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Keywords:

  • effectiveness;
  • GI tract;
  • prokinetic agents;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

Prokinetic agents are effective not only for disease of the gastrointestinal (GI) tract but also for those external to the GI tract such as the central nervous system, and the respiratory, urologic, and metabolic organs. This article reviews the effectiveness of prokinetic agents against diseases external to the GI tract. Studies were identified by computerized and manual searches of the available literature. A Medline search was performed (1975–July, 2008) using the following medical subject headings: prokinetic agent, metoclopramide, domperidone, trimebutine, cisapride, itopride, mosapride, tegaserod, and human. The identified diseases for which prokinetic agents may be effective are various: bronchial asthma, chronic cough, hiccup, spontaneous bacterial peritonitis, cholelithiasis, diabetes mellitus, acute migraine, Parkinson's disease, anorexia nervosa, Tourette's disorder, urologic sequelae of spinal cord injury and of radical hysterectomy for cervical cancer, laryngeal dysfunction and so on. These agents are also useful for prevention of aspiration pneumonia during anesthesia, and in tube-fed patients. Prokinetic agents should be a valuable addition to our currently limited pharmacological armamentarium not only for functional bowel disease, but also for diseases external to the GI tract.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

Prokinetic agents, including metoclopramide, domperidone, trimebutine, cisapride, itopride, mosapride and tegaserod, stimulate digestive tract motility. These agents are mainly used for treatment of diseases of the gastrointestinal (GI) tract, such as functional dyspepsia (FD), gastroesophageal reflux disease (GERD), diabetic gastroparesis (gastropathy) and postoperative ileus,1–3 and for prevention of postoperative emesis.4–7

These prokinetic agents act through varying mechanisms. Metoclopramide and domperidone are peripherally acting dopamine antagonists.8,9 The action of trimebutine in the gastrointestinal tract is mediated via an agonist effect on peripheral mu, kappa and delta opiate receptors, and the release of gastrointestinal peptides such as motilin, and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin, and glucagons.10 Trimebutine accelerates gastric emptying by inducing premature phase III activity of the migrating motor complex in the intestine. Cisapride acts on the serotonin receptors 5-HT1, 5-HT2, and 5-HT3 as well as 5-HT4.11 Tegaserod is thought to act on the serotonin receptors such as 5-HT4.12 Various 5-HT receptors (5-HT1, 5-HT2, and 5-HT3) exist in diverse body systems, such as the central nervous system (CNS) and vascular system. Mosapride acts selectively on the 5-HT4 receptor.12,13 The 5-HT4 receptor exists mainly in the intestine. It stimulates antroduodenal motility and accelerates gastric emptying in patients with delayed gastric emptying. However, cisapride and tegaserod can cause heart rhythm abnormalities that can be fatal.14

Detailed reviews on the function of domperidone, mosapride, and tegaserod against GI tract diseases were published recently.13,15–17 In addition, we previously reported the results of meta-analyses of the effects of prokinetic agents in patients with FD was reported.18,19 The main finding was that compared with placebo, prokinetic agents have a 30% higher probability of producing a response in patients with FD.

Prokinetic agents are effective not only for disease of the GI tract but also for those external to the GI tract such as those of the CNS, and the respiratory, urologic, and metabolic organs. This fact is very interesting. Prokinetic agents are not simply prokinetic, and have effects in various medical fields outside of gastroenterology as well. Until now, however, there have been no review articles on the effectiveness of prokinetic agents against diseases external to the GI tract.

Studies on the effectiveness of prokinetic agents against diseases external to the GI tract were identified by computerized and manual searches of the available literature. A Medline search (1975–July, 2008) was performed using the following medical subjects headings: prokinetic agent, metoclopramide, domperidone, trimebutine, cisapride, itopride, mosapride, tegaserod, and human. Only papers published in English were considered. Enlisted were papers that the criteria for successful treatment were clearly outlined, and treatment success was not measured in terms of illness severity scores or the intensity of single symptoms or single examination result.

