The effectiveness of a long-acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study

A prospective, double-blinded, positive-controlled, multicenter, noninferiority clinical study was conducted to evaluate the safety and effectiveness of a long-acting transdermal fentanyl solution (TFS) for the control of postoperative pain. Four hundred forty-five client-owned dogs of various breeds were randomly assigned to receive a single dose of TFS (2.6 mg/kg [～50 μL/kg]) (N = 223) applied 2-4 h prior to surgery or buprenorphine (20 μg/kg) (N = 222) administered intramuscularly 2-4 h prior to surgery and every 6 h through 90 h. There were 159 (35.7%) males and 286 (64.3%) females ranging from 0.5 to 16 years of age and 3 to 98.5 kg enrolled. Pain was scored using the modified Glasgow Composite Pain Scale with an a priori dropout criteria of ≥ 8 (20 maximum score). The one-sided upper 95% confidence interval of the mean difference between fentanyl and buprenorphine treatment failures was 5.6%, which was not greater than the a priori selected margin difference of 15%. Adverse events attributed to either treatment were minimal in impact and were approximately equal between groups. Sustained plasma fentanyl concentrations provided by a single pre-emptive dose of TFS are safe and effective and are noninferior to repeated injections of buprenorphine in controlling postoperative pain over 4?days. This long-acting fentanyl formulation provides veterinarians with a novel, registered option for the control of postoperative pain in dogs that improves dosing compliance and potentially mitigates the disadvantages of oral, parenteral, and patch delivered opioids.     

Population pharmacokinetics of transdermal fentanyl solution following a single dose administered prior to soft tissue and orthopedic surgery in dogs

A novel, long-acting transdermal fentanyl solution (TFS) that delivers sustained plasma fentanyl concentrations following a single application for the control of postoperative pain has recently been approved for use in dogs. The pharmacokinetics (PKs) of this formulation have been evaluated in healthy laboratory dogs, but they have not been reported in a clinical population of dogs for which it is indicated. Plasma fentanyl concentrations were determined from 215 dogs following a single, small-volume (～50 μL/kg) dose of TFS administered 2-4 h prior to orthopedic or soft tissue surgery. A population PK model was fit, and a 1-compartment open PK model with first-order absorption and an absorption lag-time best described the data. No tested clinical covariates had a significant effect on the PKs. The final model adequately described the population PKs and gave results consistent with laboratory PK studies in healthy dogs. The PKs were primarily characterized by a rapid initial increase in plasma fentanyl concentrations and a long terminal half-life of 74.0 (95% C.I. [54.7-113]) h governed by flip-flop kinetics for the typical subject. The plasma fentanyl concentrations were sustained over days in the range considered to be analgesic for postoperative pain in dogs.     

The safety and effectiveness of a long‐acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized,multicentered clinical study

A prospective, double‐blinded, positive‐controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client‐owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2–4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2–4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score ≥8 or adverse event necessitating withdrawal. Four TFS‐ and eight oxymorphone‐treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone‐treated, but no TFS‐treated dogs were withdrawn due to severe adverse events. The one‐sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was −5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study.     

Pharmacokinetics and the effect of application site on a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles

Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg/kg (50 μL/kg) dose of a novel, long-acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng/mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (C(max)) and the area under the curve (AUC) were not contained within the 80-125% interval. The C(max) was 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng/mL for the ventral and dorsal application groups, respectively. The terminal elimination half-lives (t(1/2)) for both groups were similar with values of 137 ± 58.9 and 117 ± 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of ≥ 2 μg · kg/h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2-4 h prior to surgery with analgesia lasting a minimum of 4 days.     

The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs

Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 μL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.     

