Ultrasonographic assessment of the effect of metoclopramide, erythromycin, and exenatide on solid-phase gastric emptying in healthy cats.

BACKGROUND: Available data on the effect of gastrointestinal motility-modifying drugs in cats are limited. Most recommendations for drug usage and dosage are based on collective clinical experience. OBJECTIVES: To assess the effects of metoclopramide, erythromycin, and exenatide on gastric emptying (GE) and gastric motility in comparison to placebo. We hypothesized that metoclopramide and erythromycin would have prokinetic gastric effects, whereas exenatide would prolong GE times and decrease the motility index (MI) of antral contractions. ANIMALS: Eight healthy domestic shorthair cats. METHODS: Each cat had 4 separate ultrasonographic assessments. In a prospective, randomized, double-blind, 4-way crossover design, cats received placebo, metoclopramide, erythromycin, or exenatide for 2 days followed by a minimum 5-day washout period. Ultrasonographic GE times and MI were compared to placebo. RESULTS: When compared to placebo, the rate of GE was significantly faster after administration of metoclopramide and erythromycin. Significant differences were found at all fractions of GE after administration of erythromycin and all but 1 fraction after metoclopramide when compared to placebo. The rate of GE in the first half of the GE curve was significantly slower after exenatide administration. The total area under the Ml curve was significantly larger after administration of metoclopramide and erythromycin than after placebo. CONCLUSIONS AND CLINICAL IMPORTANCE: Metoclopramide and erythromycin shorten GE times and increase the MI of antral contractions, thus having a prokinetic effect in the stomach of healthy cats, whereas exenatide causes an initial delay in GE.

Effects of preoperative oral carbohydrates on patients undergoing ESD surgery under general anesthesia: A randomized control study.

BACKGROUND: Preoperative oral carbohydrate (POC) has been recommended as an important element of the enhanced recovery after surgery (ERAS) protocol, but its effect on patients undergoing endoscopic submucosal dissection (ESD) remains unclear. Our study aims to investigate the effects of POC for ESD surgery, with particular focus on perioperative well-being and gastric peristalsis. METHODS: A prospective, randomized, and controlled study of patients undergoing ESD was conducted. Seventy-three patients were assigned to 2 groups: experiment (36 patients) and control (37 patients). The experiment group received oral carbohydrate solution 710 mL the night before and 355 mL 2 hours prior to operation. The control group fasted for 10 hours prior to operation. Gastric empty assessment, peristaltic score, and operation score were measured. In addition, visual analogue scale (VAS) scores for 6 parameters (thirst, hunger, mouth dryness, nausea, vomit, and weakness) of wellbeing were compared perioperatively. Preoperative basic conditions of patients, postoperative complications, and their clinical outcomes were also recorded. RESULTS: Before anesthesia induction, gastric sonography score was higher in experiment group, while sucked fluid by gastroscopy was similar between 2 groups. And no patient had regurgitation. Moreover, gastric peristaltic score and operation score before operation were both lower in experiment group. Importantly, VAS scores for 3 parameters (thirst, hunger, and mouth dryness) were significantly lower in experiment patients. In addition, clinical outcomes including first time exhaust, first time for drinking water, the usage of hemostasis, postoperative complication, lengths of hospital stay, and in-hospital expense were not significantly different between 2 groups. CONCLUSIONS: Oral administration of carbohydrates preoperatively instead of fasting improves the feelings of thirst, hunger, and mouth dryness in patients following ESD surgery without enhancing risk of regurgitation. And, avoiding preoperative fasting with POC can decrease the degree of gastric peristalsis that may facilitate the successful completion of ESD surgery.

Pharmacological, Toxicological, and Dose Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile-Associated Infection.

Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of Clostridium difficile infection. The lead compounds were selected from a library of over 700 single- and multiple-substitution variants of the lantibiotic mutacin 1140 (MU1140). The best performers in vitro and in vivo were further used to challenge Golden Syrian hamsters orally in a Golden Syrian hamster model of Clostridium difficile-associated disease (CDAD) in a dose-response format, resulting in the selection of OG716 as the lead compound. This lantibiotic was characterized by a 50% effective dose of 23.85 mg/kg of body weight/day (10.97 µmol/kg/day) in this model. Upon oral administration of the maximum feasible dose (≥1,918 mg/kg/day), no observable toxicities or side effects were noted, and no effect on intestinal motility was observed. Compartmentalization to the gastrointestinal tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics for the treatment of several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model.

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-µg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Anti-diarrhoeal therapeutic potential and safety assessment of sulphated polysaccharide fraction from Gracilaria intermedia seaweed in mice.

Sulphated polysaccharides extracted from algae have been extensively studied for their diverse biological activities. Thus, the purpose of this study was to evaluate the chemical composition, the anti-diarrhoeal effect and acute toxicity of a sulphated polysaccharide fraction obtained from Gracilaria intermedia (SP-Gi). Initially, the FT-IR of SP-Gi revealed to be an agaran with sulphation at C-6 of the l-galactosyl residues. The anti-diarrhoeal activity of SP-Gi was evaluated in a castor oil-induced diarrhoea model. The effects of SP-Gi on enteropooling, Na +-K +-ATPase activity, gastrointestinal transit, and gastric emptying were then examined. Subsequently, the effect of SP-Gi on diarrhoea induced by cholera toxin (CT) and Escherichia coli was examined. In addition, an acute toxicity test was conducted in accordance with OECD guideline 423. Pre-treatment with SP-Gi reduces the total faeces, total diarrhoeal faeces, and enteropooling. SP-Gi (30mg/kg p.o.) increased Na+/K+-ATPase activity and reduced gastrointestinal transit through anticholinergic mechanisms. ELISA demonstrated that SP-Gi can interact with GM1 receptors and CT. SP-Gi reduced diarrhoea induced by E. coli and prevented weight loss in the animals. Moreover, SP-Gi did not induce any toxicity signs. These results suggest that SP-Gi is a possible candidate for the treatment of diarrhoeal illnesses.

Ultrasound Assessment of the Prokinetic Effect of Erythromycin in Trauma Patients with a Full Stomach: A Case Series.

In this preliminary prospective noninterventional study, we assessed the prokinetic effect of 3 mg•kg erythromycin in nonfasted emergency trauma patients. Ultrasonographic measurements of the antral area were performed 30 minutes and immediately before the erythromycin infusion and serially at 30, 60, and 90 minutes after the start of the infusion. Gastric emptying rates before and after erythromycin infusion, and at each 30-minute period after erythromycin infusion, were then calculated. We found that gastric emptying rates were increased after erythromycin infusion although gastric content and volume remained similar.

Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure.

CONTEXT: The gut hormone, oxyntomodulin, is a proglucagon product with body weight-lowering potential. It binds to both the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor; however, the mechanism behind the body weight-lowering effect remains elusive. OBJECTIVE: We wanted to delineate the contributions of separate and combined GLP-1 receptor and glucagon receptor activation to the body weight-reducing mechanisms of oxyntomodulin. DESIGN: This was a double-blinded, randomized, crossover study. SETTING: The study was conducted at a specialized research unit. PARTICIPANTS: Fifteen young healthy male volunteers (aged 22 [range 18-32] y; body mass index 23 [21-26] kg/m(2); fasting plasma glucose 5.1 [4.4-5.4] mmol/L; and glycated hemoglobin A1c 40 (37-42) mmol/mol). INTERVENTIONS: Five 4-hour liquid meal tests during the infusion of saline, GLP-1 (1 pmol × kg(-1) × min(-1)), glucagon (0.86 pmol × kg(-1) × min(-1)), oxyntomodulin (3 pmol × kg(-1) × min(-1)), or glucagon+GLP-1 (same doses). MAIN OUTCOME MEASURES: We evaluated resting energy expenditure (measured as oxygen uptake, gastric emptying (GE), composite appetite scores (CAS), and food intake. RESULTS: Oxyntomodulin, GLP-1, and GLP-1+glucagon slowed GE and reduced CAS, whereas glucagon did not affect GE and CAS. All infusions caused a similar decrease in food intake compared with saline (total intake (g [95% confidence interval]), saline 811 [729, 892], GLP-1 669 [586, 750], glucagon 686 [604, 768], oxyntomodulin 689 [608, 771], and glucagon+GLP-1 688 [606, 769]). Oxygen uptake did not change significantly from baseline in response to any peptide infusion compared with saline. CONCLUSIONS: Oxyntomodulin, GLP-1, and glucagon decreased food intake but with no additional effect of combining GLP-1 and glucagon.

