WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Ugwu et al.

World Journal of Pharmacy and Pharmaceutical Sciences

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Volume 4, Issue 06, 1457-1466.

Research Article

ISSN 2278 4357

COMPARATIVE STUDY OF THE GASTROKINETIC EFFECTS OF

ERYTHROMYCIN AND AZITHROMYCIN IN HEALTHY SUBJECTS:
SONOGRAPHIC STUDY.
Ugwu AC1, Agwu KK2, *Umeh EC1, Imo AO3 and Ohuegbe C4
1

Department of Radiography and Radiological Sciences, Nnamdi Azikiwe University, Nnewi

Campus, Anambra State, Nigeria.
2

Department of Medical Radiography and Radiological Sciences, Nnamdi Azikiwe

University, Enugu Campus, Enugu State, Nigeria.

Department of Radiology, Ebonyi State University Teaching Hospital, Abakaliki, Ebonyi

State, Nigeria.
4

AEEC BOURNEMOUTH (Bournemouth University) United Kingdom.

Article Received on
10 April 2015,
Revised on 02 May 2015,
Accepted on 26 May 2015

ABSTRACT
AIM: The purpose of this study was to investigate the comparative
gastrokinetic effects of erythromycin and azithromycin in apparently
healthy subjects. METHODOLOGY: Ultrasonographic evaluation of
changes in gastric antral areas were undertaken in 24 subjects after a

*Correspondence for

liquid meal at five minutes interval for thirty minutes. These were

Author
Umeh EC

performed in pre-prandial states in a cross over method between

Department of

erythromycin and azithromycin ingestion. The gastric antral areas were

Radiography and

calculated as compared used paired t test as a measure of relative

Radiological Sciences,

motilities induced by these drugs. P<0.05 was used as a criterion of

Nnamdi Azikiwe

statistical significance. RESULT: This showed that azithromycin

University, Nnewi
Campus, Anambra State,
Nigeria.

enhance gastric motility better than erythromycin. No significant

difference after the 15th minute might imply that emptying of this
liquid meal was concluded in the first 15 or 20 minutes.

CONCLUSION: Azithromycin hence could be adopted as a prokinetic alternative to

erythromycin based on its tolerance and added efficacy in gastric motility.
KEYWORDS: Erythromycin, Azithromycin, gastrokinesis, ultrasonography.

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INTRODUCTION
Delayed gastric emptying,[1] antral hypomotility,[2] and impaired gastric accommodation[3]
have been reported in patients with functional dyspepsia. Cross sectional studies have shown
that gastric emptying is delayed in as many as 50% of diabetic patients, causing symptoms
such as postprandial early safety, abdominal fullness, nausea, vomiting, and

early

postprandial hypoglycemia.[4] Gastric emptying is recognized as a major determinant of

postprandial glycemia in both healthy[5] and patients with types 2 diabetes.[6] Interventions
that reduce postprandial hyperglycemia, but modulating the rate of gastric emptying, have the
potential to become mainstream therapies in the treatment of diabetes. Nevertheless,
observations in both animal models and diabetic patients have, in general, been consistent
with those obtained in healthy humans.[6]
Prokinetic agents, such as neostigmine, metoclopramide, cisapride are commonly used for
treatment of such conditions but no agent has yet proved to be ideal so, there is always a
search for new agents. Neostigmine produces, a lot of muscarinic adverse effects,
metoclopramide produces extra pyramidal effects while the use of cisapride is limited
because of its cardiac toxicity.[7]
The Macroclide antibiotic, erythromycin has been known to be associated with increased
gastrointestinal motility since its introduction more than 45years ago.[8] It acts on gut motility
as an agonist of the receptors for motility and possibly via a cholinergic pathway or
endogenous motilin release.[9] Some studies have shown that its administration at smaller
doses than those used for antibiotic properties enhances gastric emptying of meals in healthy
volunteers, as well as in critically ill patients and those with gastroparesis related to several
pathologies, including diabetes.[10] Erythromycin has been found to be useful as a prokinetic
agent in children with chronic constipation and presenting mega rectum and fecal
impaction.[11]
Erythromycin is poorly tolerated because of its adverse gastrointestinal effects.[11]
Compliance with therapy has been found to be better with azithromycin than with
erythromycin.[12] The prokinetic effect of this second macrolide (azithromycin) has been
established in a recent study,[7] but no study, to the best of knowledge has compared the
gastrokinetic effects of these two macrolides. This study was designed to compare the
gastrokinetic effect of acute oral administrations of erythromycin and azithromycin.

