Fasting Dogs Research Articles

Nicotinic Acid Accelerates HDL Cholesteryl Ester Turnover in Obese Insulin-Resistant Dogs.

AimNicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides.MethodsHDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured.ResultsNA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification.ConclusionNA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile.

Pharmacological profile of AS-9705, a novel benzotriazolecarboxamide derivative, as a gastroprokinetic agent with potent anti-emetic activity.

The pharmacological profile of AS-9705 ((R)-N-(1-ethyl-1H-hexahydroazepin-3- yl)-6- methoxy-1H-benzotriazole-5-carboxamide fumarate monohydrate, CAS 219622-61-4), a novel gastroprokinetic agent with potent anti-emetic activity, was investigated in the present study. AS-9705 inhibited [3H]spiperone binding to human dopamine D2.long receptors, and [3H]R(+)-7-OH-DPAT binding to human dopamine D3 receptors (IC50 values of 58.5 +/- 14.0 and 60.8 +/- 7.8 (nmol/l), respectively) and had negligible affinity (IC50 > 10 mumol/l) for other neurotransmitter recognition sites examined. Moreover, in ferrets or dogs, AS-9705 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT and apomorphine with ID50 values of 0.05 mg/kg p.o. and 0.04 mg/kg p.o., respectively. AS-9705 dose-dependently enhanced normal gastric emptying and potently inhibited the delay in gastric empting induced by apomorphine, morphine, cisplatin, clonidine and cholecystokinin in rats. Furthermore, in conscious fasting dogs, AS-9705 dose-dependently stimulated gastric motility. In conclusion, AS-9705 is a novel gastroprokinetic agent with potent antiemetic activity and minimal CNS adverse effects and is, therefore, worthy of clinical investigation.

Modification of gastric pH in the fasted dog

The aim was to compare the ability of pretreatments to consistently adjust gastric conditions to low or high pH in the fasted state in dogs. Four male Labrador/Labrador-cross dogs weighing 25-35 kg were surgically equipped with a ventricle fistula cannula in the stomach and a jejunal nipple valve stoma. Dogs were fasted overnight before the experiments, with free access to water. The pH in the dogs' stomach was modified either orally with buffers (0.1 mol/l HCl-KCl, 0.05 mol/l glycine-HCl, 0.1 mol/l citrate or 0.1 mol/l BIS-TRIS) or intravenously with pharmacological agents (pentagastrin 4-6 microg/kg, ranitidine 50 mg or omeprazole 1 mg/kg). Intragastric pH was recorded continuously for 2 h with an electrode connected to an ambulatory pH meter. Chyme was collected simultaneously from the jejunal stoma as an approximate measure of gastric emptying. 0.1 mol/l HCl-KCl buffer p.o. and 1 mg/kg omeprazole i.v. attained low and high gastric pH more reproducibly (11/11 and 6/7 experiments met target values of pH < 3 and > 4, respectively) and for a longer duration (average time exceeding target value 90 and 103 min, respectively) than the other buffers and pharmacological pretreatments. The starting pH did not alter the modifiers' capacity to increase or decrease the pH. However, the lag time before chyme appeared at the jejunal stoma appeared to be longer when the pH was low and shorter when the pH was high. To achieve a consistently low gastric pH in fasting dogs, 0.1 mol/l HCl-KCl buffer should be administered orally, 15 min before the dosage form. To elevate the gastric pH reproducibly, omeprazole 1 mg/kg should be administered intravenously at least 90 min before oral administration of the dosage form.

Bioavailability of riboflavin from a gastric retention formulation

A gastric retention formulation (GRF) made of naturally occurring carbohydrate polymers and containing riboflavin was tested in vitro for swelling and dissolution characteristics as well as in fasting dogs for gastric retention. The bioavailability of riboflavin, a drug with a limited absorption site in the upper small intestine, from the GRF was studied in fasted healthy humans and compared to an immediate release formulation. It was found that when the GRF is dried and immersed in gastric juice it swells rapidly and releases its drug content in a zero-order fashion for a period of 24 h. In vivo studies in dogs showed that a rectangular shaped GRF stayed in the stomach of fasted dogs for more than 9 h, then disintegrated and reached the colon in 24 h. Endoscopic studies in dogs showed that the GRF hydrates and swells back to about 75% of its original size in 30 min. These in vivo results correlated with in vitro results. Pharmacokinetic parameters determined from urinary excretion data from six human subjects under fasting conditions showed that bioavailability depended on the size of the GRF. The biostudy indicated that bioavailability of riboflavin from a large size GRF was more than triple that measured after administration of an immediate release formulation. Deconvolved input functions from biostudy data suggest that the large size GRF stayed in the stomach for about 15 h.

