Pharmacokinetics of an immediate and extended release oral morphine formulation utilizing the spheroidal oral drug absorption system in dogs.

This study investigated the pharmacokinetics of a human-labeled oral morphine formulation consisting of both immediate and extended release components in dogs. In a randomized design, 14 dogs were administered either 1 or 2 mg/kg morphine orally. Blood samples were collected up to 24 h post drug administration. Plasma concentrations of morphine were measured using high-pressure liquid chromatography with electrochemical coulometric detection. For both groups, maximal concentration occurred at 3 h post drug administration followed by a gradual decrease in morphine concentration over 24 h. There was substantial variability in morphine concentrations among dogs. The higher dose group produced a greater exposure (higher area-under-the-curve), higher peak concentration, longer half-life and a shorter time to peak concentration (t(max)). The specific oral morphine formulation used in this study produced sustained plasma morphine concentrations over 24 h compared with previous intravenous dosing and immediate-release oral morphine studies. However, the low morphine plasma concentrations and high variability produced from this formulation, suggest that the clinical application of this formulation at the doses evaluated in this study are limited.

Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) do not always provide sufficient pain relief in dogs with osteoarthritis (OA). HYPOTHESIS: The use of amantadine in addition to NSAID therapy will provide improved pain relief when compared with the use of nonsteroidal analgesics alone in naturally occurring OA in dogs. ANIMALS: Thirty-one client-owned dogs with pelvic limb lameness despite the administration of an NSAID. METHODS: The study was randomized, blinded, and placebo controlled with parallel groups (days 21-42). On day 0, analgesic medications were discontinued. On day 7, all dogs received meloxicam for 5 weeks. On day 21, all dogs received amantadine (3-5 mg/kg once daily per os) or placebo for 21 days, in addition to receiving meloxicam. Assessments were performed before the study and on days 7, 21, and 42. Primary outcome measures were blinded owner assessments of activity using client-specific outcome measures (CSOM) on days 0, 7, 21, and 42. Data were analyzed by a mixed model approach. RESULTS: For CSOM activity, there was a significant time by treatment effect (P=.009). On the basis of the planned post hoc t-tests of postrandomization means, there was a significant difference between treatment groups on day 42 (P=.030), with the amantadine group being more active. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with osteoarthritic pain refractory to an NSAID, physical activity is improved by the addition of amantadine. Amantadine might be a useful adjunct therapy for the clinical management of canine osteoarthritic pain.

Use of naloxone to reverse carfentanil citrate-induced hypoxemia and cardiopulmonary depression in Rocky Mountain wapiti (Cervus elaphus nelsoni).

With the use of a crossover study design, we investigated the respiratory and cardiovascular effects of naloxone administration in eight healthy Rocky Mountain wapiti (Cervus elaphus nelsoni) anesthetized with carfentanil (10 microg/kg i.m.) and xylazine (0.1 mg/kg). Anesthetized animals showed profound hypoxemia with mild hypercapnia, tachycardia, hypertension, and acidosis prior to naloxone administration. After monitoring equipment was placed, animals were administered either naloxone (2 microg/microg carfentanil i.v.) or an equivalent volume of normal saline. Mean values for PaO2, PaCO2, heart rate, and respiratory rate were significantly different between naloxone- and saline-treated groups, but mean blood pressure, hematocrit, and serum electrolyte concentrations were not. Mean PaO2 was 23.0 +/- 4.1 mm Hg prior to administration of naloxone or saline and increased to 50.2 +/- 7.3 mm Hg after naloxone administration. Mean PaO2 of saline-treated animals did not change significantly. Electrocardiograms of three saline-treated animals suggested myocardial hypoxia. Hypoxemia appeared to be caused by respiratory depression, hemodynamic alterations, and lateral recumbency. All but one animal remained anesthetized after naloxone administration. Anesthesia in all animals was reversed in < or = 4 min with naltrexone (100 mg/mg carfentanil i.v. s.c.) and yohimbine (0.1 mg/kg i.v.). One bolus of naloxone improved oxygenation in carfentanil-xylazine-anesthetized wapiti.

The effect of raloxifene on coronary arteries in aged ovariectomized ewes.