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MATERIALS AND METHOD

STUDY DESIGN
This was a randomized, single blind, placebo- controlled two way crossover study in
apparently healthy adult male volunteers of Ibo origin.
ETHICAL CONSIDERATION
Approval for this study was obtained from the Human Research Ethics Committee of Nnamdi
Azikiwe University, Nnewi Campus, Anambra State, Nigeria. The procedure were
explained to the participants(subjects) and each subjects signed a consent form before
enrolling into the study. All subjects were aware of their option to withdraw from the study
anytime they desired.
SAMPLE SIZE/SAMPLING
This study involved 24 apparently healthy male volunteers who received financial
compensation for their participation in the study. This number of subjects was considered to
have sufficient power based on prior- experience in studies with a similar design.[13,14]
Subjects selection
Twenty four apparently healthy male subjects were recruited for this study as it was easier to
recruit males than females. Darwiche et al[15] reported a non significant difference in gastric
emptying rates of males and females. Potential study subjects underwent medical history,
fasting blood sugar tests, occult blood tests and physical examinations. Exclusion criteria
included history of hepatobiliary diseases, gastro intestinal diseases or metabolic disease (eg
diabetes), the presence or history of gastro-oesophageal reflux, peptic ulcer disease and
irritable bowel syndrome. The subjects had no previous abdominal surgery (except for
appendectomy). The subjects were instructed not to take drugs affecting gastrointestinal
motility[16] at least 10 days before each day of examination. Patients with abnormal
defecation, such as constipation or diarrhea were excluded from the study.
Smoking and Snuff taking were prohibited for eight hours before and during the study.[15]
The fasting blood sugar was conducted using a portable blood glucose meter (Companion 2
metre; Medisense, Waltham, MA) on the first day. Subjects were advised not to drink water
or any other thing after 7.30am on the of examination or at least one hour before the
procedure.

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DRUGS
Erythromycin (Medopharm, India) and azithromycin (Swiss pharma PVT, LTD) were
supplied in 500mg. Single doses of drugs were administered. During the inter digestive state
in humans, erythromycin 40mg induces a premature activity front that start in the stomach,
while erythromycin 200mg induces a prolonged period of enhanced antral contractile
activity.[17] In a similar study by potincassa et al[18] subjects received erythromycin(600 mg
per oral) 30 minutes before the ingestion of a standard 200ml liquid test meal.
TEST MEAL
Immediately before the procedure, each subjects took a tin of full cream peak brand
milk(157ml,170g,contents; vitamins and iodine, milk fat 9%, milk solids not fat 22%, milk
stabilizer E339, brand of friesland foods, WAMCO Nig PLC) immediately before the
procedure. This was immediately followed by drinking of 30cl of ion free water (Eva water,
coca cola Co, PLC).[19] This gave 457 ml of liquid. One minute was allowed for both milk
and water intake as longer period might give rise and water intake as longer period might
give rise to little residual fluid in the stomach, both water and milk were stored in a large
flask at room temperature.
PROCEDURE
Through computer generation of random numbers, the subjects were divided into groups A
and B. group A (12 in number) started with erythromycin and crossed over to azithromycin
after a wash out period of at least 10 days. Group B (12 subjects) started with azithromycin
and crossed over to erythromycin (group A) after a wash out period of at least 10 days. This
wash out period is similar to that observed in a similar study.[20] The participants were
scanned on two separate visits to compare the effect of erythromycin and azithromycin on
gastric motility using cross sectional area of the antrum at different time intervals. On arrival
to the centre, the basal gastric antral area was measured as a guide to its location.
Subsequently, erythromycin or azithromycin was taken with 20ml of water, 30 minutes
before the procedure.
This 30 minutes timing and 500mg dosage have been applied in a similar study.[21] Subjects
were scanned between 0700 hours and 0900 hours.
The subjects were examined with a 3.5 MHZ curvilinear transducer(siemens sonoline SL-2,
Issaquah, USA). Immediately before the procedure, the subjects ingested the milk and water

