Pharmacokinetics and pharmacodynamic effects of oral transmucosal and intravenous administration of dexmedetomidine in dogs

Brian T. Dent 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Turi K. Aarnes 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Vincent A. Wavreille 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Jeffrey Lakritz 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Phillip Lerche 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Butch KuKanich 2Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Carolina H. Riccó Pereira 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Richard M. Bednarski 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Abstract

OBJECTIVE

To determine pharmacokinetic and pharmacodynamic properties of the injectable formulation of dexmedetomidine administered via the oral transmucosal (OTM) route to healthy dogs.

ANIMALS

6 healthy dogs.

PROCEDURES

Injectable dexmedetomidine was administered IV (5 μg/kg) or via the OTM route (20 μg/kg) in a blinded, single-observer, randomized crossover study. Dogs received dexmedetomidine and a sham treatment at each administration. Serial blood samples were collected from a catheter in a saphenous vein. Heart rate, respiratory rate, and subjective sedation score were assessed for 24 hours after administration. Plasma samples were analyzed for dexmedetomidine concentrations by use of ultraperformance liquid chromatography–tandem mass spectrometry.

RESULTS

For the OTM route, the mean ± SD maximum plasma concentration was 3.8 ± 1.3 ng/mL, which was detected 73 ± 33 minutes after administration. The mean maximum concentration for the IV dose, when extrapolated to the time of administration, was 18.6 ± 3.3 ng/mL. The mean terminal-phase half-life was 152 ± 146 minutes and 36 ± 6 minutes for OTM and IV administration, respectively. After IV administration, total clearance was 8.0 ± 1.6 mL/min/kg and volume of distribution at steady state was 371 ± 72 mL/kg. Bioavailability for OTM administration of dexmedetomidine was 11.2 ± 4.5%. Peak sedation scores did not differ significantly between routes of administration. Decreases in heart rate, respiratory rate, and peak sedation score were evident sooner after IV administration.

CONCLUSIONS AND CLINICAL RELEVANCE

OTM administration of the injectable formulation of dexmedetomidine resulted in a similar degree of sedation and prolonged duration of action, compared with results for IV administration, despite relatively low bioavailability.

Abstract

OBJECTIVE

To determine pharmacokinetic and pharmacodynamic properties of the injectable formulation of dexmedetomidine administered via the oral transmucosal (OTM) route to healthy dogs.

ANIMALS

6 healthy dogs.

PROCEDURES

Injectable dexmedetomidine was administered IV (5 μg/kg) or via the OTM route (20 μg/kg) in a blinded, single-observer, randomized crossover study. Dogs received dexmedetomidine and a sham treatment at each administration. Serial blood samples were collected from a catheter in a saphenous vein. Heart rate, respiratory rate, and subjective sedation score were assessed for 24 hours after administration. Plasma samples were analyzed for dexmedetomidine concentrations by use of ultraperformance liquid chromatography–tandem mass spectrometry.

RESULTS

For the OTM route, the mean ± SD maximum plasma concentration was 3.8 ± 1.3 ng/mL, which was detected 73 ± 33 minutes after administration. The mean maximum concentration for the IV dose, when extrapolated to the time of administration, was 18.6 ± 3.3 ng/mL. The mean terminal-phase half-life was 152 ± 146 minutes and 36 ± 6 minutes for OTM and IV administration, respectively. After IV administration, total clearance was 8.0 ± 1.6 mL/min/kg and volume of distribution at steady state was 371 ± 72 mL/kg. Bioavailability for OTM administration of dexmedetomidine was 11.2 ± 4.5%. Peak sedation scores did not differ significantly between routes of administration. Decreases in heart rate, respiratory rate, and peak sedation score were evident sooner after IV administration.

CONCLUSIONS AND CLINICAL RELEVANCE

OTM administration of the injectable formulation of dexmedetomidine resulted in a similar degree of sedation and prolonged duration of action, compared with results for IV administration, despite relatively low bioavailability.

Anxiety and fear-related aggression among veterinary patients is a common and difficult problem faced daily in practices, which may limit or prevent adequate patient care and pose a safety risk to patients and veterinary health-care providers. Aggression is the most common behavioral complaint reported by dog owners. It is the primary reason for behavioral referral in the United States and the most frequently cited cause of animal relinquishment.1,2 Up to 60% to 78.5% of dogs reportedly exhibit fearful or aggressive behavior.3,4 This behavior diminishes patient welfare and client satisfaction and can make it more difficult to handle patients, which can potentially lead to physical danger.

Sedation is a cornerstone for allowing physical examination and medical treatment of fearful and aggressive patients. However, achieving satisfactory sedation can be challenging and may lead to counterproductive outcomes associated with patient over-stimulation.3,4 Administering sedatives by the OTM route has several potential advantages over other routes for parenteral drug administration. Use of the OTM route typically is less painful and requires less restraint for drug administration than other routes of administration, and OTM administration can often be performed by owners prior to veterinary visits. In addition, the rich blood supply of the oral mucosa can promote rapid transmucosal absorption and circumvent gastric acid degradation and first-pass liver metabolism of lipophilic drugs.5–7 Anxiolytics that are administered orally (eg, trazodone and selective serotonin reuptake inhibitors) are commonly used in veterinary medicine to treat animals with separation anxiety or thunderstorm phobia.8 However, they often fail to provide the degree of sedation required for performing a thorough physical examination or basic procedures (eg, placement of an IV catheter) in fractious animals.

