Effects of oral clarithromycin and amoxycillin on interdigestivegastrointestinal motility of patients with functional dyspepsiaand Helicobacter pylori gastritis

M. BORTOLOTTI, F. BRUNELLI, P. SARTI, C. MARI M. MIGLIOLI

Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy

Accepted for publication 18 June 1998

INTRODUCTION

Clarithromycin and amoxycillin are antibiotics com-

monly used alone or in association for Helicobacter pylori

eradication1±3, also in cases with functional dyspepsia.4

Because this treatment is sometimes associated with

gastrointestinal symptoms (borborygma, epigastric

cramps, diarrhoea, etc.),2±4 while treatment with om-

eprazole alone is not, we believe that these gastrointes-

tinal symptoms could be due to one or both of these

antibiotics. As these symptoms suggest a stimulation of

gut motility, we investigated the effects of the admin-

istration of these antibiotics on the interdigestive motor

activity of the gastroduodenal tract of patients.

The fasting state of most mammalian species, includ-

ing humans, is characterized by the cyclic appearance of

a motor pattern called the interdigestive `migrating

motor complex' (MMC)5, 6 which at intervals of about

90 min sweeps through the stomach and the small

intestine down to the ileo-caecal valve, clearing the gut

SUMMARY

Background: Clarithromycin and amoxycillin are antibi-

otics commonly used in association for Helicobacter

pylori eradication. Because this treatment, which lasts

1±2 weeks, is frequently associated with gastrointesti-

nal symptoms, we investigated the effects of these

antibiotics on gastrointestinal motility.

Patients and methods: Gastroduodenal motility was

recorded in 14 patients with functional dyspepsia and

H. pylori gastritis by means of a low-compliance man-

ometric system with four recording ports in the stomach

and four in the duodenum. Two tablets of clarithromy-

cin 250 mg (seven patients, clarithromycin group) or

one of amoxycillin 1 g (seven patients, amoxycillin

group), ground and dissolved in 20 mL of water, were

given randomly and in double-blind manner 30 min

after the end of the ®rst activity front (AF) of the

migrating motor complex (MMC) or, in the absence of

AFs, after at least 200 min of recording. Recording

continued until an AF was observed during the

subsequent 200 min.

Results: Clarithromycin administration was followed by

a typical gastroduodenal AF in a signi®cantly higher

number of patients than for amoxycillin administration.

In addition, the time lag between clarithromycin

administration and the appearance of AFs was

48 min � 8.5 (mean � s.d.), signi®cantly shorter than

after amoxycillin (121 min � 29). The clarithromycin-

related duodenal AFs showed a duration of

6.6 min � 1.5, signi®cantly longer than that of the

spontaneous AFs (3.6 min � 1.2, P < 0.01), while the

amoxycillin-related AFs were not signi®cantly different

from the spontaneous ones.

Conclusion: Clarithromycin stimulated cyclic gastroduo-

denal motility, while amoxycillin was ineffective. It is

likely that symptoms during the eradication treatment

are due to this effect of clarithromycin.

Correspondence to: Prof. M. Bortolotti, Via Massarenti 48, 40138 Bolo-

gna, Italy.E-mail: mhbor@tin.it

Aliment Pharmacol Ther 1998; 12: 1021±1025.

Ó 1998 Blackwell Science Ltd 1021

lumen of non-digestible food residues, secretions, bac-

teria, etc.; for this reason it is called the `gastrointestinal

housekeeper'.7 The MMC consists of three or four phases

easily recognizable with a manometric examination, the

most important of which is a phase of intense propulsive

motor activity lasting a few minutes, called phase III or

activity front (AF), preceded by a phase of increasing

motor activity (phase II) and followed by a phase of

motor silence (phase I)

METHODS

The study was carried out on 14 patients complaining

of functional dyspepsia (six males and eight females,

mean age 30 years, range 21±49 years), in whom

H. pylori gastritis was diagnosed by means of endos-

copy and histobiopsy. Exclusion criteria were organic

lesions, operations and diseases known to affect gut

motility (diabetes, scleroderma, etc.). Informed consent

was obtained from all patients. The gastroduodenal

pressure variations were recorded by means of a

manometric probe with eight side-holes, 5 cm apart,

which were continuously perfused with distilled water

by means of a low compliance capillary infusion

system (Arndorfer Medical Specialties, Greensdale, WI)

at a rate of 0.4 mL/min and were connected to

external pressure transducers (Statham P 23 Db,

Laboratories Inc, Puerto Rico) and a polygraph

(Beckman R 612, Schiller Park, IL). After an over-

night fast of at least 12 h, the four distal recording

ports were positioned under ¯uoroscopic control,

distally to the pylorus in such a way that the most

proximal port was located near the limit between

corpus and fundus. This position of the probe allowed

us to study the occurrence of MMCs involving the

corpus, antrum and duodenum even in cases where

the probe was displaced for some centimetres during

the propulsive motility phase. The position of the

probe was continuously checked by visual inspection

of the tracing: the phasic wave frequency of each port

indicated the antral or duodenal recording sites in

such a way that in all cases three or four recording

ports were kept proximal to the pylorus. The distance

of 5 cm between the recording ports in the stomach is

suf®cient to record a gastric AF of the migrating

motor complex. In fact for an AF to be effective, it

must involve powerful contractions not only of the

distal antrum, but also of the proximal antrum and

the corpus.

Drug administration

After a basal period suf®cient to record an AF of the MMC,

two tablets of clarithromycin 250 mg (seven patients) or

one of amoxycillin 1 g (seven patients), ground and

dissolved in 20 mL of water, were given with a probe

randomly and in double-blind manner 30 min after the

duodenal AF. If during the basal period no AF was

observed, the drugs were administered after 200 min of

basal recording. After drug administration, the recording

was continued until an AF was observed during the next

200 min of recording.