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(Test meals). Gastric emptying were monitored indirectly by determining the longitudinal
and anteroposterior diameters of a single section of the gastric antrum, using the abdominal
aorta and the left lobe of the liver as internal landmarks to obtain the same standardized
scanning level consistently(fig 1).[22] At each observation the longitudal (D1) and antero
posterior (D2) diameters were used to calculate the antral area. The measurements of the
gastric antrum were taken from the outer profile of the wall and obtained between antral
contractions to provide a measure of the relaxed width of the antrum.[22] At this level, the scan
showed the stomach shape as either a circle or an ellipse, so the gastric antral cross-sectional
area (GAA) was calculated by the following formulaGAA= = x D1 x D2
4
The subjects were studied in supine position with the ultrasound transducer applied with the
abdominal compression. Between examinations, the subjects were raised seated in a chair.
Measurements were taken immediately before the test meal, 5, 10, 15, 20, 25 and 30 minutes
after ingestion of a test meal. The decision for the 30 minutes timing was based on the result
of a pilot study which showed that this test meal emptied completely from the stomach in 25
to 30 minutes in controls. The subjects lay on the couch for transabdominal sonography. The
methods for this procedure have been validated in healthy controls, correlating well with
scintigraphic measurements.[15,22]
At the end of the procedure, subjects heights were measured on a calibrated vertical wall and
weight measured on a weighing scale (Model H 89LT Blue). The ages of subjects were also
obtained. All acquisitions were performed by one scientist to limit variability in statistical
analysis.
Descriptive and inferential statistical analyses were conducted using SPSS software version
16.0(SPSS INC.) Chicago, Illinois, USA). Gausian responses of GAA at each time which
served as indicator of motility were tested using Kolmogorov-Smirnoff test. Paired (repeated
measures) t test was used to test for the differences in GAAs at each time interval during
erythromycin and azithromycin administration. Significantly lower GAA indicated greater
motility. P<0.05 was used in the criterion of statistical significance.

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Hepatic

V
Ao

Fig 1: Line drawing showing the aorta Ao, Left lobe of the liver and the antrum V.
RESULTS
Twenty four male subjects (age range: 27-40 years) entered and completed the study. Their
mean age standard deviation was 33.75 4.12 years.
Their weight (55-69 kg) and heights (1.62-1.76m) were records as 65 5.96kg and 1.68
0.06m respectively.
Table 1 shows a comparative study between gastric antral areas at different periods during
erythromycin and azithromycin ingestion with lower GAAs at the 10th and the 15th minute
post prandials. This showed that azithromycin enhance gastric motility better than
erythromycin. No significant difference after the 15th minute might imply that emptying of
this liquid meal was concluded in the first 15 or 20 minutes thereby giving no difference in
GAA after these periods.
Table 4: Comparative Stimulation of gastric emptying after administration of
erythromycin and Azithromycin
T5
T10
T15
T20
T25
Mean
778.05
806.07
511.03
481.71
386.54
GAA(Erythromycin+
fatty meal)
Mean
668.66
569.21
357.07
384.41
353.83
GAA(Azithromycin
+fatty meal)
P
0.053
0.013
0.006
0.075
0.261
GAA, gastric area in mm3, Tx, time at which GAA was obtained in minutes

T30
399.41

428.15

0.67

DISCUSSION
Macrolides have been found to have pharmacodynamic properties beyond their antimicrobial
mode of action,[23] some of these include anti- inflammatory and immunomodulatory effects.