The effect of agar jelly on energy expenditure, appetite, gastric emptying and glycaemic response.

BACKGROUND AND PURPOSE: Agar contains a high amount of soluble fibre and has been shown to delay gastric emptying (GE) without impacting on glycaemic response (GR). The current study aimed to further the limited data on the effect of agar on metabolism by assessing the effects on GE and GR as well as appetite- and diet-induced thermogenesis (DIT). METHODS: In this randomized control trial, eleven healthy volunteers were tested on two occasions following an overnight fast. Following baseline and resting measurements, volunteers were either fed a fruit-flavoured drink (liquid) or consumed a fruit-flavoured jelly (jelly). The two were exactly the same in composition except the jelly contained 4 g of agar crystals. Both contained 50 g of available carbohydrate. DIT was measured using indirect calorimetry, GE using the (13)C sodium acetate breath test, appetite using visual analogue scale and GR using finger prick blood samples. RESULTS: The jelly significantly delayed GE across all time points-latency phase (p = 0.07), lag phase (p = 0.04), half-time (p < 0.0001), ascension time (p = 0.025). The jelly also increased all appetite parameters-hunger (p = 0.006), fullness (p = 0.035), desire to eat (p = 0.03) and prospective consumption (p = 0.011). However, there were no significant differences in either GR or postprandial DIT between the liquid and jelly. CONCLUSION: Agar delays GE and increases appetite but does not change GR or DIT most probably due to the increase in viscosity caused by the agar jelly.

Simultaneous assessment of gastric emptying and secretion in rats by a novel computed tomography-based method.

Gastric emptying and gastric secretion are two major physiological functions of the stomach. The assessment of these functions in particular in small animals is challenging; no method currently available allows the simultaneous measurement of both functions, and methods used are lethal or invasive and often limited by spatial, temporal, or quantitative resolution. Here, we report the establishment and validation of a quantitative noninvasive high-throughput computed tomography-based method to measure simultaneously gastric emptying and secretion in rats in vivo. The imaging strategy enables one to visualize stomach anatomy and to quantify stomach volume and stomach contrast agent content. The method was validated by comparing the results to classical lethal methods (stomach phenol red content and stomach wet weight). Additionally, we showed that the use of a mild anesthetic does not interfere with normal gastric function, thereby enabling high-resolution temporal studies within single animals. These combined advantages were applied to reevaluate the impact of cholecystokinin (CCK), histamine, and oral glucose solutions on gastric function with high temporal resolution. CCK inhibited gastric emptying completely for 20 min, leading to the accumulation of gastric juice in the stomach. The CCK antagonist devazepide blocked this effect. Histamine stimulated both gastric secretion and delayed emptying. Oral glucose solution emptied at a fixed rate of 24-31 cal/min and stimulated gastric secretion. These results confirm previous observations and add volumetric changes as a new dimension. As computed tomography scanners become broadly available, this method is an excellent approach to measure the combined gastric functional readout and to reduce the number of animals used.

Clinical assessment of delayed gastric emptying and diabetic complications using gastric emptying scintigraphy: involvement of vascular disorder.

