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Comparison of the Effect of Azithromycin Versus Erythromycin on Antroduodenal Pressure Profiles of Patients with Gastroi...

Permanent Link: http://ufdc.ufl.edu/UFE0025109/00001

Material Information

Title: Comparison of the Effect of Azithromycin Versus Erythromycin on Antroduodenal Pressure Profiles of Patients with Gastrointestinal Dysmotility
Physical Description: 1 online resource (38 p.)
Language: english
Creator: Moshiree, Baharak
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: antroduodenal, azithromycin, erythromycin, gastrointestinal, gastroparesis, macrolide, prokinetics, small
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Current treatments for gastroparesis (GP) with prokinetic agents have been disappointing due to the limited options available. Erythromycin ethylsuccinate (EES) is a potent prokinetic agent that stimulates gastric emptying. Recently, EES has been possibly linked to the occurrences of sudden cardiac death due to prolongation of QT intervals thought to be related to its interaction with inhibitors of cytochrome P-450 3A isoenzymes. Azithromycin (AZI) is a semisynthetic macrolide similar in structure to EES but unlike EES it does not interact with the cytochrome P-450 isoenzymes. The purpose of our study was to determine if AZI stimulates gastric antral activity and small bowel activity in patients with chronic gastrointestinal pain and refractory GP. In the first phase, small bowel manometric data on 30 patients undergoing clinical evaluation for chronic digestive problems or documented refractory GP were reviewed. For the second phase, another consecutive series of 21 patients with gastrointestinal dysmotility were prospectively studied. Antral and duodenal activity was measured after infusion of EES 250 mg IV and AZI (500 mg IV or 250 mg IV) given at different intervals during the small bowel manometry. The parameters measured included the total duration of effect, mean amplitude of antral contractions, duration of the highest antral contraction phase, number of cycles per minute, and the motility index (MI). The data were analyzed using repeated measures ANOVA for comparison of each medication. Comparison of EES and AZI showed that the mean amplitude and duration of antral activity, and the motility index were significantly increased with AZI (p = 0.006, p = 0.03, and p = 0.007, respectively as compared to EES). Overall comparison of AZI and EES in the duodenum showed that AZI induced more migratory motor complexes in the duodenum with origin of activity fronts in the antrum than did EES (p value = 0.03). We conclude that AZI stimulates antral activity similar to EES and moreover has a longer duration of effect and may even promote small bowel motility. However, AZI unlike EES does not have significant drug-drug interactions and may be a potential new and safer treatment for gastrointestinal dysmotility.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Baharak Moshiree.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Limacher, Marian C.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0025109:00001

Permanent Link: http://ufdc.ufl.edu/UFE0025109/00001

Material Information

Title: Comparison of the Effect of Azithromycin Versus Erythromycin on Antroduodenal Pressure Profiles of Patients with Gastrointestinal Dysmotility
Physical Description: 1 online resource (38 p.)
Language: english
Creator: Moshiree, Baharak
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: antroduodenal, azithromycin, erythromycin, gastrointestinal, gastroparesis, macrolide, prokinetics, small
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Current treatments for gastroparesis (GP) with prokinetic agents have been disappointing due to the limited options available. Erythromycin ethylsuccinate (EES) is a potent prokinetic agent that stimulates gastric emptying. Recently, EES has been possibly linked to the occurrences of sudden cardiac death due to prolongation of QT intervals thought to be related to its interaction with inhibitors of cytochrome P-450 3A isoenzymes. Azithromycin (AZI) is a semisynthetic macrolide similar in structure to EES but unlike EES it does not interact with the cytochrome P-450 isoenzymes. The purpose of our study was to determine if AZI stimulates gastric antral activity and small bowel activity in patients with chronic gastrointestinal pain and refractory GP. In the first phase, small bowel manometric data on 30 patients undergoing clinical evaluation for chronic digestive problems or documented refractory GP were reviewed. For the second phase, another consecutive series of 21 patients with gastrointestinal dysmotility were prospectively studied. Antral and duodenal activity was measured after infusion of EES 250 mg IV and AZI (500 mg IV or 250 mg IV) given at different intervals during the small bowel manometry. The parameters measured included the total duration of effect, mean amplitude of antral contractions, duration of the highest antral contraction phase, number of cycles per minute, and the motility index (MI). The data were analyzed using repeated measures ANOVA for comparison of each medication. Comparison of EES and AZI showed that the mean amplitude and duration of antral activity, and the motility index were significantly increased with AZI (p = 0.006, p = 0.03, and p = 0.007, respectively as compared to EES). Overall comparison of AZI and EES in the duodenum showed that AZI induced more migratory motor complexes in the duodenum with origin of activity fronts in the antrum than did EES (p value = 0.03). We conclude that AZI stimulates antral activity similar to EES and moreover has a longer duration of effect and may even promote small bowel motility. However, AZI unlike EES does not have significant drug-drug interactions and may be a potential new and safer treatment for gastrointestinal dysmotility.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Baharak Moshiree.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Limacher, Marian C.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0025109:00001


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1 COMPARISON OF THE EFFECT OF AZITHROMYCIN VERSUS ERYTHROMYCIN ON ANTRODUODENAL PRESSURE PROFILES OF PATIENTS WITH GASTROINTESTINAL DYSMOTILITY By BAHARAK MOSHIREE A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY O F FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2009

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2 2009 Baharak Moshiree

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3 To Mehri & Massoud Moshiree and Nanneh and to all patients suffe ring from gastroparesis