Analysis of tracings

Visual inspection identi®ed along the entire tracing the

most distal antral recording port as that with waves at

not less than 20 s intervals (up to 3 waves/min), just

proximal to the port which showed pressure waves at no

more than 5 s intervals (up to 12 waves/min) or a

mixture of antral and duodenal waves. An AF was

identi®ed in the stomach by a sequence of 2±3 waves/

min for at least 2 min, followed by a phase of motor

silence (phase I) and in temporal relationship with a

duodenal AF. The latter was identi®ed as a propagated

burst of pressure waves with a frequency of 11±12/min

for at least 2 min, followed by a phase of motor silence.

The following parameters were calculated by a person

unaware of the drug administered: (i) the number of

patients with AFs occurring during the basal period

(spontaneous AFs) and that of patients with AFs

following drug administration (drug-related AFs) in each

group; (ii) the time interval between drug administration

and the appearance of AFs in both groups; (iii) the

duration of spontaneous and drug-related duodenal AFs

in both groups.

The following statistical comparisons were carried out

by means of chi-squared and Wilcoxon tests for paired

and unpaired data, where appropriate:

� the number of patients with spontaneous antral AFs

vs. the number of patients with drug-related AFs in

each group;

� the number of patients with antral AFs in the

clarithromycin group vs. the amoxycillin group;

� the time interval between drug administration and

the appearance of AFs in the clarithromycin group

vs. the amoxycillin group;

� the duration of spontaneous duodenal AFs vs. that of

drug-related AFs in each group;

1022 M. BORTOLOTTI et al.

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 1021±1025

� the duration of drug-related duodenal AFs in the

clarithromycin group vs. the amoxycillin group.

RESULTS

During the basal period AFs were observed in only three

patients in the clarithromycin group and in four

patients in the amoxycillin group, starting from the

stomach in one and two patients, respectively. Clari-

thromycin administration was followed by AFs

(Figure 1) in six patients, starting from the stomach in

®ve of them (P < 0.05 vs. the basal period and vs. the

amoxycillin-related AFs) (Figure 2). In the amoxycillin

group, drug administration was followed in two patients

by AFs, which started from the stomach in only one

(P � N.S. vs. the basal period) (Figure 2). The time lag

between drug administration and the appearance of AFs

was 40.8 min � 8.5 (mean � s.d.) in the clarithromy-

cin group and 121 min � 29 in the amoxycillin group

(P < 0.02) (Figure 3). The clarithromycin-related duo-

denal AFs showed a duration of 6.6 min � 1.5 in the

clarithromycin group, signi®cantly longer than that of

the spontaneous AFs (3.6 min � 1.2; P < 0.01) and

that of amoxycillin-related AFs (Figure 4), while in the

amoxycillin group the amoxycillin-related AFs were not

signi®cantly different from the spontaneous ones. No

signi®cant difference was observed between the basal

periods of the two groups.

DISCUSSION

Clarithromycin was able to stimulate cyclic gastroduo-

denal motility, while amoxycillin was ineffective. It is

likely that the gastrointestinal symptoms during the

eradication treatment are due to the prokinetic effect of

clarithromycin. This property of clarithromycin is not

Figure 1. Gastroduodenal manometric re-

cording in a patient of the clarithromycin

group showing an activity front recorded

after drug administration. 1 � corpus; 2, 3

and 4 � antrum; 5, 6, 7 and 8 � duode-

num.

Figure 2. In the clarithromycin group the occurrence of patients

showing an activity front starting from the stomach after drug

administration is signi®cantly higher than during the basal period

and after amoxycillin, while in the amoxycillin group the number

of patients showing an activity front starting from the stomach

after drug administration is not signi®cantly different than that of

patients showing an AF during the basal period. No signi®cant

differences (P � N.S.) were observed between the basal periods of

the two groups.

CLARITHROMYCIN AND GASTROINTESTINAL MOTILITY 1023

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 1021±1025

unexpected, because this antibiotic is a 14-membered

macrolide the same as erithromycin, the prokinetic

activity of which is well known.8±11 The in¯uence of

this `prokinetic lash', lasting 1±2 weeks, on the evolu-

tion of dyspeptic symptoms after H. pylori eradication

should be taken into account when the effects of

H. pylori eradication on both gastrointestinal motility

and dyspeptic symptoms are evaluated. This is especially

important in dyspeptic patients with alterations in

interdigestive and digestive gastrointestinal motility.12±

15 It is possible that the potent prokinetic activity of this

antibiotic used for H. pylori eradication may produce an

improvement in the gastroduodenal motility and in the

dyspeptic symptoms that could be attributed to H. pylori

eradication. On the other hand, cisapride has been

added to a triple therapy, not including clarithromycin,

to improve both gastroduodenal motor dysfunctions

and symptoms of patients with H. pylori infection and

functional dyspepsia.15 Consequently, it would be

interesting to investigate whether the triple therapy,

including clarithromycin, is able to produce the same

results without the addition of a prokinetic drug. This

stimulation of gastroduodenal motor activity induced by

clarithromycin administration deserves further study,

which could be extended to other sections of the

digestive apparatus, including the biliary system, where

this drug appears to show a cholecystokinetic effect.16

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Figure 4. The duration of the clarithromycin-related duodenal

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that of the amoxycillin-related AFs. No signi®cant differences were

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Figure 3. Time interval between drug administration and the AF

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dividual values, while the horizonal bars designate the mean va-

lue for each group.

1024 M. BORTOLOTTI et al.

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