Gastric emptying response to variable oral erythromycin dosing in diabetic gastroparesis

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Digestive Diseases and Sciences, Vol. 40, No. 1 (January 1995), pp. 141-146

Gastric Emptying Response to Variable Oral Erythromycin Dosing in Diabetic Gastroparesis STEVEN G. DESAUTELS, MD, W I L L I A M R. HUTSON, MD, PAUL E. CHRISTIAN, BS, JOHN G. MOORE, MD, and FRED L. DATZ, MD

Intravenous erythromycin has been shown to improve gastric emptying in diabetic gastroparesis. Oral erythromycin also accelerates gastric emptying, but to a lesser degree. To determine if this is a dose-dependent phenomenon, gastric emptying was measured in 10 insulin-requiring diabetic patients with gastroparesis after administration of either 250 mg or 1000 mg of erythromycin or placebo. The drugs were orally administered in a randomized, double-blind fashion 30 min prior to ingestion of a meal containing [99rnTc]sulfur colloid-labeled beef stew and [11hIn]DTPA-labeled orange juice. Anterior and posterior gastric images were recorded for 3 hr at 15-min intervals using an externally positioned gamma camera. The results demonstrated that both doses of oral erythromycin significantly improved solid-phase gastric emptying. The mean half-emptying time of solids was decreased from 151 _+ 40 min with placebo to 58 -+ 10 min and 40 _+ 9 min with 250 mg and 1000 mg of erythromycin, respectively. However, a dose-dependent relationship was not demonstrated with the two doses of erythromycin employed. These results suggest that for most patients with diabetic gastroparesis, a single 250-mg dose of erythromycin will significantly improve gastric emptying. It is possible that a dosedependent relationship will be demonstrated with doses of erythromycin less than 250 mg. KEY WORDS: gastric emptying; diabetes mellitus; erythromycin.

Diabetics mellitus affects 2-4% of the U.S. population, with as many as 20-30% of diabetics having demonstrable gastric motor abnormalities (1, 2). Gastroparesis may result in symptoms such as early satiety, abdominal distension, nausea, vomiting, heartburn, and anorexia and lead to the development of gastric bezoars (3). In addition, gastric Manuscript received August 2, 1993; revised manuscript received January 10, 1994; accepted January 18, 1994. From the Division of Gastroenterology and Hepatology, Department of Medicine, and Division of Nuclear Medicine, Department of Radiology, University of Utah School of Medicine, Salt Lake City, Utah. Address for reprint requests: Dr. William R. Hutson, Division of Gastroenterology and Hepatology, University of Pittsburgh Medical Center, MUH, E 323, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213.

stasis may result in deterioration of glucose control secondary to decreased delivery of food for absorption to the small bowel (4). Efforts to circumvent these gastric motor abnormalities with gastrokinetic agents has been an area of renewed research interest. One of the most promising gastrokinetic agents presently is erythromycin. Erythromycin, a macrolide compound, appears to act as a motilin-receptor agonist to induce phase III gastrointestinal contractile activity (5). Recent studies by Janssens et al demonstrated improved solid and liquid gastric emptying in diabetic gastroparesis by intravenous erythromycin (6). Gastric emptying was also found to improve after four weeks of oral erythromycin, but to a lesser degree than that seen

Digestive Diseases and Sciences, Vol. 40, No. 1 (January 1995)

