Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`Longer Occupancy of Opioid Receptors by
`Nalmefene Compared to Naloxone as Measured
`In Vivo by a Dual-Detector System
`
`Jr., Victor L. Villemagne, Pan-Fu Kao, Robert F. Dannals, Hayden T. Ravert, Tenshang Joh,
`Stanley Kim, Henry N. Wagner,
`Rosina B. Dixon and A. Cahid Civelek
`Divisions ofNuclear Medicine and Radiation Health Sciences, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
`and Ohmeda, Inc., Liberty Corner, New Jersey
`
`ii ecentraleffectsofopioidsaremediatedbymultipleopiate
`
`one must be monitored carefully in the recovery phase to
`prevent respiratory depression caused by anesthesia. On the
`other hand, administration of very large doses of naloxone can
`create too sudden a reversal of the narcotic effect, causing
`exacerbation of postsurgical pain or onset of withdrawal
`symp
`toms in persons who are physically dependent on narcotics
`(6,7).
`Nalmefene (8,9), a pure opiate antagonist, has shown promise
`in the reversal of opioid anesthesia (10,11), with a longer
`duration
`of action than naloxone
`(12—14). Because
`opioid
`antagonists
`are not
`indicated after a procedure
`in which mod
`erate or severe postoperative
`pain is anticipated,
`the advantage
`of nalmefene resides in its dose-dependent duration of action,
`preventing respiratory depression due to renarcotization in
`those patients in whom pain is effectively controlled by oral
`analgesics such as ibuprofen (because it outlasts the duration of
`action of commonly used narcotics) and also reducing pro
`longed observation times of patients who have received narcot
`ics for their procedures
`(10).
`Carfentanil is a potent, high-affinity synthetic opiate agonist
`that is 90 and 250 times more selective for mu than for delta and
`kappa opiate receptors subtypes, respectively (15). Carbon-i 1-
`cafentanil
`has been
`successfully
`used in PET studies
`to
`evaluate opiate receptors in humans in vivo (15, 16). Carbon
`11-cafentanil
`and a simple dual-detector
`system (1 7) have been
`proven to be useful
`in the determination of duration of opioid
`receptor occupancy by naltrexone (18) and in the in vivo
`characterization
`of different
`receptor
`ligands (19)
`The purpose of this study was to compare the duration of
`opiate receptor occupancy by nalmefene and naloxone
`in a
`randomized, cross-over
`study, using a simple dual-detector
`system and [1‘CJcarfentanil,and to relate the duration of opiate
`receptor occupancy to the plasma half-life of each opiate
`antagonist.
`
`MATERIALS AND METhODS
`Eight healthy volunteers (four men, four women; age range
`18—65yr; mean age 30.3 ±15.5 yr) were recruited through local
`newspaper advertisements
`and paid for their participation. The
`study presented here was approved by the Institutional Review
`Boards of the Johns Hopkins Medical Institutions. All subjects
`gave written informed consent. The subjects were deemed healthy
`after a complete physical examination, including electrocardiogram
`and blood and urine assays. The subjects were instructed to abstain
`from nicotine, caffeine, alcohol and medication 24 hr before the
`study and were asked to fast overnight. All eight volunteers were
`randomly assigned to receive an intravenous administration of
`either 2 mg of naloxone and 1 mg of nalmefene (high doses) or 2
`
`Surgical procedures usually involve the administration of narcotic
`drugs as anesthetics or adjuvants.To reversethe effects of anes
`thesia, opioid antagonists such as naloxone are commonly used.
