The effect of multiple doses of KC 11458, a new motilin agonist, on gastric emptying of a solid test meal in healthy male volunteers

A842 AGAABSTRACTS

GASTROENTEROLOGYVoL 114, No. 4

G3455 KC 11458, A NEW MOTILIN AGONIST, IS EFFECTIVE IN THE ACCELERATION OF GASTRIC EMPTYING AFTER INFUSION IN HEALTHY MALE VOLUNTEERS. H. Steinbrede*, S. Aygen #, G. Eibes ÷, C. Steinborn ÷. *FOCUS Clinical Drug Development GmbH, Neuss, #INFAi GmbH, Bochum; +Solvay Pharmaceuticals GmbH, Hannover, Germany. Background: KC 11458 is a new macrolide with motilin agonistic properties but without antibiotic activity. Aims: Evaluation of gastric emptying of a solid test meal after intravenous infusion of KC 11458. Methods: In a single, rising dose double-blind study KC 11458 has been administered to 24 volunteers. Each volunteer has received a 30 minutes infusion of 1, 4 and 8 mg KC 11458 and placebo each. 12 hours after fasting the test meal was administered directly at the end of the infusion. Measurements were performed in the morning of each day. Gastric emptying was measured using the 13C-octanoic acid breath test as described in the literature with slight modifications. Results: The table summarizes the mean values ( _+ standard deviation) for the half gastric emptying time (tl/2) and lag-time (tlag). tw [min]

th~ [min]

treatment placebo

mean 99.57

s.d. 35.31

mean 58.65

s.d. 26.32

1 mg

i01.31

41.50

63.23

37.30

4 mg 8 mg

91.55 75.12

42.26 27.95

46.73 36.88

31.92 25.32

mg KC 11458 administered intravenously did not reduce tu2 and tlag, 4 mg has shown only slight decreases, but 8 mg was effective in the acceleration of gastric emptying. Conclusion: KC 11458, a new motilin agonist, is effective in reducing gastric emptying parameters tl/2 and tlag but higher doses should be investigated to increase the effects on gastric emptying. This study was fully sponsored by Solvay Pharmaceuticals GmbH, Hannover, Germany • G3456 THE EFFECT OF MULTIPLE DOSES OF KC 11458, A NEW MOTILIN AGONIST, ON GASTRIC EMPTYING OF A SOLID TEST MEAL IN HEALTHY MALE VOLUNTEERS. H. Steinbrede*, S. Aygen#, G. Eibes ÷, C. Steinborn ÷ *FOCUS Clinical Drug Development GmbH, Neuss, #INFAI GmbH, Bochum, *Solvay Pharmaceuticals GmbH, Hannover, Germany. Background: KC 11458 is a new macrolide with motilin agonistic properties but without antibiotic activity. Aims: The aim of the present study was the evaluation of gastric emptying of a solid meal after administration of multiple doses of KC 11458. Methods: In this oral repeated-dose, placebo-controlled double-blind balanced incomplete crossover study, 30 patients have received placebo and 8 rag, placebo and 16 mg or 8 mg and 16 mg KC 11458 three times daily over a period of 6 days. Gastric emptying was assessed after the first single dose in the morning, on day 4 in the afternoon and after the last dose of KC 11458 in the morning. KC 11458 was administered as an enteric coated acid stable formulation two hours before each test meal. Gastric emptying was measured using the 13C-octanoic acid breath test as described in the literature with slight modifications. Results: The following table summarizes the results of the half gastric emptying time (h/2) and lag-time (qag) given as means of the individual differences between the treatments. Group

Time point

tia~ [min]

8 mg-p 8 mg-p 8 mg-p

first dose day 4 (afternoon) last dose

-14.63 -4.63 -14.24

p-value 0,02 0,28 0,03

] t,~ [min] -30.97 -33.76 -30,49

p-value < 0,01 0,06 < 0,01

16 mg-p 16 mg-p 16 mg-p

first dose day 4 (afternoon) last dose

-31.66 -15.17 -12.91

< 0,01 0,04 0,04

-46.92 -65.56 -27.99

< 0,01 < 0,01 < 0,01

8 and 16 mg significantly decrease gastric emptying times compared to placebo after first administration. Due to high variability in the afternoon measurements only 16 mg was significantly better than placebo. The significant effect is still present after 6 days but difference between 8 and 16 mg disappeared. Conclusion: KC 11458, a new motilin agonist, is highly active in decreasing gastric emptying times after multiple dose. However, after high multiple doses of 16 mga slight tachyphylactic phenomenon cannot be ruled out. This study was fully sponsored by Solvay Pharmaceuticals GmbH, Hannover, Germany