Evaluation of the efficacy and safety for use of two sedation and analgesia protocols to facilitate assisted ventilation of healthy dogs

OBJECTIVE: To determine the effectiveness and safety of 2 sedative-analgesic protocols to facilitate assisted ventilation in healthy dogs. ANIMALS: 12 healthy dogs. PROCEDURES: Dogs were randomly assigned to 2 groups. Mean dosages for protocol 1 were diazepam (0.5 mg/kg/h [n = 3 dogs]) or midazolam (0.5 mg/kg/h [3]), morphine (0.6 mg/kg/h [6]), and medetomidine (1.0 microg/kg/h [6]). Mean dosages for protocol 2 were diazepam (0.5 mg/kg/h [n = 3]) or midazolam (0.5 mg/kg/h [3]), fentanyl (18 microg/kg/h [6]), and propofol (2.5 mg/kg/h [6]). Each dog received the drugs for 24 consecutive hours. All dogs were mechanically ventilated with adjustments in minute volume to maintain normocapnia and normoxemia. Cardiorespiratory variables were recorded. A numeric comfort score was assigned hourly to assess efficacy. Mouth care, position change, and physiotherapy were performed every 6 hours. Urine output was measured every 4 hours. RESULTS: Use of both protocols maintained dogs within optimal comfort ranges > 85% of the time. The first dog in each group was excluded from the study. Significant decreases in heart rate, oxygen consumption, and oxygen extraction ratio were evident for protocol 1. Cardiac index values in ventilated dogs were lower than values reported for healthy unsedated dogs. Oxygen delivery, lactate concentration, and arterial base excess remained within reference ranges for both protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Use of both protocols was effective for facilitating mechanical ventilation. A reduction in cardiac index was detected for both protocols as a result of bradycardia. However, oxygen delivery and global tissue perfusion were not negatively affected.     

Warfarin in the dog: pharmacokinetics as related to clinical response

Warfarin was administered intravenously (i.v.) as a single dose of 1.5 mg/kg to healthy dogs and the pharmacokinetic parameters were investigated. Elimination could be described by a one-compartment open model. Values for the elimination half-life and apparent specific volume of distribution were 14.5 ± 4.1 h and 0.22 ± 0.04 litre/kg, respectively. Oral maintenance doses were calculated from the data collected following i.v. administration and administered every 12 h for a total of five doses after an initial i.v. loading dose of 1.5 mg/kg. Prothrombin times increased from a control value of 8.6 ± 0.3 sec to 55.2 ± 5.2 sec over a period of 96 h. Prothrombin time returned to control values by 62 h after withdrawal of the drug. We propose a dosage regimen of warfarin for anticoagulant therapy in the dog of 0.22 mg/kg to be given orally every 12 h. Prothrombin time should be monitored during therapy and the dose of warfarin modified according to the degree of suppression of coagulation factors desired.     

Influence of medetomidine on stress-related neurohormonal and metabolic effects caused by butorphanol, fentanyl, and ketamine administration in dogs

OBJECTIVE: To examine stress-related neurohormonal and metabolic effects of butorphanol, fentanyl, and ketamine administration alone and in combination with medetomidine in dogs. ANIMALS: 10 Beagles. PROCEDURE: 5 dogs received either butorphanol (0.1 mg/kg), fentanyl (0.01 mg/kg), or ketamine (10 mg/kg) IM in a crossover design. Another 5 dogs received either medetomidine (0.02 mg/kg) and butorphanol (0.1 mg/kg), medetomidine and fentanyl (0.01 mg/kg), medetomidine and ketamine (10 mg/kg), or medetomidine and saline (0.9% NaCI) solution (0.1 mL/kg) in a similar design. Blood samples were obtained for 6 hours following the treatments. Norepinephrine, epinephrine, cortisol, glucose, insulin, and nonesterified fatty acid concentrations were determined in plasma. RESULTS: Administration of butorphanol, fentanyl, and ketamine caused neurohormonal and metabolic changes similar to stress, including increased plasma epinephrine, cortisol, and glucose concentrations. The hyperglycemic effect of butorphanol was not significant. Ketamine caused increased norepinephrine concentration. Epinephrine concentration was correlated with glucose concentration in the butorphanol and fentanyl groups but not in the ketamine groups, suggesting an important difference between the mechanisms of the hyperglycemic effects of these drugs. Medetomidine prevented most of these effects except for hyperglycemia. Plasma glucose concentrations were lower in the combined sedation groups than in the medetomidine-saline solution group. CONCLUSIONS AND CLINICAL RELEVANCE: Opioids or ketamine used alone may cause changes in stress-related biochemical variables in plasma. Medetomidine prevented or blunted these changes. Combined sedation provided better hormonal and metabolic stability than either component alone. We recommend using medetomidine-butorphanol or medetomidine-ketamine combinations for sedation or anesthesia of systemically healthy dogs.     

Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles

Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals.     

Correlation of serum phenytoin (diphenylhydantoin) with the administration of oral and intravenous phenytoin in dogs

The concentration of serum phenytoin was determined in normal dogs following the administration of phenytoin by either the intravenous or oral route. An intravenous dose of 11 and 33 mg/kg of body weight was given to six dogs and a further dose of 44 mg/kg was given to two dogs. Serial blood samples were taken following the three doses for determination of pharmacokinetic parameters. The mean half-life was 3.35, 3.84 and 4.57 h as the dose was increased. Signs of toxicity occurred immediately following the infusion of phenytoin (emesis, ataxia and seizures). In the first oral studies, serial blood samples were taken for 2 consecutive days following a dose of 11 and 88 mg/kg, t.i.d. The time—concentration profiles of phenytoin varied significantly from one day to the next in the same dog. In the second oral study, blood samples were taken at 3 and 7 h following a dose of 11, 22, 44, 66 and 88 mg/kg, t.i.d. There was a poor correlation between the size of the oral dose and the concentration of serum phenytoin. Due to the short half-life and poor absorption of phenytoin in dogs, it was concluded that the oral administration of phenytoin in dogs produces sub-therapeutic and erratic serum concentrations of phenytoin which makes its efficacy as an anti-convulsant questionable.     

Comparison between meloxicam and transdermally administered fentanyl for treatment of postoperative pain in dogs undergoing osteotomy of the tibia and fibula and placement of a uniplanar external distraction device

OBJECTIVE: To compare the efficacy of meloxicam administered perioperatively with transdermal administration of fentanyl via a patch placed preoperatively in dogs undergoing orthopedic surgery. DESIGN: Prospective study. ANIMALS: 16 dogs. PROCEDURE: Unilateral or bilateral osteotomy of the tibia and fibula was surgically performed, and a uniplanar external distraction device was placed in each limb. Postoperative pain and lameness were assessed 24, 48, and 72 hours after administration of the first of 3 doses of meloxicam (0.2 mg/kg [0.09 mg/lb], IV, given preoperatively, followed by 0.1 mg/kg [0.045 mg/lb], IV, after 24 hours, and 0.1 mg/kg, PO, after 48 hours) or preoperative placement of a transdermal fentanyl patch (50 microg/h) left in place for 72 hours. RESULTS: No significant differences in total pain scores were detected between groups. Mean +/- SD lameness scores assessed at 24 and 72 hours were lower in dogs in the meloxicam group than dogs in the fentanyl group. Lameness scores decreased with time in a similar manner in both treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Perioperative administration of meloxicam or preoperative placement of a transdermal fentanyl patch provided effective and similar postoperative analgesia in dogs undergoing orthopedic surgery. However, because of its anti-inflammatory effects, treatment with meloxicam reduced the degree of lameness and resulted in rapid functional recovery of the limb.     

Effects of lidocaine constant rate infusion on sevoflurane requirement, autonomic responses, and postoperative analgesia in dogs undergoing ovariectomy under opioid-based balanced anesthesia

