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Treatment of Gi dysmotility in scleroderma with the new enterokinetic agent prucalopride
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 1, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(01)03958-2
Treatment of GI Dysmotility in Scleroderma With the New Enterokinetic Agent Prucalopride G. E. Boeckxstaens, M.D., Ph.D., J. F. W. M. Bartelsman, M.D., L. Lauwers, M.D., and G. N. J. Tytgat, M.D., Ph.D. Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Janssen Research Foundation, Beerse, Belgium
ABSTRACT Scleroderma is a multisystem disorder frequently resulting in disturbed GI motility. Although, especially early in the disease, symptomatic improvement is achieved with prokinetic agents, more severe GI manifestations of scleroderma may be difficult to treat, leading to parenteral feeding and hospitalization. Recently, a new serotonin (5-HT4) receptor agonist prucalopride was shown to have remarkable prokinetic properties, resulting in symptomatic improvement and increased frequency of defecation in patients with chronic functional constipation. Here we report two cases of scleroderma with GI manifestation in which previous prokinetic treatment failed, but where the patients were successfully treated with prucalopride. Our data suggest that prucalopride may be a promising and effective drug to treat GI motility disorders in scleroderma. However, further placebo-controlled double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma. (Am J Gastroenterol 2002;97:194 –197. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Scleroderma or progressive systemic sclerosis is a multisystem disorder of the small arteries resulting in skin abnormalities, Raynaud’s disease, polyarthritis, and lung, heart, and kidney involvement (1). About 90% of the patients will develop GI manifestations, most commonly involving the esophagus with dysphagia and gastroesophageal reflux. Also, gastric emptying can be delayed because of sluggish motility of the stomach in 57–75% of the patients (2). Involvement of the small intestine, occurring in approximately 40 –50% of the patients, results in abdominal bloating, distension, nausea, and vomiting (3). In addition, abnormalities or even absence of phase III activity of the migrating motor complex and impaired contractility may result in intestinal stasis with bacterial overgrowth (4). Patients can also present with episodes of ileus in case of pseudo-obstruction. Finally, constipation (5) or anal incontinence due to involvement of the internal anal sphincter occurs in 10 –50% of the patients (1, 3). Treatment of these motility disorders is often difficult.
Prokinetic agents such as metoclopramide (6), erythromycin (7), and cisapride (8) have been shown to be effective in some patients, especially in the early course of the disease. However, in more advanced disease, the therapeutic effect of these agents often attenuates dramatically, necessitating hospitalization and parental feeding. Recently, the new serotonin (5-HT4) receptor agonist prucalopride was shown to have remarkable colonic prokinetic properties, accelerating colonic transit in healthy volunteers (9), and to induce mass movements in dogs (10). These properties resulted in symptomatic improvement and in increased frequency of defecation in patients with chronic functional constipation (11). Here we report on the effect of this new prokinetic agent in two patients with scleroderma and disordered intestinal transit in whom previous treatment with laxatives, other prokinetics, or octreotide has failed. Prucalopride treatment increased GI motility, which led to subjective improvement.
CASE REPORTS Case 1 The first patient was a 60-yr-old female with arterial hypertension, chronic obstructive pulmonary disease, and a history of hysterectomy and ovariectomy. She was also known to have long-standing scleroderma, first diagnosed 19 yr ago, with skin involvement, severe constipation, and incontinence due to paradoxical diarrhea. At presentation the patient did not have spontaneous defecation, without laxatives, despite high fiber intake. She also complained of dysphagia, pyrosis, early satiety, and abdominal distension. Because of fecal incontinence, she was markedly socially disabled. A physical examination revealed thickened skin, at both hands, but no typical scleroderma facies. No other abnormalities were found. Blood pressure was 140/90 mm Hg. She weighed 74 kg for a length of 168 cm. A routine laboratory examination revealed no abnormalities. Antinuclear antibodies, antiribonucleoprotein, anti– SS-A, and anti–SS-B were negative. A plain abdominal x-ray showed a dilated colon filled with stool. On esophageal manometry, a typical picture of absent peristalsis and absent lower esophageal pressure was noted. Anorectal ma-
AJG – January, 2002
GI Dysmotility in Scleroderma and Prucalopride
195
Figure 1. Small intestinal manometry showing postprandial motility (A) before and (B) during treatment with prucalopride (2 mg once daily) in case 1. The tip of a multilumen manometric catheter was introduced beyond the angle of Treitz under fluoroscopic control. The position of the catheter was continuously monitored using transmucosal potential difference measurement. The tracings of three antral channels (1.5 cm apart) and six small intestinal channels (10 cm apart) are shown.
