NDA 21-038
`
`
`parameter
`
`lmcg/kg -"
`dexmedetomidine
`
`
`
`
`
`atipamezole
`
`
`
`
`
`
`
`
`"m
`
`
`
`
`
`
`* p<0.05 vs baseline;
`& p<0.05 dog HF vs goat;
`
`# p<0.05 dogs HF compared to dogs CU;
`+ p<0.05 dogs CU vs goat
`
`Summit
`The cardiovascular effects of dexmedetomidine start with peripheral vasoconstriction by alpha2
`stimulation. Upon entering the CNS, dexmedetomidine alpha2 stimulation initiates a centrally
`mediated sympatholytic effect and hypotension predominates due to the reduced heart rate and
`contractility.
`
`Dexmedetomidine had similar effects on heart rate and cardiac function in different model
`systems with differing species and anesthetics. However, the changes in blood pressure and
`vascular resistance did differ, indicating anesthetic can influence the sympatholytic action. The
`CU dogs had high sympathetic activity and the hypertensive response was shorter than in the HF
`dogs although the systemic vascular resistance did not differ.
`
`There were also species differences which may be due to different numbers of vascular alpha2
`receptors. In the goat, smaller increases in vascular'resistance and shorter duration of
`hypertensive responses were seen than observed in the dog. This was also accompanied by a
`smaller decrease in arterio-coronary oxygen saturation.
`
`########
`
`
`[171
`
`’
`
`'-
`
`- _
`
`We: Comparison of the hemodynamic and coronary vascular effects of
`dexmedetomidine and clonidine in the anesthetized dog. In: The effect of dexmedetomidine on
`the circulation and the normoxic and ischemic heart
`
`v :
`
`(#61)
`
`
`
`

`

`NDA 21-038
`
`Wm -———.____.,—-—’
`
`W3 19.91, 1992
`
`-.
`
`l
`
`Methods:
`Healthy mongrel dogs, 15, were used in the study. They were premedicated with fentanyl,
`aneSthesia~ induced with thiopental and maintained with 40%/60% oxygenmitrous oxide and
`halothane when necessary to maintain the depth of anesthesia. The dogs were intubated,
`mechanically ventilated and additional fentanyl was supplied to maintain heart rate between 80
`and 100 BPM. After instrumentation and stabilization, 8 dogsreceived clonidine in increasing
`'doses of l, 3, 10 and 30 meg/kg and 7 dogs received dexmedetomidine at 0.1, 0.3, 1, 3 and 10
`mcg/kg. The recording of effects was at the peak, 1-2 minutes, and at 15 minutespostdosing.
`Afier recovery from either treatment, the dogs were injected with the alpha,-antagbnist prazosin,
`100 meg/kg, and the ascending doses of clonidine or dexmedetomidine and the measurements
`were repeated. Finally, the dogs were injected with the specific aphaz-antagonist atiparnezole,
`250 mcg/kg and the measurements repeated. The measured parameters were mean arterial
`pressure (MAP), heart rate (HR), cardiac output (CO), systemic vascular resistance (SVR), mixed
`venous oxygen saturation (SVO2), coronary flow (CF), coronary vascular resistance (CVR),
`coronary venous oxygen saturation (CV02) and first positive derivative of left ventricular
`pressure (LVdp/dtmax).
`
`Resigns:
`MAP: The pressure initially increased with both clonidine and dexmedetomidine _in dose-
`dependent manner and all MAP had returned to normal by 15 minutes, except for.
`dexmedetomidine at 10 meg/kg. Dexmedetomidine was about 3x as potent as clonidine.
`HR: There were dose related decreases in HR with both compounds. At the highest dose of each
`compound, superventricular and ventricular extrasystoles were seen immediately after injection.
`CO: The cardiac output declined'in dose related fashion with both compounds. The highest dose
`of clonidine induced a 60% decrease and with the highest of dexmedetomidine the CO was
`reduced 57%.
`SVR: The resistance increase was dose related with both compounds and the highest dose of
`clonidine increased the resistance by 260% and dexmedetomidine, by 230%.
`SVOZ: These changes paralleled the changes in cardiac output, but less pronounced.
`CF: the coronary flow was little changed, only reduced 15 min after clonidine at 39ug/kg.
`Effects of prazosin, alpha,-antagonist: CO and SVR were reduced while coronary flow, coronary
`vascular resistance and CV02 returned to baseline. Lvdp/dtmax was further reduced in clonidine
`dogs but recovered in dexmedetomidine dogs.
`
`Effects on Atipamezole - alphaz-antagonist: a greater decrease in MAP was observed in the
`dexmedetomidine dogs but the HR increase was greater in the clonidine dogs. CO returned to
`baseline in clonidine dogs but remained low in the dexmedetomidine dogs.
`
`39
`
`”
`
`

