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The aim of this study was to assess the impact of three ampicillin dosage regimens on ampicillin resistance among Enterobacteriaceae recovered from swine feces by use of phenotypic and genotypic approaches. Phenotypically, ampicillin resistance was determined from the percentage of resistant Enterobacteriaceae and MICs of Escherichia coli isolates. The pool of ampicillin resistance genes was also monitored by quantification of bla(TEM) genes, which code for the most frequently produced beta-lactamases in gram-negative bacteria, using a newly developed real-time PCR assay. Ampicillin was administered intramuscularly and orally to fed or fasted pigs for 7 days at 20 mg/kg of body weight. The average percentage of resistant Enterobacteriaceae before treatment was between 2.5% and 12%, and bla(TEM) gene quantities were below 10(7) copies/g of feces. By days 4 and 7, the percentage of resistant Enterobacteriaceae exceeded 50% in all treated groups, with some highly resistant strains (MIC of >256 microg/ml). In the control group, bla(TEM) gene quantities fluctuated between 10(4) and 10(6) copies/g of feces, whereas they fluctuated between 10(6) to 10(8) and 10(7) to 10(9) copies/g of feces for the intramuscular and oral routes, respectively. Whereas phenotypic evaluations did not discriminate among the three ampicillin dosage regimens, bla(TEM) gene quantification was able to differentiate between the effects of two routes of ampicillin administration. Our results suggest that fecal bla(TEM) gene quantification provides a sensitive tool to evaluate the impact of ampicillin administration on the selection of ampicillin resistance in the digestive microflora and its dissemination in the environment.

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OBJECTIVES: To investigate and validate noninvasive methods for the quantitative evaluation of postinjection muscle damage. ANIMALS: 5 adult sheep. PROCEDURES: Muscle lesions were induced twice in the lumbar region of the longissimus dorsi muscles (2 sides) by IM administration of a 20% formulation of long-acting oxytetracycline (20 mg/kg of body weight). Clinical signs and local cutaneous temperature above the injection site were recorded. Muscle lesions were quantitatively evaluated by ultrasonography and by use of pharmacokinetic analysis of plasma creatine kinase activity, and both were compared with a comprehensive planimetric computer-assisted analysis of the injection sites after euthanasia. RESULTS: Transient cutaneous hypothermia (temperature change, -3.9+/-0.62 C) and subsequent persistent hyperthermia (3.1+/-1.35 C) were observed after the administrations. Despite coefficient of variation < 10% for precision of ultrasonographic measurement of normal muscle, measurements of the lesions, with coefficient of variation > 60% for precision, were systematically underestimated. Quantitative evaluation of muscle damage by use of pharmacokinetic analysis of creatine kinase (12.1+/-4.96 g) was in agreement with results of macroscopic planimetric evaluation (10.8+/-3.64 g). CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonography cannot be used for quantitative assessment of postinjection muscle damage. Pharmacokinetic analysis of creatine kinase provides an accurate quantitative evaluation of macroscopic muscle damage after IM administration of drugs.

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Although gastrointestinal complications are common in patients with renal disease, the effects of renal dysfunction on bowel motility and gut transit times are not well known. We assessed gastrointestinal electromyographic activity, gastric emptying rate, orocolonic transit time, oroanal transit time, and xylose absorption before and after surgically inducing a 66% decrease in glomerular filtration rate in dogs. Moderate renal failure induced no gross or microscopic gastrointestinal lesions but caused a 16-42% increase in gastrointestinal motility indexes. We found a 24% decrease in the propagation velocity of the myoelectrical migrating complex in the duodenojejunal segment, a 30% decrease in phase I duration in duodenal and jejunal regions, a 20% increase in the total irregular electrical activity of the small intestine, and a 22% increase in duration of the meal response in the duodenum and jejunum. Renal failure did not change xylose absorption, gastric emptying rate, and orocolonic transit time but decreased colonic transit time by 38%. The mean weight of feces was increased. These results indicate that moderate renal failure alters duodenojejunal motility and decreases colonic transit time.