nometry showed a very low basal sphincter pressure of 15 mm Hg with a decreased squeeze pressure of 25 mm Hg. Before treatment with prucalopride, fasting small intestinal manometry revealed phase III activity in the antrum with lowered amplitude and absence of contractile activity in the small intestine. After ingestion of a standardized meal (pancake, 660 kcal), sparse contractile activity was recorded in the antrum but almost no contractions in the small intestine (areas under the curve [AUCs] during the first hour: antrum, 761 mm Hg 䡠 s; small intestine, 621 mm Hg 䡠 s) (Fig. 1). Colonic transit was determined according to Bouchoucha et al. (12). Briefly, after ingestion of 10 radiopaque markers daily during 6 consecutive days, an abdominal x-ray was taken on day 7. The number of markers multiplied by 2.4 equals the whole gut transit time in hours (normal ⬍ 88 h). In this patient, all 60 markers were still present on day 7 (whole gut transit time ⬎ 144 h). In the past, she had been
treated unsuccessfully with several laxatives, including bisacodyl and anthrachinon derivatives, and prokinetics such as domperidone and cisapride. During treatment with 2 mg of prucalopride once daily, symptoms significantly improved; especially, appetite increased, abdominal distension decreased, and the patient obtained a daily defecation pattern. In addition, fecal incontinence improved, allowing a return to normal daily activities. Dysphagia only slightly improved. Repeat manometric study revealed increased postprandial motility both in the antrum (AUC during the first hour ⫽ 23,817 mm Hg 䡠 s) and in the duodenum (AUC during the first hour ⫽ 13,304 mm Hg 䡠 s) (Fig. 1). Total colonic transit time decreased to 124 h. After several months of treatment, prucalopride was stopped temporarily. Within a few days symptoms returned, with, again, absent spontaneous defecation, abdominal bloating, and loss of appetite. When treatment was resumed
196
Boeckxstaens et al.
symptomatic improvement occurred after 2 wk. At present, the patient has taken prucalopride (2 mg every other day) for more than a year and leads a normal social life. Case 2 The second patient was a 30-yr-old female known to have scleroderma and Sjo¨ gren’s syndrome, diagnosed 5 yr ago. Her main complaints were keratoconjunctivitis, xerostoma, Raynaud’s phenomenon, dysphagia, nausea, loss of appetite, abdominal pain, and abdominal distension. She also complained of episodic constipation, with sometimes up to 9 days without stools, alternating with episodes of diarrhea. On physical examination no abnormalities were found and no cutaneous involvement could be detected. Blood pressure was 128/80 mm Hg. She weighed 44 kg for a length of 150 cm. Routine laboratory examination was normal. Antinuclear antibodies were positive, whereas antiribonucleoprotein, anti–SS-A, and anti–SS-B were negative. A plain abdominal x-ray was normal. In 1996, esophageal manometry still revealed normal peristaltic waves after swallowing. Because of increasing complaints of dysphagia, esophageal manometry was repeated in 1999, showing simultaneous contractions in the presence of otherwise preserved esophageal peristaltic activity after a wet swallow and normal lower esophageal sphincter pressure of 20 mm Hg. Gastric emptying was normal for liquids, but was delayed for solids (13.6% empyting/h [normal range ⫽ 35– 60%]). Small intestinal manometry in 1997 showed a disordered phase III activity with the presence of clustered small intestinal contractions. The amplitude of the contractions in both the antrum and the duodenum were normal, however. Repeat small intestinal manometry in 1998 (before treatment with prucalopride) showed an abnormal phase III of the migrating motor complex progressing to the small intestine. Treatment consisted initially of cisapride with variable success. To diminish abdominal distension, the patient inserted a rectal cannula t.i.d. Later on, octreotide (100 g) was added to the treatment. Initially, the episodic diarrhea improved, but octreotide was stopped after 1 month because of attenuation of the efficacy. Thereafter, the patient was treated with 2 mg of prucalopride once daily. The first few days she reported nausea and diarrhea, but soon she regained appetite, abdominal distension decreased, and defecation normalized. In contrast, dysphagia persisted. During treatment with prucalopride, postprandial motility (AUC in the first postprandial hour) increased in the antrum from 8,490 mm Hg 䡠 s to 11,802 mm Hg 䡠 s and in the small intestine from 6,484 mm Hg 䡠 s to 25,194 mm Hg 䡠 s. Colonic transit time accelerated from 98 h before treatment to 26 h during treatment. Symptoms recurred when the treatment was stopped temporarily but improved again after the restart of prucalopride. At present, the patient is treated with 2 mg of prucalopride once daily, which she has been taking for more than a year with maintenance of subjective improvement.