`

`NDA 21-038
`
`Summary:
`The hemodynamic effects of dexmedetomidine are similar to clonidine effects in anesthetized
`dogs. The investigators state “good clinical results achieved with'alpha2 agonists may be due to
`their use in doses which cause sympatholysis without tozo ~rzriuch vasoconstriction.”
`
`##############################################################
`
`[18]
`
`Wine: Changes in cardiac function induced by dexmedetomidine, as determined
`by pressure-.volume analysis. In; The effect of dexmedetomidine on the circulation and
`the normoxic and ischemic heart
`
`(#65)
`
`Mghm: The experimental protocol was copied from the submission (V26/pg 055-059):
`Nine dogs were used in this protocol, which were premedicated with 200 meg/kg fentanyl im.
`Anesthesia was induced by 30 mg/kg thiopental iv. The animals were ventilated with oxygen in
`nitrous oxide (40/60) with 0.5-1.0 % Halothane.
`1
`-.
`
`,
`Pressure-volume analysis
`Two lefi ventricular catheters were introduced via‘th‘e lefi atrium, one to measure pressure by tip-
`micro manometer, the other to measure volume by conductance. The position of the tip of the
`conductance catheter in the apex was verified by inspection of the segmental conductance
`signals; a correct position was assumed if the signals from at least the four most distal segments
`displayed a typical phasic lefi ventricular-volume tracing. If the most proximal segment reflected
`typical phasic atrial volume changes, this segment was excluded from the calculation of total
`ventricular volume. Correct positioning of the conductance catheter was further facilitated by on-
`line display of the left ventricular contour, derived from the five segmental conductance signals.
`
`Left ventricular volume measurement
`The conductance catheter determines lefi ventricular volume (V.v) on-line by measuring time-
`varying electrical conductances of five segments of intraventricular blood. Total ventricular
`volume is calculated from these measurements using formulas which have been described
`previously. The pigtail catheter used was especially designed and equipped with ten electrodes.
`The electrodes, each 1 mm long were spaced to have the distance between electrodes 1 and 8
`
`40
`
`
`
`

`

`NDA 21-038
`
`match the lefi ventricular base to apex dimension. In practice they were 10 or 11 mm apart
`depending of the size of the heart and the catheter used. An alternating current of 0.03 mA at 20
`kHz passed through electrodes 1 (apex) and 8 (mitral valve) and voltages were measured between
`the five adjacent electrode pairs 2-3 through 6-7, from which five conductances were calculated.
`Electrodes 9 and 10 were not'used. An analog signal conditioner-processor (SigmaS. Leycom.
`Oestgeest. The Netherlands) provided the current source and processed the segmental
`_
`conductanCes producing an on-line display of the left ventricular contour as well as a continuous
`and instantaneous volui‘ne signal. The volume signal was combined with the LV-pressure signal
`on a X-Y oscilloscope in order to display instantaneous pressure-volume loops continuously. To
`obtain correction on the volume signal for parallel conductance caused by tissues Surrounding the
`left ventricular cavity, a bolus of 5 ml hypertonic saline (10%) was injected in the central venous
`"compartment? ’As the bolus mixes with the fluid in the ventricular cavity, its conductivity
`increases, causing the overall conductance signal to increase while the parallel component
`remains constant. End-systolic overall conductance then is plotted as a firnction of end-diastolic
`overall conductance during the mixing of the bolus and the parallel conductance is equal to the
`intersection point between the regression line of these values and the line of identity. This
`procedure was performed before and after administration of dexmedetomidine during 10 sec. of
`respiratory arrest to avoid ventilation induced changes in LV pressure and volume. Blood
`resistivity was measured by 5 ml blood in a four electrode cuvette prior to a preload reduction in
`the assessment of ESPVR, in order to correct for changes caused by temperature and hematocrit.
`The conductance stroke volume was calibrated over three respiratory cycles at each sample time
`by stroke volume simultaneously measured by the thennodilution technique. Possible
`inaccuracies in determining the parallel conductance were avoided since comparisons were made
`in the same animal,‘before and after cardiopulmonary bypass. ‘
`._
`_
`
`-
`Experimental protocol
`Each pressure-volume analysis consisted of triplemeasurements of cardiac output lefi ventricular
`conductance and pressure during periods of ventilatory arrest and measurement of lefi ventricular
`conductance and pressure during a 10 sec occlusion of the inferior caval vein, during and after
`ventilatory arrest.
`
`Afier baseline measurements had been performed in this way, the lefi anterior descending
`coronary artery (LAD) was completely occluded during 2 minutes using a tantalum clamp (n=3)
`or narrowed for 15 min using an inflatable occluder. The pressure-volume analysis was repeated
`afier l min occlusion or'12 min coronary stenosis (sample 2) and 15 min after release of the
`occlusion or stenosis (sample 3). After these measurements, dexmedetomidine was administered
`iv at a dose of l meg/kg over 2 min. Fifteen min later pressure-volume analysis was repeated
`during normal perfiision (sample 4), during another period of ischemia (either occlusion or
`stenosis. sample 5), and 5 min after release of the coronary obstruction (sample 6).
`
`
`
`

