Juhana Honkavaara

The effects of L-659,066, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs

OBJECTIVE To investigate the influence of L-659,066, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and reduction in pulse rate (PR) in dogs. STUDY DESIGN Randomized, cross-over. ANIMALS Six healthy laboratory Beagles. METHODS All animals received dexmedetomidine (5 μg kg-1 IV, DEX) alone or in combination with L-659,066 (250 μg kg-1 IV, DEX + L) with a 7-day rest period between treatments. Sedation was assessed using a composite sedation score and PRs were recorded. Atipamezole (50 μg kg-1 IM, ATI) was administered to reverse the sedation. Overnight Holter-monitoring was carried out to obtain a minimum heart rate (MHR) at rest. RESULTS Bioequivalence was shown for clinical sedation between DEX and DEX + L. Heart rate was significantly higher with DEX + L during the period of sedation. Bioequivalence was demonstrated between MHR and PR in the DEX + L group during the period of sedation. Recoveries after ATI were uneventful. CONCLUSIONS L-659,066 did not affect the quality of dexmedetomidine-induced sedation whilst it attenuated the reduction in PR. Thus, L-659,066 could prove a useful adjunct to reduce the peripheral cardiovascular effects attributed to dexmedetomidine in dogs. CLINICAL RELEVANCE The clinical safety of α2-adrenoceptor agonists could be markedly improved with less peripheral cardiovascular effects.OBJECTIVE To investigate the influence of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and reduction in pulse rate (PR) in dogs. STUDY DESIGN Randomized, cross-over. Animals Six healthy laboratory Beagles. METHODS All animals received dexmedetomidine (5 microg kg(-1) IV, DEX) alone or in combination with L-659,066 (250 microg kg(-1) IV, DEX + L) with a 7-day rest period between treatments. Sedation was assessed using a composite sedation score and PRs were recorded. Atipamezole (50 microg kg(-1) IM, ATI) was administered to reverse the sedation. Overnight Holter-monitoring was carried out to obtain a minimum heart rate (MHR) at rest. RESULTS Bioequivalence was shown for clinical sedation between DEX and DEX + L. Heart rate was significantly higher with DEX + L during the period of sedation. Bioequivalence was demonstrated between MHR and PR in the DEX + L group during the period of sedation. Recoveries after ATI were uneventful. CONCLUSIONS L-659,066 did not affect the quality of dexmedetomidine-induced sedation whilst it attenuated the reduction in PR. Thus, L-659,066 could prove a useful adjunct to reduce the peripheral cardiovascular effects attributed to dexmedetomidine in dogs. CLINICAL RELEVANCE The clinical safety of alpha2-adrenoceptor agonists could be markedly improved with less peripheral cardiovascular effects.

The effects of increasing doses of MK-467, a peripheral alpha2-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs

Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 μg/kg [D]), MK-467 (250 μg/kg [M250] or dexmedetomidine (10 μg/kg) with increasing doses of MK-467 (250 μg/kg [DM250], 500 μg/kg [DM500] and 750 μg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidines systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function.

The effects of L‐659,066, a peripheral α2‐adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep

We investigated whether administration of L-659,066, a peripheral α(2) -adrenoceptor antagonist, or verapamil, a calcium-channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross-over design: dexmedetomidine (5 μg/kg, DEX); DEX with L-659,066 (250 μg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 ± 10.7 to 120.8 ± 11.7 mmHg), central venous pressure (CVP) (3.3 ± 3.2 to 14.7 ± 5.0 mmHg) and systemic vascular resistance (SVR) (1579 ± 338 to 2301 ± 523 dyne s/cm(5) ), and decreases in cardiac output (CO) (5.36 ± 0.87 to 3.93 ± 1.30 L/min) and heart rate (HR) (88.6 ± 15.3 to 49.7 ± 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 ± 226 dyne s/cm(5) ) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 ± 6.8 to 89.3 ± 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2-20 min with no differences between treatments. L-659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral α(2) -adrenoceptors, whereas the effects of verapamil were marginal.