AJG – Vol. 97, No. 1, 2002
DISCUSSION Prucalopride is the first member of a novel chemical class, termed benzfuran carboxamides, with selective 5-HT4 receptor agonist and enterokinetic properties (10). In vitro, it enhances electrically induced nonadrenergic contractions and facilitates cholinergic neurotransmission (13). In vivo, prucalopride enhances canine colonic motility with induction of high amplitude contractions and mass movements (10). Similarly, colonic transit time is significantly accelerated in healthy volunteers during treatment with prucalopride (9, 14). This prokinetic effect most likely underlies the significant symptomatic improvement and increase in defecation frequency observed in patients with chronic constipation during treatment with prucalopride relative to a placebo (11, 15, 16). Here we have reported cases from two patients, one with longstanding scleroderma and one with scleroderma and Sjo¨ gren’s syndrome, successfully treated with prucalopride. Both patients had symptoms of GI scleroderma with dysphagia, early satiety, abdominal distension, and constipation. This was confirmed by abnormal esophageal and small intestinal manometry, delayed gastric emptying at scintigraphy, and prolonged colonic transit time. In contrast to previous treatments, including cisapride and octreotide, which only had a temporary beneficial effect, prucalopride significantly improved symptoms long term, with return to normal social activity in one of the two patients. This patient, who reported having no spontaneous bowel movements, had normal daily defecation during treatment with prucalopride. The other patient complained mainly of abdominal distension, initially treated symptomatically by the introduction of a rectal cannula t.i.d. She also had constipation alternating with diarrhea. During treatment, abdominal distension decreased significantly, necessitating rectal cannulation only once every 3 days. Moreover, return of normal defecation was achieved. Most likely, improvement of symptoms results from increased GI motility. As in healthy volunteers (9, 17), whole gut transit time was decreased during treatment with prucalopride in both patients. Most likely, this results from the acceleration of overall colonic transit, particularly of the proximal colon, as shown by scintigraphic measurements in healthy volunteers (14). This prokinetic effect in colonic motility therefore most likely mainly explains the return of normal defecation in our patient. We also showed an increase in antroduodenal motility, especially in case 1, as shown in Figure 1. This is of great interest, as Bouras et al. (14) recently showed that prucalopride did not affect gastric and small bowel motility in healthy volunteers. However, this does not exclude a beneficial effect of prucalopride in cases of disturbed motility. For example, cisapride also increases gastric emptying in patients with progressive systemic sclerosis (8) but not in healthy volunteers (18). Similarly, prucalopride improves gastric emptying in a model of delayed gastric emptying, showing that the effect of pru-
AJG – January, 2002
calopride is not confined to the colon (19). Although we did not assess gastric emptying during treatment, the increase in antroduodenal motility further corroborates the concept that prucalopride is an enterokinetic rather than a colokinetic agent. However, further studies evaluating this effect of prucalopride on antroduodenal motility and coordination and upper GI motor disorders is warranted. One might argue that the prokinetic action of prucalopride is dependent upon normal neural and smooth muscle function, which, however, is often impaired in scleroderma. Especially in case 1, small intestinal manometry revealed markedly disturbed small intestinal motility with absent contractile activity. Nevertheless, as shown in Figure 1, postprandial antroduodenal motility clearly improved during treatment. Furthermore, whole gut transit time accelerated in both patients, suggesting that prucalopride was indeed able to stimulate GI motility, even when the neuromuscular function of the gut was hampered. Whether this effect will persist or holds true for scleroderma patients with more pronounced GI manifestation remains to be studied. In conclusion, our data suggest that prucalopride may be a promising and effective drug for treating GI motility disorders in scleroderma, even when other prokinetic agents or octreotide have failed. Further placebo-controlled, double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma. Reprint requests and correspondence: G. E. Boeckxstaens, M.D., Ph.D., Division of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Received July 16, 1999; accepted Feb. 22, 2000.