0163-2116/95/0100-0141507.50/0© 1995PlenumPublishingCorporation

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DESAUTELS ET AL with intravenous erythromycin (6). To date, no study has investigated the effect of high doses of oral erythromycin in diabetics with impaired gastric emptying. W e hypothesized that high oral dosages of erythromycin m a y approximate the gastric emptying rates observed with intravenous erythromycin without the necessity for intravenous delivery. Our aim was to examine the effects on gastric emptying of two different oral dosages of erythromycin in patients with diabetic gastroparesis. M A T E R I A L S AND M E T H O D S Ten male patients with diabetes mellitus (median age 61.5 years, range 26-70 years) underwent dual radionuclide gastric emptying studies. Only males were studied so that gender differences would not influence the results of the study (7). The median duration of diabetes mellitus was 16 years (range 3-38 years) and median insulin requirement was 10.5 years (range 1-37 years). Glycosylated hemoglobin levels ranged from 6.7% to 12.9% (mean, 10.1%). Each participant had a normal creatinine concentration. All patients were demonstrated to have gastroparesis based on a previous gastric emptying radionuclide study, and all had symptoms of early satiety, abdominal distension, and periodic nausea and vomiting. None of the subjects had a history of gastrointestinal surgery or utilized medications known to affect gastrointestinal motility. The research protocol was approved by the Institutional Review Board of the University of Utah. Informed written consent was obtained from each subject. Gastric Emptying Studies. The subjects were randomized in a double-blind fashion on separate days to placebo, erythromycin base 250 mg, and erythromycin base 1000 mg. Each participant underwent an overnight fast of at least 8 hr prior to the study. All potentially interfering medication, as well as caffeine, alcohol, and tobacco were discontinued 24-48 hr prior to each study. Each session was initiated with measurement of blood glucose followed by administration of the subject's usual dosage of NPH and/or regular insulin followed by ingestion of the placebo or erythromycin tablet. Blood glucose was measured hourly for the duration of the study in an effort to maintain blood glucose levels at less than 140 mg/100 ml, since it is known that hyperglycemia > 140 mg/100 ml inhibits antral motility (8). Regular insulin was given subcutaneously during the study to certain subjects as necessary in order to achieve this objective. Thirty minutes after test medication administration, the subjects ingested a radionuclide meal consisting of 150 g of beef stew, and 50 g of canned liver patr, labeled with 600 ~zCi of [99mTc]sulfur colloid, and 150 g of orange juice labeled with 100 txCi of 11~In diethylenetriaminepentaacetic acid (DTPA). The meal contained 204 kcal, (67% carbohydrate, 15% protein, and 18% fat) and was ingested within 5 min by all subjects. An external 99mTcpoint source was taped to the abdomen to allow accurate horizontal and vertical repositioning of the subject between images. Sequential l-rain images were taken immediately after ingestion of the meal using an externally positioned gamma camera with a

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medium energy collimator (Picker, Northford, Connecticut). The pulse height analyzer was set at the 140-keV photopeak with a 20% window for [99mTc]SC and at 247 keV with a 20% window for [HIln]DTPA. Anterior and posterior counts of the gastric region of interest were obtained in the standing position at 10-rain intervals for 3 hr. Geometric means were calculated and corrected for radioactive decay, compton scatter, and gamma ray attenuation. The gastric emptying curves for solid and liquid components were plotted as the fraction of meal remaining against time; the counts obtained at time zero were considered to represent 100%. The time at which 50% of each respective radionuclide exited the stomach was interpolated by computer analysis to derive 50% emptying times (T1/2). Statistical Analysis. A repeated-measures analysis of variance (ANOVA) was used to determine if there was a statistically significant difference among the three treatment groups. If such a difference appeared, a Scheff6 test was utilized to determine which of the treatments were different from one another. P < 0.05 was considered significant. RESULTS

Gastric Emptying of Liquids. Liquid emptying in each case approximated a monoexponential pattern. Figure i demonstrates the percentage of liquid marker remaining in the stomach with respect to time after the administration of placebo and 250 mg and 1000 mg of e r y t h r o m y c i n . T h e m e a n halfemptying times (T1/2) are shown in Table 1. Although there was some i m p r o v e m e n t in liquidphase gastric emptying c o m p a r e d to placebo, this was not statistically significant. Gastric Emptying of Solids. Gastric emptying of the solid c o m p o n e n t of the meal w a s slower than that of liquids and was characterized by a lag phase followed b y linear emptying (Figure 2). Table 1 demonstrates the mean half-emptying times. Erythromycin accelerated the severely impaired gastric emptying of solids to normal (45-109 min in our institution) (9). There was a highly significant difference in gastric emptying between placebo, erythr o m y c i n 250 mg, and erythromycin 1000 mg (P = 0.0007). At a 5% significance level, the Scheff6 test demonstrated that placebo was different than both 250-mg and 1000-rag erythromycin doses, but that the 250-mg dose was not different than the 1000-rag dose (Figure 3). Side Effects. One subject developed diarrhea after ingestion of the 1000-rag dose of e r y t h r o m y c i n , which resolved several hours after the study. N o other side effects were observed. Blood Glucose Levels. Table :2 depicts blood glucose m e a s u r e m e n t s prior to the meal, and at 1, 2, Digestive Diseases and Sciences, Vol. 40, No. 1 (January 1995)