Parenteral administration of sedatives typically is necessary for refractory patients, although this often requires more substantial and potentially aggressive restraint methods. Such episodes can negatively imprint on forcibly restrained animals, which increases the challenge and risk for animals and handlers during subsequent veterinary visits.9 Dogs conditioned by prior negative episodes (eg, aggressive handling) are more likely to respond out of fear in the future.4

Dexmedetomidine is a potent α2-adrenoreceptor agonist approved for IV and IM administration to cause sedation in dogs and cats10 and is used orally in people for perioperative anxiolysis.11–13 Dexmedetomidine causes dose-dependent sedation, muscle relaxation, and analgesia in dogs and cats, thus facilitating examinations and minor procedures in most fractious animals. In addition, it reduces requirements for inhalation anesthetics.14,15 The injectable form of dexmedetomidine is effective in cats when administered via the OTM route alone or in conjunction with buprenorphine.16–18 A novel gel formulation of dexmedetomidine has been approved by the US FDA for treatment of noise aversion in dogs. However, with a reported bioavailability of 28%, the volume of this product required for comparable sedation would be prohibitive. Similarly, a related α2-adrenoceptor agonist, detomidine, is marketed in a gel formulation for sublingual administration to horses7 and has been evaluated for use in dogs.19 Although effective sedation has been achieved in dogs, the limited availability of the equine gel formulation to small animal practitioners and the difficulty in titrating doses at small volumes pose ongoing challenges to implementing this formulation in clinical practice.19

The purpose of the study reported here was to evaluate the pharmacokinetics and pharmacodynamics of dexmedetomidine after OTM administration to dogs. We hypothesized that OTM administration of injectable dexmedetomidine would result in clinically effective plasma concentrations with sedation and cardiopulmonary effects similar to those associated with IV administration.

Materials and Methods

Dogs

Six purpose-bred adult dogs (3 males and 3 females) were included in the study. The mean ± SD age of the dogs was 9.2 ± 1.5 months, and mean body weight was 25.2 ± 1.8 kg. Dogs were considered healthy on the basis of results of a preenrollment physical examination, CBC, and biochemical analysis. All protocols were evaluated and approved by the Institutional Animal Care and Use Committee of The Ohio State University (No. 2017A00000039).

Experimental procedures

The study was conducted in accordance with a blinded, single-observer, randomized crossover design. One observer (BTD) assessed all pharmacodynamic parameters. Food was withheld from all dogs for at least 12 hours before drug administration. A 20-gauge, 3.2-cm cathetera was placed aseptically in a cephalic vein for drug administration. A 16-gauge, 20-cm over-the-wire catheterb was placed aseptically in a lateral saphenous vein for collection of blood samples. After placement of catheters was completed, all dogs were allowed to acclimate to the laboratory environment for at least 45 minutes before drug administration and sedation scoring.

Each dog received 2 treatments at each of 2 administrations in a randomized crossover manner; there was a 1-week washout period between administrations. For one administration, dogs received dexmedetomidinec (5 μg/kg, IV) with a sham OTM treatment. For the other administration, dogs received dexmedetomidine (20 μg/kg) via the OTM route with a sham IV treatment. Doses were determined from preliminary experiments conducted to evaluate the plasma concentrations for various doses of injectable dexmedetomidine administered via the OTM route. Sterile saline (0.9% NaCl) solution was used for the sham IV treatment, and tap water was used for the sham OTM treatment. Order of treatment was assigned by use of sealed envelopes; half of the dogs received IV administration of dexmedetomidine followed by OTM administration, and the other half of the dogs received the treatments in the opposite order.

Sedation was evaluated by use of 2 validated sedation scoring systems.20,21 The first system involved evaluation of the responsiveness to increasing amounts of auditory and physical stimuli and was scored on a scale of 0 to 3 (0 = no appreciable sedation, 1 = signs of sedation but a response to auditory stimuli, 2 = lack of response to auditory stimuli but a response to physical stimuli, and 3 = no response to physical or auditory stimuli).20 The second scoring system involved assigning numeric values to multiple physical variables, including body posture, palpebral reflex, eye position, and response to auditory stimuli (total possible score, 12).21

Sedation scores were obtained immediately before drug administration (time 0; baseline) and 1, 2, 5, 10, 15, 30, 45, 60, 75, 90, and 105 minutes and 2, 4, 8, 12, and 24 hours after dexmedetomidine administration. Baseline resting heart rate and respiratory rate were also obtained. Sedation scores at each time point were recorded first followed by respiratory rate and by heart rate. Respiratory rate was determined by counting chest excursions during a 15-second period and multiplying the value by 4. When dogs had an altered respiratory pattern (eg, Biot breathing), chest excursions were counted during a 60-second period. Heart rate was determined by cardiac auscultation during a 15-second period and multiplying the number of audible beats by 4.

Blood samples were collected at each time point after pharmacodynamic parameters were evaluated. Venous blood samples (6 mL) were collected by use of a 3-syringe technique from the catheter in the saphenous vein at 0, 1, 2, 5, 10, 15, 30, 45, 60, 75, 90, and 105 minutes and 2, 4, 8, 12, and 24 hours after dexmedetomidine administration. The catheter in the cephalic vein was removed after collection of the 30-minute sample. The catheter in the saphenous vein was removed after the 12-hour sample. The 24-hour blood sample was collected via conventional phlebotomy from a cephalic or saphenous vein.

