What is the effect of cisapride on the LES pressure ?
M Katschinski (Marburg)
Cisapride, a substituted piperidinyl benzamide chemically related to metoclopramide (figure /), is a newly available compound thought to promote gastrointestinal motility. The drug acts at least in part through a mechanism involving enhancement of physiological release of acetylcholine from postganglionic nerve endings of the myenteric plexus [1].
Figure 1. Chemical structure of cisapride. Role of lower esophageal sphincter in reflux disease
There is good evidence that a well-functioning lower esophageal sphincter (LES) is probably the single most important factor in the prevention of gastroesophageal reflux [2]. In spite of its limitations LES pressure (LESP) is the current standard to measure LES performance. Assessment of the effect of cisapride on LES function is essential to provide a pathophysiological basis for its therapeutic use in reflux disease.
Effects of cisapride on LESP
Influence of single intravenous or oral doses in healthy volunteers
Cisapride given orally or intravenously at single 5 to 20 mg doses generally increases LESP by about 20 to 50 p. cent although some studies have shown less consistent effects after oral use : in an uncontrolled study, Case and Williams [3] found a single intravenous bolus of cisapride 10 mg to significantly enhance LESP in the fasting state (p<0.01). Correspondingly, Gilbert et al. [4] demonstrated cisapride 10 mg intravenously to increase LESP within 15 min in the fed state (p < 0.05). The effect persisted throughout the 60 min test period, the maximal increase amounting to 33 p. cent. In the same study, significant increases of LESP after oral administration of cisapride 5, 10 or 20 mg were confined to the 20 mg dose : the initial significant response was evident at 45 min after drug administration. The peak response of 36 p. cent occurred at 75 min. Increases in LESP with escalating doses of cisapride were associated with commensurate increases in plasma cisapride levels. Bontempo et al. [5], however, reported a single oral 10 mg dose to significantly raise LESP in healthy volunteers (p < 0.01). The effect started between 10 and 70 min and lasted until 140-170 min after drug administration.
Efficacy in patients with reflux disease
Greater increases in LESP have been observed in patients than in healthy subjects although this finding is not unchallenged : Ceccatelli et al. [6] detected a 145 p. cent increase of LESP in reflux patients with low baseline value (8.7 mmHg for patients vs 19.3 mmHg for controls) distinctly exceeding the response in healthy volunteers (figure 2). In this study, cisapride 10 mg was intravenously given. On the other hand, Bontempo et al. [5] reported at least equal cisapride-induced LESP increments in healthy volunteers than reflux patients. In another trial in reflux disease without a control group, intravenous cisapride 8 mg and oral cisapride 10 mg raised LESP (p<0.01 and p<0.05, respectively) [7].
Administration of repeated doses
Administration of repeated doses of cisapride to healthy subjects has elicited elevations of LESP approximating the effect of single doses: Smout et al. [8] investigated six subjects receiving cisapride 0.5 mg/h intravenously preceded by a three day oral loading at 10 mg and matching placebo. By computer analysis, this study proved cisapride to significantly enhance interdigestive and postprandial LESP : interdigestive and post-meal peak responses amounted to 36 p. cent (phase 1 of interdigestive motility) and 37 p. cent (121-150 min post-meal). In the early postprandial periods, no effect of cisapride on LESP was observed. In another study, an approximately 20 p. cent increase (p < 0.002) was visible in ten healthy subjects having received cisapride 10 mg orally tid for four days [9]. Moreover, Katschinski et al. [unpublished data] studied the effect of oral cisapride 10 and 20 mg preceded by a three day oral loading at 10 mg qid and matching placebo. LESP was continuously scored by specially designed computer algorithms. This constant recording accounting for the temporal variability of LESP better reflects physiology
Figure 2. Effect of cisapride on resting LESP in normal volunteers (fig 2a) and in reflux patients with a LESP below 10 mmHg (fig 2b). Cisapride restores the decreased LESP in the reflux group (from [6], with permission).
of sphincter performance. LESP was significantly (p = 0.02) elevated by both dosages: Responses amounted to 40 p. cent (l0mg) and 32 p. cent (20 mg). An especially profound stimulatory effect of oral cisapride on LESP is represented by figure 3.
Comparison to metoclopramide
The influence of cisapride on LESP equals or exceeds that of metoclopramide. Wienbeck et al. [10] compared the effects of single intravenous doses of cisapride 4 mg and metoclopramide 10 mg on LES tone in healthy volunteers. The maximum effects were attained 30 min after injection, amounting to 83 p. cent for metoclopramide and 95 p. cent for cisapride as compared to placebo. Katschinski et al. [11] have investigated the influence of single intravenous 10 mg doses of cisapride and metoclopramide on LESP. Continuous scoring by computer analysis offered the
Figure 3. A motility record from a healthy subject showing an LESP of 12mmHg under placebo (right panel; traces 5 and 6 represent LESP and fundic pressure) and a distinct increase of LESP to 41 mmHg under cisapride 10 mg p.o. (left panel).
opportunity of defining the net effect of both drugs over 60 min. Whereas metoclopramide did not significantly elevate LESP in this setting, cisapride caused a 28 p. cent increment, figure 4 portrays a clear effect of cisapride on LESP in an individual subject. Accordingly, Weiser and colleagues [ 12] reported significant enhancement of LESP following single intravenous cisapride 10 mg (p<0.01).
Figure 4. Stimulatory influence of intravenous cisapride (10mg) on LESP in a healthy individual: It raises LESP (left panel; traces 5 and 6 portray LESP and fundic pressure) by 26 % as compared to placebo (right panel).
Metoclopramide only slightly but insignificantly (p = 0.065) raised LESP, with the response being of shorter duration.
Conclusion
The data reviewed above form a large body of evidence indicating that cisapride effectively increases LESP. Enhancement of LES tone was proved for fasting and fed states, for intravenous and oral administration, for healthy subjects and reflux patients. As cisapride seems to be able to restore the decreased LESP in reflux disease it is a promising drug.
References