`Dueto its short lastingeffects, patients receMng naloxonemust be
`monitored carefully. Nalmefene, a pure opiate antagonist with a
`longer duration of action than naloxone, has shown promise in the
`reversal of opioid anesthesia. Methods A simple dual-detector
`positron radiationdetector system and 1'1C]carfentanilwere usedto
`compare the duration of blockade of cerebral mu opioid receptors
`by naloxoneandnalmefeneineightnormalvolunteers.Carbon-i1-
`carfentanilbrain kineticswere monitoredfor 5 mmand 2, 4, 8 and 24
`hr afterthe administrationof eithernalmefene(1mg or 1 p@g/kg)or
`naloxone (2 mg or 2 @.tg/kg).Blood samples were Obtainedat the
`same times for plasma determinations. Results Clearance half
`times from opioid receptors were 28.7 ±5.9 hr for 1 mg of
`nalmefeneand 2.0 ±1.6 hr for 2 mg of naloxone. Brain clearance
`times were about 21.1 and 3.4 times slower than plasma clearance
`times for nalmefeneand naloxone,respectively.Conclusion These
`findingssuggestthattheprolongedeffectsof nalmefenearerelated
`to the slowdissociationof nalmefenefromopoid receptors,which
`are not reflectedin the plasmacurve. This longerblockade of opioid
`receptors by nalmefene represents an advantage in the clinical
`management of postsurgical reversal of narcotic anesthesia and
`opioidsideeffectsaswellasthe reversalof opioidoverdose.
`Key Words positron emission; carfentanil; naloxone; nalmefene;
`dual-detector probe
`J Nuci Med 1997;38I726—173I
`
`receptor subtypes (1). The mu opiate subtype is highly concen
`trated in the thalamus and has been associated with analgesia
`and respiratory depression. The delta subtype is localized in the
`basal ganglia and may be involved in reward behavior and
`seizures, whereas kappa receptors are most highly concentrated
`in the cerebral cortex and amygdala and may be responsible for
`sedation. Surgical procedures
`usually involve the administra
`tion of narcotic drugs as anesthetics or adjuvants (2). Opioid
`antagonists are commonly used to reverse the effects of anes
`thesia (3) or to reverse the effects of a narcotic overdose. To
`date, intravenous administration of the opioid antagonist nalox
`one has been used at the end of surgery for postanesthesia
`reversal. Because
`the effects of
`the most commonly used
`anesthetics outlast
`those ofnaloxone,
`repeated administration or
`continuous infusion ofnaloxone often becomes necessary (4,5).
`Due to its limited duration of action, patients receiving nalox
`
`ReceivedNov.5, 1996;revisionacceptedApr.15,1997.
`Forcorrespondenceor reprintscontactHenryN.Wagner,Jr.,MD,DMsionsof
`Nudear Medians
`and Radiabon Health Scisnces, The Johns Hopldns Medical
`Institu
`tions,615NorthWolfeSt.,Baltimore,MD21205-2179.
`
`1726
`
`THEJOURNALOFNUCLEARMEDICINE•Vol. 38 •No. 11 . November 1997
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 1 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`24hr
`
`NaIm
`Naim
`
`NaIm
`
`TABLE I
`Summary of SUbjectSPar@cipalirigin the Study
`
`DoseTime
`
`Baseline
`
`Total
`blockade
`
`injection4hr8hr
`
`5mm
`
`2hrpost-drug
`
`+
`+
`+
`+
`+
`+
`+
`+
`—
`
`+
`+
`+
`+
`+
`+
`+
`+
`—
`
`+
`+
`+
`+
`Nalox
`—
`+
`
`—
`
`+
`+
`+
`+
`+
`+
`+
`+
`
`+
`
`+ + + + + + + +
`
`+ +
`
`+
`+
`+
`+
`+
`+
`
`HH
`
`L
`L
`H
`L
`L
`H
`H
`
`Age
`(yr)
`
`66
`37
`21
`28
`22
`25
`19
`24
`22
`
`Subject
`no.
`
`Sex
`
`MMMFFMFFM
`
`123456789
`
`*
`
`PETstudyonly.
`H = highdose:Nalmefene,1 mg,andnaloxone,2 mg;L = lowdose:Nalmefene,1 @g4cg,andnaloxone,2 @sg/kg;+
`done;Nalox= studywithnaloxoneonly Naim= studywithnalmefeneonly.
