Objective—To quantitate the dose and time-related
effects of morphine sulfate on the anesthetic sparing
effect of xylazine hydrochloride in halothane-anesthetized
horses and determine the associated plasma
xylazine and morphine concentration-time profiles.
Animals—6 healthy adult horses.
Procedure—Horses were anesthetized 3 times to
determine the minimum alveolar concentration (MAC)
of halothane in O2 and characterize the anesthetic
sparing effect (ie, decrease in MAC of halothane) by
xylazine (0.5 mg/kg, IV) administration followed
immediately by IV administration of saline
(0.9% NaCl) solution, low-dose morphine (0.1 mg/kg),
or high-dose morphine (0.2 mg/kg). Selected parameters
of cardiopulmonary function were also determined
over time to verify consistency of conditions.
Results—Mean (± SEM) MAC of halothane was
1.05 ± 0.02% and was decreased by 20.1 ± 6.6% at
49 ± 2 minutes following xylazine administration. The
amount of MAC reduction in response to xylazine was
time dependent. Addition of morphine to xylazine
administration did not contribute further to the
xylazine-induced decrease in MAC (reductions of
21.9 ± 1.2 and 20.7 ± 1.5% at 43 ± 4 and 40 ± 4 minutes
following xylazine-morphine treatments for low-and
high-dose morphine, respectively). Overall, cardiovascular
and respiratory values varied little among
treatments. Kinetic parameters describing plasma
concentration-time curves for xylazine were not
altered by the concurrent administration of morphine.
Conclusions and Clinical Relevance—Administration
of xylazine decreases the anesthetic requirement
for halothane in horses. Concurrent morphine
administration to anesthetized horses does not alter
the anesthetic sparing effect of xylazine or its plasma
concentration-time profile. (Am J Vet Res 2004;
Objective—To determine effects of cisapride and 5-hydroxytryptamine (5-HT) on the jejunum of horses.
Sample Population—Jejunal muscle strips from 8
Procedure—Muscle strips were suspended in isolated
muscle baths. Isometric stress responses to 5-HT
and cisapride, with and without specific antagonists,
Results—Muscle strips incubated with atropine and
tetrodotoxin responded to 5-HT and cisapride with an
increase in contractile force. The 5-HT caused a concentration-dependent increase in contractile amplitude,
with a maximum response (Emax) of 1,151 ± 214
g/cm2 and a molar concentration that induces contractile
force equal to 50% of maximum response
(EC50) of 0.028 ± 0.002 µM. Prior incubation with the
5-HT2 antagonist ketanserin decreased the Emax (626
± 147 g/cm2) and potency (EC50, 0.307 ± 0.105 µM) of
5-HT. Prior incubation with the 5-HT3 antagonist tropisetron
decreased the efficacy (Emax, 894 ± 184
g/cm2) to 5-HT. Cisapride also caused a concentrationdependent
increase in contractile amplitude, with an
Emax of 331 ± 82 g/cm2 and an EC50 of 0.302 ± 0.122
µM. Prior incubation with ketanserin decreased the
Emax (55 ± 17 g/cm2) and potency (EC50, 0.520 ± 0.274
µM) of cisapride.
Conclusion and Clinical Relevance—Stimulatory
effects of 5-HT and cisapride on circular smooth muscle
of equine jejunum are mediated primarily through
a noncholinergic effect. The effects of 5-HT are mediated,
at least partially, by 5-HT2 and 5-HT3 receptors,
whereas the effects of cisapride are mediated primarily
by 5-HT2 receptors. This may impact treatment of
horses with postoperative ileus. (Am J Vet Res
Objective—To investigate accumulation of extracellular
adenosine (ADO) by equine articular chondrocytes
and to compare effects of adenosine kinase inhibition
and adenosine deaminase inhibition on the amount of
nitric oxide (NO) produced by lipopolysaccharide
Sample Population—Articular cartilage from
metacarpophalangeal and metatarsophalangeal joints
of 14 horses.
Procedure—Chondrocytes were cultured as monolayers,
and cells were incubated with LPS, the adenosine
kinase inhibitor 5'-iodotubercidin (ITU), or the
adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-
nonyl)adenine hydrochloride (EHNA). Concentrations
of ADO in cell supernatants were measured by use of
reverse-phase high-performance liquid chromatography.