The effects of constant rate infusion (CRI) of lidocaine on sevoflurane (SEVO) requirements, autonomic responses to noxious stimulation, and postoperative pain relief were evaluated in dogs undergoing opioid-based balanced anesthesia. Twenty-four dogs scheduled for elective ovariectomy were randomly assigned to one of four groups: BC, receiving buprenorphine without lidocaine; FC, receiving fentanyl without lidocaine; BL, receiving buprenorphine and lidocaine; FL, receiving fentanyl and lidocaine. Dogs were anesthetized with intravenous (IV) diazepam and ketamine and anesthesia maintained with SEVO in oxygen/air. Lidocaine (2mg/kg plus 50μg/kg/min) or saline were infused in groups BL/FL and BC/FC, respectively. After initiation of lidocaine or saline CRI IV buprenorphine (0.02mg/kg) or fentanyl (4μg/kg plus 8μg/kg/h CRI) were administered IV in BC/BL and FC/FL, respectively. Respiratory and hemodynamic variables, drug plasma concentrations, and end-tidal SEVO concentrations (E'SEVO) were measured. Behaviors and pain scores were subjectively assessed 1 and 2h post-extubation. Lidocaine CRI produced median drug plasma concentrations <0.4μg/mL during peak surgical stimulation. Lidocaine produced a 14% decrease in E'SEVO in the BL (P<0.01) but none in the FL group and no change in cardio-pulmonary responses to surgery or postoperative behaviors and pain scores in any group. Thus, depending on the opioid used, supplementing opioid-based balanced anesthesia with lidocaine (50μg/kg/min) may not have any or only a minor impact on anesthetic outcome in terms of total anesthetic dose, autonomic responses to visceral nociception, and postoperative analgesia.     

Plasma salicylate concentrations in immature dogs following aspirin administration: comparison with adult dogs

Aspirin disposition in immature and adult dogs, assessed by plasma salicylate concentrations following single doses of aspirin given orally (p.o.) and intravenously (i.v.), was compared. Using a cross-over design, four immature (12–16-weeks-old) and eight adult (1– 2-years-old) dogs were given a single dose of aspirin at 17.5 mg/kg body weight i.v. and a single dose of buffered aspirin at 35 mg/kg body weight p.o. Blood was collected from the jugular vein for 24 h following each dose. A fluorescence polarization immunoassay was used for determination of salicylate in plasma. Significant differences in aspirin disposition were identified between the two groups. Immature dogs had significantly shorter salicylate half-life, lower mean residence time, and more rapid salicylate clearance than adult dogs. The difference in volume of distribution between the two groups was not significantly different. Immature dogs had lower mean (± SD) peak plasma salicylate concentrations (64.5 ± 2.38 mg/L) than adult dogs (95.9 ± 12.2 mg/L) following a single oral dose of buffered aspirin at 35 mg/kg body weight. Predicted plasma salicylate concentration-time curves were constructed for various aspirin dosage regimens. This analysis showed that the previously recommended buffered aspirin dose for adult dogs of 25 mg/kg body weight p.o. every 8 h would be ineffective in maintaining plasma salicylate concentrations > 50 mg/L in immature dogs.     

Blood pressure response to phenylephrine infusion in halothane-anesthetized dogs given acetylpromazine maleate

To quantitate acetylpromazine-induced alpha-adrenergic receptor blockade, phenylephrine was infused into dogs. The amount of phenylephrine necessary to increase the mean arterial blood pressure (MAP) 50% above base line, with or without the prior administration of acetylpromazine, served to quantify the degree of acetylpromazine-induced alpha-adrenergic receptor blockade. Seven dogs were anesthetized with thiopental, maintained on halothane in oxygen, and mechanically ventilated. All infusions were made through a catheter in the cephalic vein. Continuous recordings were made of MAP and a lead II ECG. After induction of anesthesia, instrumentation, and stabilization of heart rate, MAP, and ventilation, 6 group I dogs were infused with phenylephrine until a 50% increase in MAP was recorded (phenylephrine control). On subsequent research days, each dog was anesthetized, instrumented as described, and given (IV) 1 of 3 dosages of acetylpromazine in the following order--0.05, 0.125, and 0.25 mg/kg. The dose of phenylephrine necessary to increase MAP 50% in the presence of acetylpromazine was recorded. Five group II dogs were studied as in group I, but each dog was given (IM) atropine (0.04 mg/kg) before anesthetization. Two dosages of acetylpromazine were studied in the following order--0.05 and 0.25 mg/kg. Group I dogs, when compared with their phenylephrine controls, were given significantly more phenylephrine to raise MAP 50% at each dose of acetylpromazine studied. The same trend was observed in group II dogs, but at smaller doses of phenylephrine, probably as a result of the positive chronotropic effect of atropine on the heart.     