`
`studiesdone;- = studiesnot
`
`@.tg/kgnaloxone and 1 pg/kg nalmefene (low doses) (Table 1). A
`ninth subject, a 22-yr-old man, received 2 mg of naloxone and 1
`mg of nalmefene before [‘‘C]carfentanilPET studies.
`Data acquisition was performed using a simple dual-detector
`probe system that detects positron annihilation by coincidence
`detection of 51 l-keV gamma-ray pairs (1 7). The high sensitivity of
`the probe system allows quantification of changes in receptor
`occupancy studies to be performed with 1/50 of the dose required
`for a PET study, thus permitting the repetition of studies in the
`same subject (1 7). The subject's head was positioned between the
`detectors so that the field ofview (5 cm in diameter) would include
`the thalamus, caudate nucleus, putamen and overlying cerebral
`cortex (Fig. 1) using bone landmarksand a stereotactic frame. Each
`subject was fitted with a molded thermoplastic face mask that
`served as a head-stabilization device and alignment guide. Marks
`were drawn on the mask in the center of the field of view to ensure
`reproducibility of alignment between studies.
`Carbon-i 1-carfentanil was synthesized according to published
`methods (20). All preparations were sterile and apyrogenic.
`On the first study day, subjects were injected with 400—800 @Ci
`of high-specific activity [‘1C]carfentanil(specific activity, >1000
`Cilmmol; injected mass of carfentanil ranging from 0.1 to 0.6 @g
`per injection). Time—activity curves were generated for 60 mm
`after radiotracerinjection. This baseline study was used to estimate
`total binding of [‘1C]carfentanil.After the [‘‘C]carfentanilbaseline
`study was obtained,
`total blockade ofthe subject's opioid receptors
`was achieved by: an intravenous dose of 0.4 mg/kg naloxone 30
`
`mm before a second radiotracer injection; an additional 10 mg of
`naloxone 5 mm before the radiotracer;and a continuous infusion of
`21 pg/kg/hr naloxone that was started immediately after the
`injection of [‘‘C]carfentanil.This dosage regimen of naloxone is
`known to block more than 90% ofthe available opioid receptors in
`the human brain (21). This study was used to estimate nonspecific
`binding.
`received a
`study days, each subject
`During the 2 subsequent
`bolus intravenous injection of either naloxone or nalmefene at one
`of the two dose levels (see Table 1). Carbon-i l-carfentanil was
`injected at 5 mm, 2, 4, 8 and/or 24 hr after the administration of the
`naloxone or nalmefene, and time—activitycurves were generated as
`previously described. After a l-wk washout period, each subject
`returned for study with the opposing drug, at the corresponding
`dosage level, and data were acquired after the same procedures.
`Heart rate and blood pressure were monitored during each study.
`Data were corrected for system dead time, random coincidences
`and radioactive decay. Activity was normalized to injected dose
`and body weight. Between 40 and 60 mm after [‘‘Cicarfentanil
`injection, the radiotracer reaches equilibrium (21); therefore, all
`normalized activity values obtained between 40 and 60 mm were
`averaged for subsequent analysis. The criteria used to estimate
`receptor occupancy included percent specific blockade of mu
`opioid receptors, clearance half-time (representing the disappear
`ance of the blockade) and the washout rate of[' ‘C]carfentanil.The
`percent specific blockade was obtained using Equation 1:
`
`@
`
`I
`
`__
`
`FIGURE1.Thedual-probesystemused
`for detecting coincident 511-keV annihi
`lation gamma rays. Nal = sodium @d@e
`crystals;PMT = photomuttiphertube.
`
`IN VIvo OCCUPANCYOF OPI0ID RECEPTORS•Kim et al.
`
`1727
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 2 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`Lb 24 hours aftsr
`
`I mg nslmof.ns
`
`S hours sft.r I m@n&m•fsn•
`2 hours aft•r1 mg nalmsfsn•
`5 mlnutse aft., 1 mg nslmsfn
`
`600
`
`cc@:L@:
`
`.
`
`400 —
`
`A
`
`300
`
`200
`
`100—
`
`C.)