DIABETIC GASTROPARESIS AND ERYTHROMYCIN 100

80

60

g ~ 40 .

o

'~ 20 . . . .

Placebe E250 E 1000 I

0

i

i

I

I

I

i

J

r

I

180

0

Fig 1. Gastric emptying of the liquid component of the meal over 180 min following ingestion of

placebo, erythromycin250 rag, and erythromycin 1000rag. demonstrate that the acute administration of oral erythromycin significantly improved gastric emptying rates for solid-phase meal components, but not for liquids in patients with diabetic gastroparesis. There appeared to be no dose-dependent effect of oral erythromycin on gastric emptying above the dose of 250 rag. These results are in agreement with Janssens et al, who reported improved solid-phase gastric emptying after four weeks of oral administration of 250 mg of erythromycin (6). In that study, monoexponential emptying curves were found for both solids and liquids using intravenous erythromycin. The pathogenesis of delayed gastric emptying in diabetics may be multifactorial. Gastric emptying of liquids in healthy subjects is thought to result from a differential pressure gradient between the gastric

and 3 hr in each of the three groups. There were no significant differences in glucose levels during the study between placebo, erythromycin 250-mg, or erythromycin 1000-mg administrations. DISCUSSION To our knowledge, our study is the first to compare the effects on gastric emptying of two different doses of erythromycin and placebo. Our results TABLE1. GASTRICEMPTYINGPARAMETERS(MEAN-- SEM) Placebo Erythromycin 250 mg Erythromycin 1000 mg

Liquid T1/2 (min)

Solid T1/2 (min)

58 - 20 39 ± 5 27 _+ 6

156 - 40* 57 ± 9* 39 ± 9*

*P = 0.0007. 100

80

:~ 60 tO

40

Placebo

o "E

~

20

~

E250 EIO00

I

0

I

I

I

0

I

I

I

I

I

I

180

Fig 2. Gastric emptyingof the solid componentof the meal over 180 min followingingestion of placebo,

erythromycin 250 mg, and erythromycin 1000 mg. Digestive Diseases and Sciences, Vol. 40, No. 1 (Jan u a ~ 1995)

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DESAUTELS ET AL 500

450-

400-

350-

300-

e,,

~, 250. I200

150

100

50-

PLACEBO

250 mg

1000 mg

Fig 3. Individual gastric emptying half-times following administration of placebo, erythromycin 250 mg, and erythromycin 1000 rag.

fundus and duodenum. This is created by rapid phasic contractions superimposed on slow sustained contractions and is a property of gastric fundal musculature (10). In contrast, solid-phase emptying is controlled largely by antral contractions (10). The role of vagal innervation and denervation in diabetic gastroparesis is controversial. Some groups have described a reduction in unmyelinated axons in support of vagal denervation as an

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TABLE 2. BLOOD GLUCOSE LEVELS

Blood glucose (mg/lO0 ml)* Placebo Pre-meal 1 hour 2 hour 3 hour

139 181 172 143

_ -

20 21 17 20

Erythrornycin 250 mg 136 147 154 143

-+ 36 - 24 _ 25 _+ 30

Erythromycin 1000 rng 165 163 166 125

+- 35 - 27 _+ 25 -+ 13

*Mean +_ SEM.