GI Dysmotility in Scleroderma and Prucalopride
5. 6.
7.
8. 9. 10. 11.
12. 13. 14. 15.
16.
REFERENCES 1. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am 1998;27: 563–94. 2. Wegener M, Adamek RJ, Wedmann B, et al. Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig Dis Sci 1994;39:2209 –15. 3. Weston S, Thumshirn M, Wiste J, et al. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am J Gastroenterol 1998;93:1085–9. 4. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on
17.
18. 19.
197
intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991;325:1461–7. Hamel-Roy J, Devroede G, Arhan P, et al. Comparative esophageal and anorectal motility in scleroderma. Gastroenterology 1985;88:1–7. Johnson DA, Drane WE, Curran J, et al. Metoclopramide response in patient with progessive systemic sclerosis. Effect on esophageal and gastric motility abnormalities. Arch Intern Med 1987;147:1597– 601. Fiorucci S, Distrutti E, Gerli R, et al. Effect of erythromycin on gastric and gallbladder emptying and gastrointestinal symptoms in scleroderma patients is maintained medium term. Am J Gastroenterol 1994;89:550 –5. Horowitz M, Maddern GJ, Maddox A, et al. Effects of cisapride on gastric and esophageal emptying in progressive systemic sclerosis. Gastroenterology 1987;93:311–5. Emmanuel AV, Kamm MA, Roy AJ, et al. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut 1998;42:511– 6. Briejer MR, Ghoos E, Eelen J, et al. Serotonin 5HT4 receptors mediate the R093877-induced changes in contractile patterns in the canine colon. Gastroenterology 1997;112:A705. Coremans G, Kertstens R, De Pauw M, et al. Effects of a new enterokinetic drug, prucalopride, on symptoms of patients with severe chronic constipation: A double-blind, placebo-controlled pilot study. Gastroenterology 1999;116(4):A978. Bouchoucha M, Devroede G, Arhan P, et al. What is the meaning of colorectal transit time measurement? Dis Colon Rectum 1992;35:773– 82. Briejer MR, Meulemans AL, Bosmans J-P. In vitro pharmacology of the novel enterokinetic R093877. Gastroenterology 1997;112:A705. Bouras EP, Camilleri M, Burton DD, et al. Selective stimulation of colonic transit by the benzofuran 5HT(4) agonist, prucalopride, in healthy humans. Gut 1999;44:682– 6. Otten M, Schneider H, Wurzer H, et al. A double-blind, placebo-controlled evaluation of the savety and efficacy of 12-week, twice-daily treatment with prucalopride in patients with chronic constipation. Gastroenterology 1999;116(4): A1055. Felt-Bersma RJF, Bouchoucha M, Wurzer H, et al. Effects of a new enterokinetic drug, prucalopride, on symptoms of patients with chronic constipation: A double-blind, placebocontrolled, multicenter study in Europe. Gastroenterology 1999;116(4):A992. Poen AC, Felt-Bersma RJF, van Dongen PAM, et al. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther 2000;13:1493–7. Edwards CA, Holden S, Brown C, et al. Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects. Gut 1987;28:13– 6. Briejer MR, Meulemans AL, Wellens A, et al. R093877 dosedependently accelerates delayed gastric emptying in conscious dogs. Gastroenterology 1997;112:A705.