`a)
`
`E0
`
`.U
`
`total blockade .—@‘A
`with naloxone
`
`—.-—-@
`
`30
`time (mm)
`
`I
`
`40
`
`p
`
`50
`
`60
`
`0
`
`10
`
`20
`
`—
`
`ITB —PB]
`Percent specific blockade = LTB
`NSj X 100%, Eq. 1
`
`where TB is total binding, the averaged activity between 40 and 60
`mm in the control study; PB is partial blockade,
`the averaged
`activity between 40 and 60 mm in the studies 5 min, 2, 8 or 24 hr
`post-intravenous administration of either naloxone or nalmefene;
`and NS is the nonspecific binding, the averaged activity between
`40 and 60 mm in the total blockade study. The percent specific
`blockade for each time point for each drug dosage was averaged for
`the four subjects.
`The clearance half-time of blockade was determined by fitting
`the percent blockade values at the different time points after
`naloxone or nalmefene administration to a monoexponential func
`tion. The washout of [I ‘C]carfentanilfrom the brain was estimated
`from the slope of the normalized time—activitycurve obtained
`between 5 and 15 mm for each study. The slope, determined by
`linear
`regression, gives an indication of how rapidly unbound
`radiotracer leaves the brain, which is inversely proportional
`to the
`percentage of available receptors (18). Data were compared using
`paired, two-tailed Student's t-tests. The criterion for significance
`was p < 0.05. No corrections for multiple comparisons were made.
`Blood samples to measure plasma concentration of nalmefene
`and naloxone were collected before each radiotracer
`injection.
`Naloxone and nalmefene plasma concentrations were measured
`using specific radioimmunoassay methods (22,23). The plasma
`clearance half-lives for each drug was determined by fitting the
`plasma concentrations
`at
`the different
`time points to a double
`exponential function: C
`AC_at + Be@, where C is the plasma
`concentration and A and B are coefficients
`for the initial rapid
`distribution (a) and elimination ((3) phases, respectively. Plasma
`data were compared using paired, two-tailed Student's t-tests. The
`criterion for significance was p < 0.05. The relationship between
`receptor occupancy and plasma concentrations was analyzed using
`a Pearson correlation.
`The duration of
`the effect of morphine and heroin ranges
`between 3 and 5 hr (6). To illustrate the difference in opioid
`receptor occupancy at a point
`in time in which an opioid abuser
`might be most vulnerable to seek renarcotization,
`two PET scans
`
`FiGURE2.Time-actMtycurvesat5 mm
`(@)and2(•),8(O)and24Uhrafterthe
`administrationof 1 mg of nalmefene.The
`radk@activftypeaked around 10-15 mm
`after injectionof the radiotracer,followed
`byaslowdecline.
`
`were performed on a ninth subject 8 hr after the administration of
`nalmefene and naloxone, respectively. Seven hours after receiving
`2 mg of naloxone,
`the subject was positioned in the PET scanner,
`and a transmission scan was performed to allow for attenuation
`correction. Eight hours after receiving 2 mg of naloxone,
`the
`subject was injected with 18 mCi of[' ‘C]carfentanil.PET scanning
`began immediately after [l ‘C]carfentanilinjection. Scanning con
`tinued for 90 mm using the GE 4096+ PET tomograph in the
`high-resolution mode (—6.5 mm FWHM). Fifteen simultaneous
`slices were acquired (8 direct planes and 7 cross-planes). The
`lowest plane was —35 mm below the canto-meatal
`line. PET
`images were reconstructed from the raw data with a standard
`filtered backprojection algorithm and a high-resolution Shepp
`Logan filter. A week later, the subject underwent the same study 8
`hr after receiving 1 mg of nalmefene.
`
`RESULTS
`Naloxone and nalmefene were well tolerated in all subjects.
`One subject reported light-headedness after the injection of 1
`mg of nalmefene. No changes in blood pressure or heart rates
`were observed in any of the subjects.
