Administration In Beagle Dogs Research Articles

Tapetal Effect of an Azalide Antibiotic Following Oral Administration in Beagle Dogs

Tapetal Effect of an Azalide Antibiotic Following Oral Administration in Beagle Dogs. Fortner, J. H., Milisen, W. B., Lundeen, G. R., Jakowski, A. B., and Marsh, P.M. (1993). Fundam. Appl. Toxicol. 21, 164-173. An azalide antibiotic (CP-62,993) was administered at 100 mg/kg by oral gavage once daily for 35 consecutive days to 3 normal Beagle dogs (tapetal) and 3 Beagle dogs lacking a clinically apparent ocular tapetum (atapetal). The total dose delivered was approximately 100-fold the recommended clinical dose. Bilateral ophthalmoscopic changes were observed in the treated tapetal dogs on Day 36, consisting of mild to moderate tapetal decoloration with loss of the normal color change at the junction with the nontapetal fundus and muting of reflectivity of the normally highly reflective tapetum: treated atapetal and all control tapetal and atapetal dogs had no ophthalmoscopic changes. Microscopic examination of ocular tissue revealed rudimentary tapetal cell layers in the correct location in untreated, clinically atapetal eyes. Tapetal cells from treated tapetal and atapetal dogs were swollen and vacuolated, and contained intracytoplasmic, electron-dense debris but no recognizable tapetal rodlets. Lysosomal lamellar bodies were observed in the retinal ganglion cells of both treated groups and were neither enhanced nor reduced by the presence of a functional tapetum. Necrosis and inflammation were not observed in any ocular tissue. The altered ophthalmoscopic appearance of treated tapetal dogs was not influenced by the retinal changes because any effect on retinal transparency would have been seen in treated atapetal dogs. The decoloration and muting of reflectivity observed clinically in the tapetal fundus of dogs following prolonged exposure to high levels of CP-62,993 result from unique changes within the ocular tapetum itself and cannot be interpreted to be of consequence to nontapetal species including humans.

Tapetal Effect of an Azalide Antibiotic Following Oral Administration in Beagle Dogs

An azalide antibiotic (CP-62,993) was administered at 100 mg/kg by oral gavage once daily for 35 consecutive days to 3 normal Beagle dogs (tapetal) and 3 Beagle dogs lacking a clinically apparent ocular tapetum (atapetal). The total dose delivered was approximately 100-fold the recommended clinical dose. Bilateral ophthalmoscopic changes were observed in the treated tapetal dogs on Day 36, consisting of mild to moderate tapetal decoloration with loss of the normal color change at the junction with the nontapetal fundus and muting of reflectivity of the normally highly reflective tapetum; treated atapetal and all control tapetal and atapetal dogs had no ophthalmoscopic changes. Microscopic examination of ocular tissue revealed rudimentary tapetal cell layers in the correct location in untreated, clinically atapetal eyes. Tapetal cells from treated tapetal and atapetal dogs were swollen and vacuolated, and contained intracytoplasmic, electron-dense debris but no recognizable tapetal rodlets. Lysosomal lamellar bodies were observed in the retinal ganglion cells of both treated groups and were neither enhanced nor reduced by the presence of a functional tapetum. Necrosis and inflammation were not observed in any ocular tissue. The altered ophthalmoscopic appearance of treated tapetal dogs was not influenced by the retinal changes because any effect on retinal transparency would have been seen in treated atapetal dogs. The decoloration and muting of reflectivity observed clinically in the tapetal fundus of dogs following prolonged exposure to high levels of CP-62,993 result from unique changes within the ocular tapetum itself and cannot be interpreted to be of consequence to nontapetal species including humans.

The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage.

The hemodynamic effects of hyperdynamic hemodilution induced by prolonged (for 1 week) intravenous albumin or low-molecular-weight dextran administration were studied in the beagle two-hemorrhage model. Drug infusion was started immediately after the induction of a subarachnoid hemorrhage and continued for 7 days thereafter, according to the following treatment schedule: Group 1 (physiological saline); Group 2 (10% low-molecular-weight dextran, 0.8 g/kg per day); Groups 3, 4, and 5 (25% albumin, 1, 2, and 3 g/kg per day, respectively). On Day 0 (before subarachnoid hemorrhage) and Day 7, the cardiopulmonary parameters and the blood flow of the vertebral artery (VAF) were measured by the use of the Swan-Ganz catheter and an electromagnetic flowmeter, respectively. Cerebral angiography was carried out on Days 0 and 7. Only the albumin-treated groups showed a significant increase in plasma osmotic pressure, cardiac output, and VAF, as well as a decrease in the hematocrit on Day 7. The increase in cardiac output and VAF was maximal in Group 4. In Group 5, signs of pulmonary edema in the chest roentgenogram were noted in two of the four animals. The angiographic spasm of the basilar artery on Day 7 was not significantly ameliorated by either albumin or dextran. In the albumin-treated groups, the VAF was shown to increase in parallel with the increase of the cardiac output, within the range between 50 and 150%. Thus, this study indicates that the hemodynamic changes induced by prolonged albumin administration improve the cerebral circulation hindered by chronic vasospasm, whereas the increase in cardiac output is considered to be the most reliable indicator regarding the determination of the optimal dosage of albumin.