`

`NDA 21-038
`
`-
`-
`Results:
`The data on cardiac output and end-systolic (Ees) and end-diastolic elastance (Ed) are presented
`in Table 065- 1. Dexmedetomidine significantly decreases cardiac output (by approximately
`40%). whereas regionaljschemia (induced by either coronary occlusion or stenosis) did not affect
`this variable.
`
`Regional myocardial ischemia did not affect Ees and Ed. In contrast. dexmedetomidine.(l
`meg/kg) tended to decrease Ees and significantly increased Ed. Fifieen min afier
`dexmedetomidine lmcg/kg (sample 4), Ees was on the average 30% lower than at baseline
`(sample 1) and 15 min after the first period of ischemia (sample 3; p<0.08 in both Cases).
`Subsequently, Ees showed a tendency to increase during ischer'riia (sample 5) as well as afier
`subsequent reperfiision (sample 8). Ed increased by approximately 70 % afier administration of
`dexmedetomidine (p<0.05 at samples 4 and 5, compared to samples 1 and 2). The data in the
`following table was extracted from the submission (V26/p62):
`'
`
`Table 065-1:
`
`- (l/min)
`
`
`
`
`End—Systolic
`End-Diastolic
`Cardiac
`Elastance
`Elastance
`Output
`
`
`
`
`(mml-lg/ml)
`(mmHg/ 100ml)
`
`
`
`baseline
`
`dexmedetomidine
`1 meg/kg
`
`1.41 (0.61)
`
`1.24 (0.40)
`
`1.9.0.59.
`
`0.92 (0.34)
`
`10.8 (3.0)
`
`9.8 (2.2)
`
`.07....)
`
`16.7 (6.4)‘
`-
`'
`
`4.77 (1.08)
`
`3.80 (0.70)
`
`7.3.0.7.)
`
`~
`
`2.87 (0 59)‘
`
`1.25 (0.24)
`
`18.0 (5.7)‘
`
`2.63 (0.38)‘
`
`a...”
`
`.7...»
`
`1.9.7.057,-
`
`
`
`
`
`
`
`
`
`
`
`* p<0.05 compared to corresponding sample time before administration of dexmedetomidine
`
`Summary
`The results indicate that dexmedetomidine reduces contractility and the ability of the left
`ventricle to fill. The effects are most likely related to the sympatholytic activity and are energy
`sparing cf the heart. However, this should be considered when used in patients with impaired
`cardiac function.
`
`############################
`
`
`
`