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The disposition of the two enantiomers of carprofen (CPF), the (R)-CPF and the (S)-CPF, was investigated after iv administration of the racemate (4 mg/kg) in dogs equipped with a chronic bile duct catheter. Studies in dogs with diverted bile flow showed that both enantiomers were extensively excreted in bile with 74% of the (R)-enantiomer and 92% of the (S)-enantiomer from the iv administered dose being recovered in the bile as the respective glucuronide conjugates. The direct administration of acidic bile containing acyl-glucuronides of CPF in the duodenum showed that both conjugated enantiomers led to high CPF enantiomer systemic availability. However, comparison of CPF pharmacokinetics between dogs with nondiverted bile flow and dogs with diverted bile flow suggested that CPF was subjected to enantioselective enterohepatic recycling (EHC) and that only the (S)-CPF was recycled. The absence of EHC for the (R)-CPF is hypothesized to be the result of formation of glucuronidase-resistant isoglucuronides (epimers) to a greater extent for the (R)-CPF than for the (S)-CPF.

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Patterns of gallbladder contraction induced by a meal or cerulein were examined by means of real-time ultrasonography in conscious dogs. The postprandial gallbladder emptying was characterized by two parameters of the power-exponential function: the gallbladder half emptying time T1/2 = 47.3 +/- 4.7 min and the curve shape parameter S = 0.866 +/- 0.036. Cerulein infused at stepwise increasing rates of 0.7, 2.2, 7.4, 22.2, and 66.5 pmol/kg/hr, administered each for 10 min, evoked a gallbladder contraction to 87.4 +/- 3.8%, 66.7 +/- 2.4%, 44.5 +/- 1.5%, 25.9 +/- 2.1%, and 11.9 +/- 2.0% of the basal volume, respectively. The dependence of the gallbladder emptying on the dose of cerulein was described by the equation of linear regression y - 21.33 [ln(dose + 1)] + 95.81 (r = -0.963, P < 0.001). Accordingly, the cerulein dose required to evoke a 50% reduction of the gallbladder volume amounted to 7.6 pmol/kg/hr (95% confidence interval: 6.8-8.6 pmol/kg/hr). A plateau at the level of about 44% of the basal gallbladder volume characterized the time-course of the gallbladder emptying between 20 and 60 min of the infusion at a constant rate of 7.4 pmol/kg/hr. On the other hand, the 1-hr infusion of 22.2 pmol/kg/hr evoked a continuous decrease in the gallbladder volume with a nadir of 10.2 +/- 0.7% achieved at 60 min. Refilling of the gallbladder, contracted after a 1-hr infusion of cerulein, was complete within 30 and 60 min after the end of infusion for rates of 7.4 pmol/kg/hr and 22.2 pmol/kg/hr, respectively. The time course of the gallbladder filling after cessation of 1-hr infusion of cerulein at 7.4 pmol/kg/hr was described by the equation of linear regression of relative gallbladder volumes vs time: y = 1.732x + 48.61 (r = 0.739, P < 0.001). Refilling of the gallbladder was faster during the first 30 min (y = 2.191x + 7.13, r = 0.885, P < 0.001) and slower between 30 and 60 min (y = 1.218x + 74.97, r = 0.533, P < 0.001) after the end of a 1-hr infusion of cerulein at a rate of 22.2 pmol/kg/hr.

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The motor responses of the jejunum and colon to stimulation of alpha 2-adrenoceptors by medetomidine and clonidine were investigated in four dogs. In fasting dogs, medetomidine, at a dose rate of 30 micrograms/kg i.v., disrupted the migrating myoelectric complex (MMC) pattern of the small intestine for about 2 h. Similar, but shorter-lasting effects were also induced by clonidine (30 micrograms/kg i.v.) on the jejunum. The administration of alpha 2-agonists inhibited colonic motility in fasting dogs, although medetomidine-induced inhibition was preceded by a short period of increased muscle tone. All these effects were reversed by the alpha 2-antagonists atipamezole (0.15 mg/kg i.v.) and yohimbine (0.20 mg/kg i.v.). In fed dogs, medetomidine (30 micrograms/kg i.v.) induced a strong increase of the tone on the proximal colon, while the activity of the medium and distal colon was completely suppressed. Yohimbine (0.50 mg/kg i.v.) immediately restored the activity of the colon and induced a propagated giant contraction and defaecation by the animal. These data confirm the importance of alpha 2-adrenergic receptors in the control of intestinal and colonic motility in the dog.