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In these clinical situations, it is noteworthy that the macrolides are being used, often
primarily, for their antibiotic effects on the diseases and the aforementioned extraantibiotic effects are an addition to this.
More recently, another extra-antibiotic effect of macrolides has been exploited; their function
as a gastrointestinal prokinetic.[24] Prokinetic agents are drugs that increase contractile force
and accelerate intraluminal transit.[25] Many studies have been carried out in a wide variety of
patient populations and disorders, including gastro esophageal reflux in children,[26] diabetic
gastroparesis[27] and functional dyspepsia.[28] This has been investigated in erythromycin
severally and to a lesser extent in other macroides.
Table 4 shows a faster emptying rate (gastric motility) induced by azithromycin over
erythromycin in the 10th and 15th minute. There was no point at which erythromycin showed
a higher impact on gastric motility than azithromycin. This indicates a gastrokinetic
superiority of azithromycin over erythromycin. A previous study7 on rabbit duodenum also
indicated a prokinetic effect of azithromycin.
Hence, from both the efficacy and tolerance point of view, azithromycin would be a preferred
gastrokinetic agent to erythromycin.
The gastric antral areas over times were compared at different phases. This choice of paired ttest was favoured due to the crossover nature of the study, which removed the effects of
confounding variables.
A non commercially available analogue of erythromycin has previously been produced and
reported in literature.[29] As macrolide bacterial resistance is a key disadvantage in the
gastrokinetic use of macrolides below therapeutic doses, it is therefore commended that
analogues of azithromycin, without antibiotic properties be commercially produced as
gastrokinetic agents. This study has shown a gastrokinetic advantage of azithromycin and
would have vast clinical applications in gastrokinesis.
Conflict of interest
None declared.

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REFERENCES
1. Stanghelline V, Tosetti C, Paternico A. Risk indicators of delayed gastric emptying of
solids in patients with fundctional dyspepsia. Gastroenterology 1996, 110(4): 1036-1042.
2. Kusunoki H, Haruma K, Hata J, Tani H, Okamto E, Sumi K, Kajiyama G. real-time
ultrasonographic assessment antroduodenal motility after ingestion of soild and liquid
meals by patients with functional dyspepsia. Journal of Gastroenterology 1998: 115(6):
1346-1352.
3. Tack J, Piessevaux H, Coulie B, Caenpeal P, Janssens J. Role of impaired Gastric
Accomodation to a meal in function Dyspepsia. Gastroentenology 1998: 115(6): 13461352.
4. Vantrappen G. Methods to study gastric emptying. Digestive Diseases and Sciences 1994:
39: 591.
5. Horowitz M, Edelbroek MA, Wishart IM, Struanat IW. Relationship between oral
glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 1993; 36:
857-862.
6. Rayner CK, Samson M, Tone KL, Horowitz M. Relationship of upper gastrointestinal
motor and sensory function with glycemic control. Diabetes care 2001; 24: 371-381.
7. Chiragh S, Begum A, Karim S. Prokinetic effect of clarithromycin and azithromycin: invitro study on rabbit duodenum. Biomedical 2006; 22: 130-134.
8. Adams HR, Veterinary pharmacology and therapeutics 5th eds. Ames: Towa State
University Press 2001; 876-882.
9. Bruley Des Varannes S, parys V, Ropert A. Erythromycin enhances fasting and
postprandial proximal gastric tone in humans. Gastroenterology 1995; 109: 32-39.
10. Bovin MA, Carey MC, levy H. Erythromycin accelerates in healthy subjects.
Pharmacotherapy. 2003; 23: 5-8.
11. Bellomo- Branddao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the
treatment of severe chromic constipation in children. Brazillian Journal of Medical and
Biological Sciences 2003; 36(10): 1391-1396.
12. Langley JM, Halperin SA, Boucher FD, Smith B. Azithromycin is as effectives as b etter
tolerated tham erythromycin estolate for the treatment of pertusis, pediatric 2004; 114(1):
96-101.
13. Schlauch D, Gladisch R, Elfner R, Heene DL. A Model for the comparison of
pharmacologic agents influencing gallbladder contraction. Journal of ultrasound in
medicine 1998; 7: 15-19.