The effect of the prokinetic agent is divided as follows: direct and indirect effect of motility stimulating property, and side effect.

Critical care

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Feeding tolerance (direct effect due to improvement of GI tract)

Slow gastric emptying has been noted in more than 50% of unselected mechanically ventilated patients.20 Most (80%) of patients with increased intracranial pressure after head injury have been found to have slow gastric emptying.21

Early enteral feeding is recognized as one of the fundamentals of critical care practice. Enteral nutrition increases gut blood flow, thereby protecting the gastric mucosa. Early feeding results in fewer septic complications, decreased catabolic response to injury, decreased stress ulceration, improved gut immune function and improved wound healing.22 Booth et al. systematically reviewed the evidence for the use of prokinetic agents in critical care.23 Sixty citations were reviewed and 18 articles met their inclusion criteria.24–41 The context of the review was that prokinetic agents appear to have a beneficial effect on gastrointestinal motility in critically ill patients. Administration of metoclopramide appears to increase physiological indexes of gastrointestinal transit and feeding tolerance. They concluded that concerns about safety of the treatment, and lack of effect on clinically important outcomes, preclude a strong treatment recommendation. More recent reports also recommend the use of prokinetics in critically ill patients with feed intolerance.42–46 Nguyen et al. recommend combination therapy with erythromycin and metoclopramide in critically ill patients with feed intolerance as the first line of treatment.47

Respiratory disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Bronchial asthma (direct effect of motility stimulating property)

Gastroesophageal reflux has been named as a possible etiological factor in bronchial asthma. Ibero et al. examined 34 asthmatic infants (28 boys and 6 girls) aged 19.4 ± 4.8 months whose asthma began at a mean age of 7.5 months (1 to 28 months).48 Patients with pathological 24-h intraesophageal pH monitoring were treated with cisapride while the rest were considered to be controls. In the cisapride group, wheezing crisis frequency decreased from 4.9 ± 2.0 to 0.75 ± 1.2 (P < 0.0002), and only 10% of patients required basic pharmacological treatment. In the controls, wheezing crisis frequency decreased from 4.6 ± 2.4 to 0.75 ± 1.8 (P < 0.01), but 44% required basic pharmacological treatment (P < 0.05). In another study, 36 asthma patients (22 males and 14 females; median age 75.5 months) were given cisapride (0.2 mg/kg q.i.d.) for 3 months. Improvement in both clinical symptoms and results of the pH study were highly significant (P < 0.0001).49 These results suggest that cisapride treatment reduces wheezing crisis frequency and antiasthmatic drug consumption in asthma patients. On the other hand, Nolan et al. reported a brittle asthma patient whose asthma worsened after cisapride administration.50

Jiang et al. assessed the effects of antireflux treatments (omeprazole 20 mg once a day and domperidone 10 mg three times a day), on bronchial hyper-responsiveness and lung function in asthmatic patients with GERD.51 They reported that antireflux therapy may improve pulmonary function and inhibit bronchial hyper-responsiveness in asthmatic patients with GERD. Several researchers have reported similar results.52

2. Chronic cough (direct effect of motility stimulating property)

In a case report of one patient suffering from chronic cough associated with irritable esophagus syndrome53 the most frequent causes of chronic cough were ruled out. Twenty-four hour esophageal pH-monitoring showed a close correlation between gastroesophageal reflux episodes and cough attacks. The patient was successfully treated with cisapride. Poe et al. examined 56 patients with GERD–related cough. A once-daily dose of a proton-pump inhibitor (PPI) was prescribed. A prokinetic agent was added if esophageal dysfunction was suspected or the response was inadequate. Proton pump inhibitor therapy was successful in 24 (43%) patients, and 18 (32%) more patients responded when metoclopramide or cisapride was added.54 In another study, cough at night disappeared completely in 12 out of 13 children with reflux-associated bronchopulmonary disease after treatment with cisapride (0.3 mg/kg t.i.d.) for 1 month.55 These results suggest that anti-GERD therapy (PPI and/or prokinetic agent) may decrease chronic cough as well as GERD. Gupta reported that metoclopramide had rapid antitussive action in 12 of 14 patients with severe paroxysmal cough.56