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The role of the migrating motor complex (MMC) of the small intestine in the absorption of an enterally administered marker (tolfenamic acid, TA) used to investigate enterohepatic recycling was studied in the fasted dog. TA was rapidly and extensively absorbed in the duodenum as well as in the ileum. In contrast, the conjugated form of TA (CTA) was not absorbed in the duodenum but only in the ileum, i.e., after bacterial hydrolysis. By administering CTA in the duodenum at different phases (I and II) of the MMC, it was shown that CTA had to be propelled from the duodenum to the ileum by the motor activity of the MMC. Under these conditions, the peak plasma TA concentration was only observed when phase II of the MMC present in the duodenum at the time of CTA administration arrived in the ileum. The estimated mean transit time of CTA from the duodenum to ileum was 45 min and the mean hydrolysis time of CTA to TA was about 75 min. It was concluded that 1) in the fasted dog, a relatively long delay must exist between bile excretion of a conjugate and the reabsorption of its free moiety in the ileum and 2) a realistic physiological model of enterohepatic recycling must take into account the MMC pattern of the intestine when drugs are administered to animals in the fasted state.

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An ultrasonographic measurement of the gallbladder volume based on an ellipsoid approximation of the gallbladder shape was validated in vivo in the dog. The mean difference between the ultrasonographically determined and the true gallbladder volumes amounted to 2.0 +/- 1.6 cm3 (mean +/- SD), whereas the regression line computed for the ultrasonographically measured versus true gallbladder volumes was y = 0.892x + 3.0, r = 0.955, p much less than 0.001. The ultrasonographic method enabled a noninvasive, repetitive measurement of either a meal- or caerulein-induced gallbladder emptying in the dog.

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The effects of intraperitoneal, intrathecal and intracerebroventricular injections of the peptide galanin (GAL) on duodenojejunal and colonic motility were studied in conscious fed rats. At 0.3-3.0 nmol/rat, intraperitoneal GAL restored the 'fasted pattern' of duodenojejunal activity, i.e. the migrating myo-electric complex (MMC) was restored for a short period of time, and the MMC frequency was not significantly different from that observed before feeding. In addition, the activity of the proximal but not of the distal colon was significantly increased by GAL administration. The intracerebroventricular administration of GAL (0.03-0.3 nmol/rat) induced an MMC fasted pattern on the duodenojejunum after a latency period of about 1 h. In these experiments proximal colonic motor activity was significantly increased for 120-180 min. GAL given intrathecally (0.03-0.3 nmol/rat) induced a long-lasting fasted pattern of the intestinal activity within 10-20 min which was not dose dependent in duration, while the motility index of the proximal colon was significantly increased. Pretreatment with naloxone prevented the specific effects of GAL, given intracerebroventricularly or intrathecally, on the duodenojejunum and colon and the colonic response, but not the restoration of the MMC pattern on the duodenojejunum, induced by GAL given intraperitoneally. Ketoprofen pretreatment was completely ineffective. These observations indicate a plurality of sites of action of GAL on digestive tract motility including local duodenal receptors and suggest the importance of a spinal component in the control of motility by GAL when given intrathecally. Moreover the present results indicate the involvement of opioid receptors in the fasted pattern induced by GAL given intracerebroventricularly or intrathecally and in the colonic effects regardless of the route of administration.

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The effects of intragastric antibiotics in rats were examined on fecal microflora and excretion and through transit time and cecocolonic myoelectric activity. A solution of nonabsorbable antibiotics infused into the stomach for 20 days had a dramatic effect on the quantity, composition, and bacterial content of rat feces. Both the dry weight and the water content of feces were increased. The amount of short-chain fatty acids in the feces was dramatically lowered. However, neither total nor cecocolonic transit time of solids was affected. The cyclic organization of cecocolonic myoelectric activity was altered by antibiotic treatment, and the motility index, ie, the quantity of myoelectric activity recorded on the colon, progressively increased. An infusion of short-chain fatty acids modified this motor pattern but did not restore activity to a level comparable to that of control animals. In conclusion, intragastric antibiotics dramatically reduced intestinal microflora and increased fecal excretion of dry matter and water but did not affect the transit time of solid gut contents, although they did influence cecocolonic motility.

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In the rat, topographic and X-ray studies of the caecum and ascending colon, together with microscopic anatomic observations of the ileal papilla and caecocolonic valve, showed that junction structures contribute to prevent the backflow of the caecal content into the ileum and to direct the ileal content within the caecum whatever the various positions of the caecum in the abdominal cavity.