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4 ACKNOWLEDGMENTS I would like to express my appreciation for the protected research time I have received as an assistant professor, from the Division of Gastroenterology and the Department of Medicine at the University of Florid a to complete the requir ements of this Master of Scienc e I am also especially grateful to the Chief of Gastroenterology, Christopher E. Forsmark M.D., for sheltering me from the clinical load so that I can further pursue my research goals. Additio nally, I thank Philip P. Toskes M.D. for his selfless guidance, mentorship and enthusiasm for my career advancement and for this project. I am grateful als o to Thomas Baumgartner, Pharm. D. ions and Jane Y. Douglas Ph.D. for her eager help with the manuscript writing portion. I appreciate Marian Limacher M.D. greatly for starting the Advanced Postgraduate Program in Clinical Investigation (APPCI) in the first place and nurturing Junior Facul James I. Slaff, M.D. who was such a passionate physician scientist, friend colleague and a true inspiration to anyone interested in academic medicine.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF FIGURES ................................ ................................ ................................ ......................... 7 LIST OF ABBREVIATIONS ................................ ................................ ................................ .......... 8 ABSTRACT ................................ ................................ ................................ ................................ ..... 9 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 11 Diagnosis of Gastroparesis ................................ ................................ ................................ ..... 11 Pathophysiology ................................ ................................ ................................ ..................... 12 Treatments ................................ ................................ ................................ .............................. 13 Erythromycin and Cardiac Risk ................................ ................................ .............................. 13 Rationale for Using Azithromycin ................................ ................................ .......................... 14 Study Aims ................................ ................................ ................................ ............................. 14 2 RESEARCH METHODS AND DESIGN ................................ ................................ .............. 16 Study Design ................................ ................................ ................................ ........................... 16 Patient Selection ................................ ................................ ................................ ..................... 16 Manometric Technique ................................ ................................ ................................ ........... 17 Data Analysis ................................ ................................ ................................ .......................... 18 Measurements ................................ ................................ ................................ ......................... 19 Phase One Measurements ................................ ................................ ................................ ....... 20 Phase Two Measurements ................................ ................................ ................................ ...... 21 Statistical Analysis ................................ ................................ ................................ .................. 21 3 RESULTS ................................ ................................ ................................ ............................... 23 Phase One Results ................................ ................................ ................................ ................... 23 Phase Two Results ................................ ................................ ................................ .................. 24 4 DISCUSSION ................................ ................................ ................................ ......................... 29 5 FUTURE GOALS ................................ ................................ ................................ .................. 33 LIST OF REFERENCES ................................ ................................ ................................ ............... 34 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ......... 38

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6 LIST OF TABLES Tabl e page 3 1 Effect of Erythromycin (EES) and Azithromycin (AZI) on postprandial antral motility ................................ ................................ ................................ ............................... 25 3 2 Effect of Erythro mycin (EES) and Azithromycin (AZI) on postpr andial antroduodenal motility ................................ ................................ ................................ ....... 25

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7 LIST OF FIGURES Figure page 2 1 Antroduodenal manometry tracing after a dministration of Azithromycin (AZI). ............. 22 3 1 Comparison of erythromycin (EES) and azithromycin (AZI) with respect to mean amplitudes of antral contraction ................................ ................................ ......................... 26 3 2 Comparison of duration of highest antral contractions in the postprandial period during antroduodenal manometry (ADM) ................................ ................................ ......... 26 3 3 Comparison of the motility index for each prokinetic during Antroduodenal Manometry (ADM) ................................ ................................ ................................ ............ 27 3 4 Duration of activity fronts (AFs) and migratory motor complexes (MMCs) in the duodenum at baseline and after administration of Erythr omycin (EES) and Azithromycin (AZI) in minutes ................................ ................................ ......................... 28 3 5 Mean amplitude of migratory motor complexes in the duodenum at baseline and after administration of Erythromycin (EES) and Azithromycin (AZ I) in mm Hg. ........... 28

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8 LIST OF ABBREVIATIONS ADM Antroduodenal manometry AF Activity front ANOVA Analysis of Variance AZI Azithromycin BL Baseline CYP3A Cytochrome P450 3A EES Erythromycin GERD Gastrointestinal reflux disease G ES Gastric emptying scintigraphy GID Gastrointestinal dysmotility GP Gastroparesis IRB 01 Institutional Review Board 01 IBS Irritable bowel syndrome IV Intravenous MI Motility index MMC Migratory motor complex PSC Primary sclerosing cholangitis SEM St andard error of the mean SSRIs Selective reuptake inhibitors TdP Torsades de pointes UC Ulcerative colitis

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9 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for th e Degree of Master of Science COMPARISON OF THE EFFECT OF AZITHROMYCIN VERSUS ERYTHROMYCIN ON ANTRODUODENAL PRESSURE PROFILES OF PATIENTS WITH GASTROINTESTINAL DYSMOTILITY By Baharak Moshiree August 2009 Chair: Marian Limacher Major: Medical Sciences C linical and Translational Science Current treatments for gastroparesis (GP) with prokinetic agents have been disappointing due to the limited options available. Erythromycin ethylsuccinate (EES) is a potent prokinetic agent that stimulates gastric emptyin g. Recently, EES has been possibly linked to the occurrences of sudden cardiac death due to prolongation of QT intervals thought to be related to its interaction with inhibitors of cy tochrome P 450 3A isoenzymes Azithromycin (AZI) is a semisynthetic macrolide similar in structure to EES but unlike EES it does not interact with the cytochrome P 450 isoenzymes. The purpose of our study was to determine if AZI stimulates gastric antral activity and small bowel activity in patients with chronic gastroin tes tinal pain and refra ctory GP In the first phase, small bowel manometric data on 30 patients undergoing clinical evaluation for chronic digestive problems or documented refractory GP were reviewed. For the second phase, another consecutive series o f 21 patients with gastrointestinal dysmotilit y were prospectively studied Antral and duodenal activity was measured after infusion of EES 250 mg IV and AZI (500 mg IV or 250 mg IV) given at different intervals during the small bowel manometry. The p arameters

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10 measured included the total duration of effect, mean amplitude of antral contractions, duration of the highest antral contraction phase, number of cycles per minute, and the motility index (MI). The data were analyzed using repeated measures ANOV A for comparison of each medication. Comparison of EES and AZI showed that the mean amplitude and duration of antral activity, and the motility index were significantly increased with AZI (p = 0.006, p = 0.03, and p = 0.007, respectively as compared to EES ). Overall comparison of AZI and EES in the duodenum showed that AZI induced more migratory motor complexes in the duodenum with origin of activity fronts in the antrum than did EES (p value = 0.03). We conclude that AZI stimulates antral activity similar to EES and moreover has a longer duration of effect and may even promote small bowel motility. However, AZI unlike EES does not have significant drug drug interactions and may be a potential new and safer treatment for gastrointestinal dysmotility.