All blood samples were placed immediately into evacuated sodium heparin-containing plastic collection tubesd; samples were centrifuged (2,000 × g for 20 minutes in a cooled centrifuge at 4°C) within 30 minutes after collection. Plasma supernatant was separated and stored at −70°C until UPLC-MS-MS was performed.

Sample preparation

An internal standard of dexmedetomidine-d4 (50 ng/mL) was prepared with 4% phosphoric acid in water. Stock solutions of dexmedetomidine and the internal standard were prepared in methanol, and serial dilution was used to prepare standard curves with concentrations of 0.1, 0.25, 0.5, 1, 2.5, 5, 10, 25, 50, 100, 250, and 500 ng/mL.

An aliquot (120 μL) of blank dog plasma and plasma samples from dogs after OTM and IV administration of dexmedetomidine was pipetted into wells of a 48-multiwell plate.e Then, 170 μL of 4% phosphoric acid in water as well as 50 μL of internal standard (dexmedetomidine-d4; 50 ng/mL) were added to each well. Plates were placed on a shaker for 30 minutes at 400 oscillations/min, after which plates were centrifuged at 3,500 × g for another 30 minutes.

Each sample was loaded into a 96-multiwell platef for solid-phase extraction and washed with 300 μL of water with 5% methanol, which was followed by elution with 50 μL of a solution of acetonitrile and methanol (90:10). Fifty microliters of 0.1% formic acid in water was added to each well of the plate, which was then shaken manually before being subjected to UPLC-MS-MS analysis.

UPLC-MS-MS analysis of dexmedetomidine concentrations

Plasma concentrations of dexmedetomidine were determined with UPLC-MS-MS by use of positive electrospray ionization conditions. Sample extracts were analyzed on a columng (length, 30 mm; internal diameter, 2.1 mm; and particle size, 1.8 μm). Column temperature was maintained at 40°C, and sample temperature was maintained at 5°C. Injection volume was 2 μL. The mobile phase consisted of 2 solutions (solution A was 0.1% formic acid in water, and solution B was 0.1% formic acid in acetonitrile). Initial flow rate was 0.6 mL/min with 95% solution A and 5% solution B. The gradient was modified over the initial 48 seconds to 95% solution B before it was returned to initial conditions by 67 seconds. The m/z for dexmedetomidine and dexmedetomidine-d4 was 201.10 and 205.10, respectively. The m/z of the product ions for dexmedetomidine was 67.94 (qualifying) and 94.96 (quantifying), whereas the m/z of the product ions for the internal standard was 71.27 (qualifying) and 98.92 (quantifying), respectively.

Accuracy and precision of the assay were determined with 5 replicates at each of 3 concentrations. Accuracy at concentrations of 10, 25, and 50 ng/mL was 9.8%, 5.4%, and 1.1%, respectively. Precision (ie, coefficient of variation) at concentrations of 10, 25, and 50 ng/mL was 2%, 2%, and 1%, respectively. Limit of detection was < 0.1 ng/mL (signal-to-noise ratio, 47 at 0.1 ng/mL), but accuracy was greater than ± 20%. Lower limit of quantification was 0.25 ng/mL (signal-to-noise ratio, 96), with accuracy less than or equal to ± 15%.

Pharmacokinetic, pharmacodynamic, and statistical analysis

Pharmacokinetic values were determined by use of noncompartmental analysis with commercially available software.h Default software parameters were used in the analysis, with a few exceptions. Concentration values were weighted as 1/C, where C is the actual plasma dexmedetomidine concentration. Also, the noncompartmental analysis was set to incorporate a missing value for each data point with a concentration less than the lower limit of quantification (0.25 ng/mL). The greatest plasma concentration of dexmedetomidine was recorded as Cmax for OTM administration, and the corresponding time to reach Cmax was designated as tmax. For IV administration, concentration at the time of administration (concentration extrapolated to time zero) was estimated by back extrapolation of the concentration-time curve to the y-axis at the point of the intercept. Log-linear regression of time versus the natural logarithm of the concentration, which incorporated at least the last 3 plasma concentration-versus-time data points, was used to estimate λz. Half-life of the terminal phase was calculated as (ln 2)/λz. The log-linear trapezoidal rule was used to calculate AUC. The area from Clast until infinity was calculated as Clastz and added to AUC to yield AUC0–∞. The MRT after IV administration was estimated as AUMC from time zero extrapolated to infinity/AUC0–∞. The mean absorption time was calculated as the MRT from time zero extrapolated to infinity for OTM administration minus the MRT from time zero extrapolated to infinity for IV administration. Terminal-phase and steady-state volumes of distribution for IV administration were calculated as IV dose/(λz × AUC0–∞) and (IV dose/AUC0–∞) × MRT from time zero extrapolated to infinity respectively. Clearance after IV administration of dexmedetomidine was estimated by dividing the administered dose by AUC0–∞. The AUMC from time zero extrapolated to infinity was calculated as plasma concentration × time × time. Fractional absorption of dexmedetomidine after OTM administration was achieved by normalizing data to account for differing doses; fractional absorption was then calculated as the AUC after OTM administration divided by the AUC after IV administration. Pharmacokinetic parameters were reported as mean ± SD.

Cardiorespiratory data were evaluated for normality by use of the Kolmogorov-Smirnov test. The data were not normally distributed, and results were reported as median and range. Cardiorespiratory data for both the IV and OTM routes of administration were evaluated by use of a Friedman test with a Dunn post hoc test. A Wilcoxon matched-pairs test was performed on all sedation score data. Significance was set at P < 0.05.

