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PubMed1985

Demonstration of non-opioid sigma binding with (d)3H-SKF 10047 in guinea pig brain.

A non-opioid binding site to (d)3H-SKF 10047 (N-allyl-normetazocine), the prototypic ligand for the sigma or PCP-like receptor, was demonstrated. The (d) isomer of 3H-SKF 10047 was used to demonstrate a stereospecific low affinity binding site with a Kd of 173nM. It was naloxone insensitive with an IC50 of greater than 10,000nM, which defined it as non-opioid. Traditional mu compounds like morphine and FK 33824 were also inactive, with IC50's of greater than 10,000nM. Kappa compounds such as ethylketocyclazocine and U-50,488H were active as were all of the benzmorphans tested, with butorphanol the least active. The known antipsychotic haloperidol was the most active compound tested, with an IC50 of 11nM. Other antipsychotics which demonstrated activity were chlorpromazine and pimozide. The atypical antipsychotic clozapine was inactive.

Animals↗
PubMed1986

Kappa opiate agonists modulate the hypothalamic-pituitary-adrenocortical axis in the rat.

Systemic injections of opiate agonists were made in male rats to elucidate the involvement of multiple opioid receptors in the stress response. As an index of activity in the hypothalamic-pituitary-adrenocortical axis, plasma corticosterone was measured by radioimmunoassay. Rats were injected with ethylketocyclazocine (EKC), U50488H, MR2034, bremazocine or tifluadom and sacrificed 1 hr later. These kappa agonists produced potent, dose-dependent, stereospecific increases in plasma corticosterone levels at doses far below those needed to elicit analgesia. These effects were reversed by opiate antagonists, naloxone or Win 44441-3, which by themselves caused dose-dependent decreases in plasma corticosterone. Animals made tolerant to the prototype kappa agonist, U50488H, showed an attenuated response to an acute injection of the drug. However, when animals made tolerant to morphine were injected acutely with U50488H, the drug caused a dramatic increase in corticosterone levels. In hypophysectomized rats, U50488H and L-EKC did not increase plasma corticosterone. The agonist/antagonists, butorphanol and cyclazocine, when injected, behaved like kappa agonists and increased plasma corticosterone levels potently. The mu opiates, morphine and etorphine, also had similar effects but were less potent and efficacious than the kappa agonists. The delta agonist D-Ala-D-Leu enkephalin showed similar results, confirming a mu and delta opioid input into the hypothalamic-pituitary-adrenocortical axis. There were concomitant increases in plasma adrenocorticotropin in morphine-, D-Ala-D-Leu enkephalin-, L-EKC- and U50488H-treated rats which were also seen in adrenalectomized rats. D-EKC and D-cyclazocine, which bind to sigma sites, had no effect on corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Opioid regulation of food intake and body weight in humans.

Relatively few studies of humans have evaluated the effects of opioids on food intake and body weight. Most have focused on the potential role of opioids in the etiology of obesity. Measurements of endogenous opioids in plasma or spinal fluid of humans reveal higher levels, particularly of beta-endorphin, in obese subjects. Opioid agonists such as methadone and butorphanol tartrate stimulate food intake, and all studies with naloxone, an opioid antagonist, demonstrate a reduction of short-term food intake in obese or lean humans. Long-term studies with naltrexone, an antagonist similar to naloxone, show no effect on food intake or body weight. Opioid agonists or antagonists have little effect on nutrient selection in humans. The effects on feeding-related hormones is equivocal. Further studies with more specific opioid receptor activities are needed.

Animals↗
PubMed1986

Comparison of opioid self-injection and disruption of schedule-controlled performance in the baboon.