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11 CHAPTER 1 INTRODUCTION Gastroparesis (GP) is a debilitating chronic gastrointestinal motility disorder resulting from impaired transit of intraluminal gastric contents from the stomach into the duodenum associated with delayed gastric emptying in the ab sence of any mechanical outlet obstruction. Symptoms of GP are variable but include early satiety, nausea, vomiting, epigastric abdominal pain, weight loss and bloating. The prevalence of GP is very difficult to estimate due to the incomplete correlation of symptoms with gastric emptying, the large number of misdiagnosed patients who actually have this disorder, and the lack of widely available and standardized diagnostic tests or treatments. Although the true prevalence of the disorder is unknown, an es timated one third of diabetic patients in tertiary care settings have abnormal gastric emptying studies (4). In addition, up to 4% of the adult population suffers with symptoms of this condition. Furthermore as many as 25 40% of adults and children initia lly diagnosed with dyspepsia are subsequently properly diagnosed with GP (4). Such misdiagnosis can result in significant healthcare costs due to work days lost and prolonged hospitalizations (5, 6). Our extensive clinical experience with abdominal pain in chronic pancreatitis indicates that a remarkably large number of patients initially diagnosed with chronic pancreatitis in fact have gastroparesis and/or small bowel dysmotility which responds to prokinetic therapy (7). Diagnosis of Gastroparesis After demonstrating no evidence of obstruction and a normal upper endoscopy, the diagnosis of GP is usually made by finding a delayed gastric emptying time using gastric emptying scintigraphy (GES). This method is regarded as the gold standard for the diagnosis of GP. Another sensitive indicator of gastrointestinal dysmotility (GID), however, is a less commonly used method, antroduodenal manometry (ADM). Currently in the U.S., ADM is

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12 available in only a handful of tertiary referral centers with expertise in tre ating patients with GID. Antral hypomotility diagnosed using ADM correlates well with gastric stasis found using GES showing a prolongation of solid lag time and slower emptying rates of solids as compared with controls (8). However, ADM is more invasive and far less available a diagnostic tool than GES. Regardless of the method used for diagnosis of GP however, once the diagnosis is made, treatment is based on the underlying etiology. For example, in the diabetic patient, correction of the glycemic cont rol is a pivotal part of management and prokinetics such as EES are not effective unless hyperglycemia is first corrected (9,10). Pathophysiology The etiology of gastroparesis in adults is multifactorial. The three most common etiologies are diabetes, id iopathic, and post surgical, especially if surgery causes damage to the vagus nerve which is involved in inducing gastrointestinal motility. Other causes are certain medications, collagen vascular disorders, thyroid dysfunction, liver disease and cirrhosis chronic obstruction and other miscellaneous causes (4). The slow waves responsible for gastric motility originate in the region of the interstitial cells of Cajal (ICCs) and are responsible for initiating the electrical impulses across the stomach and toward the pylorus. These slow waves do not directly result in contraction of the gastric smooth muscle but instead they cause a simultaneous release of neurotransmitters from the enteric nerve end ings, leading to smooth muscle contraction (11). Although the complete neuro humoral control of gastric emptying is incompletely understood, both motilin and ghrelin are peptides secreted by the gastrointestinal endocrine cells that have been shown to incr ease gastric motility (14 17).

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13 In general, several factors affect gastric motility. These include motor dysfunction such as pyloric spasm, sensory dysfunction (such as impaired fundic relaxation, accommodation and abnormal sensation), electrical dysfunction (such as gastric arrhythmias and abnormal propagation), central nervous system effects resulting in nausea and vomiting, and others such as bacterial overgr owth in patients with GID (18). But, in most patients, including those with diabetes mellitus, treatment is still challenging due to the lack of available effective treatment options in the U.S. and abroad and the many side effects of the prokinetics curre ntly available. Treatments Currently, the most potent treatment for GP is erythromycin (EES) which accelerates gastric emptying and promotes the dumping of food and nondigestible material from the stomach into the duodenum (14 16). The prokinetic effects o f EES have been well documented in several studies done in both humans and dogs and are thought to occur through its effects as an agonist on smooth muscle motilin receptors (19 22). However, studies have failed to conclusively establish that the antral co ntractions EES triggers are solely mediated by release of motilin (17). Presently, treatment of GP has focused on the acceleration of gastric emptying to relieve symptoms of nausea, vomiting and abdominal pain. Furthermore, EES has been shown to be better than other commonly used prokinetics such as metoclopramide, cisapride and domperidone with EES resulting in as much as 30 60% improvement in gastric emptying (23). Erythromycin and Cardiac Risk For all of its benefits, EES still has its drawbacks. First several reports of arrhythmias associated with use of either oral or intravenous (IV) EES have been published (1, 24, 25). Second, in 2004, a large cohort study of Tennessee Medicaid patients from 1988 to 1993 showed a possible association between EES wi th risk of sudden cardiac death through its extensive metabolism by the cytochrome P 450 3A isoenzymes (CYP3A) (1). In this study, the adjusted

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14 rate of sudden death from cardiac causes was five times higher in patients on EES than in patients on other an tibiotics such as amoxicillin. The incidence rate ratio was 5.35 (95% CI 1.72 16.64; p=0.004) among those patients on EES and concurrently on CYP3A inhibitors such as calcium channel blockers, statin drugs, and Selective Serotonin Reuptake Inhibitors (SSR Is). Furthermore, of all the macrolides, erythromycin has the greatest arrhythmogenic liability while azithromycin (AZI) has the least (24, 25). Rationale for Using Azithromycin Given these potentially problematic drug drug interactions with use of EES, w e sought to study another macrolide, AZI, for use in patients with GP given its lack of inhibition of the cytochrome isoenzymes as compared with other macrolides (26). Initially approved by the FDA for use as an antibiotic in November, 1991, AZI is now ava ilable even in generic form. In a single blinded, placebo controlled manometric study of eleven healthy patients comparing oral AZI, midecamycin acetate to placebo, Sifrim et al. found that oral AZI significantly increased the postprandial antral motility index as compared with placebo (p < .05). (27). Furthermore, a recent case report using AZI in an elderly patient with diabetic GP showed symptom improvement after a three day treatment with IV AZI (28). Nevertheless, no data exist demonstrating the effe ctiveness of AZI in patients with GP confirmed by either ADM or GES in comparison to EES. Finally, although EES at high doses does not induce migratory motor complexes (MMC) in the small bowel, we do not yet know the effect of AZI on small bowel activity in patients with documented small bowel dysmotility (29, 30). Study Aims As a result, we sought out to study the effect of AZI in comparison to EES on ADM parameters of patients with GID as diagnosed by ADM. The aim of our present study therefore was to determine whether AZI stimulates antral activity similar to EES and if

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15 effectiveness can be demonstrated using previously defined ADM parameters. We hypothesized that AZI will stimulate antral activity similar to EES given that both medications a re motilin agonists and should then act similarly to promote antral activity. A secondary aim of this study was to investigate the effect of AZI as compared to EES on duodenal activity in patients with gastrointestinal dysmotility (GID).