3. Hiccup (indirect effect of motility stimulating property)

Idiopathic chronic hiccup (ICH) is defined as recurring hiccup attacks that last for longer than an arbitrary time limit (e.g. 1 month) and for which no organic cause can be discerned. Cisapride and omeprazole are thought to reduce an assumed afferent input from the periphery to a putative supraspinal hiccup center through facilitation of gastric emptying and reduction of gastric acid production, respectively. Fifteen male patients who had recurring hiccup attacks for a mean duration of 100.8 ± 134.1 months (range, 12 to 564 months) were treated with a combination of cisapride, omeprazole, and baclofen.57 The therapy led to a total disappearance of hiccup in 6 (40%) patients. An additional 3 (20%) patients experienced substantial relief. The treatment may be an effective empiric therapy in at least some patients with ICH. Duffy et al. also reported a patient whose hiccup resolved after administration of cisapride.58 Metoclopramide has also been observed to relieve intractable hiccup.59,60

Metoclopramide is effective not only for ICH but also for other types of hiccup including anesthesic drug or treatment-induced, and migraine-associated. During induction of general anesthesia methohexital may produce hiccup. In one study, 211 female patients received methohexital for induction and maintenance of general anesthesia for short gynecological procedures. One-hundred and nine patients were randomly selected to receive metoclopramide before induction of anesthesia. Seven patients had hiccup in the metoclopramide premedicated group, as compared to 17 patients in the control group (P < 0.05).61 Pinczower reported the effectiveness of metoclopramide against hiccups that developed after inserting a laryngeal mask airway after a propofol induction of anesthesia.62 A case of migraine-associated hiccup where metoclopramide swiftly controlled both hiccup and the associated migraine headache has also been reported.63

4. Prevention of aspiration pneumonia during anesthesia (direct effect of motility stimulating property)

Kluger et al. reported the results of a national survey of anti-aspiration prophylaxis during anesthesia in New Zealand.64 Anti-aspiration prophylaxis is deemed important for morbidly obese patients, those in the third trimester of pregnancy, and those with a hiatal hernia. Histamine type 2 receptor antagonists and prokinetic agents such as metoclopramide were used commonly. Orr et al. reported that, while omeprazole is useful for prophylaxis of pulmonary aspiration during anaesthesia for elective Caesarean section, the addition of the prokinetic agent metoclopramide, seems to be necessary to maximize its effect.65

5. Prevention of aspiration pneumonia in tube-fed patients (direct effect of motility stimulating property)

A prospective randomized two-period crossover study was performed to determine the effectiveness of cisapride for preventing aspiration of gastric contents in tube-fed patients.66 Eighteen intubated, mechanically ventilated patients were studied. Tc-99 m sulfur colloid (80 megabecquerels) was administered via nasogastric tube for two consecutive days. Patients randomly received cisapride (10 mg, via nasogastric tube) one day and a placebo the other. Bronchial secretions were obtained before and for five consecutive hours after Tc-99 m administration. The cumulative bronchial secretion radioactivity obtained when patients received cisapride was significantly lower than when patients received a placebo: 7540 ± 5330 cpm and 21 965 ± 16 080 cpm, respectively (P < 0.05). These results suggest that cisapride may decrease the amount of gastric contents aspirated by intubated and mechanically ventilator-associated pneumonia patients.