Eight opioid agonist, mixed agonist/antagonist or antagonist compounds were compared in baboons. In the first experiment, i.v. drug self-injection procedures involved a fixed-ratio schedule with a 3 hr time-out after each injection. Doses of a test drug were substituted for cocaine for 12 or 15 days. Codeine, morphine, butorphanol, nalbuphine and pentazocine all maintained self-injection above vehicle control levels. These compounds differed in their relative potencies, and morphine did not maintain maximal drug self-injection rates. Buprenorphine maintained self-injection in only one of four baboons, and SKF-10,047 and naloxone did not maintain self-injection. In a second experiment, another group of baboons responded on a fixed-ratio 50 schedule of food pellet delivery. Intravenous injections were given 30 min before test sessions that lasted 30 min. All eight drugs produced dose-related decreases in response rates, and the buprenorphine dose-response curve was more shallow and not parallel to the others. Comparison across experiments suggested that the failure of morphine to maintain maximal self-injection rates is due to its relatively high potency in suppressing schedule-controlled performance. The results of this study confirm those of previous studies demonstrating that opioids with morphine-like subjective effects in man are self-administered by laboratory animals.

Animals↗
PubMed1983

A kappa opioid effect: increased urination in the rat.

The effects of various opioids (mu agonists, kappa agonists and mixed agonists/antagonists) were determined on urination in the normally dehydrated rat. Opioids considered as kappa agonists (bremazocine, ethylketazocine and ketazocine) produced a marked dose-related increase in urination. The mixed agonists/antagonists (cyclazocine, butorphanol and nalorphine) produced less urination than the kappa agonists, but more than the mu agonists (morphine and l-methadone). The mu agonists did not increase urine output compared with controls. The increased urination effect was blocked by opioid antagonists in a potency order which indicated that the effect was due to an action at a kappa opioid receptor. The data suggest the hypothesis that dynorphin, a kappa agonist, acts as an endogenous ligand for an autoreceptor which inhibits the corelease of dynorphin and antidiuretic hormone from the neurohypophysis. This decrease in antidiuretic hormone levels produces the increased urination. Increased urination is a simple in vivo test for studying the actions of compounds at kappa opioid receptors.

Animals↗
PubMed1983

Discriminative stimulus effects of dextrorphan in pigeons.

Pigeons were trained to discriminate between dextrorphan (10 mg/kg) and saline in a task in which 20 consecutive key pecks on either the left or right key, depending on whether dextrorphan or saline had been administered, produced food. During sessions in which stimulus generalization to other drugs was evaluated, 20 consecutive responses on either the dextrorphan- or saline-appropriate key produced food. Dextromethorphan and dexoxadrol produced dose-related stimulus control of behavior similar to that produced by dextrorphan. In contrast, the l-isomers of these compounds, levomethorphan, levoxadrol and levorphanol, at doses up to and including those that markedly decreased the rate of responding, produced responding primarily on the saline-appropriate key. In addition, both the d- and l-isomers of methadone, codeine, morphine, butorphanol and profadol resulted in predominantly saline-appropriate responding. l-Cyclorphan, dl-, l- and d-SKF-10,047 and l- and d-cyclazocine produced dose-related dextrorphan-appropriate responding, whereas, l-oxilorphan (the 14-hydroxymorphinan analog of cyclorphan), dl-, l- and d-pentazocine, l- and d-ethylketazocine and l-naltrexone resulted in either responding exclusively on the saline-appropriate key or responding that was intermediate between that appropriate for saline and dextrorphan. Although levorphanol alone produce little or no dextrorphan-appropriate responding, the coadministration of naltrexone (1.0 mg/kg) and high doses of levorphanol, but not levoxadrol, resulted in responding similar to that produced by dextrorphan.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Evaluation of nalbuphine hydrochloride.

The chemical properties, animal and human pharmacology, analgesic efficacy, relative potency, administration, and adverse effects of nalbuphine, a recently marketed, parenteral, strong analgesic with narcotic antagonist properties, are reviewed. Acute, subacute, and chronic toxicity studies in animals revealed no unusual adverse effects. The abuse potential of nalbuphine in man is probably similar to pentazocine. Respiratory depression produced by usual therapeutic doses of nalbuphine is equivalent to that of morphine; at higher than usual doses, nalbuphine produces less respiratory depression. Nalbuphine has few effects on cardiovascular hemodynamics in patients without cardiac disease or with stable ischemic disease. In patients with acute myocardial infarction, nalbuphine has an advantage over morphine, pentazocine, and butorphanol of not producing hypotension. Nalbuphine is as effective and has the same potency as morphine as an analgesic, with about the same onset, peak, and duration of action. Sedation is the most common adverse effect and occurs about as often as with other strong analgesics. Nausea and vomiting occur less often. In contrast to pentazocine, the frequency of psychotomimetic reactions apparently is very low. On the basis of presently available evidence, nalbuphine appears to have fewer disadvantages than any other parenteral strong analgesic.