AIM: Delayed gastric emptying, including gastroparesis, is a common complication in diabetes mellitus. The association between delayed gastric emptying and overall diabetic complications remains to be studied in detail. We analysed this association. METHODS: We performed gastric emptying scintigraphy of (99m) Tc-diethylenetriaminepentaacetic acid in 34 patients with diabetes to measure the gastric emptying half-times (T1/2) of the whole stomach (WS), proximal stomach (PS) and distal stomach (DS). We assessed T1/2, diabetic-related factors and complications. RESULTS: The prevalence of autonomic neuropathy was higher in the group with delayed T1/2 of the WS than in the normal group. Analysis of intima-media thickness (IMT) and ankle brachial pressure index (ABI), which are risk indicators for vascular disorder, showed that IMT of the carotid bulb was greater in the group with delayed T1/2 of the WS than in the normal group (2·41 mm [1·50-2·81] versus 1·40 mm [0·81-2·08], P = 0·015). T1/2 of the WS correlated positively with IMT of the carotid bulb (r = 0·391, P = 0·027) and negatively with ABI (r = -0·389, P = 0·028). These correlations were mainly attributed to PS and were the same in patients without autonomic neuropathy. In seven of nine patients who received scintigraphy again after diabetic treatment, glycosylated haemoglobin (HbA1c) levels decreased and T1/2 of the WS shortened compared with before treatment. CONCLUSION: Vascular disorder, among other cofactors such as autonomic neuropathy, could be involved in the pathophysiology of delayed gastric emptying. Medium- to long-term glycaemic control was associated with gastric emptying.

Effect of DA-9701 on gastric emptying in a mouse model: assessment by ¹³C-octanoic acid breath test.

AIM: To evaluate the effects of DA-9701 on the gastric emptying of a solid meal using the ¹³C-octanoic acid breath test in a mouse model. METHODS: Male C57BL/6 mice aged > 8 wk and with body weights of 20-25 g were used in this study. The solid test meal consisted of 200 mg of egg yolk labeled with 1.5 L/g ¹³C-octanoic acid. The mice were placed in a 130 mL chamber flushed with air at a flow speed of 200 mL/min. Breath samples were collected for 6 h. The half-emptying time and lag phase were calculated using a modified power exponential model. To assess the reproducibility of the ¹³C-octanoic acid breath test, the breath test was performed two times at intervals of one week in ten mice without drug treatment. To assess the gastrokinetic effects of DA-9701, the breath test was performed three times in another twelve mice, with a randomized crossover sequence of three drug treatments: DA-9701 3 mg/kg, erythromycin 6 mg/kg, or saline. Each breath test was performed at an interval of one week. RESULTS: Repeatedly measured half gastric emptying time of ten mice without drug treatment showed 0.856 of the intraclass correlation coefficient for the half gastric emptying time (P = 0.004). The mean cumulative excretion curve for the ¹³C-octanoic acid breath test showed accelerated gastric emptying after DA-9701 treatment compared with the saline control (P = 0.028). The median half gastric emptying time after the DA-9701 treatment was significantly shorter than after the saline treatment [122.4 min (109.0-137.9 min) vs 134.5 min (128.4-167.0 min), respectively; P = 0.028] and similar to that after the erythromycin treatment [123.3 min (112.9-138.2 min)]. The lag phase, which was defined as the period taken to empty 15% of a meal, was significantly shorter after the DA-9701 treatment than after the saline treatment [48.1 min (44.6-57.1 min) vs 52.6 min (49.45-57.4 min), respectively; P = 0.049]. CONCLUSION: The novel prokinetic agent DA-9701 accelerated gastric emptying, assessed with repeated measurements in the same mouse using the ¹³C-octanoic acid breath test. Our findings suggest that DA-9701 has therapeutic potential for the treatment of functional dyspepsia.