`

`
`
`NDA 21-038
`
`[19]
`
`W: Comparison of hemodynamic stabilizing effects of dexmedetomidine and esmolo]
`.;
`-_
`(#70)
`MW:
`Winn: “ ~~—~__ ”at
`2am: July 1997
`
`Methods: The methods were extracted from the submission (V26/p83-86):
`.
`I
`.
`i
`.
`.
`All experiments were performed in accordance with the “Guiding Principles in the care and use
`of animals” as'a'pproved by the counsel of the American Physiological Society and under the
`regulations of the Animal Care Committee of the University of Limburg. Eleven adult mongrel
`dogs either sex weighing 20 - 40 kg were anesthetized with an intravenous injection of thiopental
`(25 mg/kg ) and intubated with a cuffed tube. They were connected to a volume controlled
`respirator and ventilated at a rate of 16 breaths per minute (5 cm H20 PEEP). During preparation
`and instrumentation, anesthesia was maintained with 1% halothane in oxygen/nitrous oxide (33%
`02/67% N20). End-expired carbon dioxide concentration was continuously monitored by a
`
`capnographf-
`—~— .Arterial blood gases were frequently analyzed during the
`study (ABL 3 radiometer), and when necessary, ventilation was adjusted or sodium bicarbonate
`solution (4.2%) was administered intravenously. Body temperature was kept between 37 and 39
`°C by means of a thermostatically regulated heating pad. Fluid ('NaCl, 0.9% or Haemaccel), was
`administered intravenously in order to keep end-diastolic lefi ventricular pressure between 5-10
`5
`mmHg. Heart rhythm was monitored from lead 11 of theelectrocardiogram.
`
`Balloon catheters for variation of pre- and afier-load were introduced througha jugular vein into
`the inferior caval vein and through a femoral artery into the thoracic aorta, respectively.
`
`Lefi ventricular cavity and ascending aortic pressure were measured with a double sensor
`catheter-tipped micro manometer inserted via the right femoral artery. To enable pressure
`calibration during the experiment, the fluid-filled lumen of the catheter-tipped micro manometer
`was connected via a three-way cock at the level of the lefi atrium to an external pressure
`transducer.
`
`Left and right common carotid arteries were dissected free over a distance of about 1.5 cm and
`care was taken to ensure that nerve branches from the vagosympathetic trunk remained intact.
`Umbilical tape was placed loosely around each carotid artery, and the two ends of the ties were
`passed through stiff plastic tubing to form a snare occluder. Lefi carotid pressure was measured
`with a catheter introduced into the cranial thyroid artery connected to a pressure transducer.
`
`The chest was opened through the lefi fifth intercostal space and the heart was suspended in a
`pericardial cradle. An ultrasonic transit-time flowprobe . ‘N—J‘ ;) was placed
`
`43
`
`
`
`

`

`around the proximal part of the left descending coronary artery (LDCA) for measurement of
`phasic and mean coronary blood flow. To obtain coronary venous blood a polyethylene catheter
`was inserted into a coronary vein of the perfusion area of the LDCA. For measurement of
`regional myocardial mechanical function, three inductivecoils were sutured to the epicardium of
`the left lateral ventricular wall in an equilateral triangle configuration. The area decrease of the
`epicardial region enclosed by the coils was calculated from the relative length changes in the
`threedifferent directions. Assuming that the volume of a myocardial wall segment does not
`change dunng the cardiac cycle, systolic area decrease15 directly related to systolic wall
`thickening.
`For continuous beat to beat measurement of aortic flow, a transit-time flowprobe Was placed
`around the ascending aorta. A pulmonary artery catheter was introduced via the left jugular vein
`into the pulmonary artery and connected to a thermodilution cardiac output computer f—\
`_I. During the experiment cardiac output, as obtained by averaging triplicate
`thennodilution values. was compared regularly with the aortic flow measurementThese were
`always in accordance with each other.
`
`Hemodxnamisjataanabms
`All hemodynamic signals were prearnplified and then digitized with a 16 channel, 12 bit
`interface in an IBM-AT Compatible PC. The sampling frequency was 200 Hz for each channel.
`These signals were continuously displayed on the computer screen, and stored on the hard disk
`for off-line processing. The calculated hemodynamic variables were displayed real time on the
`computer screen as well and at sample times were stored on the hard disk. The amplifiers and
`
`software were developed in the '.
`—————7 of the University of Maastricht. The stored
`data were further processed as a datafile for Microsofl EXCEL.
`
`Peak of first derivative of left ventricular pressure (LVdP/dtmax) and end diastolic left
`ventricular pressure (LVEDP) were calculated from the lefi ventricular pressure signal. Systemic
`vascular resistance (SVR) was calculated as the ratio of mean aortic pressure and aortic blood
`flow. For the measurements during the protocol, the average of each hemodynamic variable over
`a stable hemodynamic period of 30-60 seconds was calculated.
`
`NDA 21-038
`
`
`
`Analxsjmflaboramizarametm
`Arterial (A) and coronary venous (CV) blood gas tensions were assessed with a radiometer
`blood gas analyzer. Hemoglobin content (Hb) and oxygen saturation (Ozsat) were assessed with a
`radiometer OSM-2 hemooxymeter, Blood oxygen content (O,cont.(mmol/l), myocardial oxygen
`extraction (M02 extr.) and myocardial oxygen consumption (MVOZ, mmol /ml.min.100g') were
`calculated as:
`
`Ozcont ( Hb(mmol/L) (Ozsat) + (0.0102 (P 02 (kPa)).
`MOzextr = ( (Ozcont (A) - Ozcont (CV))/Ozcont (A)
`MVO2 ((Ozcont (A) Ozcont (CV)in mmol/L) (coronary flow (Ll100g)
`
`
`
`