`Receptor occupancy by nalmefene lasted significantly longer
`than receptor occupancy by naloxone. Normalized
`time—activ
`ity curves indicated that the 8-hr postnalmefene curve was not
`significantly different (p > 0.05) from the total blockade curve
`(Fig. 2). Normalized time—activity curves 8 hr postnaloxone
`were not significantly different (p > 0.05)
`from the control
`curve (Fig. 3). The clearance half-time of the blockade was
`28.6 ±5.9 hr for nalmefene and 2.0 ±1.6 hr for naloxone (Fig.
`4).
`The percent specific blockades by nalmefene and naloxone at
`high- and low-dose treatment regimens are presented in Table 2.
`At 5 mm,
`the degree of receptor occupancy by 1 mg of
`nalmefene was higher than that for 2 mg of naloxone, although
`the increase was not statistically significant. At 2, 4 and 8 hr
`after the administration of
`the opioid antagonists,
`I mg of
`nalmefene showed a significantly (p > 0.05) higher degree of
`receptor occupancy than did 2 mg of naloxone. The same
`pattern was observed for the low-dose
`treatment regimens,
`
`1728
`
`THEJOURNALOFNUCLEARMEDICINE•Vol. 38 •No. 11
`
`November 1997
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 3 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`FiGURE3. @flme-actMtycurvesat5 mm
`
`(0)and2 (•),4 (L@:@)and8 (0)hrafterthe
`administrationof 2 mgof naloxone.
`
`control
`
`8 hours ails, 2 mg nalozons
`4 hours aftsr 2 mg naloxons
`
`2 hours aftsr 2 mg naloxons
`
`5 mlnutss aftsr 2 mg naloxons
`
`a' A@AAA
`A
`
`total blockade
`with naloxone
`t—@
`-@---@
`
`30
`tIme (mm)
`
`40
`
`50
`
`60
`
`A
`AA
`A
`
`@)
`
`600@
`
`.
`
`.
`
`500@
`
`C
`
`400@
`
`A
`
`300
`
`.
`200@
`
`100•
`
`0 a
`
`)
`
`aE0
`
`.U
`
`@
`
`0@
`
`0
`
`I
`
`10
`
`l@
`
`20
`
`although the degree of receptor occupancy was much lower for
`both opioid antagonists
`(Table 2), and the differences between
`them were not significant.
`[‘‘C]carfentanil from the brain, as
`The washout
`rate of
`measured by the slope index, was faster for nalmefene than that
`for naloxone (Table 3). The lower dose treatments did not show
`a noticeable difference in the slopes.
`from plasma had a
`The clearance of 1 mg of nalmefene
`half-time of 1.36 ±0. 17 hr, compared to 0.59 ±0.28 hr for 2
`mg of naloxone
`(Table 4). Pearson correlation coefficients
`between plasma values and percent specific blockade were 0.31
`for nalmefene and 0.04 for naloxone.
`
`The summed 40—60-mm PET images from each study (Fig.
`5) illustrate
`the difference
`between
`the degree of occupancy
`of
`opioid receptors 8 hr after the administration of nalmefene and
`naloxone. The PET images are in agreement with the results
`obtained with the dual-probe system, showing greater receptor
`occupancy by nalmefene than naloxone.
`
`DISCUSSION
`regimes or to
`A rational approach to developing dosage
`designing and monitoring
`drug treatments
`in human subjects
`can be achieved by obtaining kinetic information over the
`specific site of pharmacological action rather than relying on
`
`100
`
`NaimefeneI mg
`
`2 mg
`
`@
`
`0
`
`0
`
`I
`
`3
`
`I
`
`6
`
`.@ T112=28.7±5.9hs r=0.97
`---C.-
`T1/2
`= 2.0 ±I .6 hs
`r
`0.97
`
`I
`
`9
`
`•
`
`12
`time (h)
`
`I
`
`15
`
`I
`
`18
`
`.
`
`21
`
`24
`
`FIGURE4. Comparisonoftheclearance
`half-time of
`the percent blockade for
`each of the two antagonists. Nalmefene
`(S) showeda longerclearancehalf-life
`than naloxone(A).