Molecular weight of barley ß-glucan influences energy expenditure, gastric emptying and glycaemic response in human subjects.

Barley ß-glucan (BG) has been shown to reduce glycaemic response (GR) in some studies. It is hypothesised that this reduction may be a function of its physical properties that delay gastric emptying (GE). The effect of these changes in GR and GE on diet-induced thermogenesis (DIT) is not known. The aim of the present study was to assess the effect of BG of different molecular weights and purities on GR, GE and DIT in healthy subjects. This was a randomised, single-blind, repeated-measures design where fifteen healthy subjects were tested on three occasions following an overnight fast. Following the baseline measurements, the volunteers were fed a soup containing high-molecular-weight BG (HBG), a soup containing low-molecular-weight BG (LBG) or a control soup with no BG (CHO). Following the consumption of the breakfast, GR was measured using finger-prick blood samples, GE was determined using the 13C-octanoic acid breath test and DIT was measured using indirect calorimetry. There was a difference in GR AUC between the soups after 60 min but not after 120 min. The CHO and LBG meals had a greater GR than the HBG meal. There were differences in all GE time points, with the HBG meal having the slowest GE time. There was a correlation between the GR and the initial GE times. There were differences in total DIT between the three test meals with the HBG meal having the lowest DIT. The present study indicates that HBG has the ability to delay GE due to increased viscosity, resulting in a decreased GR and DIT.

An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability.

INTRODUCTION: Gastrointestinal adverse effects contribute significantly to drug attrition as well as reduced patient compliance. Determination of gastrointestinal liability early in a compound's preclinical development would be a valuable tool. We evaluated the non-invasive faecal pellet method in the rat, assessed the feasibility of adding the endpoint to other study types and investigated correlation with the charcoal meal method. METHODS: Han Wistar rats, pair housed in metabolism cages, received a single dose of vehicle, atropine, bethanechol, loperamide or metoclopramide. The number, weight and appearance of pellets produced were assessed over 10 h and at 24 h post-dose. The endpoint was also added to a modified Irwin screen (testing atropine, theophylline, clonidine, amphetamine, baclofen or quinine) and a whole body plethysmography study (testing theophylline or bethanechol). Pellets were collected from home cages out to 4 h post-dose (Irwin) or following a 45 minutes plethysmography session. To assess correlation with stomach emptying and intestinal transit charcoal meal data was generated where published data was not available. RESULTS: Atropine decreased, while bethanechol and metoclopramide increased the number and weight of faecal pellets produced. Atropine produced darker, harder pellets and bethanechol lighter, softer pellets. Loperamide reduced pellet production at later time points only. Theophylline increased (Irwin and plethysmography) and atropine (Irwin) decreased pellet number and weight. Effects were maximal at the T(max) and detected in all study environments. Primary data generation was not affected by pellet collection. Pellet findings were generally comparable to charcoal meal transit data, with compounds showing an inhibition (atropine, loperamide, amphetamine, baclofen, clonidine, quinine) or stimulation (bethanechol) in both models. DISCUSSION: We have demonstrated that the faecal pellet method can detect expected reference compound induced changes in pellet transit. The technique is a useful non-invasive 'add-on' to other study types allowing gastrointestinal effects to be flagged earlier in preclinical development.

Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes.

AIMS: Liraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect. METHODS: The comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide-placebo), B (placebo-glimepiride) or C (glimepiride-liraglutide). Assessments were performed at the end of each 4-week treatment period. RESULTS: Energy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC(0-60 min) and C(max) were less (p<0.01) and fasting peptide YY was lower (p ≤ 0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0 kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones. CONCLUSION: Liraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure.

Assessment of gastrointestinal propulsive activity using three different models of peristalsis in vivo in the mouse.