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1. The myoelectrical activity of the large intestine of fed and fasted rats was recorded with chronically implanted nichrome wire electrodes after destruction of the spinal cord, after spinal cord transection, and after spinal anaesthesia. 2. After spinal cord ablation, the cyclical organization of the colonic electrical spiking activity, as well as the gastrocolic reflex and accompanying postprandial enhancement of the cyclical pattern of activity, persisted on the proximal and distal colon. On the transverse colon, however, the spiking activity was considerably increased. This latter effect obliterated the gastrocolic response due to feeding but not the subsequent postprandial enhancement of the cyclical pattern of activity. 3. After spinal cord transection, the level of spiking activity also increased on both the transverse and distal colon, but no major changes in cyclical activity or in postprandial responses were recorded. 4. Spinal anaesthesia produced by intrathecal lidocaine increased the motility of the transverse colon to a level which masked the gastrocolic reflex. 5. These results suggest a prevertebral ganglia and/or a local control mechanism for the cyclical organization of the spiking activity of the colon. The central control mechanisms involve mostly spinal inhibitory influences on the transverse colon and supraspinal inhibitory influences on the distal colon.

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The effects of subcutaneous (s.c.), intraperitoneal (i.p.), intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of dermorphin (DER) on intestinal myoelectrical activity were examined in fed rats with chronically implanted electrodes on the small and large bowel. DER s.c. restored the 'fasting' pattern of duodenal activity, i.e., the migrating myoelectric complex (MMC), corresponding to an inhibition by about 40% of the fed pattern for 120 min at a dose as small as 0.5 nM per rat. DER i.p. strongly inhibited (about 65%) the fed pattern for 120 min. A fasting pattern lasting 80 min, or a marked inhibition lasting 150 min were recorded after 0.5 nM DER i.t. or i.c.v., respectively. On the contrary, the colonic pattern of activity was inhibited by DER whatever the route used, although the duration of inhibition was different from each other. For both the small and large intestine, similar doses of DER were more efficient by i.c.v. than by i.t. routes, and by i.p. than by s.c. routes. A plurality of sites of action is suggested, including local receptors which are activated, particularly at the duodenal level by i.p. DER (0.5 nM). The supraspinal component of the immediate effects of i.c.v. DER (0.1 nM) were demonstrated by a preferential effect on the colon that was even more intense than after i.t. DER.

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Electrical spiking activity of different parts of the colonic wall was studied in relation to the mechanical events in conscious rats fitted with chronically implanted nichrome wire electrodes and miniaturized strain-gauge transducers. The progress of barium sulphate introduced into the caecum and measured radiographically at fixed intervals was used as an index of transit rate of colonic contents in both the fasted and fed state. The basic pattern of colonic myoelectrical activity was characterized by randomly occurring spike bursts at a higher frequency in the proximal (0.9/min) than the distal colon (0.5/min). Their duration in the fasted state, which was shorter in the proximal (5.5 +/- 1.7 s) than the distal colon (12.7 +/- 2.9 s), was similar following a meal. In the fasted state, integrated records showed cyclical periods of more intense electrical activity lasting about 20 and 40 min in the proximal and the distal colon, respectively. The cyclical pattern following a meal occurred at shorter intervals in the different parts of the colon. Conversely, the propulsion of the marker over the whole colon, which lasted 180-200 min, was accelerated by 30% after feeding. Laxatives disrupted these cyclical motor events on the colon, by inducing mass movements which impeded the pellet formation and increased the rate of transit. The cyclical motor activity was also disrupted following the administration of opiate agonists, the rate of transit being decreased and propulsive activity inhibited. The results are consistent with the concept of cyclical motor pattern playing an important part in the control of pellet formation and movement of digestive contents within the colon of the rat.

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This method of analysing gastrointestinal motility involves data collection for 12 h periods and calculations from electromyographic signals at 15 s intervals; results are printed for successive 20 min epochs. In addition, phases of regular spike activity are recognized during the interdigestive periods. The system has been used in a series of comparative measurements of duodenal activity before and after feeding, and in studies involving drug-induced regular spike activity.