Results

Pharmacokinetic analysis

The mean ± SD dose of dexmedetomidine administered by the OTM route was 19.7 ± 0.3 μg/kg, which corresponded to a mean volume of 1.0 ± 0.1 mL. The mean dose for IV administration of dexmedetomidine was 5.0 ± 0.1 μg/kg. Plasma dexmedetomidine concentration over time was determined for both routes of administration (Figure 1).

Figure 1—
Figure 1—

Mean ± SD plasma concentrations of dexmedetomidine after OTM (20 μg/kg; black squares) and IV (5 μg/kg; gray circles) administration of an injectable formulation to 6 healthy dogs. There was a 1-week washout period between successive administrations.

Citation: American Journal of Veterinary Research 80, 10; 10.2460/ajvr.80.10.969

The mean ± SD Cmax for dexmedetomidine after OTM administration was 3.8 ± 1.3 ng/mL, and the tmax was at 73 ± 33 minutes (Table 1). The mean lag time for absorption of dexmedetomidine after OTM administration was 9 ± 2 minutes. For IV administration, the mean concentration of dexmedetomidine at time 0 was 18.6 ± 3.3 ng/mL. The mean absorption time was 204 ± 200 minutes. The mean terminal-phase half-life of dexmedetomidine after OTM administration was 152 ± 146 minutes, compared with 36 ± 6 minutes after IV administration. The Clast of dexmedetomidine after OTM administration was 1.3 ± 1.2 ng/mL, which was detected 320 ± 123 minutes after administration. For IV administration, the Clast was 1.4 ± 0.3 ng/mL, which was detected 110 ± 15 minutes after administration. Total clearance of dexmedetomidine after IV administration was 8.0 ± 1.6 mL/min/kg, and the volume of distribution at steady state was 371 ± 72 mL/kg. Absolute bioavailability of dexmedetomidine after OTM administration was 11.2 ± 4.5%.

Table 1—

Mean ± SD results of noncompartmental analysis of plasma concentrations of dexmedetomidine after OTM (20 μg/kg) and IV (5 μg/kg) administration of an injectable formulation to 6 healthy dogs.

VariableOTMIV
R2 (no units)0.97 ± 0.030.99 ± 0.01
λz (1/min)0.007 ± 0.0040.020 ± 0.004
t1/2 (min)152.0 ± 146.036.4 ± 6.4
tlag (min)9 ± 2
tmax (min)73.0 ± 33.01.5 ± 0.6
Cmax (ng/mL)3.8 ± 1.3
C0 (ng/mL)18.6 ± 3.3
tlast (min)320 ± 123110 ± 15
Clast (ng/mL)1.3 ± 1.21.4 ± 0.3
AUClast (min•ng/mL)728 ± 356583 ± 126
AUC0–∞ (min•ng/mL)1,091 ± 801655 ± 148
AUCExtrapolated (%)23.0 ± 18.010.9 ± 1.8
AUMC0–∞ (min•min•ng/mL)403,328 ± 612,17831,648 ± 12,260
MRT0–∞ (min)251.0 ± 197.047.2 ± 8.8
Bioavailability (%)11.2 ± 4.5
Vdss (mL/kg)371 ± 72
Cl (mL/min/kg)8.0 ± 1.6
Vdz (mL/kg)420 ± 8
MAT (min)204 ± 200

AUCExtrapolated = Percentage of AUC that was extrapolated. AUMC0–∞ = AUMC from time zero extrapolated to infinity. C0 = Plasma concentration extrapolated to time zero. Cl = Total plasma clearance after IV administration. MAT = Mean absorption time. MRT0–∞ = MRT from time zero extrapolated to infinity. R2 = Coefficient of determination. t1/2 = Terminal-phase half-life. tlag = Time from administration of dexmedetomidine until quantifiable plasma concentrations reached. tlast = Time of the last plasma concentration above the lower limit of quantification. VdSS = Apparent volume of distribution at steady state after IV administration. Vdz = Volume of distribution of the terminal phase after IV administration.

— = Not applicable.

Pharmacodynamic analysis

Heart rate and respiratory rate differed over time after administration of dexmedetomidine by the IV and OTM routes (Table 2). The mean heart rate was significantly lower than the baseline value between 30 and 120 minutes after OTM administration. Heart rate decreased more rapidly and returned to the baseline value more rapidly after IV administration, compared with results for OTM administration; heart rate after IV administration differed significantly from the baseline value between 5 and 15 minutes and between 60 and 105 minutes. The mean respiratory rate was significantly lower than the baseline value between 60 and 120 minutes after OTM administration, whereas respiratory rate was lower than the baseline value between 15 and 75 minutes after IV administration, except it was not significantly different from the baseline value at 45 minutes after IV administration.

Table 2—

Median (range) values for cardiopulmonary variables before and after IV (5 μg/kg) and OTM (20 μg/kg) administration of dexmedetomidine to 6 healthy dogs.