Analgesics↗
PubMed1982

Properties of pentazocine as a discriminative stimulus in the squirrel monkey.

Squirrel monkeys were trained to discriminate i.m. injections of pentazocine (3.0 mg/kg) from vehicle. Stimulus control was considered to have been established when the monkeys reliably completed at least 22 of the 25 trials (i.e. 88%) on the appropriate lever in both pentazocine and vehicle sessions. In cross-generalization tests, two groups of drugs were shown to produce pentazocine-like discriminative effects: 1) the pure opiate agonists morphine, levorphanol and levomethorphan and 2) cyclazocine, phencyclidine and dextrorphan, drugs previously shown to have common discriminative effects. In addition, l-pentazocine proved to be about twice as potent as the racemic mixture. Butorphanol, SKF 10,047 and dextromethorphan produced pentazocine-appropriate responding in 80% of the trials, whereas ketocyclazocine, ethylketocyclazocine and nalbuphine produced less than 50% pentazocine-appropriate responding. Four nonopioid drugs from a variety of pharmacologic classes (apomorphine, d-amphetamine, secobarbital and mescaline) failed to show any discriminative properties in common with pentazocine. In antagonism studies, naltrexone completely blocked the discriminative effects of pentazocine, whereas haloperidol produced only a partial blockade. The discriminative effects of l-pentazocine and levorphanol could also be antagonized by naltrexone, but those of dextrorphan could not. The results suggest the pentazocine has both a morphine-like component of action and a component shared with the nonmorphine-like opioids.

Animals↗
PubMed1995

[Management of epidural anesthesia in a patient with aortitis syndrome].

We report an anesthetic management of a patient with severe vascular occlusion case caused by Aortitis syndrome. The patient, 61 yr-old woman, was scheduled for sigmoidectomy. Her bilateral common carotid arteries and left main coronary artery were totally occluded, but she had been asymptomatic for over thirty years. Epidural anesthesia was chosen to provide pain control, cardiovascular stability, and also to maintain consciousness during operation for cerebral circulatory evaluation. Following intravenous administration of lactated Ringer's solution (about 1000 ml), epidural blockade was maintained with 1 to approximately 1.5% lidocaine and butorphanol. Our findings in this case indicate that it is important for coronary and cerebral perfusion to have normal central venous pressure (preload) and arterial pressure during sympathetic blockade resulting from epidural anesthesia.

Adenocarcinoma↗
PubMed1995

Large colon impaction in horses: 147 cases (1985-1991)

Medical records from all horses with large colon impaction admitted between 1985 and 1991 were examined. Large colon impaction was diagnosed in 147 of 1,100 (13.4%) horses with colic. One hundred thirty horses were admitted for further evaluation of acute onset of abdominal pain after having been examined and treated by referring veterinarians, and 17 horses that were hospitalized for unrelated medical problems developed large colon impaction. Female horses (92/147; 62.6%) were more commonly affected than males. The age ranged from 1 to 29 years (median, 7.1 years). Mean duration of clinical signs of abdominal pain prior to referral was 32 hours. At admittance, signs of abdominal pain were not detectable in 70/147 (48%) horses, and were mild in 50 (34%), moderate in 16 (11%), and severe in 11 (7%). Heart rate ranged from 30 to 86 beats/min (median, 44 beats/min), and most horses had a decrease in gastrointestinal sounds. Transrectal palpation was used to identify the impaction location as being the pelvic flexure in 103 (70.1%) horses, colon on the left side in 30 (20.4%) horses, and colon on the right side in 14 (9.5%) horses. All 147 horses received fluids i.v. and nonsteroidal anti-inflammatory medications or sedatives, including flunixin meglumine (124 horses, 84.3%) xylazine hydrochloride (81, 55%), butorphanol (6, 0.04%), and detomidine hydrochloride (9, 0.04%). Duration of medical treatment required to resolve the impaction ranged from 1 to 6 days (mean, 2 days). In addition to medical treatment, 24 (16.3%) horses also required surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Husbandry↗
PubMed1994

Evaluation of anesthetic protocols for neutering 6- to 14-week-old pups.