Pareek et al. conducted a retrospective study to evaluate the clinical benefit of a prokinetic agent in aspiration pneumonia in patients with developmental disabilities.67 They reviewed records of 22 tube-fed patients for a mean of 22.7 months before and 38.9 months during cisapride therapy. Numbers of hospital admissions per patient-year from before to during cisapride administration were reduced from 2.75 to 0.61, with a relative risk of admission reduction of 4.5 times. Days of hospitalization were reduced from 32.3 to 6.4. Sartori et al. carried out an open study. in which 29 patients who were fed via percutaneous endoscopic gastrostomy (PEG), were coadministered 10 mg cisapride routinely via PEG.68 These patients were followed for a total of 4935 days of feeding (mean time per patient 170 days; range, 47–508 days). No episode of probable/possible aspiration pneumonia was observed during this follow-up period. In another study, the rate of pneumonia and pneumonia-related mortality after PEG in elderly stroke patients fed using a PEG tube who were treated with or without mosapride was examined.69 Seventy-five patients were enrolled, and the patients were randomly assigned to either mosapride treatment (15 mg via PEG tube t.i.d.) or control (no mosapride). During one year of follow-up, the rate of pneumonia was significantly lower in patients with treated with mosapride than in controls (18/38 (47%) vs 30/37 (81%), P = 0.004). The cumulative survival rate was also significantly higher in the mosapride group than in the controls (28/38 (74%) vs 15/37 (41%), P = 0.01). Thus, mosapride treatment significantly decreased the rate of pneumonia compared with controls, and also improved the cumulative survival rate. These results suggest that the prokinetic agent mosapride may help prevent aspiration pneumonia and have a beneficial effect on the survival rate of elderly stroke patients fed via PEG.

Digestive disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Spontaneous bacterial peritonitis (indirect effect of motility stimulating property)

Spontaneous bacterial peritonitis (SBP) is a serious complication of cirrhosis with ascites, having a high recurrence despite prophylactic treatment. Small bowel dysmotility and bacterial overgrowth have been documented to be related to SBP. A prospective single blind, randomized controlled trial was conducted in high-risk cirrhotic patients with ascites who had either recovered from an episode of SBP or who had low ascites fluid protein.70 Norfloxacin 400 mg once daily (group I) or norfloxacin 400 mg once daily with cisapride 20 mg twice daily (group II) was given. The probability of developing SBP at 12 months in group I was 56.8% and in group II, 21.7% (P = 0.003). In a study by Madrid et al. thirty-four patients with liver cirrhosis were randomly allocated to receive cisapride and an alternating regimen of norfloxacin and neomycin or placebo during a 6 month period.71 After 6 months, both cisapride and antibiotics significantly improved fasting cyclic activity, reduced the duration of orocecal transit time, and decreased small-intestinal bacterial overgrowth. In addition, an improvement in liver function was observed at 3 and 6 months in patients treated with both cisapride and antibiotics. These results indicate that prophylaxis with antibiotics and prokinetic agents may reduce the incidence of SBP.

2. Cholelithiasis (side effect)

Farup et al. evaluated the effect of 20 mg cisapride twice daily on biliary drainage by dynamic cholescintigraphy in 19 patients with post cholecystectomy syndrome.72 Treatment with cisapride hastened biliary drainage. Several researchers also reported improvement of gallbladder motility after cisapride treatment.73–78 Mechanisms via which cisapride may interact with gallbladder function are multiple and include direct effects on gallbladder and the sphincter of Oddi, as well as indirect effects involving gastrointestinal hormone levels, gastric emptying, gallbladder refilling, interdigestive migrating motor cycle, and small intestinal transit.79 Phamacologically, the direct effects of cisapride on myenteric end neurons should increase fasting gallbladder tone. Various peptides modulate gallbladder motility. Cholecystokinin (CCK) plays a role in the postprandial initiation of gallbladder contraction; its release being induced by fat entering the duodenum. Nuerotensin, substance P, and neuropeptide Y promote gallbladder contraction, while somatostatin, vasoactive intestinal polypeptide and pancreatic polypeptide (PP) promote relaxation. Administration of cisapride has been shown to increase plasma CCK and PP levels to varying extents, while not affecting other hormones.

