recommended to use the solution envisaged for this purpose and to respect the methods of reconstitution and use.
• The sodium concentration will have to lie between 30 and 60 m mol/l, the solution with less sodium content (30 m mol/l) being reserved for not very severe dehydrations.
• A potassium and chlorine contribution is necessary in order to correct the digestive losses.
• The concentration recommended in glucose ranges between 74 and 110 m mol/l
• The addition of hydrolyzed proteins or amino acids does not seen to improve the rehydration nor the nutritional state.
• As an indication, the volume suggested of solution of oral rehydration must be equivalent to the lost weight that is to say 50 to 100 ml/kg for dehydration from 5 to 10% of the weight of the body.
• In the event of severe or prolonged diarrhoea, of significant vomiting or refusal of food, a rehydration by intravenous way will have to be considered.
• In the event of infectious diarrhoea with clinical demonstrations, suggesting an invasive phenomenon, to resort to antibacterials with good systemic diffusion.

 

 

Breast feeding:

    If there exists, the breast feeding will have to be continued. In other case, the removal of milk and dairy produces will have to be considered with individually.

 

Diabetes:

    In the event of diabetes, to take account of the quantity of sugar contained in the drug formulation.

 

Dysenteries:

    Racecadotril should not be used as treatment of first intention in the acute dysenteries with presence of blood and significant fever.

 

Broad Spectrum Antibiotic

    Racecadotril should not be used in the event of diarrhoea occurring during broad spectrum antibiotic treatment.

 

Adverse reactions

    Somnolence

Rash

Constipation (Rare)

 

Side effects

• Central nervous system:
  Dizziness, malaise, and headache have accompanied therapy of acute diarrhoea in a few patients.
• Metabolic:
  Persistence of hypokalemia has been reported infrequently in children with severe watery diarrhoea.

 

Efficacy similar to Loperamide

    Racecadotril appeared to have similar efficacy to loperamide for the treatment of adults and children with acute diarrhoea in several double-bind comparative trials. Both racecadotril (1.5 mg/kg 3 times daily) and loperamide (0.03mg/kg 3 times daily) resulted in resolution of acute diarrhoea with 1-2 days of initiation of treatment in a double blind comparison carried out in 102 children aged to 2-10 years. No significant differences in the time to first formed stools (32.2 hrs for racecadotril, and 30.6 hrs for loperamide) or for the recurrence of diarrhoea were detected.

 

    Racecadotril and loperamide also appeared to have similar efficacy in a double bind comparison conducted in 147 adults with acute diarrhoea. The mean duration of diarrhoea and the mean number of stools until recovery were similar for both treatment groups.

 

Fewer adverse effects than Loperamide:

    Racecadotril treatment resulted in fewer adverse events, particularly constipation, than loperamide in both adults and children. Constipation (defined as >/ = 1 day with out a stool) occurred significantly more frequently with loperamide than with racecadotril in children receiving treatment for acute diarrhoea. The incidence of vomiting was the next most frequent adverse event occurring with similar frequency in both treatment groups. ⁷

 

    Figure – incidence of constipation and other gastro intestinal and adverse events occurring during treatment for acute diarrhoea with racecadotril or loperamide in children added 2 to 10 years.

 

Prescribing and formulary considerations

    Oral rececadotril has been shown to reduce the duration and frequency of acute diarrhoea in adults and children as young as 2 months of age. It is significantly more effective than placebo and shows similar or slightly reduced efficacy compared with loperamide. However racecadotril appears to be better tolerated than loperamide resulting in lower instances of post-treatment constipation and abdominal distension. The good tolerability profile in children </ = 4 years of age is particularly important since loperamide is not recommended for use in infants and young children. Racecadotril appears to be as effective in children with rotavirus infection as it is in those negative for this infection. However it was not effective in HIV positive adults infected with the protozoan, cryptosporidium, but it requires further investigations. ⁷

 

Comparison of racecadotril and loperamide

    Racecadotril is an enkephalinase inhibitor, presented as a purely antisecretory agent with advantages over the opiate-receptor agonist loperamide in the treatment of diarrhoea. A critical review of the literature and the models used was performed. Although pretreatment with high doses of racecadotril reduced cholera toxin-induced secretion and although clinical efficacy was demonstrated in young infants – a population characterized by 10-fold higher plasma enkephalin concentrations compared with adults, the analysis calls in to question the peripheral antisecretory selectivity and relative clinical efficacy. Conversely, loperamide can be proposed as an antisecretory agent at therapeutic concentrations. Its efficacy is well established in acute and chronic diarrhoea. Current experimental and clinical comparitive studies of both drugs have problems with regard to the selection of the doses, the validity of models and/or the trial design. ¹³

 

    The conclusion is that more research is needed before reliable conclusions can be drawn on the place of racecadotril in diarrhoea treatment.