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16 CHAPTER 2 R ESEAR CH METHODS AND DESIG N Study Design This study is a case series analysis of all patients who underwent ADM testing with provocative testing in the Clinical Motility Laboratory at the University of Florida from 2005 2007. In the first phase of the study, AD M data on 30 consecutive patients who were evaluated for either refractory GP or chronic functional abdominal pain were analyzed. In the second phase of the study, ADM data on 21 consecutive patients with GID were analyzed using similar parameters to comp are the effect of AZI and EES on duodenal motility indices. The research protocol was approved by the University of Florida Health Science Center Institutional Review Board (IRB 01 Project #: 552 2004) on November 7, 2004. Patient Selection Thirty consec utive patients (mean age 50 14 years, age range 24 75) with suspected functional or organic dysmotility had ADM performed routinely as part of their medical workup to clarify the physiology for their continued abdominal pain and to rule out an underlying gastrointestinal motility disorder. Symptoms on presentation included chronic abdominal pain in 23, abdominal distension in 3, nausea and vomiting in 13, weight loss in 4, constipation in 3, and spital records, we included 30 patients in the study. Prior surgeries in these patients included liver transplantation in one patient with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) with normal hepatic function, umbilical hernia surg ery, and cholecystectomy. All patients had a normal physical examination with exclusion of any obstructive symptoms. Other patient diagnoses for those included in the study at the time of presentation for the ADM were as follows: Gastrointestinal Reflux D isease

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17 UC in 1, chronic cholecystitis in one who had cholecystectomy, chronic idiopathic intestinal pseudo obstruction in 2, post trauma in 2, hypothyroidism in 3, small bowel bacterial overgrowth in 3, chronic pancreatitis in 4, and irritable bowel syndrome (IBS) in 5. Twelve of the thirty patients who underwent GES testing, were diagnosed with GP based on GES studies showing a half time (t ) > 90 minutes. A n ormal gastric emptying study was defined as an emptying t of 45 90 minutes. This study excluded patients with a prior history of obstruction, psychiatric illness, eating disorders, malignancy, and those with allergies to any macrolide antibiotics. Pati ents with systemic diseases other than diabetes and collagen vascular diseases were also excluded. None of the patients was on any chronic narcotic analgesia for at least three days prior to the study. In the second phase of the study, we studied the eff ect of AZI and EES on duodenal motility in 21 consecutive patients referred to our Clinical Motility Lab. These patients were undergoing ADM for evaluation of chronic abdominal pain and found to have small bowel dysmotility by ADM criteria (31). Only thos e patients with GP and small bowel dysmotility were included. The same criterion for diagnosis of GP applied to these patients. Manometric Technique Thirty patients underwent ADM at the University of Florida for complaints of chronic digestive problems fr om 2005 to 2007. Since no standardized protocol for performing ADM exists, we describe here our protocol here at the University of Florida. A solid state six Hampton, New Hampshire, Type: K10600 L5 0353 D) was placed intranasally under fluoroscopic guidance and advanced through the pylorus into the duodenum and positioned so that the distal tip was seen at the ligament of Treitz (30). Our recording started in the morning at 7:30 a.m. routin ely after an overnight fast that started at 10:00 p.m. the night before the patients

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18 arrived to the motility laboratory and was stopped after 23 24 hrs. Patients were required to stop all medications that can affect gastrointestinal motility 72 hours prior to the study. The manometric probe was calibrated just before the study with external application of atmospheric zero and 50 mm Hg by means of water column and was then passed under fluoroscopy. The calibration device was used to adjust and check all the sensors of the pressure transducer catheter. The pressure sensors were then adjusted to an accuracy of the sensitivity of 2% at 100 mmHg. The catheter used had a 7mm diameter with three distal transducers placed 5 cm apart in the duodenum and three prox imal transducers 10 cm in the distal antrum for a total of six pressure transducers. A portable digital pressure recorder was used to record the antroduodenal pressures seen onto an MS DOS server for later retrieval and as an online display. An event keyb oard was also used to record patient symptoms, time for sleep, meal times, and medications administered (EES and AZI). Once the catheter was positioned, the interdigestive and digestive motor activity in the distal antrum was analyzed with the proximal th ree probes located in the stomach and the next three in the duodenum. The catheter was then secured in place with tape at Data Analysis software and by visua l inspection. For analytical purposes, the total recording time was divided into three periods: a fasting (interdigestive) period of 5 6 hours, followed by a therapeutic portion including a 2 hour fed (digestive) period during which patients were given a s tandard meal consisting of two cans of Two Cal HN each 470 calories, and a postprandial (interdigestive) period during which an intravenous (IV) injection of EES then AZI was given. In this postprandial period after the two hour fed state, patients were fi rst given an IV injection of Erythromycin Lactobionate over 20 minutes. After 4 hours of observation, patients were then

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19 given an IV injection of AZI infused over 30 minutes with another four hours for observation. The motility recording was continued fo r 4 hours after EES infusion to allow for enough time for washout of EES which has a hepatic excretion time of 1.5 hours. The two medications were therefore given with the same ordering for each patient and sequentially after 4 hours. Characterization of the different phases of the MMC was done according to accepted criteria (31). Although all 30 patients received EES, 15 patients were given 500 mg of IV AZI (Group AZI A) and the other 15 patients received 250 mg IV of AZI (Group AZI B). For the 21 patie nts with small bowel dysmotility and GP in the second portion of the study, all patient received AZI and EES at a dose of 250 mg IV. In each patient, the pressure activity was analyzed for the amplitude, frequency of antral pressure activity and characteri stics of the activity front (AF) of the MMC (32). The ADM reading for all 30 patients was consistent with postprandial antral hypomotility as per the simplified criteria by Thumshirn et al., defining an average of less than one contraction per minute postp randially as significant hypomotility (33). Nineteen of these patients had only decreased antral activity during the postprandial state, 10 had antral hypomotility and small small bowel hypomotility consistent with myopathy. All 21 patients in the second portion of the study had GP and small bowel dysmotility. Antral and duodenal motility before and after each medication was analyzed with medication induced AFs compared for each medication. Measurements 4.3.0.47 from Alpine Biomedical APS Medical Devices. Measurements taken included the antral activity after postprandial infusion of EES 250 mg IV and AZI either 500 mg IV (AZI A, n=15) or 250 mg IV (AZI B, n=15) at different intervals during the ADM. The fasting state