`

`
`
`NDA 21-038
`
`For determination of plasma catecholamine and dexmedetomidine levels, arterial blood samples
`- were collected in chilled propylene tubes. The tubes were kept in ice and centrifuged within 30
`minutes at + 4 °C to separate the plasma. The plasma samples were stored at -70°C until
`analyzed. Plasma concentrations of endogenous catecholarnines noradrenaline (NA) and
`adrenaline (A) were assayed using high performance liquid chromatography with coulometric
`electrochemical detection. Intra-assay coefficients of variation with this method are 2% for NA
`and 1.0% for A. Plasma concentrations of dexmedetomidine were analyzed at the
`'
`phannacokinetics laboratory Orion Corporation. 'W
`
`Experimentalfimtnml
`After surgical preparation halothane anesthesia was changed into a-chloralose anesthesia
`(intravenous loading dose 40 mg/kg maintenance 8 mg/kg/h). Chloralose was dissolved in water
`to a concentration of 7.5 mg/ml. Thereafter; the animals were ventilated with 30% oxygen in
`room air and all dogs were allowed to stabilize for at least 60 minutes.
`'
`All experimental medication was given through the proximal infusion port of the pulmonary
`artery catheter. At first esmololHCl. was administered as bolus dose of 500 ug/kg/min for 2
`minutes followed by a continuous infusion of 300 ug/kg/min. Every dog was examined if the
`above mentioned regimen resulted in a complete B,-_adrenergic blockade. This was done as
`follows. Before administration of esmolol we assessed that 13i2 ug/min of isoprenaline was
`needed to increase heart rate more than 20%. During esmolol (300 ug/kg/min) this dose of
`isoprenaline caused a heart rate increase of less than 5%.
`Subsequently dexmedetomidine (dissolved in NaCl 0.9%) was administered with a target plasma
`concentration of 0.5 ng/ml. To this purpose a bolus of l ug/kg was given over 20 minutes,
`followed by a continuous infusion of 1.5 ug/kg/hourduring 30 min, 0.4 ug/kg hour during the
`next 30 min, 0.2 ug/kg/hour during the next 60 min and 0.1 ug/kg/hour during theiremainder of
`the experiment. The doses of esmolol and dexmedetomidine used were shown to attenuate
`hemodynamic stress reaction for esmolol and for dexmedetomidine.
`
`During esmolol and dexmedetomidine infusion three kinds of measurements were performed:
`1)-steady state measurements of all hemodynarnic variables and blood sampling for
`arterial and coronary ventsas“ oxygen content‘and arterial catecholamine and
`dexmedetomidine plasma concentrations.
`2)-measurernents during the last minute of a 3 min bicarotid artery occlusion;
`3)-barosensitivity tests: i.e. decrease or increase of aortic pressure by inflation of a
`balloon1n the inferior caval vein or descending thoracic aorta, respectively, with
`steps of 2 mm. This represents stimulation of all barosensors. The effect on heart
`rate was recorded.
`
`After the last measurements, during continued dexmedetomidine infitsion, also infusion of
`esmolol was started. After steady state and bicarotid occlusion measurements, esmolol infusion
`was stopped. Half an hour later the vagolytic agent glycopyrrolate was administered (dose 40
`ug/kg iv) , followed by steady state and bicarotid occlusion measurements.
`
`.-.—.
`
`_-
`
`’
`
`45
`
`
`
`

`

`
`
`NDA 21-038
`
`Afier finalizing the protocol the LDCA was occluded and methylene blue dye was injected
`intracoronary distal to the occlusion, to mark the perfusion area of the LDCA. Subsequently the
`animal was killed with an overdose of pentobarbital sodium. The weight of the methylene blue
`stained portion of the myocardium was determined in ordetto express LDCA blood flow in
`ml/min/l 00g
`
`5
`._
`.
`I
`l
`.
`:
`Values are expressed as the mean and standard deviation. Because of missing values the number
`of observations was not the same for each variable (n ranging from 8-11). The effect of
`administration of medication and the effect of bicarotid occlusion at each experimental condition
`were compared within each animal. The hemodynarnic effectsof bicarotid occlusion during
`administration'o'f medication were also compared with those obtained in the period before
`administration of medication
`‘
`
`The non-parametric Wilcoxon Signed Ranked test was used for evaluating statistical
`significance. In case of multiple comparisons a Bonferroni correction was applied. A value of
`p<0.05 was considered significant.
`
`-.
`~
`Realms:
`Dexmedetomidine decreased HR and increased systemic vascular resistance more than esmolol
`and these effects were reversed by glycopyrrolate. The circulating catecholarnines were
`decreased by dexmedetomidine and increased by esmolol.
`
`
`Hemodynamic parameter
`‘
`
`
`pre - post
`
`esmolol
`
`535::“sEa
`
`.
`
`'
`
`'
`
`onin/ 100
`
`-0.02 :t 0.22
`
`“E
`
`AOPsyst - systolic aortic pressure
`
`systemic vascular resistance
`
`Coronary blood flow
`
`coronary oxygen consumption
`
`
`
`
`
`
`
`
`plasma noradrenaline
`
`“ p<0.05
`** p<0.01
`
`a
`pre-post
`dexmedetomidine
`
`19 :t 14'
`
`
`
`
`
`
`
`
`24 :t 21‘
`
`-4 :h 5‘
`
`-0.01 :t 0.07
`
`
`
`
`The analysis is for pre versus post within each column
`
`nmol/l
`
`0.25 i 0.22’
`
`-0.23 t 0.42‘
`
`46
`
`
`
`