`
`IN VIvo OCCUPANCYOFOPI0ID RECEPTORS•Kim et al.
`
`1729
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 4 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`TABLE 2
`Percent Specific Blockade
`
`Treatment
`5.4N/ANalmefene,
`Naloxone,2 mg80.6
`10.0Naloxone,
`1 mg99.5
`11.4N/ANalmefene,
`2 @.tg4cg42.6
`1 p.g/kg52.2
`
`5 mmn
`
`2 hr
`
`±2.647.2
`±7.890.3
`±8.96.2
`±12.433.1
`
`Time post-drug injection
`4 hr
`±7.37.1
`±2.0*85.7
`±10.010.0
`±3.526.5
`
`±4.043.8
`±4.7k96.0
`±6.333.1
`±21.247.5
`
`8 hr
`±
`±7.6*53.3
`±
`±16.00
`
`24 hr
`
`±
`
`p < 0.05.
`t-test,
`by Student's
`*5e@j@@@ly significant
`Eachvalueis the mean ±s.e.m.for 3 or 4 subjects.The percentspedfic blockadewas Obtainedusing Equation1 (seetext). N/A = not applicable.
`
`the drug. The dual-detection system is of
`blood levels of
`particular value in assessing stereoselective
`binding of drugs to
`receptors
`in vivo and helps elucidate the pharmacokinetics
`(18)
`and dose—response characteristics
`of various opiate receptor
`ligands
`(19)
`in the human
`brain. With the dual-detection
`system,
`it is possible to determine the minimum dose of a drug
`required to block or occupy a certain receptor site, avoiding
`higher than needed doses and reducing side effects. Further
`more, valuable data is obtained with very low radiation expo
`sure to the subject
`(1 7). The use of specific
`radiotracers
`in
`combination with the dual-detection system has allowed us to
`examine the pharmacokinetics of nalmefene and naloxone in
`human subjects.
`indicate that nalmefene blocked mu opioid
`Our results
`receptors for a significantly longer period of time than nalox
`one. This persistence of occupancy by nalmefene was also
`manifested by a faster clearance ofthe unbound [l ‘C]carfentanil
`from the brain. In contrast, naloxone-treated subjects, having
`greater receptor availability, showed a slower clearance of the
`radiotracer from the brain. Both drugs block the opioid recep
`tors in the brain for a longer period than might be suggested by
`the plasma values. The discrepancy between the clinical effect
`of nalmefene (13, 14,24) and its plasma t112can be explained by
`
`the persistent binding of nalmefene to the receptors, as sug
`gested by a higher in vitro affinity for the central mu receptor
`subtype (IC50 values of 1.0 nM and 4.0 nM for nalmefene
`and
`naloxone, respectively)
`(25)
`One milligram ofnalmefene was shown to be a longer-lasting
`opioid antagonist
`than was 2 mg of naloxone when given
`intravenously. Our results indicate that nalmefene might offer a
`clinical advantage to prevent complications,
`such as respiratory
`depression, from narcotic anesthesia for a longer period of time.
`Our results also indicate that nalmefene might prove to be a
`better opiate antagonist in the management of the reversal of
`opioid overdose.
`
`CONCLUSION
`The dual-detector system is a suitable tool for the evaluation
`of the pharmacokinetic characteristics of drugs at the specific
`site of pharmacological
`action. These findings suggest
`that the
`prolonged effects of nalmefene are related to the slow dissoci
`ation of nalmefene
`from opioid receptors, which are not
`reflected in the plasma curve. This longer blockade of opioid
`receptors by nalmefene might
`represent
`an advantage
`in the
`clinical management of the reversal of narcotic anesthesia
`and
`of opioid overdose.