Effect of inhibition of enzymatic metabolism of
ADO on induced NO production was evaluated by
exposing cells to a combination of LPS and ITU or LPS
Results—Articular chondrocytes accumulated extracellular
ADO when exposed to LPS or ITU.
Chondrocytes exposed to ITU accumulated ADO in a
time-dependent manner. Unstimulated chondrocytes
did not accumulate ADO. Similarly, EHNA alone did
not produce detectable ADO concentrations; however,
addition of EHNA and ITU resulted in a synergistic
effect on accumulation of ADO. Lipopolysaccharideinduced
NO production was more effectively suppressed
by exposure to ITU than to EHNA
Conclusions and Clinical Relevance—Equine articular
chondrocytes release ADO in response to the
proinflammatory stimulus of bacterial LPS. Inhibition
of the metabolism of ADO increases accumulation of
extracellular ADO. Autocrine release of ADO from
chondrocytes may play a role in the cellular response
to tissue damage in arthritic conditions, and pharmacologic
modulation of these pathways in joints of
arthritic horses could be a potential method of therapy.
(Am J Vet Res 2002;63:1512–1519)
Objective—To determine pharmacokinetics of azathioprine
(AZA) and clinical, hematologic, and serologic
effects of IV and oral administration of AZA in horses.
Procedure—In study phase 1, a single dose of AZA
was administered IV (1.5 mg/kg) or orally (3.0 mg/kg)
to 6 horses, with at least 1 week between treatments.
Blood samples were collected for AZA and
6-mercaptopurine (6-MP) analysis 1 hour before and
at predetermined time points up to 4 hours after AZA
administration. In study phase 2, AZA was administered
orally (3 mg/kg) every 24 hours for 30 days and
then every 48 hours for 30 days. Throughout study
phase 2, blood samples were collected for CBC determination
and serum biochemical analysis.
Results—Plasma concentrations of AZA and its
metabolite, 6-MP, decreased rapidly from plasma following
IV administration of AZA, consistent with the
short mean elimination half-life of 1.8 minutes. Oral
bioavailability of AZA was low, ranging from 1% to
7%. No horses had abnormalities on CBC determination
or serum biochemical analysis, other than 1 horse
that was lymphopenic on day 5 and 26 of daily treatment.
This horse developed facial alopecia from which
1 colony of a Trichophyton sp was cultured; alopecia
resolved within 1 month after the study ended.
Conclusions and Clinical Relevance—Overall, no
adverse effects were observed with long-term oral
administration of AZA to horses, although 1 horse did
have possible evidence of immunosuppression with
chronic treatment. Further investigation of the clinical
efficacy of AZA in the treatment of autoimmune diseases
in horses is warranted. (Am J Vet Res
Objective—To determine pharmacokinetics and
selected cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys.
Animals—6 adult male rhesus monkeys.
Procedure—Fentanyl (8 mg/kg of body weight, IV)
was administered to 6 monkeys anesthetized with
isoflurane. End-tidal isoflurane concentration and
esophageal temperature were kept constant, and
ventilation was mechanically assisted. Heart rate,
rhythm, aortic blood pressure, and blood pH, gas, and
fentanyl concentrations were determined before and
for 8 hours after administration of fentanyl.
Pharmacokinetics of fentanyl were derived by use of
noncompartmental methods based on statistical
Results—Heart rate and mean arterial pressure
decreased transiently following fentanyl administration.
Maximal decreases were observed 5 to 15 minutes
after administration. Arterial pH, PaCO2, and PaO2
ranged from 7.46 ± 0.04 to 7.51 ± 0.05 units, 29.2 ± 3
to 34.6 ± 4.4 mm Hg, and 412.6 ± 105.3 to 482.9 ±
71.2 mm Hg, respectively. The clearance, volume of
distribution area, volume of distribution steady state,
mean residence time, area under the curve, elimination
rate constant, and half-life were 32.5 ± 2.48
ml/kg/min, 9.04 ± 1.91 L/kg, 7.0 ± 1.2 L/kg, 218.5 ±
35.5 min, 0.247 ± 0.019 mg/ml/min, 0.004 ±
0.001/min, and 192.0 ± 33.5 min, respectively.