Ninety-nine 6- to 14-week-old pups were given anesthetic agents according to 10 anesthetic protocols. Mean quality rating scores were determined to compare anesthetic protocols. In male pups, IV administration of propofol (6.5 mg/kg of body weight) 15 minutes after IM administration of atropine (0.04 mg/kg) and oxymorphone (0.22 mg/kg) provided the best quality anesthesia. Intramuscular administration of midazolam (0.22 mg/kg) and butorphanol (0.44 mg/kg) instead of oxymorphone provided little sedation, but induced good analgesia. Atropine/oxymorphone/midazolam/xylazine, atropine/butorphanol/midazolam/xylazine, and tiletamine/zolazepam were unsatisfactory combinations for use in castration of 6- to 14-week-old male pups. In female pups, IV administration of propofol (3.4 mg/kg) 15 minutes after IM administration of atropine (0.04 mg/kg) and oxymorphone (0.11 mg/kg) was the most effective anesthetic protocol. Administration of the drugs according to this protocol enabled a pup to be intubated. Anesthesia was maintained with isoflurane in oxygen. If inhalational induction was preferred, IM administration of 13.2 mg of tiletamine/zolazepam/kg, 0.04 mg of atropine/kg and 0.11 mg of oxymorphone/kg, or 0.22 mg of midazolam/kg and 0.44 mg of butorphanol/kg may be used prior to mask delivery of inhalational anesthetics. In female pups, it was not advantageous to combine midazolam with oxymorphone, and use of high dosages of oxymorphone (0.22 mg/kg) or midazolam/butorphanol provided little sedation. Time of recovery after use of tiletamine/zolazepam was the longest for the combinations used, but did not adversely affect pups. Male pups were castrated via scrotal incisions, using hemostatic clips. Ovariohysterectomies were performed via a ventral abdominal midline approach, using hemostatic clips for ligation, five females developed signs of inflammation at the surgical site within 1 to 2 weeks after surgical, and were treated conservatively with warm compresses.

Analgesia↗
PubMed1994

[Inhibition by sedatives of compensatory vasoconstriction during lumbar epidural anesthesia].

Compensatory vasoconstriction in an upper extremity during lumbar epidural anesthesia contributes to the stability of hemodynamics. We measured blood flow of an index fingertip (FBF) with laser-Doppler flowmetry, surface temperature of a middle fingertip (FT), deep body temperature of the forehead (HDT) and a big toe (BDT) by an insulated thermistor probe of zero thermal flow between skin and subcutaneous tissue, and mean arterial pressure (MAP) in 16 patients undergoing elective lower abdominal surgery under lumbar epidural anesthesia. Epidural puncture was done at L1-2 (n = 2), L2-3 (n = 8) or L3-4 (n = 6), and the initial dose of 13 +/- 1 ml (mean +/- SD) of 2% plain mepivacaine (n = 14) or 2% plain lidocaine (n = 2) was injected five minutes after the test dose of 3 ml. Five minutes after the initial injection, the hypesthesia region of cold sensation examined by alcohol absorbent cotton was T9 +/- 3 (range, T2-T12) at the upper limit and S2 +/- 2 (range, L2-S3) at the lower limit. After determination of the hypesthesia region, a combination of butorphanol 1.0 +/- 0.1 mg and midazolam 2.0 +/- 0.9 mg or diazepam 7.5 +/- 2.5 mg alone was administered intravenously. The difference between HDT and BDT decreased significantly from 6.4 degrees C (P < 0.01) at the time of test dose injection to 0.4 degrees C (P < 0.001) 20 minutes after the initial dose injection of local anesthetics. FBF showed a twofold significant increase (P < 0.01) 20 minutes after the initial dose injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Chronic headache: appropriate use of opiate analgesics.

The question of the appropriate use of opiate analgesics in the management of chronic headache pain is under debate. Often, the management of headache pain is complicated by the overuse of dependency-promoting analgesics. Because of confusion about the use of analgesics in pain management, some patients are denied access to necessary opioid analgesia, whereas others receive large quantities of combination analgesics. The proper use of opiate analgesics is presented here, including a review of the pharmacology of these agents. Signs of analgesic dependence, analgesic rebound headache, and methods of withdrawal are also presented. The potential use of such new treatment modalities as butorphanol nasal spray is discussed.

