Synergic effect of erythromycin and CoAA on gallbladder contraction in patients with cholelithiasis

Abstract

AIM: To study the effect of combined use of compound amino acids (CoAA) and erythromycin in the promotion of gallbladder emptying and their mechanism of action.

METHODS: Sucralfate-NS, sucralfate-CoAA, proglumide-CoAA or erythromycin-CoAA was administered to 36 patients with cholelithiasis, and their gallbladder emptying rates (PGER) were compared by ultrasonographic measurement of gallbladder volume.

RESULTS: The PGER of the CoAA group was 40.52% ± 6.84%, which was significantly increased. The gallbladder contractive effect of CoAA could be blocked partially by the cholecystokinin (CCK) receptor blocker Proglumide. The PGER of combined erythromycin and CoAA was 54.17% ± 5.35%, being much higher than that in the group treated with CoAA alone (P < 0.05).

CONCLUSION: Rapid infusion of CoAA in patients with cholelithiasis can increase PGER, via a mechanism that is related to the release of CCK. When erythromycin is administrated at the same time, the PGER increases more significantly and the peak effect appears earlier. This finding suggests that combined use of the two has a synergic effect on gallbladder contraction, and that it is more effective than CoAA alone; thus, combined treatment might be useful in correcting gallbladder emptying impairment and preventing bile retention.

Key Words: Erythromycin; Cholelithiasis; Gallbladder; Amino acids; Sucralfate

INTRODUCTION

Gallbladder contraction impairment and bile retention are two important factors involved in gallstone formation. So far, there have been few drugs that can promote gallbladder emptying. Recent studies showed that rapid pulsatile intravenous infusion of compound amino acids (CoAA) elevated the plasma amino acids up to the level equivalent to that of a Sustagen-supplemented diet, which is able to cause gallbladder emptying and release of cholecystokinin (CCK)[1]. In contrast, erythromycin stimulates motilin activity[2]. We studied the effects of the two drugs on fasting gallbladder contraction in patients with gallstones and a brief appraisal is presented herein.

MATERIALS AND METHODS

Subjects

Thirty-six male and female patients with gallstones, ages ranging from 18 years to 65 years, were studied. Those with thickened gallbladder wall, gallstones more than one-half of the volume of the gallbladder, atrophied gallbladder with adhesions, cardiac insufficiency, active peptic ulcer, and long-term dietary restriction of greasy food were excluded. No drugs were given 3 d before the test.

Methods

The study was conducted over a 2-d period. On the first day, the 36 patients were randomly divided into three groups, each consisting of 12 cases, with similar mean age and sex distribution. The fasting gallbladder volume (FGV) was measured in all 36 patients. Group 1 was given sucralfate powder (1.0 g), after which the gallbladder volume was measured once every 15 min and continuously for 4 times, then 250 mL of 0.9% NS was infused within 30 min; the gallbladder volume was measured once every 10 min for 6 times. Group 2 was given 250 mL of 5% CoAA, and the rate of infusion, method and times of measurements were the same as those of the group 1. Group 3 received proglumide powder (0.8 g orally), and the gallbladder volume was measured once every 15 min and continuously for 5 times; then 250 mL of 5% CoAA was given in the same manner as in group 2. The FGV was measured again the next day for all patients. Erythromycin (0.5 g) was then given orally, and the gallbladder volume was measured once every 15 min and continuously for 4 times; then 5% CoAA (250 mL) was given afterwards.

The single-blind research method was used in this investigation. The gallbladder volume was measured by ultrasonography using a Siemens-450 type probe with 35 MHz and according to periphery diameter. Each volume was detected twice, and averaged. The gallbladder emptying rate (PGER) was calculated as: (FGVs-PGVs)/FGVs × 100%, where PGVs was the post-administration gallbladder volume.

RESULTS

On the first day, the gallbladder volume contracted gradually within 30-60 min after drug administration for group 2. The peak contraction time was relatively concentrated at the 40^th minute. The PGER (40.52% ± 6.84%) increased much more significantly than in group 1 (6.21% ± 3.56%) (P < 0.05). On the next day, after administration of both drugs, the gallbladder volume of all 36 patients reduced gradually within 10-30 min. The peak contraction time occurred at about the 20^th minute. The PGER (54.17% ± 5.35%) also increased more markedly than that of group 2 on the first day (P < 0.05). The PGER (34.47% ± 4.54%) of group 3 on the first day was significantly different from those of group 1 and 2 (P < 0.01; Table 1).