BACKGROUND: Ovariectomized sheep are a useful model of postmenopausal osteoporosis and other postmenopausal conditions. Estrogen may have a protective effect on the coronary arteries in postmenopausal women. The effects of raloxifene, a selective estrogen receptor modulator, on coronary arteries in aged ovariectomized ewes was investigated. METHODS AND RESULTS: Forty eight aged ewes were randomly assigned to undergo sham surgery (Sham, n = 7), ovariectomy (OVX, n = 10), ovariectomy with estradiol supplementation (OVXE, n = 8), ovariectomy with raloxifene supplementation, 0.02 mg/kg per day (RAL1, n = 10), or ovariectomy with raloxifene supplementation, 0.10 mg/kg per day (RAL2, n = 13). Contrast coronary angiography was performed 6 months after intervention. Diameters of the right main and left anterior descending coronary arteries in the RAL1, RAL2 and Sham groups were not different from each other, but were significantly greater than the OVX and OVXE groups. Intracoronary nitroglycerin did not affect the relationships of the diameters in any group. There were no differences in vascular remodeling between the groups. CONCLUSIONS: The results indicate that raloxifene in this sheep model allows greater dilation of coronary arteries than estrogen. Raloxifene may provide a significant protective functional effect on coronary arteries in postmenopausal heart disease.

The effect of differing rates and injection sites on the amount of protamine delivered before detection of hemodynamic alterations in dogs.

OBJECTIVES: To determine the effect of the route and rate of protamine administration on the amount of protamine that could be delivered before a hemodynamic reaction occurred in dogs. STUDY DESIGN: Prospective randomized experimental study. ANIMALS: Twenty adult mixed-breed dogs weighing 25.1+/-2.5 kg. METHODS: Before vascular surgery, the dogs were heparinized to reach an activated clotting time (ACT) of 300 seconds. After completion of the vascular surgery, protamine was administered intravenously until a hemodynamic reaction was recorded. The 4 groups of dogs were given protamine at 5 mg/min (slow) or 10 mg/min (fast) via the cephalic or the jugular veins. Systemic and pulmonary arterial pressures, central venous pressure (CVP), and pulmonary arterial occlusion pressure (PAOP) were recorded before and after protamine administration. The dose of protamine was recorded when a reaction occurred, which was defined as mean arterial pressure (MAP) <60 mm Hg or mean pulmonary arterial pressure (MPAP) >20 mm Hg or more than double the baseline value. RESULTS: Significant decreases in systolic arterial pressure (SAP), MAP, and diastolic arterial pressure (DAP) and significant increases in systolic (SPAP), mean (MPAP), and diastolic (DPAP) pulmonary arterial pressures were recorded after protamine administration. The cephalic slow group had significantly fewer protamine reactions than other groups (chi-square = 8.57, P = .03, df = 3). Significantly more protamine could be delivered from the cephalic vein (52.5+/-14.5 mg) compared with the jugular vein (37.6+/-16 mg) before a reaction occurred (P = .048). CONCLUSION: The rate of administration did not have an effect on the amount of protamine delivered. Adverse reactions were minimized when protamine was administered via the cephalic vein at a slow rate. CLINICAL RELEVANCE: We would recommend delivering protamine after cardiopulmonary bypass or vascular surgery through a peripheral venous route.

Acupuncture for management of pain.

Acupuncture is the technique of inserting needles into specific areas of the body to elicit a physiologic response. Although acupuncture is based on the paradigms of traditional Chinese medicine, there are numerous physiologic and clinical studies that document and validate its use. Control of pain is a major indication for the use of acupuncture. It can be used in conjunction with analgesic drugs or alone to make patients more comfortable.

Management of cancer pain.

Pain secondary to cancer in animals should be promptly addressed to alleviate suffering, stress, and anxiety and to improve quality of life. Uncontrolled cancer pain can have a negative effect on the owners and caregivers of affected animals. The pathophysiology of cancer pain is discussed in this article, along with pain evaluation and monitoring. Treatment of cancer pain should be individualized, and a step-wise approach to the management of cancer pain is presented. The use of opioids, nonsteroidal anti-inflammatory drugs, and adjuvant medications are also reviewed.

The effects of sodium ampicillin, sodium cefazolin, and sodium cefoxitin on blood pressures and heart rates in healthy, anesthetized dogs.

