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Abstract

Objective—To determine effects of short-chain fatty acids (SCFA) on canine colonic smooth muscle.

Sample Population—Colonic tissue obtained from 14 healthy dogs.

Procedure—Short-chain fatty acid (SCFA; acetate, propionate, and butyrate; 1 to 100 mmol/L)-induced contractions were compared with responses obtained with acetylmethylcholine (AMCh; 10-4 mol/L). Roles of enteric neurons, cholinergic receptors, calcium stores in the sarcoplasmic reticulum, and extracellular calcium in the SCFA-induced responses were investigated by incubating muscle strips with tetrodotoxin (1 µmol/L), atropine (1 µmol/L), ryanodine (10 µmol/L), nifedipine (1 µmol/L), ethylene glycol-bis (β-aminoethylether)-N,N,N',N'-tetra-acetate (EGTA; 0.1 mmol/L), or an extracellular calciumdepleted (zero extracellular calcium) solution prior to the addition of propionate or butyrate.

Results—Incubation with SCFA elicited isometric stress responses (0.25 to 2.15 × 104 N/m2) in colonic longitudinal smooth muscle. Maximal responses to butyrate and propionate (50 mmol/L) were 37 and 23%, respectively, of the maximal AMCh response. Acetate was least effective in stimulating contractile responses. Tetrodotoxin and atropine did not affect SCFA-induced contractions. Nifedipine and zero extracellular calcium solution abolished responses to butyrate and propionate, whereas EGTA attenuated (> 60%) but did not abolish those responses. Ryanodine did not affect SCFA-induced contractile responses. The SCFA did not affect colonic circular smooth muscle.

Conclusions and Clinical Relevance—The SCFA stimulate longitudinal but not circular colonic smooth muscle contractions via a direct effect on smooth muscle. The mechanism of the SCFA effect appears to involve the influx of extracellular calcium. These findings may account for some of the effects of canine colonisc motility. (Am J Vet Res 2002;63:295–300 )

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate whether immunosuppressive doses of cyclosporine (CsA) have an adverse effect on the liver, kidney, and pancreatic beta cells of pigs.

Animals—8 juvenile 8-week-old Landrace X Large White crossbred pigs.

Procedure—CsA (100 to 140 mg/kg) was administered orally to euglycemic pigs to reach whole blood trough concentrations of approximately 1500 ng/mL. To determine pancreatic beta cell function, plasma Cpeptide and insulin concentrations were measured in response to IV administration of glucose, glucagon, arginine, and oral administration of glucose. Effects on liver and kidney were determined by monitoring serum measurements of liver function and serum creatinine concentrations, respectively.

Results—Plasma concentrations of C-peptide were significantly lower in euglycemic CsA-treated pigs, compared with control pigs, following IV administration of glucose, glucagon, arginine, and oral administration of glucose. Furthermore, the glucose clearance rate was decreased in euglycemic CsA-treated pigs, compared with control pigs. Serum creatinine concentrations and 4 of 7 serum measurements of liver function were not adversely affected by CsA administration. Serum concentrations of bilirubin and albumin were significantly increased, and serum alanine aminotransferase activity was significantly decreased in CsA-treated pigs, compared with control pigs. Histologic evaluation of liver and kidney sections revealed no pathologic findings in CsA-treated or control pigs.

Conclusions and Clinical Relevance—In our study, immunosuppressive doses of CsA caused an impairment of porcine pancreatic beta cell function, but did not have toxic effects on the kidney. However, on the basis of changes in serum bilirubin and albumin concentrations and alanine aminotransferase activity, subclinical toxic effects on the liver did occur when immunosuppressive doses of CsA were administered. (Am J Vet Res 2002;63:1501–1506)

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in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine the physiochemical properties and pharmacokinetics of 3 midazolam gel formulations following buccal administration to dogs.

ANIMALS 5 healthy adult hounds.