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

AMPK plays a central role in influencing fuel usage and selection. The aim of this study was to analyze the impact of low-dose AMP analog 5-aminoimidazole-4-carboxamide-1-beta-d-ribosyl monophosphate (ZMP) on whole body glucose turnover and skeletal muscle (SkM) glucose metabolism. Dogs were restudied after prior 48-h fatty acid oxidation (FA(OX)) blockade by methylpalmoxirate (MP; 5 x 12 hourly 10 mg/kg doses). During the basal equilibrium period (0-150 min), fasting dogs (n = 8) were infused with [3-(3)H]glucose followed by either 2-h saline or AICAR (1.5-2.0 mg x kg(-1) x min(-1)) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FA(OX) blockade. The AICAR and AICAR + MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (R(d tissue)), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCR(g)) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACC approximately pSer(221)) increased by 50%. In the AICAR + MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and R(d tissue) responses were markedly attenuated, but MCR(g) and GF increased significantly. SkM substrates were unchanged, but ACC approximately pSer(221) rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FA(ox) blockade.

Effect of ATI-7505Y, a Selective 5-HT4 Receptor Agonist, on Gastric Emptying

Purpose: ATI-7505, a highly potent 5-HT4 receptor agonist, is being developed to treat diabetic gastroparesis and GERD. Preclinical studies and Ph 1 human trials indicate that ATI-7505 has a safe cardiac profile. ATI-7505 (IV) was previously found to increase upper gut motility in fasting dogs. We tested whether ATI-7505 accelerates gastric emptying in fed normal dogs, and fasting normal and diabetic rats. Methods: Dog Model: In 6 fasting dogs with strain gauge transducers located on the upper gut, after completion of a migrating motor contraction (MMC), test drugs (vehicle, ATI-7505, cisapride) were given IV over 20 mins, then the dogs were fed a solid meal. Dogs with control MMC values <25% of before and after drug (5/6 dogs) were used in the analysis. The MMC return time was used as an index of gastric emptying. Rat Model: Hyperglycemia was induced with streptozotozin (STZ, IV). After IP injection of the test drugs (5 rats/grp), 10 glass beads (1 mm diam), were inserted in the stomach. After 15 min (norm) or 30 min (STZ), the rats were euthanized and the number of remaining gastric beads was counted. Results: Dog Model: ATI-7505 (0.05 mg/kg) significantly shortened the time of MMC return, [figure 1] indicating acceleration of gastric emptying and was more potent than cisparide.FigureRat Model: In both normal and hyperglycemic rats, ATI-7505 was more potent than cisapride at accelerating gastric emptying. [figure 2] A dose of 0.01 mg/kg IP ATI-7505 was optimal to enhance gastrokinesis.FigureConclusions: ATI-7505 improves gastrokinetic function in normal fed dogs, and fasting normal and diabetic rats, and warrants further clinical investigation.

Selective uptake of high density lipoproteins cholesteryl ester in the dog, a species lacking in cholesteryl ester transfer protein activity: An in vivo approach using stable isotopes

Amongst the processes involved in the reverse cholesterol transport (RCT) from organs to liver, including high density lipoproteins-apolipoprotein AI (HDL-apoAI) dependent tissue uptake and cholesteryl ester transfer protein (CETP)-mediated transfers, the selective uptake of cholesteryl ester (CE) is of increasing interest through its antiatherogenic role. The purpose of this report is to develop a simple protocol allowing study of this process in an animal model with easier quantification of CE selective uptake. The dog was chosen essentially because this animal has a low CETP activity and an appropriate size to conduce a kinetic study. Tracer kinetics were performed to estimate in vivo the contributions of the pathways involved in HDL-CE turnover in dogs. Stable isotopes, 13C-acetate and D 3-leucine as labeled precursors of CE and apoAI, were infused to fasting dogs. Isotopic enrichments were monitored in plasma unesterified cholesterol and in HDL-CE and apoAI by mass spectrometry. Kinetics were analyzed using compartmental modeling. Results concerned the measurement of the activity of cholesterol esterification (0.13±0.032 h −1), rate of HDL-apoAI catabolism (0.024±0.012 h −1), HDL-CE turnover (0.062±0.010 h −1) and CE selective uptake (0.038±0.014 h −1). Our results show that CE in dogs is mainly eliminated by selective uptake of HDL-CE (60% of HDL-CE turnover), unlike in other species studied by similar methods in our laboratory. This study shows that among species used to analyze cholesterol metabolism, the dog appears to be the animal in whom HDL-CE selective uptake represents the largest part of HDL-CE turnover.