The protocols described in this unit are designed to assess the acute effects of drugs on the propulsive activity of the gastrointestinal muscles in the conscious mouse. These protocols are currently applied to investigate the pharmacological activity of novel compounds undergoing preclinical development and to obtain predictive data needed to advance drugs into clinical trials. Moreover, these methods could be useful in evaluating the functional toxicity by environmental or alimentary pollutants, like xenobiotics and naturally occurring toxins endowed with noxious activity in the control of physiologic peristalsis. The three models detailed-the measurement of gastric emptying, ileal transit, and colonic propulsion-are substantially non-invasive and do not require analgesic pretreatments or the induction of general anesthesia. In contrast to an in vitro approach, these in vivo studies provide a unified understanding of drug effects on gut functionality, in particular when the central nervous system, the extrinsic nerves, or the (neuro)endocrine system is targeted by the test drugs.

Assessment of gastric motor function by cine magnetic resonance imaging.

BACKGROUND AND AIM: The aim of the present study was to evaluate gastric motor function by magnetic resonance imaging (MRI) and investigate whether this examination is a useful tool for therapeutic efficacy or postoperative gastric motor function. METHODS: Twenty-five healthy volunteers and 10 gastric cancer patients with pylorus-preserving gastrectomy (PPG) underwent cine-MRI. Gastric volume was determined by 3D-volumetry. Gastric motility was quantified by calculating the gastric motility index (GMI). RESULTS: The image acquisition and analysis were successfully carried out for all subjects. In healthy volunteers, mean frequency, amplitude, velocity of gastric peristaltic waves and GMI 30 min after the intake of jelly were 3/min, 8.8 mm, 2.2 mm/s and 19.6 mm2/s, respectively. Mean amplitude (8.8 vs 10.4 mm, P = 0.027), velocity (2.2 vs 2.6 mm/s, P < 0.001) of peristaltic waves, and GMI (19.6 vs 26.7 mm2/s, P < 0.001) significantly increased at 30 min after giving mosapride citrate (MS). Mean gastric volume after MS administration was significantly decreased; 0 min (317.3 vs 272.9 mL, P = 0.021), 45 min (263.4 vs 206.4 mL, P = 0.004) and 60 min (228.7 vs 165 mL, P = 0.001). PPG patients with postprandial symptoms were observed having antiperistalsis-like contraction waves and reflux of gastric contents from the pyloric region into the upper part of the stomach. Mean gastric volume in PPG patients with postprandial symptoms at 30 min after intake of jelly tended to be greater than in those without such symptoms. CONCLUSIONS: The present study demonstrates that cine-MRI is a sensitive and non-invasive imaging technique for simultaneously measuring gastric motility and emptying.

Assessment of the gastric emptying velocity by the 13C-octanoate breath test: deconvolution versus a Wagner-Nelson analysis.

BACKGROUND: The dynamic change in gastric emptying on a minute-by-minute basis (gastric velocity) is evaluated by the 13C-octanoate breath test with deconvolution analysis. However, deconvolution is impractical, because it requires dual experiments to obtain 13CO2 excretion profiles following intraduodenal and oral administration of 13C-octanoate. We investigated whether the Wagner-Nelson method, used in drug absorption studies, can determine the velocity profile based on a single experiment as accurately as deconvolution, and whether the velocity assessed by the Wagner-Nelson method is sensitive enough to detect subtle changes in gastric emptying induced by butylscopolamine. METHODS: Five male volunteers underwent a 4-h breath test twice, after intraduodenal administration of 20 ml normal saline containing 100 mg 13C-octanoate and after ingestion of a 320-kcal muffin containing 100 mg 13C-octanoate. Deconvolution determined the velocity profile by subtracting duodenal from oral data, and the Wagner-Nelson method produced it from only oral data. The velocity profiles were compared between the two methods. Another six male subjects underwent the breath test by ingesting a muffin twice, once with and once without 20 mg oral butylscopolamine. The velocity profiles generated by the Wagner-Nelson analysis and the conventional 13CO2 excretion curves were compared between the two occasions. RESULTS: The two techniques yielded identical velocity profiles. The velocity profile detected a significant change in the emptying pattern induced by butylscopolamine (initial acceleration with subsequent deceleration), while the conventional breath curves failed to detect this change. CONCLUSIONS: Velocity assessment by a Wagner-Nelson analysis can precisely describe altered gastric emptying, based on a single experiment.