Metabolic disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Diabetes mellitus (indirect effect of motility stimulating property)

Glycemic control in patients with diabetes mellitus is related to gastric motility.80,81 Lysy et al. reported that delayed gastric emptying represents a significant risk factor for hypoglycemia in insulin-treated type 1 and type 2 diabetes. The authors evaluated gastric emptying in 31 insulin-treated patients who had recurrent episodes of hypoglycemia early in the postprandial period. In approximately 30% of patients, the magnitude of the delay in emptying was marked, even though none of them reported upper GI symptoms such as nausea or bloating. The authors suggest gastric emptying tests for diabetic patients with unexplained hypoglycemic events.82

Mosapride was administered to 21 type 2 diabetes patients with gastropathy.83 After a mean of 100.7 days of mosapride treatment (15 mg/day), 14 showed a statistically significant decrease in HbA1c (7.6 ± 0.3 to 7.0 ± 0.3%, P < 0.05). In another study, mosapride (15 mg per day) was administered to 36 type 2 diabetes patients with mild digestive tract symptoms for 6 months.84 In 18 of these patients, HbA1c level was decreased by more than 0.3% for 6 months. Ueno et al. also reported that mosapride treatment for 8 weeks significantly reduced fasting glucose, insulin, and HbA1c concentrations in patients with type 2 diabetes mellitus.85 These results suggest that prokinetic agents may improve insulin action in muscle, and glycemic control in type 2 diabetes patients. As for cisapride however, there are several reports that show the treatment improves diabetic gastroparesis but not glycemic control.86,87 It is unknown why mosapride improves glycemic control while cisapride treatment does not. In normal subjects, after the intravenous glucose load, plasma concentrations of C-peptide were higher on cisapride when compared with placebo. Cisapride may increase glucose-stimulated insulin secretion.88

Central nervous system disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Acute migraine (side effect)

Migraine headache is a common problem in adult populations, with 6% of men and 15–17% of women experiencing an average of around 36 episodes a year89. Metoclopramide, a peripheral dopamine2-receptor antagonist, has long been used for the treatment of nausea associated with acute migraine. In addition to its antiemetic properties, metoclopramide has the potential to enhance the absorption of other analgesics.90 In the late 1970s, anecdotal case reports suggested that patients with migraine who received metoclopramide for nausea experienced substantial pain relief before they had received an analgesic.91 Subsequent studies concluded that the dopamine antagonist properties of metoclopramide might make it effective as a single agent to treat acute migraine.92–100 Other dopamine antagonists such as prochlorperazine and chlorpromazine have also shown effectiveness for treatment of migraine.101 To assess the evidence on the efficacy of parenteral metoclopramide for acute migraine, a meta-analysis was carried out.102 In studies comparing metoclopramide with placebo,102–104 metoclopramide was more likely to provide significant reduction in migraine pain (odds ratio 2.84, 95% confidence interval 1.05–7.68). Used as the only agent, metoclopramide showed mixed effectiveness when compared with other single agents.93,94,96,97 Metoclopramide therefore, may be useful as a primary or adjunctive agent in the treatment of acute migraine.103–115 Several studies have shown that metoclopramide used in combination with other agents is similarly, or more effective for pain relief outcomes than comparison regimens (for example, hydroxyzine-meperidone, dihydroergotamine alone, valproate, ibuprofen, ketorolac and promethazine-meperidine).95,106,107,110–115 Conversely only a few reports have shown that metoclopramide does not have a better effect than placebo.116

Another peripheral dopamine2-receptor antagonist, domperidone, is also effective for migraine pain.117

On the other hand, in children Victor et al. assessed the evidence from controlled trials on the efficacy and tolerability of pharamacological agents including metoclopramide and domperidone, taken on a regular basis to prevent the occurrence of migraine attacks, and/or reduce the intensity of such attacks.118 Metoclopramide and domperidone showed no efficacy in reduction of frequency of migraine attacks in children.