Vol. 97, No. 1, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(01)03958-2
Treatment of GI Dysmotility in Scleroderma With the New Enterokinetic Agent Prucalopride G. E. Boeckxstaens, M.D., Ph.D., J. F. W. M. Bartelsman, M.D., L. Lauwers, M.D., and G. N. J. Tytgat, M.D., Ph.D. Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Janssen Research Foundation, Beerse, Belgium
ABSTRACT Scleroderma is a multisystem disorder frequently resulting in disturbed GI motility. Although, especially early in the disease, symptomatic improvement is achieved with prokinetic agents, more severe GI manifestations of scleroderma may be difficult to treat, leading to parenteral feeding and hospitalization. Recently, a new serotonin (5-HT4) receptor agonist prucalopride was shown to have remarkable prokinetic properties, resulting in symptomatic improvement and increased frequency of defecation in patients with chronic functional constipation. Here we report two cases of scleroderma with GI manifestation in which previous prokinetic treatment failed, but where the patients were successfully treated with prucalopride. Our data suggest that prucalopride may be a promising and effective drug to treat GI motility disorders in scleroderma. However, further placebo-controlled double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma. (Am J Gastroenterol 2002;97:194 –197. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Scleroderma or progressive systemic sclerosis is a multisystem disorder of the small arteries resulting in skin abnormalities, Raynaud’s disease, polyarthritis, and lung, heart, and kidney involvement (1). About 90% of the patients will develop GI manifestations, most commonly involving the esophagus with dysphagia and gastroesophageal reflux. Also, gastric emptying can be delayed because of sluggish motility of the stomach in 57–75% of the patients (2). Involvement of the small intestine, occurring in approximately 40 –50% of the patients, results in abdominal bloating, distension, nausea, and vomiting (3). In addition, abnormalities or even absence of phase III activity of the migrating motor complex and impaired contractility may result in intestinal stasis with bacterial overgrowth (4). Patients can also present with episodes of ileus in case of pseudo-obstruction. Finally, constipation (5) or anal incontinence due to involvement of the internal anal sphincter occurs in 10 –50% of the patients (1, 3). Treatment of these motility disorders is often difficult.
Prokinetic agents such as metoclopramide (6), erythromycin (7), and cisapride (8) have been shown to be effective in some patients, especially in the early course of the disease. However, in more advanced disease, the therapeutic effect of these agents often attenuates dramatically, necessitating hospitalization and parental feeding. Recently, the new serotonin (5-HT4) receptor agonist prucalopride was shown to have remarkable colonic prokinetic properties, accelerating colonic transit in healthy volunteers (9), and to induce mass movements in dogs (10). These properties resulted in symptomatic improvement and in increased frequency of defecation in patients with chronic functional constipation (11). Here we report on the effect of this new prokinetic agent in two patients with scleroderma and disordered intestinal transit in whom previous treatment with laxatives, other prokinetics, or octreotide has failed. Prucalopride treatment increased GI motility, which led to subjective improvement.
CASE REPORTS Case 1 The first patient was a 60-yr-old female with arterial hypertension, chronic obstructive pulmonary disease, and a history of hysterectomy and ovariectomy. She was also known to have long-standing scleroderma, first diagnosed 19 yr ago, with skin involvement, severe constipation, and incontinence due to paradoxical diarrhea. At presentation the patient did not have spontaneous defecation, without laxatives, despite high fiber intake. She also complained of dysphagia, pyrosis, early satiety, and abdominal distension. Because of fecal incontinence, she was markedly socially disabled. A physical examination revealed thickened skin, at both hands, but no typical scleroderma facies. No other abnormalities were found. Blood pressure was 140/90 mm Hg. She weighed 74 kg for a length of 168 cm. A routine laboratory examination revealed no abnormalities. Antinuclear antibodies, antiribonucleoprotein, anti– SS-A, and anti–SS-B were negative. A plain abdominal x-ray showed a dilated colon filled with stool. On esophageal manometry, a typical picture of absent peristalsis and absent lower esophageal pressure was noted. Anorectal ma-
AJG – January, 2002
GI Dysmotility in Scleroderma and Prucalopride
195
Figure 1. Small intestinal manometry showing postprandial motility (A) before and (B) during treatment with prucalopride (2 mg once daily) in case 1. The tip of a multilumen manometric catheter was introduced beyond the angle of Treitz under fluoroscopic control. The position of the catheter was continuously monitored using transmucosal potential difference measurement. The tracings of three antral channels (1.5 cm apart) and six small intestinal channels (10 cm apart) are shown.