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20 (interdigestive phase) was used as a guide to identify minute by minute the most distal antral recording site that recorded u p to 3 waves per minute (antral waves). The number of contractions for each recording site was also determined visually which allowed identification and characterization of the different phases of the MMC according to accepted criteria (32 34). Contraction s in the antrum were defined by changes in amplitude from baseline of more than 10mmHg (1.3kPa) and durations of more than one second. Then the amplitude and duration of luster activity was defined as a sequence containing a burst of contractions seen in at least two sensors followed by a period of motor quiescence lasting at least 15 seconds. Once these were identified, our data analysis focused on the most distal antral lead. The postprandial time was based on timing after meal and not the phases of MMC. Phase One Measurements Antral contractions with high amplitude pressure waves of frequencies of 0 4 cycles per min were identified (35, 36). The amplitude and duratio n of contractile waves were analyzed and mean values over a four hour period each after administration of EES or AZI were calculated. This analysis excluded any giant retrograde contractions. Finally, we compared AZI to EES with respect to the following parameters measured: the total duration of antral contractions (min) after administration of the drug (either EES or AZI), the mean amplitude of antral contraction (Kpa), duration of the highest AF in the antrum (minutes), number of cycles per min for each AF and the motility in total value for each parameter is the sum of all the contractions seen during the 4 hour postprandial period after administration of each medication.

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21 Phase Two Measurements For the 21 patients with both GP and small bowel dysmotility, pressure profiles were recorded similarly to that described above in three stages: baseline period (BL), fed state after the standardized meal, and postprandial after the administration of EES (250 mg IV) and AZI (250 mg IV). Only patients with known gastroparesis (diagnosed by gastric emptying Scintigraphy with t > 90 minutes) and small bowel dysmotility (antroduodenal manometric criteria of < 3 ncluded in this portion of the study. The interdigestive phases (baseline phase) was defined as follows: 1. Phase I: motor quiescence beginning after phase III ends, 2. Phase II: pressure waves of > 2 Pa occurring at a rate higher than the two per 10 min and less than the maximum frequency of the duodenum (10 12 contractions/min), and 3. Phase III: rhythmic contractile activity which begins in the antrum for at least a min with three contractions/min and duodenum (10 12 contractions/min) for at least 2 mi n. Phase III activity must be seen in at least 2 of the recording sites and followed by Phase I activity. The measured parameters included the characteristics of the MMCs and AFs such as site of origin (antrum versus duodenum), duration of phase III activ ity, amplitude of phase III MMCs in duodenum and number of cycles per minute. A manometry reading depicting phase III activity after administration of AZI is shown in Figure 2 1. Statistical Analysis The manometric data obtained during the postprandial pe riod were compared using repeated measures analysis of variance (ANOVA) with the SAS Software Version 9.1 (SAS analyzed visually with a print out of the entire record ing. All values are expressed as mean standard error of the mean (SEM). Comparisons of the two drugs, EES and AZI were completed using this method.

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22 Figure 2 1. Antroduodenal manometry tracing after administration of Azithromycin (AZI). The tracing shows a phase III contraction with activity front (AF) starting in the antrum (first three channels) and migratory motor complex (MMC) in the duodenum (last three channels). MMCs in duodenum Antral Activity F ront (AF)

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23 CHAPTER 3 RESULTS The AZI 1 group included 15 patients given 500 mg of AZI an d the AZI 2 group included patients given 250 mg IV of AZI. All patients were given EES. These two medications and the different doses of AZI given were then compared with respect to different manometric parameters (Table 3 1). The most prominent change in motility pattern observed after infusion of EES or AZI was the high amplitude antral contractions seen in the first 30 min after the start of infusions. Antral contractions were seen for an average duration of 1 hour and 44 minutes after administration of EES and for 2 hours 22 minutes on average after administration of either dose of AZI. MMC Phase One Results Repeated measures ANOVA showed no difference between EES and AZI 1 with respect to the total durat ion of antral contractions (p = 0.11) or the number of cycles per min of antral contractions seen (p = 0.31). Furthermore when EES was compared to the lower dose of AZI (AZI 2), no statistically significant difference was seen in any of the parameters mea sured. However, comparison of EES to AZI 1 showed an increased mean amplitude of antral contractions with AZI compared to EES during the postprandial period (112.4 55.4 versus 87.4 58.1, p = 0.006), duration of highest contractions (25 24 versus 16.5 13.4, p = .03), and MI (4.9 0.9 versus 4.4 1, p = 0.007) (Figures 3 1, 3 2, 3 3). When comparing the two doses of AZI (250 mg and 500 mg IV), only the duration of highest antral activity was statistically significant. The most significant results wer e seen with the 500 mg AZI dose with no differences seen between the lower dose of AZI used. No statistically significant difference was seen between EES and AZI (any group) with respect to the number of cycles per minute visualized.

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24 Overall for the two medications given, AZI induced a higher mean value of antral contractions (p = 0.0043) and higher total duration of antral contractions than EES (p = 0.05). Phase Two Results For the second phase of the study, comparison of AZI with EES was done in patien ts with both GP and small bowel dysmotility with duodenal motility indices compared with baseline (BL) interdigestive phase (Table 3 2). Overall comparison of AZI and EES showed that han did EES (18 patients with AZI versus 10 patients with EES, p value = 0.03). The average duration of MMCs and antral AFs were also longer in AZI group as compared with EES (AZI mean = 18.5 min, EES mean = 9.7 min, SEM 3.6 min, p value = 0.0172 ) ( Figure 3 4). However, this result was Further comparison of pressure profiles seen at BL in the duodenum with AZI given in the postprandial state showed statistic ally significant improvement in the number of MMCs (BL mean = 1.2, AZI mean = 2.4, SEM = 0.42, p value = 0.0024 ) ( Figure 3 5) and number of AFs in the antrum (p value = 0.0256). No significant difference between AZI and BL fasting state was seen with respe ct to the duration of MMCs or number of cycles per minute.