 

Table 1: Benefits proposed in comparative studies between Racecadotril (RAC) and Loperamide (LOP) and summary of main comments resulting from literature analysis¹³:

 

Benefit

Comments

Experimental studies No inhibition of gastro intestinal transit with RAC but with LOP     LOP but not RAC increases bacterial proliferation with E coli Clinical studies RAC is as effective as LOP in acute diarrhoea Tolerability. Less constipation with RAC than LOP Less abdominal distension with RAC than LOP

Use of a normal antidiarrhoeal dose of RAC, but more than 13 times the antidiarrhoeal dose of LOP. Pro absorptive antisecretory effects of LOP can confound the charcoal test:- There is no dose dependent inhibition of the charcoal transit by LOP at the dose level studied. Use of a germ-free neonate piglet model (altered in metabolism and bacterial colonization compared to conventional animals). The higher E coli content may reflect the response of the watery bowel content of germ free animal to the pro absorptive/antisecretory stimulation of LOP. Activation of RACE is not validated in germ free piglet model. Use of a normal experimental anti-diarrhoeal dose of RAC but of an established toxic dose of LOP irrelevant to human Pre treatment duration of diarrhoea allowed beyond 48 hours (interference of spontaneous recovery possible). Definition recovery as the time until the first normal stool (should be until the last unformed stool). Therapeutic RAC dosing, but constant LOP dosing rather than depending on diarrhoea frequency and severity (too high and therefore potentially constipating or too low, compromising efficacy). No placebo control.   Not based on clinical adverse event reporting, unless in two studies using an incorrect constant LOP dose. Calculation of the number of stool free intervals (of varying duration between studies 24 or 48 hrs) efficacy can interfere as bowel transit normally last ³ 48hr and replenishing of the bowel can last longer after effective inhibition of secretion. The mean duration of such intervals did not differ between both products Non therapeutic LOP doses were used: abdominal pain/distension was possibly induced by use of constant unneeded doses.

 

Table 2: Differential features: Comparison of various features of racecadotril and loperamide for the management of patients with acute diarrhoea¹³

 

 

Clinically effective dose and efficacy in adults

    Race cadotril is recommended at a fixed dose regimen of 100mg 3-4 times daily. This dose has been proposed based on the dose-response of enkephalinase inhibition in healthy volunteers: It results in a peak activity of 75% inhibition of the plasma enkephalinase, 1-3 hr after its oral administration. Clinical dose findings during diarrhoea are not available. In humans with castor oil induced diarrhoea, the dose eliciting more than 50% inhibition of the plasma enkephalinase for at least 6 hr was 11.2 mg/kg (about 8 times the 100 mg unit dose) and highly variable. At this high dose, stool weight and stool number were significantly reduced. ¹²

 

    Medline search did not reveal placebo-controlled studies in cholera, traveller's and chronic diarrhoea or in combination with antibiotics. Although an initial open pilot study in chemotherapy induced diarrhoea suggested efficacy of racecadotril 300 mg/day an open study including a control group showed that this dose had no significant anti-diarrhoeal effects.

 

    The dose of Loperamide in adult is flexible. 2 capsule (4mg) at start and 1 capsule (2mg) after each loose bowel movement (maximum 8 capsules). It has been studied in a cute diarrhoea, traveller's diarrhoea, and various forms of chronic diarrhoea. It acts rapidly (with in 2 hr) and significantly reduces diarrhoea duration and number of unformed stools, when compared to placebo. Loperamide is effective in combination with antibiotics. Although antisecretory effects against the cholera toxin have been shown. It is not used in cholera, with the rare exception in combination with an antibiotic.

 

Clinical efficacy in children

    In infants the dose of rececadotril (1.5mg/kg) corresponds to an average 100 mg dose in adults but would result in longer sustained levels of its active metabolites. In babies and infants (ages 3-48 months average 13 months) this dose given every 8hrs, was significantly effective in reducing stool out put, diarrhea duration, and recovery with the 1^st 24 and 48 hr, when compared to placebo. ⁸

 

    The effective dose of loperamide syrup in infants is 0.08-0.1mg/kg, two to three times daily (no dose if no passage of diarrhoea). In children older than 6 years, capsules are used but the start dose in only one capsule instead of two. Lperamide was extensively studied in infants in the 1980s. A contra indication for those younger than 2 years was implemented after 15 years of usage in pediatrics, following rare reports of drowsiness, ileus, and central depression, mostly associated with over dose of concentrated drops in the very young.

 

Comparative efficacy

    Four studies showed that racecadotril is an effective as loperamide. The methodology, however calls for caution in interpretation.