Digestive Diseases and Sciences, Vol. 40, No. 1 (January 1995)

DIABETIC GASTROPARESIS AND ERYTHROMYCIN e t i o l o g y o f d e l a y e d e m p t y i n g . F o x and B e h a r have d e m o n s t r a t e d b o t h a d e c r e a s e in the n u m b e r o f antral c o n t r a c t i o n s and in c u m u l a t i v e antral a c t i v i t y as e v i d e n c e of a v a g a l n e u r o p a t h y in d i a b e t i c gast r o p a r e s i s (11). O t h e r s , h o w e v e r , h a v e found no direct c o r r e l a t i o n (12-15). I m p a i r m e n t o f m o t o r act i v i t y results in d i s r u p t i o n o f the fundic p a c e m a k e r and u l t i m a t e l y in i r r e g u l a r i t y and l a c k of c o o r d i n a tion in e m p t y i n g (16, 17). H y p e r g l y c e m i a itself inhibits antral motility, c o n t r i b u t i n g to a l t e r a t i o n s in e m p t y i n g (8, 17, 18). I n t e r e s t i n g l y , l i q u i d - p h a s e e m p t y i n g a p p e a r s to b e less affected and g e n e r a l l y n o r m a l in d i a b e t i c s w h o exhibit d e l a y e d s o l i d - p h a s e e m p t y i n g (13, 16). E r y t h r o m y c i n has b e e n f o u n d to s t i m u l a t e m o t o r a c t i v i t y in the s t o m a c h , as well as in the small and, to a l e s s e r e x t e n t , large intestine (6, 19-22). T h e m e c h a n i s m o f e r y t h r o m y c i n ' s kinetic p r o p e r t i e s app e a r s to be s e c o n d a r y to its agonist influence on motilin r e c e p t o r s (5). Motilin is a 22-amino acid r e s i d u e originally isolated from the d u o d e n a l muc o s a of hogs and n a m e d " m o t i l i n " b e c a u s e of its p r o p e r t y o f stimulating m o t o r a c t i v i t y in the gastric fundus. Motilin a p p e a r s to stimulate the gastric migrating motor complex (MMC), by inducing p h a s e I I I c o n t r a c t i l e activity, w h i c h is often not p r e s e n t in d i a b e t i c g a s t r o p a r e s i s (22). I n t r a v e n o u s infusions of e r y t h r o m y c i n s t i m u l a t e g a s t r o i n t e s t i n a l m o t i l i t y and significantly i m p r o v e gastric e m p t y i n g in d i a b e t i c g a s t r o p a r e s i s , but p r o v i d e an i m p r a c t i c a l route of a d m i n i s t r a t i o n for clinical a p p l i c a t i o n (6). W e d e m o n s t r a t e d i m p r o v e m e n t s in gastric e m p t y ing in p a t i e n t s with d i a b e t i c g a s t r o p a r e s i s with a simplified oral r o u t e o f a d m i n i s t r a t i o n and w i t h o u t side effects. O u r s t u d y , h o w e v e r , w a s r e s t r i c t e d to s t u d y i n g o n l y the effect o f a single d o s e o f e r y t h r o m y c i n in an acute setting. In addition, t h e r e is the p o s s i b i l i t y that the n u m b e r of s u b j e c t s w a s insufificient to c o n c l u d e that a difference did not exist b e t w e e n the 250-mg and 1000-mg d o s e s o f e r y t h r o m y c i n , ie, a t y p e II error. T h e r e f o r e , there m a y be p o t e n t i a l l y g r e a t e r benefit from 1000 mg of e r y t h r o m y c i n than 250 m g o f e r y t h r o m y c i n . P r o l o n g e d clinical trials n e e d to be u n d e r t a k e n to d e t e r m i n e if t o l e r a n c e and c o n t i n u e d benefit are o b s e r v e d (6). Ongoing r e s e a r c h w i t h m a c r o l i d e a l t e r n a t i v e s without antibiotic p r o p e r t i e s have p r o m i s e to r e d u c e side effects and p o t e n t i a t e benefits of p r o k i n e t i c drugs. Digestive Diseases and Sciences, Vol. 40, No. 1 (January 1995)

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