Objective—To determine the presence of adenosine
receptor subtypes A1 and A2a in equine forebrain tissues
and to characterize the interactions of caffeine
and its metabolites with adenosine receptors in the
CNS of horses.
Sample Population—Brain tissue specimens
obtained during necropsy from 5 adult male research
Procedures—Membrane-enriched homogenates from
cerebral cortex and striatum were evaluated by radioligand
binding assays with the A1-selective ligand
[3H]DPCPX and the A2a-selective ligand
[3H]ZM241385. Functional responses to adenosine
receptor agonists and antagonists were determined
by a nucleotide exchange assay using [35S]-guanosine
5'-(γ-thio) triphosphate ([35S]GTPγS).
Results—Saturable high affinity [3H]DPCPX binding
(A1) sites were detected in cerebral cortex and striatum,
whereas high-affinity [3H]ZM241385 binding
(A2a) sites were detected only in striatum. Caffeine
and related methylxanthines had similar binding affinities
at A1 and A2a sites with rank orders of drug binding
affinities (theophylline > paraxanthine ≥ caffeine
>> theobromine) similar to other species. [35S]GTPγS
exchange revealed that caffeine and its metabolites
act as pure adenosine receptor antagonists at concentrations
that correspond to A1 and A2a receptor
Conclusions and Clinical Relevance—Results of our
study affirm the presence of guanine nucleotide binding
protein linked adenosine receptors (ie, high-affinity
A1 and A2a adenosine receptors) in equine forebrain
tissues and reveal the antagonistic actions by caffeine
and several biologically active caffeine metabolites.
Antagonism of adenosine actions in the equine CNS
by these stimulants may be responsible for some
central actions of methylxanthine drugs, including
motor stimulation and enhanced racing performance.
(Am J Vet Res 2003;64:216–224)
Objective—To determine pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar (BAL) cells of foals.
Animals—6 healthy 2-to 3-week-old foals.
Procedures—In a crossover design, clarithromycin (7.5 mg/kg) was administered to each foal via IV and intragastric (IG) routes. After the initial IG administration, 5 additional doses were administered IG at 12-hour intervals. Concentrations of clarithromycin and its 14-hydroxy metabolite were measured in serum by use of high-performance liquid chromatography. A microbiologic assay was used to measure clarithromycin activity in serum, urine, peritoneal fluid, synovial fluid, CSF, pulmonary epithelial lining fluid (PELF), and BAL cells.
Results—After IV administration, elimination half-life (5.4 hours) and mean ± SD body clearance (1.27 ± 0.25 L/h/kg) and apparent volume of distribution at steady state (10.4 ± 2.1 L/kg) were determined for clarithromycin. The metabolite was detected in all 6 foals by 1 hour after clarithromycin administration. Oral bioavailability of clarithromycin was 57.3 ± 12.0%. Maximum serum concentration of clarithromycin after multiple IG administrations was 0.88 ± 0.19 μg/mL. After IG administration of multiple doses, clarithromycin concentrations in peritoneal fluid, CSF, and synovial fluid were similar to or lower than concentrations in serum, whereas concentrations in urine, PELF, and BAL cells were significantly higher than concentrations in serum.
Conclusions and Clinical Relevance—Oral administration of clarithromycin at 7.5 mg/kg every 12 hours maintains concentrations in serum, PELF, and BAL cells that are higher than the minimum inhibitory concentration (0.12 μg/mL) for Rhodococcus equiisolates for the entire 12-hour dosing interval.
OBJECTIVE To examine effects of continuous rate infusion of lidocaine on transmural neutrophil infiltration in equine intestine subjected to manipulation only and remote to ischemic intestine.
ANIMALS 14 healthy horses.
PROCEDURES Ventral midline celiotomy was performed (time 0). Mild ischemia was induced in segments of jejunum and large colon. A 1-m segment of jejunum was manipulated by massaging the jejunal wall 10 times. Horses received lidocaine (n = 7) or saline (0.9% NaCl) solution (7) throughout anesthesia. Biopsy specimens were collected and used to assess tissue injury, neutrophil influx, cyclooxygenase expression, and hypoxia-inducible factor 1α (HIF-1α) expression at 0, 1, and 4 hours after manipulation and ischemia. Transepithelial resistance (TER) and mannitol flux were measured by use of Ussing chambers.
RESULTS Lidocaine did not consistently decrease neutrophil infiltration in ischemic, manipulated, or control tissues at 4 hours. Lidocaine significantly reduced circular muscle and overall scores for cyclooxygenase-2 expression in manipulated tissues. Manipulated tissues had significantly less HIF-1α expression at 4 hours than did control tissues. Mucosa from manipulated and control segments obtained at 4 hours had lower TER and greater mannitol flux than did control tissues at 0 hours. Lidocaine did not significantly decrease calprotectin expression. Severity of neutrophil infiltration was similar in control, ischemic, and manipulated tissues at 4 hours.
CONCLUSIONS AND CLINICAL RELEVANCE Manipulated jejunum did not have a significantly greater increase in neutrophil infiltration, compared with 4-hour control (nonmanipulated) jejunum remote to sites of manipulation, ischemia, and reperfusion. Lidocaine did not consistently reduce neutrophil infiltration in jejunum.