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25 Table 3 1. Effect of Erythromycin (EES) and Azithromycin (AZI) on postprandial antral motility Antroduodenal measures EES (n= 30) AZI 1 (n=15) AZI 2 (n=15) Mean amplitude of antral contrac tions (mm Hg) 87.4 58.1 112.4 55.4* p = .006 99.7 50.1 Duration of highest antral contraction (min) 16.5 13.4 25.0 24.2* p = 0.03 15.6 15.6 Total duration of antral contractions (min) 104.7 58.0 136.2 79.5* p = 0.05 148.1 65.3* p = 0 .05 Number of cycles/min (no/min) 2.1 2.3 2.19 2.0 1.7 .9 Motility i ndex l og (mm Hgno) 4.4 1.0 4.9 0.9* p = 0.007 4.3 1.0 The parameters assessed include mean amplitude of contractions, duration of highest contraction, total duration of ant ral contractions, number of cycles per minute and motility index. Data reported as means standard deviations. AZI 1 group was given 500 mg IV AZI and AZI 2 group received 250 mg IV AZI. P values are given for each parameter analyzed. *Denotes statistica l significance with p values given for comparison of EES to AZI. Table 3 2 Effect of Erythromycin (EES) and Azithromycin (AZI) on postprandial antroduodenal motility. Baseline (BL) is the pre prandial fasting state prior to administration of any medic ations. Recorded are numbers of Migratory Motor Complexes (MMCs) and Activity Fronts (AFs) in the duodenum. Antroduodenal measurements (mean SEM) BL EES AZI Avg # MMCs 1.2 .83 1.0 1.18 2.4 1.7 Avg # AFs 0.9 0.77 0.9 1.1 1.8 1.5 MMC d urati on (min) 7.5 4.6 5.5 6.0 8.4 6.0 AF d uration (min) 16.9 16.5 9.7 11.7 18.5 11.5 MMC mean amplitude (mmHg) 17.1 10.6 12.9 15.1 18.3 13.0 MMC cycles per minute (no/min) 3.1 1.9 1.5 1.8 3.1 1.7

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26 Figure 3 1. Comparison of erythromycin (EES) and azithromycin (AZI) with respect to mean amplitudes of antral contraction Denotes statistical significance with p values given for comparison of EES to AZI. Figure 3 2. Compariso n of duration of highest antral contractions in the postprandial period during antroduodenal manometry (ADM) Denotes statistical significance with p values given for comparison of EES to AZI. EES AZI 1 AZI 2 0 20 40 60 80 100 120 140 160 Medications Mean Amplitude of Antral Contractions (mm Hg) EES AZI 1 AZI 2 EES AZI 1 AZI 2 0 20 40 60 80 100 120 140 160 Medications Mean Amplitude of Antral Contractions (mm Hg) EES AZI 1 (500 mg) AZI 2 (250 mg)

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27 Figure 3 3 Comparison of the motility index for each prokinetic during Antroduodenal Manometry (ADM) Denotes statistical significance with p values given for comparison of EES to AZI. EES AZI 1 AZI 2 0 1 2 3 4 5 6 7 Medications Motility Index (log) EES AZI 1 AZI 2

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28 Figure 3 4. Duration of activity fronts (AFs) and migratory motor complexes (MMCs) in the duodenum at baseline and after administration of Erythromycin (EES) and Azithromycin (AZI) in minutes P value listed is for comparison of AZI and EES with Standard Error of the Mean (SEM). Figure 3 5. Mean amplitude of migratory motor complexes in the duodenum at baseline and after administration of Erythromycin (EES) and Azithromycin (AZI) in mm Hg. P values listed for comparison of EES to AZI, and Standard Error of the Mean (SEM). p = 0.0024 SEM= 0.456 Duration of AF contractions Medications P = 0.0172 SEM = 3.60 min Medications Mean amplitude of MMC contractions (mmHg)

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29 CHAPTER 4 DISCUSSION Our findings here suggest that AZI could be used as an alternative prokinetic for the treatment of GID and GP The higher dose of AZI created a statistically significant difference in the MI, the duration of highest antral contractions, and the mean amplitude of antral contractions seen in the post prandial period on ADM. Moreover, even the lower dose of AZI was as effective as EES in stimulating antral contractions thus supporting the potential use of AZI instead of EES the current most potent prokinetic for treatment of GP. Ultimately, our res ults support human studies done previously by Sifrim et al. that show AZI may act on motilin similar to EES in promoting antral contractile activity (27). In this study the effects of IV EES on postprandial ADM were compared to IV AZI a 15 membered semi s ynthetic macrolide known to have both less gastrointestinal side effects and less cardiac risk than EES. These data were obtained using prolonged ambulatory ADM in patients found to have gastric dysmotility defined by antral hypomotility. The comparison wa s done for the purpose of assessing whether AZI can be used as a substitute to EES in patients with known cardiac disease (prolonged QT) or in patients on concomitant medications which also interact with the cytochrome P 450 enzymes like EES does. Patients with unexplained abdominal pain are often on antidepressants most of which interact with the CYP3A isoenzymes as does EES. In contrast, AZI does not inhibit the CYP3A isoenzymes. Furthermore, AZI induces AFs followed by duodenal contractions more frequen tly than EES, even in patients with GID. Furthermore, analysis of duodenal MMC and AF characteristics indicates that the average duration of effect is also longer with AZI as compared to EES. As a result this study aimed to determine whether another macro lide with fewer drug interactions than EES, could treat small bowel d ysmotility.

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30 Of all the other macrolides available, AZI has the least effect on cytochrome P450 isoenzymes and is therefore not implicated in clinically significant drug drug interactions. In fact, no dosage adjustments are necessary even when AZI is given in conjunction with warfarin (26). In one study, Milberg et al. found that although EES and Clarithromycin cause early afterdepolarizations and torsade s de point e s (TdP) by lowering K+ concentrations, AZI did not cause either depolarizations or TdP and had the lowest pro arrhythmic potential out of all three macrolides (25). In some isolated case reports, QT prolongation and TdP have been reported in elderly patients taking AZI (38, 39) A one year, large randomized controlled study with patients prospectively analyzed with stable CAD to receive 600 mg AZI or placebo weekly for a year showed no alteration in the risk of cardiac events. This study concluded that AZI cannot be administered for secondary prevention of coronary events, however in the same respect, no increased risk of cardiac disease was seen with use of AZI (40). Another benefit in using AZI instead of EES and other macrolides is the lower incidence of side effects seen wit h AZI (41). Common side effects seen with EES include nausea, vomiting and diarrhea which are seen to a lesser degree with AZI. Another advantage is that AZI reaches higher intracellular concentrations, thus increasing both its duration of action and its efficacy. This outcome was seen in our data when the total duration of antral contractions was compared between EES and AZI with the finding that the duration of antral contractions was longer with AZI than with EES. Furthermore, AZI is absorbed rapidly wi th food thus increasing its absorption so that it can be taken with or without food. Moreover, in contrast to EES, AZI has a higher oral bioavailability. This bioavailability gives AZI an extensive distribution throughout the body with high tissue levels and at the same time it has poor central nervous system penetration. The second phase showed improvement of number of MMCs in the duodenum with