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap . 33 , 42–49.
Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time ( MRT ) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.     

Efficacy of Low‐ and High‐Dose Trilostane Treatment in Dogs (< 5 kg) with Pituitary‐Dependent Hyperadrenocorticism

Background

Trilostane is commonly used to treat pituitary‐dependent hyperadrenocorticism (PDH) in dogs. There are differing opinions regarding the dose and frequency of trilostane administration in dogs with PDH.

Objectives

To compare the efficacy of 2 trilostane protocols in the treatment of dogs with PDH.

Animals

Sixteen client‐owned dogs with PDH and a body weight <5 kg.

Methods

Prospective observational study. Group A (n=9; low‐dose treatment group) received 0.78 ± 0.26 mg of trilostane/kg PO every 12 h and group B (n = 7; high‐dose treatment group) 30 mg of trilostane/dog PO every 24 h. All of the dogs were reassessed at 2, 4, 8, 12, 16, and 24 weeks after the initiation of treatment.

Results

An improvement in both ACTH‐stimulated serum cortisol concentrations and clinical signs occurred more slowly in group A than in group B; however, after 20 weeks of treatment, 2/7 dog in group B had clinical signs and abnormal laboratory findings consistent with hypoadrenocorticism. At 24 weeks, an improvement in the clinical findings of all of the dogs in both groups was detected.

Conclusions and clinical importance

In dogs with PDH, twice‐daily administration of low‐dose trilostane is an effective approach to the management of PDH. In addition, our results suggest fewer potential adverse effects if trilostane is administered twice daily in the lower dose.     

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

OBJECTIVE: To determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 microg kg(-1)) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 microg kg(-1) hour(-1) lasting 1, 3 or 4 hours in dogs. Animals Fourteen healthy adult beagles (seven males and seven females). EXPERIMENTAL DESIGN: Randomized cross-over design. MATERIALS AND METHODS: Dogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 microg kg(-1)). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 microg kg(-1) hour(-1)) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography-mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). RESULTS: Plasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration-time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2alpha was 4.5 minutes), a relatively long elimination half time (t1/2beta was 45.7 minutes), a large volume of distribution (approximately 5 L kg(-1)) and high total body clearance (77.9 mL minute(-1) kg(-1)). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. CONCLUSIONS AND CLINICAL RELEVANCE: While this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.     

A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma

Twenty-eight dogs with lymphoma were treated with a 12-week, 5-drug chemotherapy protocol concluding with high-dose cyclophosphamide supported by autologous bone marrow transplants. A dose escalation design was used to determine the maximum tolerated cyclophosphamide dose (MTD) in this setting. Three cyclophosphamide dose levels were given: 300 mg/ m2 IV (groupl, 3 dogs), 400 mg/m2 IV (group 2, 12 dogs), and 500 mg/m2 IV (group 3, 13 dogs); and the MTD was 500 mg/m2 IV. Toxicity was common but mild, and the dose-limiting toxicity was myelosuppression, specifically neutropenia. No dog died as a result of treatment-related toxicity. One dog in group 3 developed fever, neutropenia, and presumed sepsis and responded promptly to routine management. No other dog required hospitalization. Lower stage and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3]) compared with the lower doses combined (groups 1 and 2) were significantly associated with longer remission duration (all P < .0001). Median remission duration for dogs in group 3 was 54 weeks, compared with 21 weeks for dogs in groups 1 and 2 combined. Factors associated with longer survival time were lower stage (P = .042) and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3] compared with the lower doses combined [groups 1 and 2]) (P = .027). Median survival time for dogs in group 3 was 139 weeks, compared with 43 weeks and 68 weeks for dogs in groups 1 and 2, respectively.     

Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs

The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six mixed breed dogs of varying ages (1-5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration-time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/- SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.