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The effects of subcutaneous (s.c.), intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of fentanyl and D-Ala2,D-Leu5-enkephalin (DADLE) on intestinal myoelectrical activity were examined in fed rats. In rats with chronically implanted electrodes on the small and large bowel, i.c.v. fentanyl and DADLE restored the 'fasted' pattern of duodenal activity, i.e. the migrating myoelectric complex (MMC) for 8-12 h at a dose as small as 1 nM/kg. In addition, the colonic pattern of activity evaluated as the number of migrating spike bursts (MSB) per min was nearly halved for 1 h following i.c.v. fentanyl (10 nM/kg). Pretreatment with naloxone, but not methylnaloxone prevented these effects on the small and large bowel. Fentanyl (100 nM/kg s.c.) significantly reduced small and large bowel motility, but DADLE (100 nM/kg s.c.) which induced a transient 'fasted pattern' on the duodenum strongly stimulated colonic motor activity. Pretreatment with methylnaloxone prevented the inhibitory effects of s.c. fentanyl but not the colonic excitatory effects of DADLE. The i.t. administration of fentanyl and DADLE did not modify the activity pattern of the bowel. Again, i.t. DADLE stimulated the colon, even after methylnaloxone treatment and at doses 100 times less than the smallest active s.c. dose. The long-lasting changes in small bowel motility and the important delay following DADLE and fentanyl i.c.v., reinforces the hypothesis of a central opioid control of the gastrointestinal motor pattern with possible involvement of released substances.(ABSTRACT TRUNCATED AT 250 WORDS)

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The effects of intracerebroventricular (ICV) vs. intravenous (IV) injection of neurotensin, substance P and calcitonin on intestinal myoelectrical activity were examined in fed rats. ICV administered neurotensin and calcitonin restored the 'fasted' pattern of intestinal activity, i.e. the migrating myoelectric complex (MMC) at a dose as low as 12 and 0.2 pmol, respectively, whereas substance P only reduced significantly (P less than 0.01) the duration of the postprandial pattern when injected ICV (48 pmol). Administered systemically at doses 100 times higher than the smallest active doses by the ICV route, calcitonin induced a fasted pattern, while neurotensin and substance P did not modify the fed pattern. The effects of ICV administration of neurotensin and calcitonin were abolished after vagotomy but the shortening effect of substance P on the duration of the postprandial pattern was still present. It is concluded that these three neuropeptides act centrally to control the pattern of intestinal motility in fed rats by shortening the 'fed' pattern for substance P and by restoring the MMC pattern for calcitonin and neurotensin, this last effect being mediated by the vagus.

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Synthetic calcitonin injected into the lateral ventricles (ICV) of rats at picomolar concentration restores the "fasted' motility pattern of the small intestine in fed rats at doses as low as 0.083 picomoles. This effect which appeared in less than 5 min and persisted at least 2 hours for 0.83 picomole, was blocked by a previous intraventricular administration of 10 micrograms/ of calcium gluconate. At 0.83 picomole ICV, calcitonin also suppressed the disruption of the "fasted' pattern induced by intravenous infusion of Pentagastrin (6 micrograms.kg-1.h-1) but not that induced by insulin (0.5 U.kg-1). These findings support the hypothesis that calcitonin acts centrally to control the pattern of intestinal motility by inhibiting the digestive influences responsible for the "fed' pattern. All of these peripheral influences are mediated by a Ca++ sensitive central structure.

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Myoelectrical and mechanical activities were chronically recorded by use of nichrome electrodes and miniaturized strain-gage transducers sutured on the serosa of the antrum, the duodenum, and the jejunum. In a first experiment (n = 6 rats) the early (0-6 h) and late (greater than 4 days) effects of streptozotocin (65 mg/kg i.v.) was recorded. In addition, the effect of insulin (1-5 IU/kg) and glucagon (6-200 micrograms/kg) administered intravenously were studied separately each in groups of seven normal and streptozotocin-induced diabetic-fed and fasted rats. The results indicated that within the 30 min following streptozotocin administration there was a significant stimulation of the duodenal and jejunal motility lasting 46 +/- 8 min. When diabetes was established as shown by the basal blood glucose level obtained in those rats (2.30 +/- 0.84 g/L), a progressive decrease of the frequency of the migrating myoelectric complex was observed along with a disorganization of the regular spiking activity phases without disturbing the basal electrical rhythm. Comparing with the basal level, a significant increase in the gastrointestinal motility indexes (MI) appeared both in fasted (p less than 0.01) and fed (p less than 0.05) normal animals, 13.1 +/- 1.6 min after an i.v. injection of 1 IU/kg insulin. Motor effects of glucagon were related to the dose. When used at 25 microgram/kg a disorganization of the spiking activity was observed with a stimulation of the contractile activity in the jejunum. At higher dosages, i.e., 100 micrograms/kg, it induced an immediate and significant decrease of motility at any level tested and lasting up to 20 +/- 7 min. The motility responses to both hormones were lower in diabetic than in normal rats.

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