G3457 IDIOPATHIC AND REFLUX-ASSOCIATED DIFFUSE ESOPHAGEAL SPASM: A LACK OF DIFFERENTIATION BY MANOMETRY. Steinlauf AF, Sandman Y, Traube M. Gastroenterology Unit, Yale University School of Medicine, New Haven, Connecticut. Introduction: Gastroesophageal reflux is associated with esophageal dysmotility, including reflux-associated spasm (R-DES). Diffuse esophageal spasm (DES) may also be idiopathi c (I-DES). Controversy exists as to whether the two can be differentiated from each other by esophageal manometry, and previous studies were sub-optimal because pH studies were not utilized to diagnose esophageal reflux. Aim: To determine whether manometric findings are useful in differentiating R-DES from I-DES. Methods: The manometry and pH Study files of our motility laboratory from 1994 through 9/97 were reviewed to identify patients who a) had manometry showing DES, defined below, and b) had undergone'ambulatory 24-hour pH monitoring. Eighty-six patients with DES were identified, of whom 26 also underwent 24-hour pH monitoring. The diagnosis of DES was defined as increased % simultaneous contractions (>25%) in the distal esophagus, with preservation of some peristalsis. Patients were categorized as having pathologic reflux when the % total reflux time (pH<4) was greater than 4.2%. Of the 26 patients identified, 16 had pathologic reflux and were placed into the R-DES group, and 10 were placed into the I-DES group. Between groups, the following parameters were compared: mean lower esophageal sphincter pressure (LESP), mean contraction amplitude (MCA), mean % simultaneous contractions (%SC), and mean % of contractions of low amplitude, defined as <37 mmHg (%LCA) in the distal esophagus. These parameters were compared using the student's t-test for unpaired data. The number of patients in both groups with low LESP (<10mmHg)and high MCA (>142mmHg) Were determined and % of patients in each group meeting these criteria were compared using a Fisher's exact test. Results: In the table below, values are mean _+SE.

I-DES R-DES p-value

LESP (mmHg) 14 -+3 16 + 2 .54

MCA (mmHg) 56 -+ 12 53 -+ 12 .86

%SC

%LCA

36 -+ 3 44 _+4 .13

46 ± 10 48 _+06 .83

Three patients in each group were observed to have low LESP. Only one patient demonstrated a high MCA (228 mmHg), and this patient was in the RDES group. There were no significant differences between the groups in any of the above manometric parameters. Conclusions: Using current manometric and pH studies, we have shown that LESP, MCA, %SC, and %LCA are equivalent in idiopathic and reflux-associated spasm. More specifically, reduced LESP and MCA do not suggest that the spasm is reflux-associated, and a high MCA does not suggest that the spasm is idiopathic. Thus, manometric characteristics do not help to differentiate idiopathic from refluxassociated esophageal spasm. G3458 PRE-TREATMENT GASTRIC TACHYARRHYTHMIA PREDICTS NAUSEA FOLLOWING CHEMOTHERAPY. R.M.Stern. P.J. Gianaros, Penn State University, University Park, PA, G.R. Morrow, J.T. Hickok, J.A. Roscoe, University of Rochester, Rochester, NY. Nausea is more likely to follow chemotherapy in females than males, and in younger rather than older patients. However, many patients of both genders and all ages experience nausea follow!ng some sessions of chemotherapy, but do not experience nausea following other sessions in which the identical antiemetics and chemotherapy drugs are administered. The literature on motion sickness suggests that treatments which increase peripheral parasympathetic nervous system (PNS) activity reduce motion sickness severity. Furthermore, we have previously shown that subjects with relatively high baseline PNS activity report less nausea during motion sickness induction. The purpose of this study was to try to predict whether or not a patient would experience nausea following chemotherapy based on non-invasive measures of gastric activity (electrogastrograms or EGGs) which are correlated with PNS activity. EGGs were recorded using a UFI Biolog recording system from 11 female chemotherapy patients (mean age=54) at the University of Rochester Cancer Center. The patients were being treated for a variety of different malignancies and received standard dosages of both anti-emetics and chemotherapy agents. Spectral analyses were performed on EGG data obtained after the patients received anti-emetics and approximately five minutes prior to chemotherapy for each of two sessions, one of which was followed by nausea and one which was not. The results showed that prior to chemotherapy, percent 3 cpm activity did not differentiate between sessions which were followed by nausea and those that were not. However, the percent gastric tachyarrhythmia prior to chemotherapy predicted whether that session would be followed by nausea (R=0.39; F (1,10)=6.5,p<.03). The mean percent tachyarrhythmia prior to nausea trials was 22.9 (SEM=3.4), and prior to no nausea trials was 12.9 (SEM=3.1). These results are comparable to those obtained in studies which have predicted susceptibility to motion sickness from baseline PNS activity, and may have value in developing new strategies to reduce the nausea of chemotherapy. Supported in part by Grant NR01905 from NINR