Effect of exercise on the mobilization of retinol and retinyl esters in plasma of sled dogs.

Fasting dogs do transport vitamin A (VA) in plasma not only as retinol but predominantly as retinyl esters. Contrary to retinol, nothing is known concerning the effects of athletic performance on plasma retinyl ester concentrations. The aim of this study was therefore to examine whether physical stress because of exercise and modification of the oxidative stress by supplementation of alpha-tocopherol influences the concentrations of retinol and retinyl esters in plasma of sled dogs. The study was carried out on 41 trained adult sled dogs, which were randomly assigned into two groups. One group (19 dogs) was daily substituted with 50 mg dl-alpha-tocopheryl acetate per kilogram body weight and the control group (22 dogs) was maintained on a basal diet during 3 months prior to exercise. The plasma concentrations of retinol, retinyl esters, alpha-tocopherol and triglycerides were measured immediately before, directly after and 24 h after exercise. The supplementation of alpha-tocopheryl acetate had no effect on plasma retinol and retinyl ester concentrations at any measurement time point. However, retinyl ester levels doubled in the non-supplemented group immediately after the race (p < 0.001), whereas in the supplemented group similar high levels were observed not until 24 h post-racing (p < 0.001). The high levels of retinyl esters were paralleled to some extent by an increase in plasma triglyceride concentrations, which were significantly higher 24 h post-racing than immediately before (p < 0.001) and after exercise (p < 0.001) in both groups. The increase in retinyl ester concentrations might be indicative of their mobilization from liver and adipose tissue. Whether plasma retinyl esters can be used as an indicator for the extent of nutrient mobilization during and post-exercise in sled dogs remains to be elucidated.

Studies on lactulose formulations for colon-specific drug delivery

A novel, colon-targeted delivery system (CODES™), which uses lactulose, was investigated in this study. Lactulose is not absorbed in the upper GI tract, but degraded to organic acids by enterobacteria in the lower gastrointestinal tract, especially the colon. A CODES™ consists of three components: a core containing lactulose and the drug, an inner acid-soluble material layer, and an outer layer of an enterosoluble material. When a CODES™ containing a pigment was introduced into the rat cecum directly after shaking in JP 2nd fluid for 3 h, pigment release was observed 1 h after introduction. A CODES™ containing 5-aminosalicylic acid (5-ASA) was orally administered to fasting and fed dogs to evaluate its pharmacokinetic profiles. 5-ASA was first detected in plasma after 3 h, which is the reported colon arrival time for indigestible solids, after dosing to fasting dogs. The T max in fed dogs was delayed by 9 h when compared to fasting dogs. This corresponds to the gastric emptying time. However, the C max and AUC under fed conditions were almost as same as those under fasting conditions. The results of this study show that lactulose can act as a trigger for drug release in the colon, utilizing the action of enterobacteria.

A pilot study of protein sparing in healthy dogs using peripheral parenteral nutrition

Total parenteral nutrition is the standard nutritional support of dogs when the enteral route is contraindicated, but it can be difficult because of cost, technical difficulties, and potential complications. Peripheral parenteral nutrition (PPN) may be a feasible option for short-term support in some cases. The objectives of this study were to determine the effect of PPN on nitrogen balance (as an indicator of the effect on protein sparing), serum folate concentrations and serum insulin-like growth factor-I (IGF - I) concentrations in fasting dogs. The effect ofPPN on these parameters has not previously been reported in dogs. Using a cross-over design, three healthy adult fasting dogs were randomly assigned to three treatments: 5 per cent amino acid solution, 5 per cent glucose solution, and a control electrolyte solution. The solutions were administered into a peripheral vein at 60 ml kg–1per day for 4 days. The amino acid infusion resulted in a positive nitrogen balance and the glucose infusion produced less nitrogen loss than the control. Amino acid, but not glucose or electrolyte infusions, decreased serum folate concentrations. Amino acid and glucose infusions resulted in higher serum IGF -I concentrations than electrolyte infusions, although the differences were small andIGF -I decreased in all cases. In conclusion, these findings suggest that PPN increases nitrogen balance in healthy dogs undergoing short-term fasting.