`

`lliliiiE
`
`g/sec
`
`
`
`
`
`
`
`
`
`
`
`BCO +
`dexmedetOmidine
`
`changes
`
`ECG
`
`changes
`
`35 $322“
`
`24 i ll"
`
`13 t 9"
`
`10:6”
`
`3&3‘
`
`17:14 “
`
`-O.l : 0.6
`
`-o.1 a 0.25
`
`-005; 0.16
`
`'
`
`5'i9 i 358”
`
`no a 117"
`
`'121 2 so"
`
`8 :t 10" 3..
`
`' 2.4 :t 2.2 ‘
`
`8 t 6“
`
`i
`
`4 :t 2”
`
`3 :b 4‘
`
`
`
`
`
`NDA 21-038
`
`Hemodynamic parameter
`
`’
`
`systolic aortic pressure
`
`'
`
`HR - heart rate
`
`CO_'-;'Cardiac output
`
`LvdP/dtmax
`
`systemic vascular resistance
`
`: Coronary bloodflow
`
`coronary oxygen consumption
`
`plasma noradrenaline
`
`.
`
`
`
`
`
`
`mmol/min/100g
`
`0.14 :kO.l3‘
`
`-
`
`.08 i 0.06"
`
`(5.08 i 0.07‘
`
`
`nmol/l
`02510.21“
`
`.26 i 0.32‘
`
`
`
`-0.08 :t 0.24
`
`* p<0.05
`
`*“ p<0.01
`
`The analysis is for pre versus post within each column
`
`Bilateral carotid occlusion (BCO) induces a rise in HR, systolic BP, LVEDP, LVdP/dtmax,
`systolic vascular resistance (SVR), coronary flow, myocardial oxygen consumption and plasma
`noradrenaline levels. Dexmedetomidine blocked the ECG induced increase in SVR and plasma
`noradrenaline rise and reduced the increase in systemic SBP and LVdP/dtmax. The BCO
`induced rise in oxygen consumption and HR were reduced insignificantly by dexmedetomidine.
`The effects of esmolol were a complete block of ECG induced HR and LvdP/dtmax increase.
`The esmolol infusion did not block the BCO induced increase in aortic pressure, EDLVP, SVR
`or plasma noradrenaline.
`*
`
`Snmmamr
`The data indicates the syrnpatholytic activity of dexmedetomidine contributes to the
`hemodynamic effects. The reduction in HR was more prominent with dexmedetomidine than
`with esmolol. While dexmedetomidine increases basal systolic aortic pressure, systemic vascular
`resistance and basal plasma noradrenaline, esmolol did the opposite. Esmolol and
`dexmedetomidine reduce the stress induced (BCO) increase in cardiac oxygen consumption,
`while dexmedetomidine reduces HR independent of the original BP.
`
`
`
`
`
` ########### - - -
`
`47 "
`
`