nometry showed a very low basal sphincter pressure of 15 mm Hg with a decreased squeeze pressure of 25 mm Hg. Before treatment with prucalopride, fasting small intestinal manometry revealed phase III activity in the antrum with lowered amplitude and absence of contractile activity in the small intestine. After ingestion of a standardized meal (pancake, 660 kcal), sparse contractile activity was recorded in the antrum but almost no contractions in the small intestine (areas under the curve [AUCs] during the first hour: antrum, 761 mm Hg 䡠 s; small intestine, 621 mm Hg 䡠 s) (Fig. 1). Colonic transit was determined according to Bouchoucha et al. (12). Briefly, after ingestion of 10 radiopaque markers daily during 6 consecutive days, an abdominal x-ray was taken on day 7. The number of markers multiplied by 2.4 equals the whole gut transit time in hours (normal ⬍ 88 h). In this patient, all 60 markers were still present on day 7 (whole gut transit time ⬎ 144 h). In the past, she had been
treated unsuccessfully with several laxatives, including bisacodyl and anthrachinon derivatives, and prokinetics such as domperidone and cisapride. During treatment with 2 mg of prucalopride once daily, symptoms significantly improved; especially, appetite increased, abdominal distension decreased, and the patient obtained a daily defecation pattern. In addition, fecal incontinence improved, allowing a return to normal daily activities. Dysphagia only slightly improved. Repeat manometric study revealed increased postprandial motility both in the antrum (AUC during the first hour ⫽ 23,817 mm Hg 䡠 s) and in the duodenum (AUC during the first hour ⫽ 13,304 mm Hg 䡠 s) (Fig. 1). Total colonic transit time decreased to 124 h. After several months of treatment, prucalopride was stopped temporarily. Within a few days symptoms returned, with, again, absent spontaneous defecation, abdominal bloating, and loss of appetite. When treatment was resumed
196
Boeckxstaens et al.
symptomatic improvement occurred after 2 wk. At present, the patient has taken prucalopride (2 mg every other day) for more than a year and leads a normal social life. Case 2 The second patient was a 30-yr-old female known to have scleroderma and Sjo¨ gren’s syndrome, diagnosed 5 yr ago. Her main complaints were keratoconjunctivitis, xerostoma, Raynaud’s phenomenon, dysphagia, nausea, loss of appetite, abdominal pain, and abdominal distension. She also complained of episodic constipation, with sometimes up to 9 days without stools, alternating with episodes of diarrhea. On physical examination no abnormalities were found and no cutaneous involvement could be detected. Blood pressure was 128/80 mm Hg. She weighed 44 kg for a length of 150 cm. Routine laboratory examination was normal. Antinuclear antibodies were positive, whereas antiribonucleoprotein, anti–SS-A, and anti–SS-B were negative. A plain abdominal x-ray was normal. In 1996, esophageal manometry still revealed normal peristaltic waves after swallowing. Because of increasing complaints of dysphagia, esophageal manometry was repeated in 1999, showing simultaneous contractions in the presence of otherwise preserved esophageal peristaltic activity after a wet swallow and normal lower esophageal sphincter pressure of 20 mm Hg. Gastric emptying was normal for liquids, but was delayed for solids (13.6% empyting/h [normal range ⫽ 35– 60%]). Small intestinal manometry in 1997 showed a disordered phase III activity with the presence of clustered small intestinal contractions. The amplitude of the contractions in both the antrum and the duodenum were normal, however. Repeat small intestinal manometry in 1998 (before treatment with prucalopride) showed an abnormal phase III of the migrating motor complex progressing to the small intestine. Treatment consisted initially of cisapride with variable success. To diminish abdominal distension, the patient inserted a rectal cannula t.i.d. Later on, octreotide (100 g) was added to the treatment. Initially, the episodic diarrhea improved, but octreotide was stopped after 1 month because of attenuation of the efficacy. Thereafter, the patient was treated with 2 mg of prucalopride once daily. The first few days she reported nausea and diarrhea, but soon she regained appetite, abdominal distension decreased, and defecation normalized. In contrast, dysphagia persisted. During treatment with prucalopride, postprandial motility (AUC in the first postprandial hour) increased in the antrum from 8,490 mm Hg 䡠 s to 11,802 mm Hg 䡠 s and in the small intestine from 6,484 mm Hg 䡠 s to 25,194 mm Hg 䡠 s. Colonic transit time accelerated from 98 h before treatment to 26 h during treatment. Symptoms recurred when the treatment was stopped temporarily but improved again after the restart of prucalopride. At present, the patient is treated with 2 mg of prucalopride once daily, which she has been taking for more than a year with maintenance of subjective improvement.