 Heart rate (beats/min)Respiratory rate (breaths/min)
TimeIVOTMIVOTM
0 min90 (88–116)94 (84–116)24 (20–28)20 (20–28)
1 min60 (44–68)76 (64–108)20 (16–28)20 (12–24)
2 min44 (36–52)74 (52–100)16 (12–20)18 (12–20)
5 min36 (24–44)*72 (52–96)20 (8–24)20 (16–24)
10 min30 (28–44)*68 (48–84)12 (11–16)18 (16–20)
15 min42 (24–48)*58 (48–92)12 (6–16)*16 (16–24)
30 min44 (28–48)40 (32–48)*12 (10–16)*12 (12–16)
45 min42 (32–48)34 (24–44)*14 (9–16)14 (8–16)
60 min40 (32–48)*36 (32–40)*12 (8–16)*12 (6–12)*
75 min40 (40–48)*34 (28–40)*12 (8–16)*12 (8–16)*
90 min38 (32–48)*34 (32–48)*12 (12–16)12 (5–12)*
105 min42 (32–44)*36 (32–36)*16 (12–24)12 (7–12)*
2 h46 (36–56)34 (28–44)*12 (12–20)12 (8–12)*
4 h66 (52–76)40 (40–52)20 (20–24)14 (12–16)
8 h68 (60–80)70 (44–76)16 (12–20)18 (16–20)
12 h70 (60–84)72 (60–80)16 (16–20)20 (16–24)
24 h84 (56–100)84 (76–96)20 (16–24)20 (14–20)

Time 0 (baseline) was the time of dexmedetomidine administration; there was a 1-week washout period between successive administrations.

Within a column, value differs significantly (P < 0.05) from the baseline value.

Sedation was evident in all dogs after treatment regardless of route of administration. Peak sedation scores did not differ between treatments as determined by use of either scoring system (Table 3). Onset of sedation was more rapid after IV administration of dexmedetomidine (median time to peak sedation was 10 minutes [range, 2 to 45 minutes]), compared with after OTM administration (median time to peak sedation was 38 minutes [range, 30 to 60 minutes]). Similarly, return to baseline sedation score was more rapid after IV administration (240 minutes) than after OTM administration (480 minutes).

Table 3—

Median (range) values for sedation variables for 6 healthy dogs after IV (5 μg/kg) and OTM (20 μg/kg) administration of dexmedetomidine to 6 healthy dogs.

VariableIVOTM
Time to onset of sedation (min)1 (1–2)30 (15–30)*
Peak sedation score
 First scoring system3 (—)3 (—)
 Second scoring system10 (8–11)11 (8–11)
 Time to peak sedation score (min)10 (2–45)38 (30–60)*
 Time to return to baseline value (min)240 (120–480)480 (—)*

The first scoring system involved evaluation of the responsiveness to increasing amounts of auditory and physical stimuli and was scored on a scale of 0 to 3 (0 = no appreciable sedation, 1 = signs of sedation but a response to auditory stimuli, 2 = lack of response to auditory stimuli but a response to physical stimuli, and 3 = no response to physical or auditory stimuli).20 The second scoring system involved assigning numeric values to multiple physical variables, including body posture, palpebral reflex, eye position, and response to auditory stimuli (total possible score, 12).21

Value differs significantly (P < 0.05) from the value for IV administration.

— = Not applicable; all values were the same.

See Table 2 for remainder of key.

One dog had mild ptyalism after OTM administration of dexmedetomidine, which resolved within a few minutes. Another dog vomited after dexmedetomidine administration by both routes of administration. No other relevant adverse effects were noted.

Discussion

The pharmacokinetic properties of dexmedetomidine following administration by the OTM route have previously been evaluated only in humans. Evaluation of the pharmacokinetics following IV, PO, IM, and OTM administration of dexmedetomidine to humans22 reveals a volume of distribution greater than that identified in dogs of the present study. Similarly, clearance and half-life of dexmedetomidine in those human subjects are greater than those for dogs of the present study. In another study,23 the pharmacokinetics of medetomidine and its enantiomers in dogs revealed a volume of distribution and clearance after IV administration of dexmedetomidine that are similar to values determined in the study reported here when adjusted for dose. Half-life of dexmedetomidine after IV administration in 1 study23 also mirrors findings of the present study. For the study reported here, half-life of dexmedetomidine was longer when administered via the OTM route than when administered IV. This was expected because of the absorption phase associated with extravascular administration that prolongs elimination of the drug and is known as the flip-flop phenomenon.24 Overall, mean dose-normalized bioavailability for OTM administration in humans is 82%.22 However, dogs in the present study had significantly lower plasma concentrations of the drug after OTM administration, compared with concentrations after IV administration, which resulted in a relatively low transmucosal bioavailability of 11.2%.

Transmucosal absorption of drugs is dependent on a number of factors that include the molecular weight and chemical behavior of the drug, partition coefficient of the drug, inherent properties of the oral mucosal epithelium, and concentration and duration of drug delivery.25 Dexmedetomidine has a molecular mass of 237 and is a relatively lipophilic compound with a partition coefficient of 2.89 in octanol:water at a pH of 7.4. The pKa of dexmedetomidine is 7.1, and it is preferentially nonionized at increasing pH, which enhances its ability to cross the oral mucosa and facilitates absorption. The pH of human saliva typically ranges from 6.2 to 7.6 (mean resting pH, 6.7)26; this should not inherently promote the absorption of dexmedetomidine. However, there is high OTM bioavailability of dexmedetomidine in humans.22 The mean salivary pH for dogs from which food has been withheld ranges from 7.93 to 8.52,27,28 which should facilitate absorption.