The Hemodynamic Effects of Prolonged Albumin Administration in Beagle Dogs Exposed to Experimental Subarachnoid Hemorrhage

The Hemodynamic Effects of Prolonged Albumin Administration in Beagle Dogs Exposed to Experimental Subarachnoid Hemorrhage

Pharmacokinetics and bioavailability of papaverine HCl following intravenous, peroral, rectal, vaginal, topical and buccal administration in beagle dogs

This in vivo study was designed to obtain bioavailability data and a definite pharmacokinetic profile of papaverine HCl in Beagle dogs following intravenous (IV), peroral (PO), rectal, vaginal, topical, and buccal administration of different papaverine HCl formulations. Blood samples were analyzed by high-performance liquid chromatography. The pharmacokinetic parameters were determined using either a curve fitting program (RESID) or a compartment model independent program (AUC-RPP). The plasma concentration-time profiles show that papaverine HCl pharmacokinetics is best described by an open two-compartment model. The absolute bioavailability of papaverine HCl was determined to be 57.2 per cent, 25.2 per cent, 53.2 per cent, 3.2 per cent and 7.5 per cent, respectively, following P.O., rectal, vaginal, topical and buccal administration.

Viscometric study of polyacrylic acid systems as mucoadhesive sustained-release gels.

This report describes a novel nonaqueous polymeric formulation that exhibits low-viscosity fluid behavior for ease of spraying with conventional nebulizer, which when sprayed into the nasal cavity, transforms to a high-viscosity gel for efficient retention and drug absorption. The transformation occurs because of the rheological changes induced by a change in the solvent composition of the polymeric formulation in the moist nasal cavity. Such a rheological change would then facilitate enhanced residence time of the drug at the site of administration in order to avoid drainage losses. This study reports the results of the effects of a variety of factors such as solvent composition and polymer concentration on the rheological properties of a polyacrylic acid polymer. An attempt to correlate viscosity enhancement effects with enhanced and sustained-release behavior of propranolol, a drug that undergoes extensive first-pass effects, from such formulations via nasal administration in beagle dogs is also described.

Pharmacokinetics and pharmacodynamics of physostigmine after intravenous administration in beagle dogs

The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [ 3H]Phy (100 μg/kg) to beagle dogs. The maximal inhibition of ChE (78%) in plasma at 2 min correlated with the largest concentration of physostigmine (124 ng/ml). The concentration of physostigmine decreased by 88% to 16 ng/ml at 45 min when the activity of ChE was still 59% inhibited. Acetylcholinesterase activity in four regions of the brain (medulla, striatum, cerebellum and cortex) was not significantly different from controls at 70 ± 5 min after administration of physostigmine. Concentrations of physostigmine and its metabolites determined by HPLC were not significantly different in different regions. In plasma, physostigmine was found, together with eseroline and two other metabolites M 1 and M 2. At 45 min, only 18% of total radioactivity was due to physostigmine and 52% was due to the major metabolite M 1. On the contrary, in regions of the brain, metabolite M 1 represented only 1.9–3.37% of total radioactivity at 70 ± 5 min. Pharmacokinetic parameters, obtained in the dog, were compared to previously published data in rat and man. The elimination half-life (β) was 30.7 min in the dog as compared to 15 min in rat and and 21.7 min in man. The V d ml/kg was higher than total body water volume in all three species: dog (1832), rat (1352) and man (664), indicating sequestration of the drug in body compartments. Clearance (ml/min/kg) was found to be 41.2 in dog, which compares to 62 in rat and 22 in man. The differences between species in these pharmacokinetic parameters suggest an interspecies variation. It is felt the pharmacokinetic data and the inhibition curves for ChE, obtained in this study, will be of value in determining dose regimens for the clinical use of physostigmine.