This study determined the effects of intravenous ampicillin, cefazolin, and cefoxitin on blood pressures and heart rates in healthy, anesthetized dogs. Forty dogs were each randomly assigned to a control, ampicillin, cefazolin, or cefoxitin group. Antibiotics or saline was delivered by intravenous bolus prior to surgical stimulation. Heart rate; systolic, mean, and diastolic arterial pressures; oxygen saturation; end-tidal halothane; and end-tidal carbon dioxide (CO2) were recorded before and every minute for 10 minutes after the test drug was administered. No significant differences were recorded between the antibiotic and control groups. The prophylactic use of these antibiotics should be considered safe in healthy, anesthetized dogs.

Influence of open surgical correction on intermediate-term outcome in dogs with subvalvular aortic stenosis: 44 cases (1991-1998).

OBJECTIVE: To compare outcome and intermediate-term survival for dogs undergoing open surgical correction of subvalvular aortic stenosis (SAS) with those for dogs with SAS that did not undergo surgery. DESIGN: Retrospective study. ANIMALS: 44 dogs with congenital SAS. PROCEDURE: Maximum instantaneous systolic pressure gradients were determined by use of Doppler echocardiography. Cardiopulmonary bypass and open surgical correction of SAS (membranectomy with or without septal myectomy) was performed in 22 dogs, whereas 22 dogs did not undergo surgical correction. Cumulative survival was compared between surgical and nonsurgical groups, using Kaplan-Meier nonparametric analysis and a Mantel-Cox log-rank test. RESULTS: Initial systolic pressure gradients were not significantly different for dogs undergoing surgery (128 +/- 55 mm Hg), compared with those that did not undergo surgery (117 +/- 57 mm Hg). Systolic pressure gradients were significantly decreased after surgery in dogs that underwent surgery (54 +/- 27 mm Hg). Cumulative survival was not significantly different between dogs in the surgical and nonsurgical groups. Censoring surgery-related mortality in the analysis still did not reveal a significant difference in cumulative survival between the surgical and nonsurgical groups. CONCLUSIONS AND CLINICAL RELEVANCE: Despite reductions in the systolic pressure gradient and possible associated improvement in exercise tolerance, a palliative benefit on survival was not documented in dogs undergoing surgery for SAS.

Determination of the minimum alveolar concentration of isoflurane in llamas.

OBJECTIVE: To determine the minimum alveolar concentration (MAC) of isoflurane (ISO) in llamas. STUDY DESIGN: Prospective study. ANIMALS: Eight adult neutered male llamas (9 +/- 1 years [x +/- SD], 177 +/- 29 kg). METHODS: Anesthesia was induced and maintained in otherwise unmedicated llamas with a mixture of ISO in oxygen administered through a standard small-animal, semi-closed circle system using an out-of-circle, agent-specific vaporizer. The time from mask placement to intubation was recorded. Inspired and end-tidal (ET) ISO was sampled continuously. At each anesthetic concentration, a constant ET ISO was maintained for at least 20 minutes before application of a noxious electrical stimulus (50 volts, 5 Hz, 10 ms for up to 1 minute). A positive or negative response to the stimulus was recorded, and ET ISO then increased (if positive response) or decreased (if negative response) by 10% to 20%. Individual MAC was the average of multiple determinations. Body temperature was maintained at 37 +/- 1 degrees C. Selected cardiopulmonary variables (heart rate [HR], respiratory rate [RR], arterial blood pressure [ABP]) and ET ISO were recorded at hourly intervals from first ISO. Arterial blood was collected for pH, PCO2, PO2 analysis and measurement of packed cell volume (PCV) and total protein (TP) at 2 hour intervals. Following MAC determination, the anesthetic was discontinued and llamas were allowed to recover. Duration and quality of recovery were noted. RESULTS: The time from start of induction by mask to completion of intubation took 19.1 +/- 4.8 minutes. The MAC of ISO corrected to one atmosphere at sea level (barometric pressure 760 mm Hg) in these llamas was 1.05 +/- 0.17%. Mean ABP increased from 70 +/- 26 mm Hg at the end of the first hour of anesthesia to 102 +/- 7 mm Hg measured at the end of the sixth hour of anesthesia. ET ISO decreased from 2.06 +/- 0.10% to 1.27 +/- 0.07% over the same time period, but MAC did not change with time. The duration from first ISO to discontinuation of ISO averaged 6.19 +/- 0.9 hours. Animals were able to support their heads in a sternal posture at 23 +/- 10 minutes, and stood 62 +/- 26 minutes following discontinuation of the anesthetic. CONCLUSION: The MAC for ISO is similar to, but slightly lower than, values reported for other species. CLINICAL RELEVANCE: Knowledge of MAC may facilitate appropriate clinical use and provide the basis for future investigation of ISO in llamas.