2. Parkinson's disease/Parkinsonism (indirect effect of motility stimulating property)

Prokinetic agents are effective for treatment of constipation in patients with Parkinson's disease/Parkinsonism. In addition, the agents improve response to L-dopa. Sempere et al. reported two patients with Parkinsonism who experienced aggravation of tremor while on therapy with cisapride.119 Impaired gastric emptying may be the cause for some response fluctuations in Parkinson's disease, especially the ‘delayed-on’ and ‘no-on’ phenomena. The efficacy of cisapride treatment was studied in an open-label trial on 15 fluctuating Parkinson's disease patients.120 In this trial, levodopa alone was administered to these patients first one week, and then levodopa and cisapride were coadministered to them the next week. Concurrent cisapride treatment significantly shortened latency to ‘on’ from 60 ± 20 to 45 ± 19 min after the morning dose and from 63 ± to 17 to 47 ± 22 min after the evening dose. Patients with ‘no-on’ phenomenon had a decreased number of dose failures from 23 beforehand, to 9 during cisapride treatment. In another study, efficacy of cisapride treatment was studied in an open-label trial on 20 Parkinson's disease patients with chronic constipation, whose response to L-dopa was suboptimal or characterized by fluctuations.121 Fourteen patients completed the study. Cisapride treatment increased peak plasma levels of L-dopa by 37% and mean plasma level of L-dopa by 13%, compared to that obtained with the same dose of L-dopa without addition of cisapride. Cisapride also improved visuo-manual coordination, and reduced gait disability. In addition, Asai et al. reported that mosapride treatment significantly shortened gastric emptying half-time, improved motor function, and prolonged ‘on’ time, consistent with a reduction in response fluctuations in all five patients studied.122 These results suggest that prokinetic agents may improve gastrointestinal function and response to L-dopa in patients with Parkinson's disease/Parkinsonism and could be a helpful add-on medication for these patients. The use of prokinetic agents is recommended in practical guidelines for management of response fluctuations to L-dopa.123

Psychiatric disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Anorexia nervosa (direct effect of motility stimulating property)

Delayed gastric emptying prevails in anorexia nervosa, with slower intestinal transit and atrophy of the smooth muscles of the gastrointestinal tract.124,125 Stacher et al. performed a double-blind trial with 12 anorexia nervosa outpatients who for 6 weeks received either cisapride (10 mg) or placebo, three times a day.126 They reported that five of the six patients who received cisapride gained weight, and symptoms of gastric retention ameliorated in four of them. With placebo, four gained weight, and one's symptoms improved. Szmukler et al. performed a double-blind trial with 29 anorexia nervosa inpatients who for 8 weeks received either cisapride (10 mg) or placebo, three times a day.127 Subjective measures were significantly better in the cisapride group; they rated them themselves as more hungry and more improved on global measures of change in their symptoms. These findings suggest that longer administration of cisapride may, by enhancing gastric motor activity, alleviate the symptoms of gastric retention and thus help to change eating behavior.

2. Tourette's disorder (side effect)

Tourette's disorder, with a prevalence of 1% to 3% in children and adolescents, is a chronic, childhood-onset neuropsychiatric illness. It is characterized by motor and vocal tics that fluctuate in severity and can be socially and physically impairing for some children and adolescents.128 The drugs most frequently used to treat tics are antipsychotics (mainly pimozide and haloperidol) and clonidine. The pattern of dopamine antagonism by metoclopramide suggests possible benefits in the treatment of tic disorders.129,130 Smirnov described the use of metoclopramide in 22 children and adolescents (age 7–16).131 When receiving doses of 20 to 30 mg daily, 19 patients showed some improvement and 13 had a reduction in their tics of more than 50%. Nicolson et al. reported the results of an 8-week double-blind, randomized, placebo-controlled trial of metoclopramide.132 Twenty-seven patients with Tourette's, or a chronic tic disorder (age 11.9 ± 2.7 years) participated in the trial. Subjects receiving metoclopramide showed a 39% reduction in their total tic score on the (Yale) Global Tic Severity Scale, while subjects receiving a placebo showed only a 13% reduction in tic severity (P = 0.001). This result suggests that metoclopramide may be an effective treatment for children and adolescents with tic disorders.