Table 1 Comparison of gallbladder volume and postprandial gallbladder emptying rate in three groups with gallstone disease (x^-± s).

	Group	n	FGV, cm3	Minimum volume after injection, cm3	PGER, %	Peak time
	1	12	28.55 ± 4.98	26.83 ± 5.12	6.21 ± 3.56
1st day	2	12	27.54 ± 4.47	16.28 ± 3.05	40.52 ± 6.84a	40th min
	3	12	33.55 ± 6.52	22.40 ± 4.83	34.47 ± 4.54b
2nd day	All	36	30.49 ± 3.45	13.91 ± 1.81	54.17 ± 5.35c	20th min

Group 2 vs group 1 on the first day (^aP < 0.05); Group 3 vs groups 1 and 2 on the first day (^bP < 0.01); All cases on the second day vs group 2 on the first day (^cP < 0.05). FGV: Fasting gallbladder volume; PGER: Postprandial gallbladder emptying rate.

DISCUSSION

CCK is involved, to a greater degree, in the postprandial gallbladder contraction phase. Recent studies showed that dose-related and rate-related gallbladder emptying in patients receiving intravenous CoAA infusion might be due to its release from CCK-containing cells stimulated either directly or indirectly. Motilin and 5-HT, as prokinetic agents, might also play some roles but the precise mechanism has not been elucidated. Nealon et al[1] found that the plasma amino acid levels were similar to those found following a Sustagen-supplemented diet at 30-60 min after intravenous CoAA infusion given at two intermediate rates (125 mg/kg·h and 240 mg/kg·h).

The 12 patients in group 2 with cholecystitis and cholelithiasis who received rapid CoAA infusion within 30 min showed a gradual decrease of gallbladder volume within 30-60 min, with a mean minimum gallbladder volume of 16.28 ± 3.05 cm³, and a peak response was observed at 40 min after infusion along with the mean PGER being 40.52% ± 6.84%. The volume of the gallbladder also increased somewhat after 1 h. Only one case showed the smallest gallbladder volume at the 20^th minute. It was confirmed that CoAA had a significant effect on gallbladder contraction; sucralfate is not absorbable and has no effect on gallbladder contraction, therefore serving as a placebo.

Proglumide has a structure similar to the active constituent of gastrin/CKK molecules, so that may play a role as gastrin/CKK blocker upon combining with each receptor. About 120 min after oral delivery of proglumide, its plasma concentration reached its peak, which was 20 min later than that after the oral erythromycin. Therefore, in group 3, the gallbladder volume measurement was carried out 5 times consecutively (i.e. once every 15 min) and CoAA was given afterwards. The mean PGER was 34.47% ± 4.54% after the infusion, and there was a significant difference between group 1 and group 2 (P < 0.05). This finding suggests that proglumide might have a significant effect on blocking the action of amino acid. Whether the latter is related to the promoting effect of proglumide in bile secretion deserves further study.

The cholinergic nerve in the cephalic phase also participates in the postprandial gallbladder contraction[3]. Erythromycin, as a motilin receptor agonist, can decrease the FGV in healthy men and patients with gallstone diseases. The plasma level peaked at 100 min after oral administration of the drug and maintained this level for 2 h. The postprandial gallbladder emptying was decreased in patients with cholelithiasis, but became normal after oral erythromycin; likewise, it had a significant increase in healthy persons[2] and its effect could be blocked by atropine[4]. It is suggested that the cholinergic neural humoral factors play a crucial role in gallbladder contraction, whereas motilin only acts as a trigger for provoking contraction and mediates strength of contraction.

In this study, the gallbladder contraction was seen about 10 min after infusion and maintained about 60 min in 36 patients with cholelithiasis who were given intravenous CoAA and oral erythromycin; the peak response was relatively concentrated and advanced at the 20^th minute. The average smallest gallbladder volume was 13.91 ± 1.81 cm³ and the mean PGER was 54.17% ± 5.35%. As compared with CoAA alone, there was a marked difference (P < 0.05). No significant adverse reactions were found after the rapid infusion of CoAA and oral erythromycin at the above dosage, except in two patients who experienced transient dizziness, nausea and gastric distress.