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31 AZI from baseline and as compared to EES in patients with GID. This is the first study to show AZI as a promisi ng prokinetic in patients with both gastric and small bowel dysmotility. Finally, the long half life of AZI being up to 68 hours can potentially allow for easier administration due to long duration of effect. Perhaps then this medication could be dosed on ce daily as opposed to four times daily administration required with oral dosing with EES. This once daily dosing may also improve patient compliance with taking the medication. This study has three significant limitations. First, like many studies don e with prokinetic agents this study lacked randomized control data and had an open label design making it methodologically weak and subject to bias. This study had an uncontrolled design, small sample size, was of short duration, failed to randomize the order of drug administration and lacked symptom assessment, all of which limited the generalizability of the study. Nevertheless, this similar prokinetic effect, but without AZI interacting with other drugs whic h are metabolized through the P 450 metabolic pathway. Second, this study is limited by the lack of standardized criteria for reading of ADM with differences in between studies in regards to meal composition, an alysis for research, and even the motility indices with differences in measurement. These different systems make comparison to other studies difficult given the marked variability in analysis and recordings with different durations for the postprandial, d igestive and interdigestive phases. Still, we tried to minimize this effect by having two gastroenterologists trained in reading ADM studies interpret the ADM separately with agreement found in 90% of studies interpreted for clinical purposes. Third, 18 o f the patients did not have GP by GES criteria but had antral hypomotility seen on ADM. Despite these limitations, we hope that in future studies, symptom improvement can be used as the endpoint using the cardinal GP symptom Index for assessment

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32 of sympto ms and for comparison of the two prokinetics in conjunction with GES or breath testing analysis. Finally, AZI stimulates postprandial antral activity to a higher degree than EES. The duration, MI and mean amplitude of contractions in patients with documen ted GP by ADM are increased with AZI. This increase may be due to agonist properties at the motilin receptor initiating the gastric antral contractions, or perhaps another yet unknown mechanism. Depoortere et al. showed that only 12 and 14 membered macrol ides displaced motilin while the others notably failed to act as motilin agonists at all (42). Therefore as a 15 membered macrolide, AZI may exhibit its prokinetic properties through another mechanism altogether. Since as many as a third of patients with GP also have concurrent small bowel dysmotility, the extension of our investigation into the small bowel effect of AZI is very promising given EES has been shown to inhibit small bowel motility. The potential mechanism for this effect of AZI on induction of MMC like AFs in the duodenum is unknown but warrants further investigation. Ultimately, further research is necessary to determine definitively whether the finding of increased antral contractions with use of IV AZI during ADM will translate into a prok inetic oral indication for use of AZI. A well designed, randomized controlled blinded study will need to be profile, using this very promising macrolide, AZI. Thi s could provide the f ocus of future studies on treatment of gastroparesis.

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33 CHAPTER 5 FUTURE GOALS cepted as of May, study aims to evaluate the effect of AZI in compariso n to EES on gastrointestinal motility by using a non invasive, inexpensive, 13C Octanoic Acid Breath Test for measurement of gastric emptying, and by monitoring of symptoms through the Gastroparesis Cardinal Symptom Index (GCSI) in a double blind, cross ov er study. This study hopes to demonstrate the effectiveness of AZI as compared to EES and later form the framework for larger randomized controlled parallel studies to investigate use of AZI for treatment of GP. Quality of life measures will also be perfor med with this pilot cross over study. This project will hopefully pave the way for more opportunities for funding from the National Institute of Health and for promoting my career in the field of motility disorders.

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34 LIST OF REFERENCES 1. Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004; 351:1089 96. 2. Moshiree B, Gupta V, Verne GN, Toskes PP. Azithromycin: A New Therapy for Gastroparesis? Gastroenterology. 2 005;128(suppl 2):A547. [Poster T1773] 3. Chini P, Moshiree B, Hou W, Toskes PP. Effect of Azithromycin on antroduodenal pressure profiles of patients with gastrointestinal dysmotility. Gastroenterology. 2008; 134 (issue 4): A538. [Poster T1355]. 4. Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long term follow up of patients with gastroparesis. Dig Dis Sci 1998; 43: 2398 404. 5. Frank L, Kleinman L, Ganoczy D, McQuai d K, Sloan S, Eggleston A, Tougas G, Farup C. Upper gastrointestinal symptoms in North America. Prevalence and relationship to healthcare utilization and quality of life. Dig Dis Sci 2000; 45: 809 18. 6. Talley NJ, Locke GR, Lahr BD, Zinsmeister AR, Tougas G, Ligozio G, Rojavin MA, Tack J. Functional dyspepsia, delayed gastric emptying, and impaired quality of life. Gut 2006; 55: 933 39. 7. Joshi P, Toskes P.P. Clinical approach to chronic pancreatitis. Journal of Clinical Outcomes Management 2005; 12(8): 419 426. 8. Malagelada Jr, Stanghellini V. Manometric evaluation of functional upper gut symptoms. Gastroentererology 1985; 88: 1223 31) 9. Camilleri M, Brown ML, Malagelada JR. Relationship between impaired gastric emptying and abnormal gastrointestinal motili ty. Gastroenterology 1986; 91:94 9. 10. Jones KL, Berry M, Kong MF, Kwiatek MA, Samson M, Horowitz M. Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the perception of postprandial hunger in normal subjects. Diabetes Care. 1999; 22(2): 339 44. 11. Ordog T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 2000, 49: 1731 1739. 12. Peeters TL. New motilin agonists: a long and winding road Neurogastroenterol Motil 2006; 18: 1 5.