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Vol 4, Issue 06, 2015.

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Ugwu et al.

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14. Mannaerts BMJL, Geurts TBP, Odink J. A randomized three way cross over study in
healthy pituitary-suppressed women to compare the bioavailability of human choronic
gonadotropin (pregnyl) after intramuscular and subcutaneous administration. Human
Reproduction 1998; 13(6): 1461- 1464
15. Darwich G, Almer L O, Bjorgell O. Measurement of gastric emptying by standardized
real-time ultrasonography in healthy subjects and diabetic patients. Journal of ultrasound
in Medicine 1999; 18: 673-682.
16. Burked TF. Actions of pharmacological agents on gastrointestinal function. In Kumar D,
Wingate D (Eds). An illustrated guide to gastrointestinal motility. 2nd ed London,
England: Churchill communication, 1993; 144-161.
17. Coulie B, Tcak J, Peeters T, Janssens J. Involvement of two different pathways in the
motor effects of erythromycin on the gastric antrum in humans. Gut 1998; 43: 395-400.
18. Portincassa P, Altomare DF, Moschetta A, Baldassarve GDI, Ciaula A, Venn Man NG et
al. the effect of acute oral erythromycin on gallbladder motility and on upper
gastrointestinal symptoms in gastrectomized patients with and without gallstones: a
randomized,

placebo-controlled

ultrasonographic

study.

Americal

Journal

of

Gastroenterology 2000; 95(12): 3444- 3451.

19. Arienti V, Corazza GR, Sorge M, Boriani L, Ugenti F, Biagi F1 et al. the effect of
Levosulpride on gastric and gallbladder emptying in functional dyspepsia. Alimentary
pharmacology and therapy 1994; 8(6): 631-638.
20. Ziessman HA, Muenz LR, Agarwal AK, Zaza AAM. Normal value of Sincalide
Cholescintigrapgy: Comparison of two methods. Radiology 2001; 221: 404-410.
21. Acalovsci M, Dumistrascu DL, Hagiu C. Oral clarithromcin enhances gallbladder
emptying induced by a mixed meal in healthy subjects. Europen Journal of Internal
Medicine 2002; 13(2): 104-107.
22. Darwiche G, Bjorgell O, Thorsson O, Almer L. Correlation between simultaneous
Scintigraphic and ultrasonographic measurement of gastric emptying in patient with type
1 diabetes mellitus. Journal of ultrasound in medicine 2003; 22: 459-466. Erratum in:
Journal of ultrasound in medicine 2003; 22: 690.
23. Amsden GW. Anti-inflammatory effects of macrolides-an underappreciated benefit in the
treatment of community acquired respiratory tract infections and chronic inflammatory
pulmonary conditions? Journal of Antimicrobial chemotherapy 2005; 55: 10-21.

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24. Janssens J, Peeters TL, Vantrappen G. Improvemnet of gastric emptying in diabetic

gastroparesis by erythromycin. Preliminary studies. New England journal of Medicine
1990; 322: 1028-1031.
25. Ramirez B, Richter JE. Review article: Promotility drugs in the treatment of gastrooesophageal reflux disease. Alimentary Pharmacology and therapy 1993; 7: 5-20.
26. Chicella MF, Batres LA, Heesters MS. Prokinetic drug therapy in children: a review of
current options. Annals of pharmaco-theraphy 2005; 39: 706-711.
27. Tack J, Janssens J, Vantrappen G. Effect of erythromycin on gastric motility in controls
and in diabetic gastroparesis. Gastroenterology 1992; 103: 72-79.
28. Arts J, Caeneped P, Verbeke K, Tack T Influence of erythromycin on gastric empying
and meal related symptoms in functional dyspepsia with delayed gastric emptying. Gut
2005; 54: 455-460.
29. Kawamura O, Sekiguchi T, Itoh Z. Effects of erythromycin derivative EM 523L on
human interdigestive gastro-intestinal tract. Digestive Disease and Science 1993; 39:
1029-1031.

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