AJG – Vol. 97, No. 1, 2002
DISCUSSION Prucalopride is the first member of a novel chemical class, termed benzfuran carboxamides, with selective 5-HT4 receptor agonist and enterokinetic properties (10). In vitro, it enhances electrically induced nonadrenergic contractions and facilitates cholinergic neurotransmission (13). In vivo, prucalopride enhances canine colonic motility with induction of high amplitude contractions and mass movements (10). Similarly, colonic transit time is significantly accelerated in healthy volunteers during treatment with prucalopride (9, 14). This prokinetic effect most likely underlies the significant symptomatic improvement and increase in defecation frequency observed in patients with chronic constipation during treatment with prucalopride relative to a placebo (11, 15, 16). Here we have reported cases from two patients, one with longstanding scleroderma and one with scleroderma and Sjo¨ gren’s syndrome, successfully treated with prucalopride. Both patients had symptoms of GI scleroderma with dysphagia, early satiety, abdominal distension, and constipation. This was confirmed by abnormal esophageal and small intestinal manometry, delayed gastric emptying at scintigraphy, and prolonged colonic transit time. In contrast to previous treatments, including cisapride and octreotide, which only had a temporary beneficial effect, prucalopride significantly improved symptoms long term, with return to normal social activity in one of the two patients. This patient, who reported having no spontaneous bowel movements, had normal daily defecation during treatment with prucalopride. The other patient complained mainly of abdominal distension, initially treated symptomatically by the introduction of a rectal cannula t.i.d. She also had constipation alternating with diarrhea. During treatment, abdominal distension decreased significantly, necessitating rectal cannulation only once every 3 days. Moreover, return of normal defecation was achieved. Most likely, improvement of symptoms results from increased GI motility. As in healthy volunteers (9, 17), whole gut transit time was decreased during treatment with prucalopride in both patients. Most likely, this results from the acceleration of overall colonic transit, particularly of the proximal colon, as shown by scintigraphic measurements in healthy volunteers (14). This prokinetic effect in colonic motility therefore most likely mainly explains the return of normal defecation in our patient. We also showed an increase in antroduodenal motility, especially in case 1, as shown in Figure 1. This is of great interest, as Bouras et al. (14) recently showed that prucalopride did not affect gastric and small bowel motility in healthy volunteers. However, this does not exclude a beneficial effect of prucalopride in cases of disturbed motility. For example, cisapride also increases gastric emptying in patients with progressive systemic sclerosis (8) but not in healthy volunteers (18). Similarly, prucalopride improves gastric emptying in a model of delayed gastric emptying, showing that the effect of pru-
AJG – January, 2002
calopride is not confined to the colon (19). Although we did not assess gastric emptying during treatment, the increase in antroduodenal motility further corroborates the concept that prucalopride is an enterokinetic rather than a colokinetic agent. However, further studies evaluating this effect of prucalopride on antroduodenal motility and coordination and upper GI motor disorders is warranted. One might argue that the prokinetic action of prucalopride is dependent upon normal neural and smooth muscle function, which, however, is often impaired in scleroderma. Especially in case 1, small intestinal manometry revealed markedly disturbed small intestinal motility with absent contractile activity. Nevertheless, as shown in Figure 1, postprandial antroduodenal motility clearly improved during treatment. Furthermore, whole gut transit time accelerated in both patients, suggesting that prucalopride was indeed able to stimulate GI motility, even when the neuromuscular function of the gut was hampered. Whether this effect will persist or holds true for scleroderma patients with more pronounced GI manifestation remains to be studied. In conclusion, our data suggest that prucalopride may be a promising and effective drug for treating GI motility disorders in scleroderma, even when other prokinetic agents or octreotide have failed. Further placebo-controlled, double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma. Reprint requests and correspondence: G. E. Boeckxstaens, M.D., Ph.D., Division of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Received July 16, 1999; accepted Feb. 22, 2000.