Analgesics↗
PubMed1993

Effects of hylan on amphotericin-induced carpal lameness in equids.

In this double-blind study, the effectiveness of and dose response to intra-articular administration of modified hyaluronan (hylan) was determined in an equine carpal lameness model over a 23-day period, using a computerized three-dimensional motion analysis system, synovial fluid variables, and synovial histologic examination. In 24 clinically sound horses, baseline motion data was acquired from horses trotting at 4 m/s on a high-speed treadmill. Then, to induce lameness, 25 mg of amphotericin B in 5 ml of sterile water was injected into the left middle carpal joint of each horse every other day for 3 treatments. Phenybutazone (2.2 mg/kg of body weight, PO, once) and butorphanol tartrate (0.1 mg/kg, IM, q 6 h, for 36 hours) were used to control signs of discomfort. Horses were assigned at random to 4 equal groups and received intracarpal administration of either 1, 2, 4 ml of hylan (8 mg/ml), or 2 ml of balanced electrolyte solution (control). Intracarpal administration of amphotericin B caused significant (P < or = 0.01) increase in subjective lameness grades over the 2-week evaluation period, and hylan administration did not significantly (P < or = 0.01) change the subjective lameness grade. Lameness induction caused significant (P < or = 0.01) decrease in head and withers excursions during the lame forelimb support phase and significant (P < or = 0.05) increase in head and withers excursions during the sound forelimb support phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed1993

Computer-assisted three-dimensional gait analysis of amphotericin-induced carpal lameness in horses.

Motion of 6 clinically sound horses trotting at a speed of 4 m/s on a treadmill was captured by video cameras before and 9, 16, and 23 days after amphotericin-induced lameness to determine the quantitative variables of three-dimensional computer-assisted image analysis that objectively describe carpal lameness. Amphotericin-B was used to induce lameness, and phenylbutazone (2.2 mg/kg of body weight, PO, once) and butorphanol tartrate (0.1 mg/kg IM, q 6 h, to effect) were used to control discomfort. Four 60-Hz cameras were symmetrically placed around the treadmill to capture 6 seconds of images from retro-reflective spheres taped to the trotting horses. Images were transferred to a video-based digitizer and a computer work station, where 4 files of two-dimensional data were reduced to 1 file of three-dimensional data. The effect of lameness on motion analyzed was assessed by use of two-way ANOVA. Differences between means were assessed, using the Student-Newman-Keul's test (P < or = 0.05). Head and withers excursions, (dorsal vertical displacement of head and withers targets, respectively) during the sound forelimb support phase were increased significantly during all lameness measurement periods. Head excursion, but not withers excursion, during the lame forelimb support phase, was decreased significantly during all lameness measurement periods. Computer determinations of stride length swing phase, stance phase, forelimb abduction, and carpal and fetlock ranges of motion did not consistently characterize the lameness. It was concluded that three-dimensional computer-assisted image analysis could be used for objective lameness evaluation in horses and that head and withers excursions were the most consistent variables for assessing equine carpal lameness.

Amphotericin B↗
PubMed1993

A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration.