PROCEDURES In phase 1 of a 2-phase study, 2 gel formulations were developed that contained 1% midazolam in a poloxamer 407 (P1) or hydroxypropyl methylcellulose (H1) base and underwent rheological and in vitro release analyses. Each formulation was buccally administered to 5 dogs such that 0.3 mg of midazolam/kg was delivered. Each dog also received midazolam hydrochloride (0.3 mg/kg, IV). There was a 3-day interval between treatments. Blood samples were collected immediately before and at predetermined times for 8 hours after drug administration for determination of plasma midazolam concentration and pharmacokinetic analysis. During phase 2, a gel containing 2% midazolam in a hydroxypropyl methylcellulose base (H2) was developed on the basis of phase 1 results. That gel was buccally administered such that midazolam doses of 0.3 and 0.6 mg/kg were delivered. Each dog also received midazolam (0.3 mg/kg, IV). All posttreatment procedures were the same as those for phase 1.

RESULTS The H1 and H2 formulations had lower viscosity, greater bioavailability, and peak plasma midazolam concentrations that were approximately 2-fold as high, compared with those for the P1 formulation. The mean peak plasma midazolam concentration for the H2 formulation was 187.0 and 106.3 ng/mL when the midazolam dose administered was 0.6 and 0.3 mg/kg, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that buccal administration of gel formulations might be a viable alternative for midazolam administration to dogs.

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in American Journal of Veterinary Research

Abstract

Objective—To determine microradiographic appearance, bone histomorphometry, and mineral density of the long bones of the metacarpophalangeal joint in horses after immobilization followed by remobilization.

Animals—5 healthy horses.

Procedure—One forelimb of each horse was immobilized in a fiberglass cast for 7 weeks, followed by 8 weeks of increasing exercise. Calcein and oxytetracycline were administered IV during the immobilization and exercise phases, respectively, for bone labeling and analysis after euthanasia. Sagittal sections of metacarpal bones and proximal phalanges were examined via radiography, dual energy x-ray absorptiometry, histomorphometry, and bone label analysis.

Results—Radiography revealed loss of bone mineral opacity in the subarticular regions of the immobilized metacarpal bones and phalanges and subchondral lesions in metacarpal bones in 2 horses. In phalanges, a significant decrease in subarticular volumetric bone mineral density was detected. There was significantly less bone volume and calcein-labeled bone surface and more vascular volume and oxytetracycline-labeled bone surface in immobilized phalanges, compared with contralateral phalanges.

Conclusions and Clinical Relevance—Eight weeks of exercise after single-limb immobilization is insufficient for recovery of volumetric bone mineral density. During immobilization and remobilization, the subchondral and trabecular bone appear to be actively remodeling. (Am J Vet Res 2002;63:276–281)

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE To compare the pharmacokinetics of various formulations of levetiracetam after oral administration of a single dose to healthy dogs.

ANIMALS 6 neurologically normal mixed-breed dogs.

PROCEDURES A crossover study design was used. Blood samples for serum harvest were collected from each dog before and at various points after oral administration of one 500-mg tablet of each of 2 generic extended-release (ER) formulations, 1 brand-name ER formulation, or 1 brand-name immediate-release (IR) formulation of levetiracetam. Serum samples were analyzed to determine pharmacokinetic properties of each formulation by means of ultra–high-performance liquid chromatography with tandem mass spectrometry.

RESULTS No dogs had clinically important adverse effects for any formulation of levetiracetam. All ER formulations had a significantly lower maximum serum drug concentration and longer time to achieve that concentration than did the IR formulation. Half-lives and elimination rate constants did not differ significantly among formulations. Values for area under the drug concentration-versus-time curve did not differ significantly between ER formulations and the IR formulation; however, 1 generic ER formulation had a significantly lower area under the curve than did other ER formulations.

CONCLUSIONS AND CLINICAL RELEVANCE All ER formulations of levetiracetam had similar pharmacokinetic properties in healthy dogs, with some exceptions. Studies will be needed to evaluate the clinical efficacy of the various formulations; however, findings suggested that twice-daily administration of ER formulations may be efficacious in the treatment of seizures in dogs.

Full access
in American Journal of Veterinary Research