Urological disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Diabetic cystoparesis (side effect)

Chaudhuri et al. reported their anecdotal experience from a single case of presumed diabetic cystoparesis in which their patient demonstrated improved bladder function after ten days of oral metoclopramide (40 mg daily).133 Another case report also exists that showed effectiveness of metoclopramide for diabetic cystoparesis.134

2. Lazy bladder (side effect)

In a case report that purportedly showed the effectiveness of cisapride for female lazy bladder,135 a 32-year-old female with lazy bladder was treated with cisapride (10 mg q.i.d.) for 3 weeks and obtained a progressive improvement of symptomatology and urodynamic parameters, but then returned to pretreatment conditions after drug withdrawal.

3. Urologic sequelae of spinal cord injury (side effect)

Cisapride has been indicated as a possible drug for the treatment of detrusor areflexia (and subsequent urinary retention) owing to the in vitro effects seen on the human detrusor muscle. Action of cisapride on the bladder was evaluated in normal subjects by Steele et al. who were admininstered cisapride (20 mg/day) over a 7-day period. There was no evidence of the drug's action on urodynamic parameters in normal patients, except for a decreased maximum cystometric capacity and increased maximum flow rate.136

Several case reports exist that show the effectiveness of cisapride against urologic sequelae of spinal cord injury.137,138 A group of 21 complete spinal cord injury patients were randomly assigned a treatment of cisapride (10 mg four times a day for 4 weeks) or placebo.139 By cystometry, a bladder stimulating effect was seen in a majority of the patients allocated to the cisapride group.

4. Urologic sequelae of radical hysterectomy for cervical cancer (side effect)

Medeiro et al. performed a double-blind, placebo-controlled trial to evaluate the effect of bethanechol and cisapride on urodynamic parameters in patients undergoing radical hysterectomy for cervical cancer.140 Seventy-nine patients were randomized to receive bethanechol (30 mg/day), cisapride (30 mg/day), bethanechol combined with cisapride (same doses) or placebo. Medication was administered postoperatively for 30 days. The rate of detrusor instability was higher in the group that used bethanechol combined with cisapride, and detrusor pressure at maximum flow was significantly higher when cisapride was used. There was a significant increase in postvoid residual volume in the placebo group. Thus, the early use of both bethanechol and cisapride after radicalhysterectomy may better modify urodynamic parameters. Bethanechol is a parasympathomimetic agent which until now has been considered the drug of choice for treatment of patients with high postvoid residual volume and no intravesical obstruction.

Gynecological disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Amenorrhea of hypothalamic origin (side effect)

Published data has demonstrated that the chronic use of metoclopramide, a dopamine antagonist, causes increased gonadotropin secretion in patients with hypothalamic amenorrhea but without triggering ovulation. It has also been observed that women with hypothalamic amenorrhea respond poorly to ovulation induction with clomiphen citrate. Mendes et al. examined the effect of metoclopramide on the response to clomiphene citrate in patients with hypothalamic amenorrhea.141 Twenty-two patients were submitted to a randomized, double-blind study in which metoclopramide (5 mg) or placebo was administered every 8 h for 2 months. They concluded that metoclopramide increased the circulation levels of LH, FSH, estradiol and ploractin in patients with hypothalamic amenorrhea and low estrogen levels, but that the combination of metoclopramide and clomiphene citrate did not improve the rate of ovulation compared with placebo.

Pediatric disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Persistent crying in infants (direct effect of motility stimulating property)

A randomized, placebo-controlled trial was performed to assess the effect of antireflux treatment on persistent crying in infants.142 One hundred and three infants were randomized to active medication (ranitidine plus cisapride), placebo, or infant mental health consultation. There was a significant reduction in crying duration from baseline to week 4 (253 ± 96.5 min vs 159 ± 92.3 min per 24 h; P < 0.001), but without difference between treatment groups. Antireflux medication and infant mental health consultation were not superior to placebo in treating infants with persistent crying. These results suggest that GERD may not be a cause of persistent crying in infants, and that prokinetic agents may not be effective for this syndrome.