Low bioavailability for dogs of the study reported here may have been a result of losses from the oral cavity, swallowing, or enzymatic degradation.29 Only 1 dog had substantial ptyalism; ptyalism has been associated with decreased systemic medetomidine availability after OTM administration to cats.30 The dog that had ptyalism in the study reported here also had the lowest Cmax. However, even in the absence of ptyalism or vomiting, mucosal contact of drugs administered via the OTM route is difficult to control in veterinary patients. The vasoconstrictive effects of dexmedetomidine and other α2-adrenoceptor agonists can act locally when administered OTM; this can result in mucous membrane pallor, which may also impact systemic absorption.31–33

Despite the low bioavailability of dexmedetomidine after OTM administration in dogs, a dose of 20 μg/kg reliably caused sedation similar to that achieved with IV administration at a dose of 5 μg/kg. There was no difference in the maximum sedation scores in dogs receiving dexmedetomidine by either route. The onset of sedation was detected between 15 and 30 minutes after OTM administration and was less rapid than after IV administration, which was detected within 1 to 2 minutes. Overall, there was a longer duration of sedative effects after OTM administration. Cardiorespiratory evaluation indicated significant decreases in heart rate and respiratory rate after dexmedetomidine administration by either route. Paralleling the patterns of sedation observed, the effects on cardiorespiratory variables were generally more rapid in onset and of shorter duration after IV administration. Cardiorespiratory and sedation data after IV administration for the present study are similar to those reported in other studies.23,24 Results for dogs after OTM administration of dexmedetomidine are comparable to the pharmacodynamic effects after IM administration of dexmedetomidine detected in 54 client-owned dogs of another study.34

Gel formulations for OTM administration of α2-adrenoceptor agonists have been marketed for sedation in horses (detomidinei) and treatment of noise aversion in dogs (dexmedetomidinej). Gel formulations of detomidine and dexmedetomidine have been administered to dogs and provide measurable sedation and anxiolysis, respectively.19,31,33 Administration of dexmedetomidine gel (125 μg/m2 via the OTM route) was repeated up to 5 times over the course of at least 8 hours to treat noise aversion, but it did not result in sedation.33 For dogs similar in size to those of the study reported here, this would equate to > 6 mL of gel formulation; thus, it would be anticipated that the volume required for a sedative effect equivalent to that after IV administration would be prohibitively difficult to achieve with OTM administration. Transmucosal administration of injectable dexmedetomidine evaluated in humans11–13,22 undergoing arthroscopic knee surgery has been found to provide equivalent sedation and anxiolysis and better analgesia, compared with effects after IM administration.13 Dexmedetomidine has been administered via the OTM route to cats alone17 and in combination with buprenorphine.16,18 The OTM administration of dexmedetomidine (40 μg/kg) alone resulted in sedation similar to that for the same dose administered IM.17 Satisfactory sedation was achieved by 20 minutes after administration for 4 aggressive dogs treated with injectable dexmedetomidine administered OTM at a mean dose of 32.6 μg/kg.32

The present study had some limitations. We used mixed-breed research hounds, which may not have adequately represented the population of clinically affected dogs. This also could have influenced pharmacokinetic findings as a result of genetic differences in drug metabolism.35 Moreover, the temperament and environmental habituation unique to laboratory dogs could have biased sedation scoring determined by use of subjective criteria, as was conducted for some of the sedation scoring in the study. In addition, the study was designed as a blinded, single-observer study for the purposes of subjective evaluation of sedation. However, the rapid rate of onset of sedation and recumbency in dogs after IV administration of dexmedetomidine made it difficult to obscure the route of administration before sedation scoring. Nevertheless, the objective pharmacodynamic data for this study, including heart rate and respiratory rate, corroborated the effectiveness of OTM administration and paralleled the findings for IM administration of dexmedetomidine to dogs.34 Other variables (eg, rectal temperature, mucous membrane color, blood pressure, or cardiac output) were not assessed in the present study.

Despite the low bioavailability of dexmedetomidine after OTM administration to dogs, adequate plasma concentrations of the drug were achieved. There was reliable sedation, similar to that after IV administration, with minimal adverse effects, which supported the clinical use of this method for drug delivery.

Acknowledgments

Supported by a grant from the Canine Research Funds of The Ohio State University.

The authors declare that there were no conflicts of interest.

The authors thank Drs. Michael Lovasz and John Hubbell for assistance with collection of pilot data. The authors also thank Dr. Hyun Joo for the plasma drug analysis.

ABBREVIATIONS

AUC

Area under the concentration-time curve

AUC0–∞

Area under the concentration-time curve from time zero extrapolated to infinity

AUMC

Area under the moment curve

Clast

Last quantifiable concentration

Cmax

Maximum plasma concentration

λz

Terminal rate constant

MRT

Mean residence time

OTM

Oral transmucosal

tmax

Time to maximum concentration

UPLC-MS-MS

Ultraperformance liquid chromatography–tandem mass spectrometry

Footnotes

a.

Abbott Laboratories Ltd, Chicago, Ill.

b.

Mila International Inc, Erlanger, Ky.

c.

Dexdomitor, Zoetis Inc, Parsippany, NJ.

d.

BD Vacutainer, Becton, Dickinson and Co, Franklin Lakes, NJ.

e.

CytoOne 48-multiwell plate (Catalog No. CC7672-7548), USA Scientific, Ocala, Fla.

f.

Oasis PRiME HLB 96-well μElution plate, Waters Corp, Milford, Mass.

g.

Acquity UPLC HSS T3 1.8-μm column, Waters Corp, Milford, Mass.

h.

Phoenix WinNonlin, version 8.0, Certara, Princeton, NJ.

i.