Gastric pH profiles of beagle dogs and their use as an alternative to human testing

Gastric pH levels were measured in samples of gastric aspirates from eight fasted beagle dogs. The gastric pH in fasting dogs fluctuated from 2.7 to 8.3, with a mean of 6.8±0.2 (SE). Each dog received the following four treatments in randomly-assigned order: (A) distilled water; (B) a placebo capsule; (C) pentagastrin, and (D) ranitidine. The gastric pH remained relatively constant after distilled water administration. In contrast, the treatments with pentagastrin and placebo capsule each lowered gastric pH. Pretreatment with pentagastrin was more successful in lowering gastric pH than that with placebo capsule. On the other hand, the pH rose above 7.0 in all dogs by the first hour after treatment with ranitidine. This animal model may be helpful in evaluating the biopharmaceutics of drugs exhibiting pH-dependent dissolution or decomposition.

Scintigraphic measurement of regional gastrointestinal transit in the dog.

Scintigraphic techniques can measure sequentially gastric emptying, small bowel transit, and colonic transit in humans, and comparable methods for experimental studies in animals would be useful. We developed such a method in dogs and examined the effects of prokinetic drugs on regional transit. Two isotopes were given to fasting dogs. Polystyrene pellets labeled with 99mTc were mixed in a can of dog food and 111In- labeled pellets were given in a gelatin capsule coated with a pH-sensitive polymer, designed to dissolve in the distal bowel. Gamma camera images were obtained for up to 24 h. Prokinetic drugs were given by intravenous injection. Duplicate baseline studies showed good agreement in seven dogs. In a second group (n = 4), intra- and interanimal variabilities were established. Two novel prokinetic drugs (AU-116 and AU-130) accelerated small bowel and colonic transit. A simple noninvasive method for measuring whole gut transit in dogs was developed and validated. Two new prokinetics accelerated small bowel and colonic transit.

Changes in colonic motility in dogs after a resection of the inferior mesenteric ganglion and plexus.

In a curative resection for advanced sigmoid or rectal cancer, an extensive dissection of the regional lymph nodes is generally required. This often necessitates the removal of the autonomic nerves around the inferior mesenteric artery. The present study was done in an attempt to clarify the influence of a neurectomy around the inferior mesenteric ganglion and plexus on the motility of the colon. In eight dogs, we resected the ganglion and plexus around the inferior mesenteric artery, together with an implantation of strain gauge force transducers in various parts of the colon, and 7-10 days later, colonic motility was examined. The percentage of contractile states and contractile forces increased at both the distal colon in fasting dogs, as well as at the middle colon in the late postprandial period. At the distal colon, contractile forces were noted in the early and late postprandial periods. These contractile abnormalities at the middle and distal colon may thus explain the frequent bowel movements or diarrhea often observed after extensive surgery in patients with sigmoid or rectal cancer.

Duodenal motility in fasting dogs: humoral and neural pathways mediating the colonic brake.

We have previously described a negative feedback loop that inhibits duodenal motility when nutrients are infused into the ileum and colon. In the present study, we examined the role of extrinsic innervation and plasma levels of peptide YY (PYY) in mediating this phenomenon. We perfused neurally intact (n = 5 dogs) or extrinsically denervated (n = 6 dogs) isolated loops of proximal colon with isomolar NaCl or a mixed-nutrient solution at 2 and 6 ml/min for 4 h during fasting or for 2 h beginning 15 min after a meal. Both rates of infusion with NaCl prolonged the cycle length of the duodenal migrating motor complex (MMC) in the group with neurally intact loops but not in the group with extrinsically denervated loops. Nutrient infusions increased the MMC cycle length in both groups. Integrated plasma concentrations of PYY were increased by nutrients but not by NaCl in both groups. These data suggest that increased volumes and unabsorbed nutrients in the proximal colon alter proximal small bowel motility. Volume-induced effects are mediated via extrinsic nerves, whereas nutrient-induced effects may be mediated by humoral factors, such as plasma PYY.

Determination of Farnesyl Pyrophosphate in Dog and Human Plasma by High-Performance Liquid Chromatography with Fluorescence Detection

A nonradioisotopic method has been developed for the determination of all-trans-farnesyl pyrophosphate (FPP), the common intermediate at the branch point of the biosynthesis of cholesterol and nonsterol end products, in dog and human plasma. FPP was cleaved to the parent alcohol, farnesol, by the direct addition of alkaline phosphatase to plasma. Farnesol extracted from plasma was converted into a fluorescent derivative with 9-anthroylcyanide. After the excess reagent was removed using an NH2-bonded phase cartridge, the derivative was separated by a column-switching high-performance liquid chromatographic system, followed by fluorescence detection. A linear response was obtained over the range of 2–18 ng/ml, when FPP was added to dog plasma in which the endogenous FPP concentrations had been lowered to undetectable levels by treatment with an HMG–CoA reductase inhibitor. The endogenous plasma FPP levels in the morning in dog and human detected for the first time by our method were 5.2 and 6.6 ng/ml, respectively. The method was utilized to examine the circadian rhythm of FPP in dog plasma, and different rhythms were observed between feeding and fasting dogs.