The effects of physostigmine on acetylcholinesterase activity of CSF, plasma and brain. A comparison of intravenous and intra ventricular administration in beagle dogs

The effects of various doses of physostigmine (Phy) on the activity of acetylcholinesterase (AChE) in plasma, cerebrospinal fluid (CSF) and brain were studied in beagle dogs. Two routes of administration were compared: intravenous (i.v.) and intracerebroventricular (i.c.v.). With intracerebroventricular administration, over 90% inhibition of the activity of AChE in CSF was reached within 5min of injection at all doses (10–120μg). Even at the smallest dose (10 μg), 50% inhibition of activity of the enzyme in CSF was still present at 90 min. The activity of AChE in plasma was only minimally inhibited by intraventricular administration of physostigmine. A different response was obtained following intravenous administration of physostigmine (250–1000 μg). The activity of AChE in plasma was inhibited but the activity of AChE in CSF was increased (36–80% at 180 min). This increase was dose-dependent and was blocked by pretreatment with atropine (1.5mg i.v.) which suggests the involvement of a muscarinic receptor mechanism. The time course of the accumulation and regional distribution of [ 3H]physostigmine in brain also varied with the route of administration. At 5 min, with intravenous administration, physostigmine (1000 μg) reached greater concentrations and caused greater inhibition of AChE in the cortex. With intraventricular administration, physostigmine (80 μg) reached greater concentrations in two regions adjacent to the ventricular surface: the striatum and hippocampus. These regions also showed greater inhibition of the activity of AChE. Moderate to severe symptoms of cholinergic hyperactivity were seen only with the largest intraventricular dose (120 μg). This study suggests that intraventricular administration of physostigmine, a reversible inhibitor of cholinesterase (ChE), may offer distinct advantages over intravenous administration. Inhibition of acetylcholinesterase in CSF was more pronounced and persisted longer when physostigmine was administered directly into the CSF than when given intravenously. The implications of this study for a cholinergic therapy of Alzheimer's disease are discussed.

Pharmacokinetic approaches to drug distribution in the cerebrospinal fluid based on ventricular administration in beagle dogs.

Two mathematical approaches are described to approximate the distribution of compounds (e.g., drugs) in the cerebrospinal fluid (CSF) downstream of or distal to both the ventricular injection site and the cisterna magna sampling site. The first approach uses a graphic representation and is, in essence, model independent; the second approach considers the geometry and physiology of CSF distribution and clearance. In all studies, radiolabeled inulin was used as an "internal standard" since it is not metabolized and is eliminated from the CSF primarily by bulk flow. Temporal comparison of the study compound to radiolabeled inulin in the cisternal CSF allowed testing of these models in beagle dogs. One use of this data is in the estimation of the drug exposure integral for antineoplastic drugs administered in the CSF to treat leptomeningeal neoplasia.

Protein binding effects of salivary excretion of phenobarbital in dogs.

The salivary excretion of phenobarbital was investigated by collecting parotid saliva (Pr) and mandibular-sublingual saliva (MS) separately after intravenous administration in beagle dogs. (1) The alterations in the proportions of saliva secreted by the different glands were produced by salivation stimulants such as citric acid, ascorbic acid, sodium chloride and sodium glutamate. (2) The phenobarbital concentrations in both Pr amd MS were lower than those in plasma. The drug concentrations in MS were significantly lower than in Pr with stimulus of 10% citric acid of 15% sodium chloride (p less than 0.05). There was a significant correlation between phenobarbital concentration in each saliva and plasma specimen ( p less than 0.05). (3) The stimulation with 10% citric acid produced higher saliva /plasma drug concentration ratios (S/P ratios: 0.923 +/- 0.175 for Pr, 0.633 +/- 0.073 for MS) than that with 15% sodium chloride (S/P ratios: 0.597 +/- 0.071 for Pr, 0.509 +/- 0.067 or MS). (4) The S/P ratios were hardly influenced by salivary flow rates, at least under the experimental conditions examined in this study. (5) The increased S/P ratios were observed with higher salivary pH and then the equation of Matin et al. 3) seemed to hold for the average values of salivary pH and S/P ratio. (6) The stimulation with 10% citric acid produced higher protein concentration in saliva and higher S/P ratio than that with 15% sodium chloride following alternate stimulations in the same dog.

Clearance of 141Ce-labeled microspheres from blood and distribution in specific organs following intravenous and intraarterial administration in beagle dogs

The clearance of 141Ce-labeled polystyrene divinylbenzene microspheres in the 3–12-μm diameter size range following intravascular administration was found to be size dependent, with the larger spheres clearing the circulation most rapidly. With spheres of high specific activity, dynamic distribution in various organs was determined by continuous whole-body scanning for the 1st hr after administration and by static imaging at selected times thereafter up to 4weeks. The 7- and 12-μm spheres were filtered mechanically and retained for prolonged periods in the lungs, while the 3- and 5-μm spheres localized and were retained in the liver and spleen. Localization of these smaller spheres appeared to be due to phagocytosis by cells of the reticuloendothelial system; with the 12-μm spheres, there was no evidence of phagocytosis by the pulmonary macrophages of the reticuloendothelial system within 4weeks postadministration. Intraarterially administered larger microspheres did not show any significantly different distribution patterns from those administered intravenously. Histological examination revealed occasional vascular engorgement about the site of multiple-sphere lodgment, but no destructive tissue phenomenon was apparent in relation to the lodgment of the microspheres.