2. Disrupted irregular sleep pattern (direct effect of motility stimulating property)

Cisapride was administered to 22 infants (4–26 weeks old) who presented with a disrupted irregular sleep pattern.143 The disrupted sleep pattern improved significantly or disappeared in all infants (P < 0.001). Gastroesophageal reflux was assessed by 24-h continuous esophageal pH monitoring, and all pH monitoring data decreased significantly after treatment with cisapride (P < 0.001). This study concluded that in a number of young infants, gastroesophageal reflux may be associated with a disturbed, irregular sleep of poor quality, which is characterized by a typical breathing pattern (multiple, irregularly repeated, short apnea).

3. Feeding tolerance of preterm infants (direct effect of motility stimulating property)

Fifty-nine premature infants were randomized into a blinded placebo-controlled trial to evaluate the efficacy of cisapride for improving tolerance of enteral feeding.144 Treatment was initiated with the introduction of enteral feeding and continued until 150 mL/kg/day of milk was tolerated. With cisapride treatment the time to tolerate full enteral feeding was shorter in the treatment group only in extremely low birth weight infants. Electrocardiogram (ECG) recordings also showed a significantly prolonged QTc interval during treatment, and two children developed cardiac rhythm disturbances. In conclusion, premature infants may not benefit from routine use of cisapride to improve enteral feeding, and seem to be more vulnerable to side effects. Because other prokinetic agents have little effect on the heart, other prokinetic agents might be beneficial for improving enteral feeding in premature infants.145

Otorhinolaryngological disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Laryngeal dysfunction (direct effect of motility stimulating property)

Laryngeal dysfunction, a common cause of dyspnea, may be misdiagnosed as asthma. Pulmonary function testing with flow volume loops can separate patients with dyspnea into true asthma or laryngeal dysfunction. In one study that used antireflux medications (ranitidine, 150 mg twice daily, and cisapride, 20 mg three times daily), the peak flows in the laryngeal dysfunction group improved by 39% compared with 15% in the asthma group.146

Miscellaneous

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

1. Lactation (side effect)

Budd et al. reported a case of improved lactation from use of metoclopramide.147 Hansen et al. investigated the effect of metoclopramide on breast milk volume and duration of breastfeeding in women who delivered preterm.148 Women were randomized to receive metoclopramide (10 mg) or placebo, starting within 96 h of birth. Fifty-seven women completed the study. There was no significant difference between breast milk volumes for each of the 17 days of the study, or duration of breastfeeding between the metoclopramide and placebo groups. Seema et al. reported no significant effect of relactation in a study that was completed with 43 women.149

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References

Prokinetic agents are effective against various diseases in the CNS, and the respiratory, urologic, and metabolic organs. There are two main mechanisms of action: the side effect of the agents, and improvement of GI tract motility. Some example diseases that are treated by side effects of the drug are use of metoclopramide for acute migraine and Tourette's syndrome and cisapride against bladder dysfunction. Metoclopramide is a peripheral dopamine2-receptor antagonist, and the receptor is located not only in the GI tract but also in the brain, and is related to migraine and Tourette's disorder. The 5-HT receptor is present in the bladder, and cisapride acts on this receptor. Examples of the latter (improvement of GI tract motility) are cisapride used for treatment of Parkinson's disease, bronchial asthma, SBP etc. Improvement of GI motility induces better L-dopa absorption, reduced reflux of gastric contents into the esophagus, and suppresses bacterial over-growth. Prokinetic agents (except for cisapride and tegaserod) are safe and can be used long term. Prokinetic agents should be a valuable addition to our currently limited pharmacological armamentarium not only for functional bowel disease, but also for diseases external to the GI tract.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Critical care
  5. Respiratory disease
  6. Digestive disease
  7. Metabolic disease
  8. Central nervous system disease
  9. Psychiatric disease
  10. Urological disease
  11. Gynecological disease
  12. Pediatric disease
  13. Otorhinolaryngological disease
  14. Miscellaneous
  15. Summary
  16. References
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