Influence of MK-467, a Peripherally Acting α2-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs

Growing evidence supports the use of (2R-trans)-N-(2-(1,3,4,7,12b-hexahydro-2′-oxo-spiro(2H-benzofuro(2,3-a)quinolizine-2,4′-imidazolidin)-3′-yl)ethyl) methanesulfonamide (MK-467), a peripherally acting α2-adrenoceptor antagonist, in conjunction with the sedative-anesthetic agent dexmedetomidine in animals to avoid hemodynamic compromise. We evaluated the possible effects of different doses of MK-467 on the plasma concentrations of dexmedetomidine in eight beagle dogs. Both drugs were administered intravenously. Each dog received five treatments: dexmedetomidine alone (10 μg/kg), MK-467 alone (250 μg/kg), and dexmedetomidine (10 μg/kg) combined with different doses of MK-467 (250, 500, and 750 μg/kg) in a randomized, crossover fashion. Selected pharmacokinetic parameters were calculated. The area under the time-concentration curve of dexmedetomidine was significantly greater after dexmedetomidine alone (by 101 ± 20%, mean ± 95% confidence interval) compared with that after dexmedetomidine and 250 μg/kg MK-467. Increasing the dose of the antagonist had no further effect on the exposure to dexmedetomidine. The apparent volume of distribution of dexmedetomidine was significantly smaller after dexmedetomidine alone compared with that after all treatments that included MK-467. Dexmedetomidine (10 μg/kg) did not significantly influence the plasma concentrations of MK-467 (250 μg/kg). The results suggest that the peripherally acting α2-adrenoceptor antagonist MK-467 markedly influenced the early disposition of dexmedetomidine without obvious effects on the later plasma concentrations of the drug.

Evaluation of bioequivalence after oral, intramuscular, and intravenous administration of racemic ketoprofen in pigs

OBJECTIVE To assess bioequivalence after oral, IM, and IV administration of racemic ketoprofen in pigs and to investigate the bioavailability after oral and IM administration. ANIMALS 8 crossbred pigs. PROCEDURES Each pig received 4 treatments in a randomized crossover design, with a 6-day washout period. Ketoprofen was administered at 3 and 6 mg/kg, PO; 3 mg/kg, IM; and 3 mg/kg, IV. Plasma ketoprofen concentrations were measured by use of high-performance liquid chromatography for up to 48 hours. To assess bioequivalence, a 90% confidence interval was calculated for the area under the time-concentration curve (AUC) and maximum plasma concentration (C(max)). RESULTS Equivalence was not detected in the AUCs among the various routes of administration nor in C(max) between oral and IM administration of 3 mg/kg. The bioavailability of ketoprofen was almost complete after each oral or IM administration. Mean +/- SD C(max) was 5.09 +/- 1.41 microg/mL and 7.62 +/- 1.22 microg/mL after oral and IM doses of 3 mg/kg, respectively. Mean elimination half-life varied from 3.52 +/- 0.90 hours after oral administration of 3 mg/kg to 2.66 +/- 0.50 hours after IV administration. Time to peak C(max) after administration of all treatments was approximately 1 hour. Increases in AUC and C(max) were proportional when the orally administered dose was increased from 3 to 6 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE Orally administered ketoprofen was absorbed well in pigs, although bioequivalence with IM administration of ketoprofen was not detected. Orally administered ketoprofen may have potential for use in treating pigs.