The squirrel monkey titration procedure was used to assess the antinociceptive effects of the novel delta opioid agonist (+/-)-4-(a-R*)-a(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxyb enzyl)- N,N-diethylbenzamide (BW373U86). Under this procedure shock increased every 15 sec from 0.01 to 2.0 mA in 30 steps. Five responses terminated the shock for 15 sec, after which the shock resumed at a lower intensity. The intensity at which the monkeys maintained the shock 50% of the time (median shock level, MSL) was determined. BW373U86 (1.0-30.0 mg/kg i.m.) increased MSL, but these increases were not dose-dependent and lasted only 15 min or less. Doses of BW373U86 that increased MSL often produced tremors and/or convulsions immediately after administration. When 1.0 mg/kg of naltrindole, a delta opioid antagonist, was given in combination with BW373U86, doses of BW373U86 up to 30 mg/kg no longer increased MSL nor did tremors and/or convulsions occur. Doses of BW373U86 (0.01-0.3 mg/kg i.m.) that did not increase MSL when administered alone shifted the dose-effect curve for the mu agonist l-methadone to the left. These shifts were antagonized dose-dependently by naltrindole. In monkeys that were tolerant to morphine, BW373U86 (0.03-0.1 mg/kg i.m.) shifted the morphine dose-effect curve leftward. In addition, BW373U86 altered the effects of the partial opioid agonists, buprenorphine, nalbuphine, butorphanol and levallorphan such that doses of these drugs that did not increase MSL when administered alone, often did so in the presence of BW373U86. Taken together, these findings indicate that BW373U86 has a delta agonist profile in the squirrel monkey; however, its antinociceptive effects in the shock titration procedure may be due to its toxic effects.

Amino Acid Sequence↗
PubMed1993

Adverse effects of administration of propofol with various preanesthetic regimens in dogs.

The effects of propofol on anesthetic induction were evaluated in 40 dogs anesthetized with isoflurane. Propofol is a rapidly acting, nonbarbiturate drug that induces anesthesia of ultrashort duration with IV administration. Four preanesthetic regimens were used: anesthesia without preanesthetic drugs; or with preanesthetic administration of acepromazine (0.1 mg/kg of body weight, IM), diazepam (0.2 mg/kg, IV), or acepromazine (0.02 mg/kg) and butorphanol (0.4 mg/kg) IM. Heart rate, systolic arterial blood pressure (SAP), respiration, quality of induction and recovery, and adverse effects were induction and recovery, and adverse effects were recorded. Intravenous propofol administration induced a variable period of apnea in 34 of 40 dogs. Cyanosis (in 2 dogs) and signs of pain on injection (in 3 dogs) were infrequently observed during induction. One dog developed ventricular premature depolarizations after propofol administration. Venous CO2 tension increased and pH decreased immediately after propofol administration, regardless of preanesthetic regimen. The SAP significantly (P < 0.05) decreased after propofol administration in dogs treated with acepromazine (SAP, 178 mm of Hg before vs 128 mm of Hg after propofol) and with acepromazine/butorphanol (SAP, 184 mm of Hg before vs 98 mm of Hg after propofol). When used for induction, propofol induces anesthetic-related adverse effects, some of which can be minimized by preanesthetic medication. Recovery characteristics varied with preanesthetic medication, independent of propofol administration.

Anesthesia, Inhalation↗
PubMed1993

Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983-1989)

The frequency of prescribing analgesics and administering them for the treatment of apparent postoperative pain in 243 dogs and 15 cats was evaluated. Surgeries performed on the animals evaluated included limb amputations, limb-sparing bone cancer resection, thoracotomy, cervical vertebral instability repair, and humeral fracture repair. Only 1 cat was treated once with an analgesic after surgery, and cats were not evaluated statistically. Dogs undergoing amputation, limb salvage procedure, or thoracotomy were more likely to be treated than dogs undergoing the other surgeries. Ninety-six (40%) of the 243 dogs were under the influence of an analgesic at any time during their postoperative hospital stay, and 69 dogs (28%) received 1 or more doses of an analgesic after recovery from general anesthesia. One hundred thirty-three dogs were cared for in the intensive care unit (ICU) immediately after surgery. Written instructions for treatment with an analgesic were given for 61 of those dogs, and 50 were given at least 1 dose of the prescribed analgesic. Dogs cared for in the ICU were twice as likely to be given an analgesic as dogs cared for in the surgery ward. The estimated duration of analgesic effect exceeded 8 hours in 46 (19%) of 243 dogs. Small and juvenile dogs were least likely to be treated. Interns and residents were twice as likely as faculty to administer analgesics. Most written interpretations of pain behavior observed in the ICU were made on the basis of vocalizations. Half of the dogs for which medical record comments suggested moderate to severe pain were not given an analgesic. The most frequently administered analgesic immediately following surgery was oxymorphone, followed by butorphanol and morphine. Aspirin was never administered to dogs in the ICU, but was used in 10 dogs that were in the surgery ward for > 74 hours.

Amputation, Surgical↗