`

`NDA 21-038
`
`[201
`
`SldeLIilie: Effect of medetomidine either as the racemate mixture or as the individual
`stereojsomers on the heart rate of anesthetized rats
`
`(#59)
`
`W204:
`
`W: J013' 1989
`
`Melinda: The subjects were male Wistar rats, 300 to 500 g. The rats were anesthetized,
`intubated and ventilated, and the left jugular was cannulated for drug administration and the right
`carotid was cannulated for blood pressure measurement. Med’éibrnidine , the racemate, and the
`s’tereoisomers were studied for hemodynamic effects alone and with receptor blocking agents
`previously administered. The blocking agents used were: atipamezole (alphaz-antagonist),
`atropine (mucarinic blocker), propanolol (Ll-blocker) and hexamethonium (ganglionic blocker).
`Drugs were administered to the initial 4 rats by slow infusion to determine MED values.
`Subsequently all administrations were by bolus injection and when blocking drugs were used, the
`animals were allowed to stabilize for 5 to 10 minutes prior to other drug administrations. The
`initial dose was the MED (0.3 ug/kg) and the subsequent doses, injected with 15 minutes
`between administrations, were: 0.3, 1, 3, 10, 30, and 100 ug/kg.
`
`Realms:
`
`.
`
`The MED for reducing heart rate to 300 bpm was 1.7 i 0.1 ug/kg for the racemate and
`0.9 i 0. 02 for dexmedetomidine. The l-isomer was inactive on HR and BP at any dose tested.
`The MED for raising bloodpressure.by 50 mmI-Ig was Q6 a: 1.7 ug/kg for the racemate and
`
`3. 9 :1:1 for dexmedetomidine.
`
`Atipamezole was very effective in blocking the medetomidine induced HR decrease. At the
`highest doses tested, 30 and 100 ug/kg, there was only a slight fall in HR. Atropine did not
`inhibit medetomidine induced bradycardia until the dose was at 3 ug/kg. Propranolol caused a
`significant drop in HR but did not prevent medetomidine from decreasing it further.
`
`The ganglionic blocker, hexamethonium, with atropine and propanolol completely blocked the
`bradycardia effect of medetomidine. Atropine appeared to block the high dose medetomidine
`induced bradycardia and propanolol, the low dose effects. Ganglionic blockade did not prevent
`the medetomidine induced bradycardia, an indicationof peripheral action. This heart rate
`lowering effect of low doses was blocked by propanolol, indicating alpha2 stimulation to inhibit
`norepinephrine release.
`
`The medetomidine induced increases in BP were due to alpha2 stimulation as atipamezole
`blocked this effect. Atropine and atropine + propanolol potentiated the hypertensive effects.
`Afier ganglionic blockade, these cholinergic and B-adrenergic blockers had no effect on the
`hypertensive effects of medetomidine because the blood pressure was low.
`
`48
`
`"
`
`

`

`
`
`NDA 21-038
`
`Summary:
`Medetomidine produced a dose-related bradycardia and blood pressure increase. These effects
`were due entirely to the d-isomer and the l-isomer was completely inactive. The bradycardia
`induction by medetornidine at high doses appeared to be peripherally mediated as it was not
`blocked by a ganglionic blocker. However, the authorssummary suggests the opposite. The low
`doses of medetomidine have a hypotensive effect due to bradycardia,-but at higher doses the
`alpha2 stimulation induces vasoconstriction and hypertension.
`
`Study 1] me:
`
`1 Effects of alpha 2-adrenoceptor agonist dexmedetomidine on human platelet
`aggregation in vitro
`.4
`(#177)
`
`W:
`
`’
`
`
`
`WW: March 1989
`
`Methods: Blood was collected from healthy adult donors The blood samples were quickly
`centrifuged and the platelet rich plasma (PRP) was collected.
`
`mug: The PRP was stabilized and the test compounds were dissolved in normal saline. ADP
`was added at optimal levels and sub-optimal levels, and light transmission through the PRP was
`the measure of platelet aggregation.
`“-—
`
`13.531152 Dexmedetomidine did not cause full aggregation when given alonein 3/5 PRP samples
`when given alone but suboptimal ADP concentrations with dexmedetomidine (3 umol/l) did
`induce full platelet aggregation. The BC» was 0.05 umol/l with ADP.
`
`Summanz!
`The investigators stated that dexmedetomidine15 only a partial agonist at platelet alpha receptors
`became it did not induce full aggregation in 3/5 PRP samples. The addition of ADP with
`dexmedetomidine did cause complete aggregation in all samples.
`
`#######- -
`
`