The effect of MK-467, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats

OBJECTIVE To determine a dose of MK-467, a peripheral α2-adrenoceptor antagonist, which, when administered intravenously (IV) concomitantly with 25 μg kg-1 of dexmedetomidine, will prevent bradycardia without altering sedation in cats. STUDY DESIGN Prospective, randomized, controlled, blinded, experimental, crossover study. ANIMALS Eight healthy, adult, purpose-bred cats. METHODS Cats were administered seven IV treatments were administered at least 2 weeks apart, consisting of dexmedetomidine 12.5 μg kg-1 (D12.5) and 25 μg kg-1 (D25), MK-467 300 μg kg-1 (M300), and D25 combined with 75, 150, 300 and 600 μg kg-1 of MK-467 (D25M 75, D25M150, D25M300 and D25M600, respectively). Heart rates (HR) were recorded via telemetry and sedation assessed with a simple descriptive score and a visual analogue scale prior to treatments and at intervals until 8 hours thereafter. RESULTS Data from one cat were excluded because it developed renal failure. Heart rate decreased significantly from baseline after all treatments except M300 and D25M600. The lowest HR for each treatment with dexmedetomidine were 99 ± 21 (D25), 103 ± 22 (D12.5), 114 ± 10 (D25M75), 117 ± 17 (D25M150), 121 ± 12 (D25M300) and 139 ± 15 (D25M600) beats minute-1. Sedation increased with all treatments that included dexmedetomidine, whereas M300 did not induce any central effects. In comparison with D25, the combination of MK-467 with dexmedetomidine reduced the duration of detectable sedation. CONCLUSIONS AND CLINICAL RELEVANCE MK-467 dose-dependently attenuated the bradycardia associated with dexmedetomidine, and shortened the sedative effect without altering its quality. MK-467 may be useful in attenuating reductions in HR in conscious cats administered dexmedetomidine.

The cardiopulmonary effects of a peripheral alpha‐2‐adrenoceptor antagonist, MK‐467, in dogs sedated with a combination of medetomidine and butorphanol

OBJECTIVE To compare the cardiopulmonary effects of intravenous (IV) and intramuscular (IM) medetomidine and butorphanol with or without MK-467. STUDY DESIGN Prospective, randomized experimental cross-over. ANIMALS Eight purpose-bred beagles (two females, six males), 3-4 years old and weighing 14.5 ±1.6 kg (mean ± SD). METHODS All dogs received four different treatments as follows: medetomidine 20 μg kg(-1) and butorphanol tartrate 0.1 mg kg(-1) IV and IM (MB), and MB combined with MK-467,500 μg kg(-1) (MBMK) IV and IM. Heart rate (HR), arterial blood pressures (SAP, MAP, DAP), central venous pressure (CVP), cardiac output, respiratory rate (fR ), rectal temperature (RT) were measured and arterial blood samples were obtained for gas analysis at baseline and at 3, 10, 20, 30, 45 and 60 minutes after drug administration. The cardiac index (CI), systemic vascular resistance index (SVRI) and oxygen delivery index (DO2 I) were calculated. After the follow-up period atipamezole 50 μg kg(-1) IM was given to reverse sedation. RESULTS HR, CI and DO2 I were significantly higher with MBMK after both IV and IM administration. Similarly, SAP, MAP, DAP, CVP, SVRI and RT were significantly lower after MBMK than with MB. There were no differences in fR between treatments, but arterial partial pressure of oxygen decreased transiently after all treatments. Recoveries were uneventful following atipamezole administration after all treatments. CONCLUSIONS AND CLINICAL RELEVANCE MK-467 attenuated the cardiovascular effects of a medetomidine-butorphanol combination after IV and IM administration.

Cardiovascular effects of dexmedetomidine, with or without MK‐467, following intravenous administration in cats

OBJECTIVE To characterize the cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous (IV) administration in cats. STUDY DESIGN Prospective Latin square experimental study. ANIMALS Six healthy adult purpose-bred cats. METHODS Cats were anesthetized with desflurane in oxygen for instrumentation with a carotid artery catheter and a thermodilution catheter in the pulmonary artery. One hour after discontinuation of desflurane, cats were administered dexmedetomidine (25 μg kg-1), MK-467 (600 μg kg-1), or dexmedetomidine (25 μg kg-1) and MK-467 (600 μg kg-1). All treatments were administered IV as a bolus. Cardiovascular variables were measured prior to drug administration and for 8 hours thereafter. Only data from the dexmedetomidine and dexmedetomidine-MK-467 treatments were analyzed. RESULTS Dexmedetomidine produced significant decreases in heart rate, cardiac index and right ventricular stroke work index, and significant increases in arterial blood pressure, central venous pressure, pulmonary artery pressure and systemic vascular resistance index. Dexmedetomidine combined with MK-467 resulted in significant but transient decrease in blood pressure and right ventricular stroke work index. CONCLUSION AND CLINICAL RELEVANCE Following IV co-administration, MK-467 effectively attenuated dexmedetomidine-induced cardiovascular effects in cats. The drug combination resulted in transient reduction in arterial blood pressure, without causing hypotension.