Dormosedan gel, Pfizer Animal Health, Madison, NJ.

j.

Sileo, Zoetis Inc, Parsippany, NJ.

References

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  • 2. Salman MD, Hutchison J, Ruch-Gallie R, et al. Behavioral reasons for relinquishment of dogs and cats to 12 shelters. J Appl Anim Welf Sci 2000;3:93106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Beaver BV. Introduction to canine behavior. In: Canine behavior: a guide for veterinarians. Philadelphia: WB Saunders Co, 1999;142.

    • Search Google Scholar
    • Export Citation
  • 4. Döring D, Roscher A, Scheipl F, et al. Fear-related behaviour of dogs in veterinary practice. Vet J 2009;182:3843.

  • 5. Robertson SA, Lascelles BDX, Taylor PM, et al. PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther 2005;28:453460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Robertson SA, Taylor PM, Sear JW. Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Rec 2003;152:675678.

  • 7. Dimaio Knych HK, Stanley SD. Pharmacokinetics and pharmacodynamics of detomidine following sublingual administration to horses. Am J Vet Res 2011;72:13781385.

    • Crossref
    • Search Google Scholar
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  • 8. Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995–2007). J Am Vet Med Assoc 2008;233:19021907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Simpson BS. Canine communication. Vet Clin North Am Small Anim Pract 1997;27:445464.

  • 10. Dexmedetomidine (dexmedetomidine hydrochloride) injectable 0.5 mg/mL [package insert]. Kalamazoo, Mich; Zoetis Inc, 2015.

  • 11. Zub D, Berkenbosch JW, Tobias JD. Preliminary experience with oral dexmedetomidine for procedural and anesthetic premedication. Paediatr Anaesth 2005;15:932938.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Sakurai Y, Obata T, Odaka A, et al. Buccal administration of dexmedetomidine as a preanesthetic in children. J Anesth 2010;24:4953.

  • 13. Karaaslan D, Peker TT, Alaca A, et al. Comparison of buccal and intramuscular dexmedetomidine premedication for arthroscopic knee surgery. J Clin Anesth 2006;18:589593.

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    • Search Google Scholar
    • Export Citation
  • 14. Dart CM. Advantages and disadvantages of using alpha-2 agonists in veterinary practice. Aust Vet J 1999;77:720721.

  • 15. Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg 2005;32:117127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16. Porters N, Bosmans T, Debille M, et al. Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats. Vet Anaesth Analg 2014;41:9096.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Slingsby LS, Taylor PM, Monroe T. Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration. J Feline Med Surg 2009;11:829834.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Santos LC, Ludders JW, Erb HN, et al. Sedative and cardiorespiratory effects of dexmedetomidine and buprenorphine administered to cats via oral transmucosal or intramuscular routes. Vet Anaesth Analg 2010;37:417424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Messenger KM, Hopfensperger M, Knych HK, et al. Pharmacokinetics of detomidine following intravenous or oral-transmucosal administration and sedative effects of the oral-transmucosal treatment in dogs. Am J Vet Res 2016;77:413420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Vettorato E, Bacco S. A comparison of the sedative and analgesic properties of pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 2011;52:426432.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Gurney M, Cripps P, Mosing M. Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route. J Small Anim Pract 2009;50:474477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Anttila M, Penttilä J, Helminen A, et al. Bioavailability of dexmedetomidine after extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691693.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Kuusela E, Raekallio M, Anttila M, et al. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23:1520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Toutain PL, Bousquet-Mélou A. Plasma terminal half-life. J Vet Pharmacol Ther 2004;27:427439.

  • 25. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery. Clin Pharmacokinet 2002;41:661680.

  • 26. Baliga S, Muglikar S, Kale R. Salivary pH: a diagnostic biomarker. J Indian Soc Periodontol 2013;17:461465.

  • 27. Iacopetti I, Perazzi A, Badon T, et al. Salivary pH, calcium, phosphorus and selected enzymes in healthy dogs: a pilot study. BMC Vet Res 2017;13:330337.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Lavy E, Goldberger D, Friedman M, et al. pH values and mineral content of saliva in different breeds of dogs. Isr J Vet Med 2012;67:244248.

    • Search Google Scholar
    • Export Citation
  • 29. Hooda R, Tripathi M, Kapoor K. A review of oral mucosal drug delivery system. Pharm Innov 2012;1:1320.

  • 30. Ansah OB, Raekallio M, Vainio O. Comparing oral and intramuscular administration of medetomidine in cats. Vet Anaesth Analg 1998;25:4146.

    • Search Google Scholar
    • Export Citation
  • 31. Hopfensperger MJ, Messenger KM, Papich MG, et al. The use of oral transmucosal detomidine hydrochloride gel to facilitate handling in dogs. J Vet Behav 2013;8:114123.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Cohen AE, Bennett SL. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs. Can Vet J 2015;56:11441148.

  • 33. Korpivaara M, Laapas K, Huhtinen M, et al. Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs—a randomised, double-blind, placebo-controlled clinical study. Vet Rec 2017;180:356362.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Granholm M, McKusick BC, Westerholm FC, et al. Evaluation of the clinical efficacy and safety of intramuscular and intravenous doses of dexmedetomidine and medetomidine in dogs and their reversal with atipamezole. Vet Rec 2007;160:891897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35. Fleischer S, Sharkey M, Mealey K, et al. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS J 2008;10:110119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Mean ± SD plasma concentrations of dexmedetomidine after OTM (20 μg/kg; black squares) and IV (5 μg/kg; gray circles) administration of an injectable formulation to 6 healthy dogs. There was a 1-week washout period between successive administrations.