`

`
`
`NDA 21-038
`
`[22]
`
`W: The Effects of Dexmedetomidine on Uterine Contraction in Rat
`
`mm: #4 of this submission
`-
`-~
`W: NDA 21-038 7/06/99 82- requested submission (Vol l/pg 1--67)
`Conducting lébQIfllflI! and lggamn. ‘ ‘V‘nffim
`
`,
`
`{#4}
`
`Methods: in vitro testing of rat uteri contractions, in-a tissue bath, induced by ascending doses of
`oxytocin. The uteri were of five different stages of estrus; diestrous, early pro-estrus, late pro-
`estrus, estrus and met-estrus. In addition estradiol induced estrus uteri were tested and uteri at
`the 16th day ofgestation. Oxytocin dose-responses were generated for each tissue and the
`minimum concentration to produce the maximum contraction was used with dexmedetomidine
`concentrations in a cumulative dose response from 1x107M to 3x10“M.
`W: dexmedetomidine HCl, Batch OT4321
`
`Begum: dexmedetomidine had negligible effects, at any tested dose, on any tissue tested.
`
`Summary
`Dexmedetomidine had no significant effect on oxytocin induced contractions of the rat uterus at
`any stage of the estrus cycle or in uteri from pregnant rats.
`
`./
`
`
`
` ######## - -
`
`1231
`
`’
`
`~.
`
`Study Title: Effect of medetomidine and dexmedetomidine on adrenocortical function in dogs
`
`Study No: 12 in this submission
`Study Source: NDA 21-038 7/06/99 BZ - requested submission (vol 1/pg. 1-240)
`Conducting laboratory and location“
`,
`~~
`— »-- ..~_:_,___._,_._._—’——~-
`Date of study initiation: May 1988
`
`Methods: Groups of Beagle dogs", male and female were treated either acutely or chronically with
`saline, medetomidine, dexmedetomidine or etomidate. the acute administrations were by im
`injection, 30 minutes prior to ACTH injections.
`'I'he‘chronic treatments were with implanted
`subcutaneous osmotic pumps for 7 days. The change in ACTH induced cortisol was measured.
`
`

`

`
`
`NDA 21-038
`
`Results: The groups and results are presented in the following tables from submission
`(VI/pgs 241A, 241B)
`
`
`
`medetorriidine, so ug/kg
`
`.
`
`dexmedetornidine 80 ug/kg
`
` Acute Treatments
`-
`
`
`
`
`
`
`‘ctomidate 1 mg/kg
`
`
`
`(N)
`
`(3)
`
`(6)
`
`(4)
`
`
`
`
`H
`
`Plasma cortisol (nmol/l)
`.
`60 mm post ACTH
`
`17.4 a 1.0
`
`6 l :9: 2.3
`
`7H5 :17
`-
`
`80.2 110.3
`
`76.0 i 8.7
`
`13.3 :h 29'
`
`Plasma cortisol (nmol/l)
`
`1
`
`before ACTH
`
`60 min post ACTH
`
`9.1:k4l
`
`115.4i2.8
`
`
`
`
`
`
`
`
`
`Treatment
`
` Chronic (7days)
`
`
`
`
`(N)
`
`—_—
`
`:3 ug/kg/h (4)
`7
`
`.
`
`* p<0.01
`
`8.8 :1: 3.5
`
`11.1 i 3.7
`
`12.7i 1.9
`
`84.6 i 6.4‘
`
`
`69.6:10'
`
`
`'.
`
`The suppression of the adrenal response to ACTH was not significant with dexmedetomidine on .X
`an acute basis, but a significant 27% to 40% reductionin ACTH stimulated cortisol was observed
`after one week of treatment.
`
`
`
`APPEARS THIS WAY..- .
`ON ORIGINAL
`
`I
`
`.
`
`- _
`
`51
`
`

`

`NDA 21-038
`
`Summary of Pharmacology, Efficacy Studies
`
`The binding studies demonstrated that dexmedetomidine is very potent as an az-agonist, and does
`not significantly interact-'with ion channels, cholinergic, dopaminergie‘or GABA receptors and
`does not inhibit monoamine oxidase.
`
`"
`.~ "Sedation--Primary Efficacy Measure
`It increased the
`Dexmedetomidineis sedative1n mice (3011g/kg iv) and rats (10 ug/kg iv).
`hexobarbital (10 11g/kg), thiobarbital (611g/kg so) and ethanol induced sleeping times in mice. It
`increased the effectivness of volatile anesthetics, decreasing theMAC for halothane (1‘0 11g/kg
`iv., rats and dogs) and isoflurane (30 11g/kg1n mice iv). The sedation1s accompanied by motor
`incoordinationas measured by the rotorod test in mice (3 11g/kg,1.v.).
`
`'
`
`i \
`
`Analgesia
`The analgesic effects have been demonstratedin mouse writhing (6 ug/kg iv) and hot-plate tests
`(3 ug/kg iv), and rat tail-flick tests (3 11g/kg iv).
`
`Anxiolytic
`The anxiolytic effects of dexmedetomidine were observed1n the Geller Conflict test with rats
`(0. 311g/kg s.c.).1n mice it increased exploration (1.0 ug/kg s.c) and rearing as an anxiolytic (2
`ug/kgSC)
`
`Summary of Safety Pharmacology
`
`:
`
`CNS protective effects
`Dexmedetomidine was shown to reduce ischemic brain damage in rats (3 ug/kg i.v.). However
`there was no anticonvulsant effect against electroshock or pentelenetrazole induced convulsions
`at doses to 600 11g/kg i.p. in mice and it was also