Conclusions and Clinical Relevance—Transient but
potentially clinically important decreases in heart rate
and mean arterial pressure were observed following
fentanyl administration. Distribution and clearance
data were similar to those reported for dogs and
humans. (Am J Vet Res 2000;61:931–934)
Objective—To determine the effect of a constant-rate
infusion of fentanyl on minimum alveolar concentration
(MAC) of isoflurane and to determine the interaction
between fentanyl and a benzodiazepine agonist
(diazepam) and antagonist (flumazenil) in isoflurane-anesthetized
Animals—8 mixed-breed adult dogs.
Procedure—Dogs were anesthetized with isoflurane
3 times during a 6-week period. After a 30-minute
equilibration period, each MAC determination was
performed in triplicate, using standard techniques.
Fentanyl was administered as a bolus (10 µg/kg of
body weight, IV) that was followed by a constant infusion
(0.3 µg/kg per min, IV) throughout the remainder
of the experiment. After determining isoflurane-fentanyl
MAC in triplicate, each dog received saline
(0.9% NaCl) solution, diazepam, or flumazenil. After
30 minutes, MAC was determined again.
Results—Fentanyl significantly decreased isoflurane
MAC (corrected to a barometric pressure of 760 mm
Hg) from 1.80 ± 0.21 to 0.85 ± 0.14%, a reduction of
53%. Isoflurane-fentanyl-diazepam MAC (0.48 ±
0.29%) was significantly less than isoflurane-fentanylsaline
MAC (0.79 ± 0.21%). Percentage reduction in
isoflurane MAC was significantly greater for fentanyldiazepam
(74%), compared with fentanyl-saline (54%)
or fentanyl-flumazenil (61%). Mean fentanyl concentrations
for the entire experiment were increased over
time and were higher in the diazepam group than the
saline or flumazenil groups.
Conclusion and Clinical Relevance—Fentanyl
markedly decreased isoflurane MAC in dogs.
Diazepam, but not flumazenil, further decreased
isoflurane-fentanyl MAC. Our results indicate that
diazepam enhances, whereas flumazenil does not
affect, opioid-induced CNS depression and, possibly,
analgesia in dogs. (Am J Vet Res 2001;62:555–560)
Objective—To evaluate the use of xylazine and ketamine
for total IV anesthesia in horses.
Procedure—Anesthetic induction was performed on
4 occasions in each horse with xylazine (0.75 mg/kg,
IV), guaifenesin (75 mg/kg, IV), and ketamine
(2 mg/kg, IV). Intravenous infusions of xylazine and
ketamine were then started by use of 1 of 6 treatments
as follows for which 35, 90, 120, and 150 represent
infusion dosages (µg/kg/min) and X and K represent
xylazine and ketamine, respectively: X35+K90
with 100% inspired oxygen (O2), X35+K120-O2,
X35+K150-O2, X70+K90-O2, K150-O2, and X35+K120
with a 21% fraction of inspired oxygen (ie, air).
Cardiopulmonary measurements were performed.
Response to a noxious electrical stimulus was
observed at 20, 40, and 60 minutes after induction.
Times to achieve sternal recumbency and standing
were recorded. Quality of sedation, induction, and
recovery to sternal recumbency and standing were
Results—Heart rate and cardiac index were higher
and total peripheral resistance lower in K150-O2 and
X35+K120-air groups. The mean arterial pressure was
highest in the X35+K120-air group and lowest in the
K150-O2 group (125 ± 6 vs 85 ± 8 at 20 minutes,
respectively). Mean PaO2 was lowest in the
X35+K120-air group. Times to sternal recumbency
and standing were shortest for horses receiving
K150-O2 (23 ± 6 minutes and 33 ± 8 minutes, respectively)
and longest for those receiving X70+K90-O2
(58 ± 28 minutes and 69 ± 27 minutes, respectively).
Conclusions and Clinical Relevance—Infusions of
xylazine and ketamine may be used with oxygen supplementation
to maintain 60 minutes of anesthesia in
healthy adult horses. (Am J Vet Res 2005;66:1002–1007)