1. Three studies used a fixed instead of flexibly dosed regimen of low-dose loperamide (eg 2mg three times daily instead of 4 mg at start and 2 mg as needed, up to 16 mg/day) until "disappearance of liquid stools, irrespective of prior liquid stool passage or until passage of two normal stools. Loperamide thus may have been under dosed in some, and over dosed in others. Repetitive unneeded doses of loperamide can slow transit (see "Effect on Gastro intestinal Motility and Transit") and may have induced the constipation and abdominal discomfort in some patients. Moreover, according to the base line features in one study, some infants were "with out" liquid stools prior to start of the study (24% loperamide group versus 11% in the racecadotril group) and hence, they received unneeded doses of loperamide. The fourth study used the recommended flexible loperamide dose regimen, but the maximum dose was not mentioned. ⁸

 

1. The duration of diarrhoea prior to the study was not given or allowed to last up to five days. Because acute diarrhoea resolves in most patients with in two to three drops. Spontaneous resolution of diarrhoea can confound differences in clinical outcome in comparative studies, especially if long pretreatment periods of diarrhoea are allowed. According to FDA definitions, acute diarrhoea is defined as lasting up to 96 hr only. Comparative treats allowing pre-treatment durations of diarrhoea beyond 48 hr should thus include a placebo group to validate conclusions. ⁸

 

1. The definition of recovery or duration of diarrhoea was not given or set as the time until "Production" of "two" normal stools or until the first normal stools, followed by no stool during the following 12 hrs.

    

    One trial (with an appropriate design) compared racecadotril and loperamide oxide in acute diarrhoea in adults. Superior to racecadotril in antidiarrhoeal and global efficacy fewer patients on loperamide had worsening of bloating when compared with rcecadotril. According to appropriate placebo-controlled studies. This prodrug of loperamide is as effective and as well tolerated as loperamide. There are no comparative studies of racecadotril in acute diarrhoea with other antidiarrhoeal treatments, such as probiotics, adsorbents, or antimicrobials. Numerous studies in acute nondysenteric diarrhoea show that loperamide is more effective than these agents, particularly with respect to its onset of action. ⁸

 

Tolerability

    In general, both racecadotril and loperamide appear to be well tolerated. In placebo controlled studies, their adverse event profile is not significantly different from that of the placebo group. Clinically, constipation has occasionally been reported with loperamide. This adverse event is also mentioned in the table of racecadotril. While in occurrence was similar with racecadrotil and placebo in the trials using 100 mg three times daily, 11% of patients on racecadotril reported constipation versus 5% on placebo in the trial with flexibly dosed raceadotril.

 

    A benefit proposed for racecadotril over loperamide is less constipation and abdominal distension. Some comparative studies in adults and children support these advantages but the relevance of the findings can be questioned: They did not use the standard therapeutic loperamide dosages, but constantly and unnecessarily prolonged dosing, there by possibly inducing these untoward effects or they used a mathematical approach by calculating intervals without stools. Following effective inhibition of secretions, it may take 24 to > 48 hr for the bowel to replenish after a diarrhoea episode (normal bowel transit takes two to four days) pseudo constipations is also observed with placebo and is likely to become more prevalent following fast and effective inhibition of intestinal secretions due to less rapid filling of the gut lumen. In this respect, it is note worthy that the average duration of the mathematically calculated constipation intervals did not differ between the racecadotril and loperamide groups. Induction is further supported by the consistent finding that in well-controlled double blind trials of acute diarrhoea normal dosing schedules of loperamide do not differ from placebo in the incidence of constipation and bloating and loperamide provides faster complete relief of gas-related abdominal discomfort than placebo. ⁸

 

Discussion

    This evidence-based analysis present an update on the antidiarhoeal action and efficacy of racecadotril and loperamide. It shows that the selection of study conditions can have a significant impact on the outcome of pharmacological and clinical studies of diarrhoea. There may however, be a difference in potency and reliability of the antidiarrhoeal action of both drugs. Loperamide is flexibly dosed as a function of diarrhoea severity and thus, according to the patient's individual need. Racecadotril is dosed at a constant regimen of 100 mg three or four times daily. This dose resulting in a peak of 75% plasma enkephalinase inhibiting in healthy volunteers, however is, much lower (on average eight fold) than the highly variable doses needed for a therapeutically effective 50% inhibition for 6 hr in humans with castor oil - induced diarrhoea. These observations together with the established high variability in enkephalin levels and their degrading enzymes as well as their fast turn over in humans, support investigation of flexible dosing of racecadotril.

 

CONCLUSION

    The comparative studies of racecadotril and loperamide do not allow us to draw conclusions on equal efficacy and/or benefits of racecadotril over loperamide. In conclusion, based on the clinical findings and physiology of enkephalins, racecadotril may have a better efficacy in infants when compared to adults. Whether racecadotril truly offers benefits over loperamide in terms of antisecretory properties, antidiarrhoeal efficacy, or tolerability in the treatment of acute and chronic diarrhoea.

 

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Cite this: M. V. Noushad, Sijo Pattam "A STUDY ON RACECADOTRIL FOR ITS EFFICACY SAFETY AND COMPARISON WITH LOPERAMIDE", B. Pharm Projects and Review Articles, Vol. 1, pp. 1024-1066, 2006. (http://farmacists.blogspot.in/)