  • 1. Beaver BV. Owner complaints about canine behavior. J Am Vet Med Assoc 1994;204:19531955.

  • 2. Salman MD, Hutchison J, Ruch-Gallie R, et al. Behavioral reasons for relinquishment of dogs and cats to 12 shelters. J Appl Anim Welf Sci 2000;3:93106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Beaver BV. Introduction to canine behavior. In: Canine behavior: a guide for veterinarians. Philadelphia: WB Saunders Co, 1999;142.

    • Search Google Scholar
    • Export Citation
  • 4. Döring D, Roscher A, Scheipl F, et al. Fear-related behaviour of dogs in veterinary practice. Vet J 2009;182:3843.

  • 5. Robertson SA, Lascelles BDX, Taylor PM, et al. PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther 2005;28:453460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Robertson SA, Taylor PM, Sear JW. Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Rec 2003;152:675678.

  • 7. Dimaio Knych HK, Stanley SD. Pharmacokinetics and pharmacodynamics of detomidine following sublingual administration to horses. Am J Vet Res 2011;72:13781385.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995–2007). J Am Vet Med Assoc 2008;233:19021907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Simpson BS. Canine communication. Vet Clin North Am Small Anim Pract 1997;27:445464.

  • 10. Dexmedetomidine (dexmedetomidine hydrochloride) injectable 0.5 mg/mL [package insert]. Kalamazoo, Mich; Zoetis Inc, 2015.

  • 11. Zub D, Berkenbosch JW, Tobias JD. Preliminary experience with oral dexmedetomidine for procedural and anesthetic premedication. Paediatr Anaesth 2005;15:932938.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Sakurai Y, Obata T, Odaka A, et al. Buccal administration of dexmedetomidine as a preanesthetic in children. J Anesth 2010;24:4953.

  • 13. Karaaslan D, Peker TT, Alaca A, et al. Comparison of buccal and intramuscular dexmedetomidine premedication for arthroscopic knee surgery. J Clin Anesth 2006;18:589593.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Dart CM. Advantages and disadvantages of using alpha-2 agonists in veterinary practice. Aust Vet J 1999;77:720721.

  • 15. Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg 2005;32:117127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16. Porters N, Bosmans T, Debille M, et al. Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats. Vet Anaesth Analg 2014;41:9096.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Slingsby LS, Taylor PM, Monroe T. Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration. J Feline Med Surg 2009;11:829834.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Santos LC, Ludders JW, Erb HN, et al. Sedative and cardiorespiratory effects of dexmedetomidine and buprenorphine administered to cats via oral transmucosal or intramuscular routes. Vet Anaesth Analg 2010;37:417424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Messenger KM, Hopfensperger M, Knych HK, et al. Pharmacokinetics of detomidine following intravenous or oral-transmucosal administration and sedative effects of the oral-transmucosal treatment in dogs. Am J Vet Res 2016;77:413420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Vettorato E, Bacco S. A comparison of the sedative and analgesic properties of pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 2011;52:426432.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Gurney M, Cripps P, Mosing M. Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route. J Small Anim Pract 2009;50:474477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Anttila M, Penttilä J, Helminen A, et al. Bioavailability of dexmedetomidine after extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691693.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Kuusela E, Raekallio M, Anttila M, et al. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23:1520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Toutain PL, Bousquet-Mélou A. Plasma terminal half-life. J Vet Pharmacol Ther 2004;27:427439.

  • 25. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery. Clin Pharmacokinet 2002;41:661680.

  • 26. Baliga S, Muglikar S, Kale R. Salivary pH: a diagnostic biomarker. J Indian Soc Periodontol 2013;17:461465.

  • 27. Iacopetti I, Perazzi A, Badon T, et al. Salivary pH, calcium, phosphorus and selected enzymes in healthy dogs: a pilot study. BMC Vet Res 2017;13:330337.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Lavy E, Goldberger D, Friedman M, et al. pH values and mineral content of saliva in different breeds of dogs. Isr J Vet Med 2012;67:244248.

    • Search Google Scholar
    • Export Citation
  • 29. Hooda R, Tripathi M, Kapoor K. A review of oral mucosal drug delivery system. Pharm Innov 2012;1:1320.

  • 30. Ansah OB, Raekallio M, Vainio O. Comparing oral and intramuscular administration of medetomidine in cats. Vet Anaesth Analg 1998;25:4146.

    • Search Google Scholar
    • Export Citation
  • 31. Hopfensperger MJ, Messenger KM, Papich MG, et al. The use of oral transmucosal detomidine hydrochloride gel to facilitate handling in dogs. J Vet Behav 2013;8:114123.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Cohen AE, Bennett SL. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs. Can Vet J 2015;56:11441148.

  • 33. Korpivaara M, Laapas K, Huhtinen M, et al. Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs—a randomised, double-blind, placebo-controlled clinical study. Vet Rec 2017;180:356362.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Granholm M, McKusick BC, Westerholm FC, et al. Evaluation of the clinical efficacy and safety of intramuscular and intravenous doses of dexmedetomidine and medetomidine in dogs and their reversal with atipamezole. Vet Rec 2007;160:891897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35. Fleischer S, Sharkey M, Mealey K, et al. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS J 2008;10:110119.

    • Crossref
    • Search Google Scholar
    • Export Citation

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