Complications and mortality associated with anesthesia in dogs and cats.

The complications and mortality associated with anesthesia of dogs and cats in a university teaching hospital were determined. During one year, 2,556 dogs and 683 cats were anesthetized by the anesthesia service. Hypotension occurred in 179 (7%) dogs and 58 (8.5%) cats. Cardiac dysrhythmias occurred in 64 (2.5%) dogs and 12 (1.8%) cats. Transfusions were required in 31 (1.2%) dogs. Hypercapnea occurred in 33 (1.3%) dogs and one (less than 1%) cat. Hypoxemia occurred in 14 (0.5%) dogs. Anesthetic complications, as defined, occurred in 12.0% of dogs and 10.5% of cats, while deaths associated with the perianesthetic period occurred in 0.43% of dogs and 0.43% of cats.

The effects of hyperoxia on the biosynthesis of cyclooxygenase products and haemodynamic response to nitric oxide synthase inhibition with L-NAME in endotoxaemic pigs.

The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2 (TXB2) and 6-keto-prostaglandin (PG) F1alpha induced by inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) in a porcine model of endotoxaemia. Twenty-two domestic, random source pigs, weighing 15.4 +/- 2.7 kg (mean +/- standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end-tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2 (Control, n = 6); Escherichia coli lipopolysaccharide (5 microg/kg/h from 1 to 2 h followed by 2 microg/kg/h from 2 to 5 h) + 30% O2 (LPS, n = 4); L-NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2 (n = 6); and L-NAME + LPS + 30% O2 (n = 6). L-NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L-NAME + LPS + 30% O2 group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L-NAME + LPS-induced increases in TXB2 and 6-keto-PGF1alpha concentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L-NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L-NAME-induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.

Ovarian ablation alone promotes aortic intimal hyperplasia and accumulation of fibroblast growth factor.

BACKGROUND: Estrogen-mediated cardiovascular protection is incompletely explained by its beneficial lipid-modifying effects. Previous studies interrogating direct vascular effects of estrogens have used models of either diet- or injury-induced atherosclerosis. The purpose of this study was to determine the influence of ovarian ablation alone on vascular remodeling. We hypothesized that estrogens are atheroprotective, independent of their influence on lipid metabolism, by directly influencing the production and effects of a prototypical atherogenic mediator, basic fibroblast growth factor (bFGF). METHODS AND RESULTS: Twenty-five female sheep were randomized to sham operation, ovariectomy, or ovariectomy plus 17beta-estradiol replacement. Serum cholesterol and triglyceride levels were serially measured for 1 year and were similar among groups and in the normal range (30 to 60 mg/dL). At 6, 9, and 12 months, ovariectomy resulted in aortoiliac intimal hyperplasia compared with sham (P<0.01) and hormone replacement (P<0.01) groups. The neointima of ovariectomized animals was characterized immunohistochemically by increased vascular smooth muscle cells (VSMCs). Levels of bFGF protein were determined in adjacent aortic segments. Ovariectomized sheep had 2-fold more FGF than sham or ovariectomized sheep that received hormone replacement. In vitro, estradiol inhibited the mitogenic effect of bFGF on human aortic VSMCs. CONCLUSIONS: Without dietary manipulation, ovarian ablation alone induces aortic intimal hyperplasia in the ewe. Estradiol abrogates this response independently of its effects on serum lipids. Hormone replacement decreases the accumulation of the atherogenic peptide bFGF in vivo and inhibits the mitogenic response of VSMCs to bFGF in vitro. These results suggest that estrogens may provide atheroprotection both by modulating local production and by attenuating the influence of bFGF on VSMC growth.