Early detection of ketoprofen-induced acute kidney injury in sheep as determined by evaluation of urinary enzyme activities

OBJECTIVE To evaluate early indicators of renal tissue destruction and changes in urinary enzyme activities in sheep during the first hours after acute kidney injury induced by administration of an overdose of an NSAID. ANIMALS 12 adult female sheep. PROCEDURES Acute kidney injury was induced in 6 sheep by administration of ketoprofen (30 mg/kg, IV) and detected by evaluation of urinary protein concentration, iohexol clearance, and results of histologic examination. Six sheep served as control animals. Blood and urine samples were collected for up to 24 hours after administration of ketoprofen. Plasma concentrations of urea, creatinine, albumin, and total protein; plasma activities of alkaline phosphatase, acid phosphatase, γ-glutamyl transpeptidase (GGT), matrix metalloproteinase (MMP)-2, and MMP-9; and urinary creatinine and protein concentrations, specific gravity, and activities of alkaline phosphatase, acid phosphatase, GGT lactate dehydrogenase, N-acetyl-β-D-glucosaminidase (NAG), MMP-2, and MMP-9 were measured. Urinary protein concentration and enzyme activities were normalized on the basis of urinary creatinine concentrations and reported as ratios. RESULTS Many urinary enzyme-to-creatinine ratios increased before the plasma creatinine concentration exceeded the reference value. Urine NAG, lactate dehydrogenase, and acid phosphatase activities were increased beginning at 2 hours after ketoprofen administration, and alkaline phosphatase, GGT, and MMP-2 activities were increased beginning at 4 hours after ketoprofen administration. Most peak urinary enzyme-to-creatinine ratios were detected earlier than were the highest plasma creatinine and urea concentrations. CONCLUSIONS AND CLINICAL RELEVANCE Urinary enzyme activities were sensitive early indicators of acute kidney injury induced by an overdose of an NSAID in sheep.

Pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular administration in male cats

OBJECTIVE To characterize the pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular (IM) administration to cats. STUDY DESIGN Prospective randomized crossover experimental study. ANIMALS A total of eight healthy adult male castrated cats aged 1-2 years. METHODS Cats were administered dexmedetomidine (25 μg kg-1) IM (treatment D25IM) or intravenously (IV; treatment D25IV); MK-467 (600 μg kg-1) IM (treatment MK600IM) or IV (treatment MK600IV); or dexmedetomidine (25 μg kg-1) IM with 300, 600 or 1200 μg kg-1 MK-467 IM (treatments D25MK300IM, D25MK600IM and D25MK1200IM). D25MK600IM was the only combination treatment analyzed. Blood samples were obtained prior to drug administration and at various times for 5 hours (D25IV) or 8 hours (all other treatments) thereafter. Plasma dexmedetomidine and MK-467 concentrations were measured using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. RESULTS A one-compartment model best fitted the time-plasma dexmedetomidine concentration data in cats administered D25IM, and the time-plasma MK-467 concentration data in cats administered MK600IM and D25MK600IM. A two-compartment model best fitted the time-plasma dexmedetomidine concentration data in cats administered D25IV and D25MK600IM, and the time-plasma MK-467 concentration data in cats administered MK600IV. Median (range) area under the time-concentration curve, absorption rate half-life, maximum concentration, time to maximum concentration and terminal half-life for dexmedetomidine in D25IM and D25MK600IM were 1129 (792-1890) and 924 (596-1649) ng minute mL-1, 4.4 (0.4-15.7) and 2.3 (0.2-8.0) minutes, 10.2 (4.8-16.9) and 17.8 (15.8-73.5) ng mL-1, 17.8 (2.6-44.9) and 5.2 (1.2-15.1) minutes and 62 (52-139) and 50 (31-125) minutes, respectively. Rate of absorption but not systemic exposure was significantly influenced by treatment. No significant differences were observed in MK-467 pharmacokinetic parameters in MK600IM and D25MK600IM. CONCLUSIONS AND CLINICAL RELEVANCE MK-467 significantly influenced the disposition of dexmedetomidine, whereas dexmedetomidine did not significantly affect the disposition of MK-467 when the drugs were coadministered IM.