`
`TABLE 3
`Slope Index for Carbon-i 1-Carfentanil
`
`Treatment
`
`5 mm
`
`2 hr
`
`Thispost-druginjection
`4 hr
`
`0.04N/ANalmefene,
`Naloxone,2 mg—0.26
`0.02Naloxone,
`1 mg—0.29
`0.04N/ANalmefene,
`2 pg/kg—0.17
`1 @Lg/kg—0.23
`
`±0.03—0.16
`±0.02—0.23
`±0.04—0.09
`±0.10—0.11
`
`±0.03—0.09
`±0.02—020
`±0.02—0.07
`±0.04—0.08
`
`±0.00—0.02
`±0.00k—0.20
`±0.02—0.06
`±0.02—0.07
`
`8 hr
`
`24 hr
`
`±
`±0.02W@0.15
`±
`±0.03—0.05
`
`±
`
`±0.00
`
`•S@4Jst@@a@lysignificantby Student's t-test, p < 0.05.
`
`Eachvalueis the mean ±s.e.m.for 3 or 4 subjects.The washout ratewas estimatedby linearregresaionfrom the sbpe of the normalizedtime—activWy
`curvebetween5 and15mm.N/A= notapplicable.
`
`5 mm
`
`Treatment
`0.17Nalmefene,
`±21.591.85
`Naloxone,2 mg38.71
`0.34kNaloxone,
`±7.214.82
`1 mg13.56
`±1.720.39
`2 @g/kg2.26
`0.27Nalmefene,
`1 @g/@çgt16.84 ±16.390.10
`
`TABLE 4
`Plasma Levels
`
`Time post-drug
`
`(hr)4
`hr8
`2 hrinjectionClearancet1,@
`±0.240.69
`±0.160.16
`±2.951.35
`±0.240.64
`±0.320.08
`±0.010.07
`±0.020.06
`±0.010.09
`
`hr
`
`DistributionElimination
`
`±0.030.33
`±0.061.15
`±0.000.33
`±0.010.32
`
`±0.141.31
`±0.29k8.30
`±0.231
`±0.1410.9
`
`±
`±
`.91 ±
`±0.25*
`
`•Statisticallysignificantby Student'st-test, p < 0.05.
`tOreatvariancewasobservedintheplasmalevelsforthelowdoseofnalmefene.Thebloodlevelswereatthelimitsofsensitivityoftheassaytethnique(23).
`Eachvalueisthe mean±s.e.m for3 or4 subjects Unitsarerig/mI Theplasmadearancet1,@wereestimatedby doubleexponentialfit ofthe plasmavalues.
`
`1730 THEJOURNALOFNUCLEARMEDICINE•Vol. 38 •No. 11 •November1997
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 5 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`11C-carfentanji
`@uiItk'Ftio):1mL@
`
`PET Images
`
`.
`
`a
`
`FIGURE5. PETscansobtained8 hraftertheadmin@trationof 2 mgof
`naloxoneQeft)and1 mgof nalmefene(right).Thebindingof r1Cjcarfentanil
`in the striatum and thalamus after nalmefene administration is significantly
`lessthanthatafternaloxoneadministration.
`
`@
`
`ACKNOWLEDGMENTS
`This study was sponsored by Ohmeda, Inc., Liberty Corner, NJ.
`We would like to thank Madge M. Murrell, Julia Buchanan, Robert
`C. Smoot, William B. Mathews, John L. Musachio, Allen B.
`Gardiner, Kathleen E. Truelove, Clem E. Whitman, Zsolt Szabo
`and Utit Pitaktong for their excellent support.
`
`REFERENCES
`I. Pasternak GW. The Opiate Receptors. New York, NY: Humana Press; 1988.
`2. Kennedy
`5K, Longnecker
`DE. History
`and principles
`of anesthesiology.
`In: Goodman
`Gilman A, Rail TW, Nies AS, Taylor P, eds. The pharmacological
`basis
`of
`therapeutics. New York, NY: Pergamon Press; 1990:260—275.
`3. JohnstoneR, Jobes DR. Kennell EM, Behar MG, Smith TC. Reversalof morphine
`anesthesia with naloxone. Anesthesiology 1974;4l :361—367.
`4. Evans JM, Hogg MIJ, Lunn JN, Rosen M. Degree and duration ofreversal by naloxone
`of effects of morphine in conscious subjects. Br Med J 1974;2:589—591.