Nitric oxide is involved in the inhibitory action of cholecystokinin octapeptide (CCK-OP) on proximal colonic motility

To determine whether nitric oxide (NO) is a possible mediator in the inhibitory action of CCK-octapeptide (CCK-OP) on circular muscle contractions of the rat proximal colon, contractile activities of the circular muscle were recorded in the proximal colon of unrestrained conscious rats in the fasting state using a miniature strain gauge force transducer and an implantable telemetry system. Regular and rhythmic phasic contractions were observed during the fasted condition, similar to the myoelectric migrating complex seen in intestinal contractions of the fasting dog. These phasic contractions were almost completely inhibited after intraperitoneal (i.p.) administration of CCK-OP at a dose of 15 μg/kg body weight. Nω-nitro-arginine, methyl ester ( l-NAME), at doses of 20 and 200 mg/kg i.p. administered prior to i.p. injection of CCK-OP, prevented the inhibitory action on the fasting phasic contractions. The degree of prevention was dose-dependent. 100 mg/kg body weight i.p. injection of l-arginine inhibited the circular muscle contractions. The same dose of d-arginine had no action on contractions of the circular muscle of the proximal colon in the fasted rat. From these data, we conclude that NO is one possible mediator in the inhibitory mechanism of CCK-OP on smooth muscle motor activity of the rat proximal colon in vivo.

Laboratory diagnosis of insulinoma in the dog: a retrospective study and a new diagnostic procedure.

Simultaneous insulin and glucose measurements from a single sample are often insufficient for the laboratory diagnosis of insulinoma in the hypoglycaemic dog. Although the simple insulin (microU/litre): glucose (mmol/litre) ratio is best, when the selected threshold is set at 13.5, it is not always efficient to confirm or refute insulinoma. The fasting test consists of collecting four samples on a given day (no accurate time period is set between any two samples) from a fasting dog for simultaneous insulin and glucose measurements to detect at least one abnormal insulinaemia peak.

Glycated blood proteins in canine diabetes mellitus.

Measurements of serum fructosamine and glycated haemoglobin are increasingly used to complement plasma glucose concentration in the fasting dog to diagnose diabetes mellitus and to monitor the response to treatment. These measurements are not affected by acute changes in the glucose concentration and reflect the average plasma glucose concentration over the preceding one to two weeks in the case of serum fructosamine and two to three months in the case of glycated haemoglobin. Both components can be measured in canine blood samples, but glycated haemoglobin is still not measured routinely; however, the serum fructosamine concentration can be measured accurately by means of simple spectrophotometric assays. The sensitivity and specificity of serum fructosamine in diagnosing diabetes mellitus in dogs with clinical signs of the disease are very high (0.93 and 0.95, respectively). Furthermore, serum fructosamine can be used as a reliable screening test to identify diabetic dogs in an average middle-aged to older hospital population. In addition, serum fructosamine can distinguish between hyperglycaemic non-diabetic dogs and hyperglycaemic diabetic dogs. Preliminary data suggest that therapy can be safely monitored and regulated on the basis of serial measurements of the serum fructosamine concentration in diabetic dogs.

Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mg.kg-1, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mg.kg-1, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mg.kg-1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the interval between feeding and drug administration on oral ampicillin absorption in dogs

Eight dogs of various breeds received single oral doses of 20 mg/kg bodyweight ampicillin at four different time intervals relative to feeding a meal. In treatment A the dogs were fasted for 12 hours before and after ampicillin administration. In treatment B the dogs received ampicillin immediately after, in treatment C one hour before and in treatment D two hours after the meal. Each dog received these treatments during a period of feeding dry and canned dog food according to an 8 x 8 Latin square design. Blood samples were taken at specified time intervals after drug administration by jugular venepuncture. Antibiotic concentrations in plasma were determined by microbiological assay. Non-compartmental pharmacokinetic parameters were calculated from the individual concentration-time curves and were compared by non-parametric statistic tests between treatments and types of food. With both dry and canned food ampicillin absorption was impaired when the drug and food were given at the same time (treatment B) as compared to the absorption in fasting dogs (treatment A and C). On dry food, drug absorption was also decreased in treatment D. It is recommended for clinical purposes to give ampicillin to fasted dogs, and to wait at least one hour before feeding. After a meal (dry food) waiting two hours until drug administration is not sufficient to avoid impaired ampicillin absorption.