Oral controlled-release formulation in veterinary medicine.

The development of controlled-release dosage forms (CRDFs) is highly desirable both from a convenience and compliance perspective. Furthermore, these formulations release drugs at a prescribed rate, leading to relatively constant blood drug concentrations or to pulse dosing. Another benefit is the ability to administer medications in infrequent regimens. For example, antimicrobial agents generally require very frequent administration regimens. In recent years, the pharmaceutical industry has realized the potential of this treatment modality and efforts have been made to develop a variety of CRDFs exclusively for veterinary use. While there are a number of controlled-release products available for veterinary applications, only a limited number of therapeutic niches (such as the application of antiparasitic drugs in cattle) are associated with products that have been developed as oral controlled-release products. In addition to reviewing potential new therapeutic areas where oral controlled-release products can be applied in veterinary medicine, this article reviews differences in the gastrointestinal tracts of various species and the significance of the dissimilarity in the development of CRDFs. Technological aspects involved in veterinary CRDFs are also assessed.

Short-term metabolic ethanol tolerance in dogs.

Metabolic ethanol tolerance was studied in a cohort of five dogs with ethanol challenge repeated weekly over a 7-week period. During the 7-week period, the area under the blood alcohol versus time curve (AUC) increased slightly while the rate of ethanol elimination also increased slightly. During the repeated ethanol dosing, ethanol absorption shifted from approximately equal absorption in the stomach and intestine to three-fold more absorption in the intestine than in the stomach. The likely cause of the shift in absorption site was probably a concomitant change in gastric emptying that occurred with repeated dosing. This shift is significant since ethanol absorption in the small intestine has been shown to be over six-fold more rapid than ethanol absorption in the stomach.

Assessment of the effects of erythromycin, neostigmine, and metoclopramide on abomasal motility and emptying rate in calves.

OBJECTIVE: To determine and compare the effects of erythromycin, neostigmine, and metoclopramide on abomasal motility and emptying rate in suckling calves. ANIMALS: 6 male Holstein calves (15 to 40 days of age). PROCEDURE: Calves were monitored for 1 hour before being fed milk replacer (60 mL/kg; time, 0 minutes) and then were monitored for another 3 hours. Calves received 6 treatments in randomized order: erythromycin (8.8 mg/kg, IM) at -30 minutes; low-dose erythromycin (0.88 mg/kg, IM) at -30 minutes; erythromycin (8.8 mg/kg, IM) at -30 minutes and neostigmine (0.02 mg/kg, SC) at -30 and 90 minutes; neostigmine (0.02 mg/kg, SC) at -30 and 90 minutes; metoclopramide (0.1 mg/kg, IM) at-30 and 90 minutes; and placebo (2 mL of saline [0.9% NaCl] solution, SC) at -30 minutes. Abomasal volume was calculated from ultrasonographic measurements of abomasal width, length, and height. Abomasal motility and emptying rate were assessed by measuring luminal pressure and change in abomasal volume over time. RESULTS: Administration of erythromycin (8.8 mg/kg) increased the frequency of abomasal luminal pressure waves and the mean abomasal luminal pressure and decreased the half-time of abomasal emptying by 37%. Administration of metoclopramide, neostigmine, and low-dose erythromycin (0.88 mg/kg) did not alter abomasal motility, mean luminal pressure, or emptying rate. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that administration of erythromycin at the labeled antimicrobial dose (8.8 mg/kg, IM) exerted an immediate, marked prokinetic effect in healthy suckling calves, whereas administration of metoclopramide or neostigmine did not alter abomasal motility or emptying rate.