GI Dysmotility in Scleroderma and Prucalopride
5. 6.
7.
8. 9. 10. 11.
12. 13. 14. 15.
16.
REFERENCES 1. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am 1998;27: 563–94. 2. Wegener M, Adamek RJ, Wedmann B, et al. Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig Dis Sci 1994;39:2209 –15. 3. Weston S, Thumshirn M, Wiste J, et al. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am J Gastroenterol 1998;93:1085–9. 4. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on
17.
18. 19.
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intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991;325:1461–7. Hamel-Roy J, Devroede G, Arhan P, et al. Comparative esophageal and anorectal motility in scleroderma. Gastroenterology 1985;88:1–7. Johnson DA, Drane WE, Curran J, et al. Metoclopramide response in patient with progessive systemic sclerosis. Effect on esophageal and gastric motility abnormalities. Arch Intern Med 1987;147:1597– 601. Fiorucci S, Distrutti E, Gerli R, et al. Effect of erythromycin on gastric and gallbladder emptying and gastrointestinal symptoms in scleroderma patients is maintained medium term. Am J Gastroenterol 1994;89:550 –5. Horowitz M, Maddern GJ, Maddox A, et al. Effects of cisapride on gastric and esophageal emptying in progressive systemic sclerosis. Gastroenterology 1987;93:311–5. Emmanuel AV, Kamm MA, Roy AJ, et al. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut 1998;42:511– 6. Briejer MR, Ghoos E, Eelen J, et al. Serotonin 5HT4 receptors mediate the R093877-induced changes in contractile patterns in the canine colon. Gastroenterology 1997;112:A705. Coremans G, Kertstens R, De Pauw M, et al. Effects of a new enterokinetic drug, prucalopride, on symptoms of patients with severe chronic constipation: A double-blind, placebo-controlled pilot study. Gastroenterology 1999;116(4):A978. Bouchoucha M, Devroede G, Arhan P, et al. What is the meaning of colorectal transit time measurement? Dis Colon Rectum 1992;35:773– 82. Briejer MR, Meulemans AL, Bosmans J-P. In vitro pharmacology of the novel enterokinetic R093877. Gastroenterology 1997;112:A705. Bouras EP, Camilleri M, Burton DD, et al. Selective stimulation of colonic transit by the benzofuran 5HT(4) agonist, prucalopride, in healthy humans. Gut 1999;44:682– 6. Otten M, Schneider H, Wurzer H, et al. A double-blind, placebo-controlled evaluation of the savety and efficacy of 12-week, twice-daily treatment with prucalopride in patients with chronic constipation. Gastroenterology 1999;116(4): A1055. Felt-Bersma RJF, Bouchoucha M, Wurzer H, et al. Effects of a new enterokinetic drug, prucalopride, on symptoms of patients with chronic constipation: A double-blind, placebocontrolled, multicenter study in Europe. Gastroenterology 1999;116(4):A992. Poen AC, Felt-Bersma RJF, van Dongen PAM, et al. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther 2000;13:1493–7. Edwards CA, Holden S, Brown C, et al. Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects. Gut 1987;28:13– 6. Briejer MR, Meulemans AL, Wellens A, et al. R093877 dosedependently accelerates delayed gastric emptying in conscious dogs. Gastroenterology 1997;112:A705.