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35 13. Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study Gut 2005; 54: 1693 1698. 14. Janssens J, Peeters TL, Vantrappen G, Tack J, Urbain JL, De Roo M, Muls E, Bouillon R.. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med 1990; 322: 1028 10. 15. Hasler WL, Heldsinger A, Chun g OY. Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors. Am J. Physiol 1992; 262:G50 5.31. 16. Tack J, Janssens J, Vantrappen G, Peeters T, Annese V, Depoortere I, Muls E, Bouillon R. Effect of erythromycin on gastric motility in controls and diabetic gastroparesis. Gastroenterology. 1992; 103(1): 72 9. 17. Sarna SK, Soergel KH, Koch TR, Stone JE, Wood CM, Ryan RP, Arndorfer RC, Cavanaugh JH, Nellans HN, Lee MB.. Gastrointestinal motor effects of erythromycin in humans. Gastroente rology 1991; 101: 1488 96. 18. Waseem S, Moshiree B, Draganov PV. Gastroparesis: Current diagnostic challenges and management considerations. World J. Gastroenterol. Jan 2009; 15(1): 25 37. 19. Otterson MF, Sarna SK. Gastrointestinal motor effects of erythromy cin. Am J Physiol 1990; 259: G355 G363. 20. Tomomasa T, Karoumi T, Arai H, Wakabayashi K, Itoh Z. Erythromycin induces migrating motor complex in human gastrointestinal tract. Dig Dis Sci 1986; 31: 157 161. 21. Itoh Z, Nakaya M, Suzuki T, Arai H, Wakabayashi K. Erythromycin mimics exogenous motilin in gastrointestinal tract activity in the dog. Am J Physiol 1984; 247: G688 G694. 22. Annese V, Janssens J, Vantrappen G, Tack J, Peeters TL, Willemse P, Van Cutsem E. Erythromycin accelerates gastric emptying by induci ng antral contractions and improved gastroduodenal coordination. Gastroenterology 1992; 102: 823 8. 23. Strum A, Holtmann G, Goebell H, Gerken G.. Prokinetics in patients with gastroparesis: A systematic analysis. Digestion 1999; 60:422 7. 24. Wisialowski T, Cri Differentiation of the antibacterials moxifloxacin, erythromycin and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability. J Pharmacol Exp Ther. 2006 ; 318(1): 352 359.

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36 25. Milberg P, Eckardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, Fleischer D, Kirchhof Fabritz L, Breithardt G, Haverkamp W. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repol arization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther. 2002; 303(1): 218 25. 26. Hopkins S. Clinical toleration and safety of azithromycin. Am J. Med. 1991; 91 (3A): 40S 45S. 27. Sifrim D, Matsuo H, Janssens J, Vantrappen G Comparison of the effects of midecamycin acetate and azithromycin on gastrointestinal motility in man. Drugs Exp Clin Res. 1994; 20(3): 121 6. 28. Sutera L, Dominguez LJ, Belvedere M, Putignano E, Vernuccio L, Ferlisi A, Fazio G, Costanza G, Barbagallo M. Azithromycin in an older woman with diabetic gastroparesis. Am J Ther. 2008; 15(1): 85 8. 29. Kashyap V, Panganamamula MD, Parkman HP. Chronic Intestinal Pseudo Obstruction. Current Treatment Options in Gastroenterology 2005, 8: 3 11. 30. Parkman HP, Trate DM, Knight LC, Brown KL, Maurer AH, Fisher RS. Cholinergic effects on human gastric motility. Gut 1999; 45:346 354. 31. Camilleri M, Malagelada JR, Brown ML, Becker G, Zinsmeister AR. Relation between antral motility and gastric emptying of solids and liquids in humans. Am J Physiol. 1985; 249(5.1): G580 5. 32. Camilleri M, Malagelada JR. Abnormal intestinal motility in diabetics with gastroparesis syndrome. Eur J Clin Invest 1984; 14(6):420 7. 33. Thumshirn M, Bruninga K, Camilleri M. Simpliflying the evaluation of postprandial antral motor function in patients with suspected gastroparesis. Am J of Gastro 1997; 92(9): 1496 500. 34. Borotolotti M, Annese V, Coccia G. Twenty four hour ambulatory antroduodenal manometry in normal subjects (co operative study). Neurogastro enterol Mot 2000; 12: 231 238. 35. Code CF, Marlett JA. The interdigestive myo electric complex of the stomach and small bowel of dogs. J Physiol 1975; 246(2):289 309. 36. Holland R, Gallagher MD, Quigly EM. An evaluation of an ambulatory manometry system in as sessment of antroduodenal motor activity. Dig Dis Sci 1996; 41:1531 7.

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37 37. Malagelada JR, Rees WD, Mazzotta LJ, Go VL. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopromide and bethanechol. Gastroenterology 1980: 78( 2): 286 93. 38. Huang BH, Wu CH, Hsia CP, Yin Chen C. Azithromycin induced torsade de pointes. Pacing Clin Electrophysiol 2007; 30(12): 1579 82. 39. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT interval prolongation and torsade de pointes in the absence of other precipitating factors. J Interv Card Electrophysiol 2007; 18(3): 243 6. 40. Grayston JT, Kronmal RA, J ackson LA Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352(16): 1637 45. 41. Rubinstein E. Comparative safe ty of the different macrolides. Int J Antimicrob Agents 2001; 18 suppl 1: S71 6. 42. Depoortere I, Peeters TL, Matthijs G, Cachet T, Hoogmartens J, Vantrappen G. Structure activity relation of erythromycin related macrolides in inducing contractions and dis placing bound motilin in rabbit duodenum. J Gastrointest Motility 1989; 1: 150 59.

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38 BIOGRAPHICAL SKETCH Baharak Moshiree received her undergraduate degree from the University of Florida in 1997 and she was accepted into the Junior Honors Program in 1996. H er medical degree is from the University of Florida where she graduated in the top 30% in her medical school class. She then completed training in internal medicine at the Medical College of Virginia in 2003. She successfully completed subspecialty training in g a stroenterology at the University of Florida in 2006 with an advanced training in m otility d isorders. She joined the College of Medicine at the University of Florida as faculty in the Division of Gastroenterology, Hepatology, and Nutrition in September, 200 7 The Master of Science with a concentration in Clinical Investigation was completed during her appointment as Assistant Professor in the Division of Gastroenterology and Hepatology. She is currently the Director of Motility at the University of F lorida and Co Director of the Pelvic Floor Program which was initiated at the University of Florida in collaboration with the c olo r ectal s urgery d ivision.