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 )
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
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)
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.
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)
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.