`
`5. Ngai SH, Berkowitz BA, Yang JC, Hempstead J, Spector S. Pharmacokinetics of
`naloxone in rats and in man. Anesthesiology
`1976;44:398 —401.
`6. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Goodman Gilman A, Rail
`TW, Nies AS, TaylorP. eds. Thepharmacological basis oftherapeutics. New York,
`NY: Pergamon Press;1990:491—531.
`7. Ling W, Wesson DR. Drugs
`of abuse:
`opiates. West J Med I990; 152:565—572.
`8. Foldes FF, Lunn iN, Moore J, Brown IMN. Allylnoroxymorphone. A new potent
`narcotic antagonist. Am J Med Sci 1963;245:23—30.
`9. Sadove MS. Balagot RC, Hatano 5, Jobgen EA. Study of a narcotic antagonist:
`N-allyl-noroxymorphone.
`J Am Med Assoc 1963;183:666—668.
`10. Barsan WG, Seger D, Danzl DF, et al. Duration of antagonistic effects of nalmefene
`and naloxone in opiate-induced sedation for emergency department procedures. Am J
`Emerg Med 1989;7:l55—161.
`11. Kaplan .JL,Marx JA. Effectiveness and safety of intravenous nalmefene for emergency
`department patients with suspected narcotic overdose: a pilot study. Ann Emerg Med
`1991;22:l87—190.
`12. Van Vugt DA, Webb MY, Reid RL. Comparison ofthe duration ofaction of nalmefene
`and naloxone on the hypothalamic-pituitary axis of the rhesus monkey. Neuroendo
`crinology 1989;49:275—280.
`13. Gal TJ, DiFazio CA. Prolonged antagonism of opioid action with intravenous
`nalmefeneinman.Anesthesiology1986;64:I75—180.
`14. Gal TJ, DiFazio CA, Dixon R. Prolonged blockade of opioid effect with oral
`nalmefene. Clin Pharmacol Ther I986;40:537—542.
`15. Frost ii, Wagner FINJr. Dannals RF, et al. Imaging opiate receptors in the human brain
`by positron tomography. J Comput Assist Tomogr 1985;9:23 1—236.
`16. Frost Ji, Mayberg HS, Sadzot B, et al. Comparison of
`[‘‘Cjdiprenorphine and
`[I ‘C]carfentanil
`binding
`to opiate
`receptors
`in humans
`by positron
`emission
`tomog
`raphy. J Cereb Blood Flow Metab 1990; 10:484—492.
`I7. Bice AN, Wagner HN Jr, Frost
`ii,
`et al. A simplified detection system for
`neuroreceptor
`studies in the human brain. J Nuci Med 1986;27:l84—19l.
`18. Lee MC, Wagner HN Jr. Tanada 5, Frost Ji, Bice AN, Dannals RF. Duration of
`occupancy of opiate receptors by naltrexone.
`J Nucl Med l988;29: 1207—1211.
`19. Villemagne VL, Frost ii, Dannals RF, et al. Comparison of
`C-diprenorphine and
`I C-carfentanil
`in vivo
`binding
`to opiate
`receptors
`in man using
`a dual detector
`system.
`Eur J Pharmacol 1994;257:195—l97.
`20. Dannals RF, Ravert HT, Frost ii, Wilson AA, Burns HD, Wagner HN Jr. Radiosyn
`thesis ofan opiate receptor binding radiotracer:
`[‘‘C]carfentanil. mt i App! Radiat
`Isot
`I985;36:303—306.
`21. Mayberg HS, Frost JJ. Opiate receptors. In: Frost JJ, Wagner HN Jr. eds. Quantitative
`imaging. New York, NY: Raven Press; 1990:81—95.
`22. Aitkenhead
`AR, Derbyshire
`DR, Pinnock CA, Achola K, Smith G. Pharmacokinetics
`of intravenous naloxone in healthy volunteers
`[Abstract]. Anesthesiology
`1984;61:
`A38 I.
`23. Dixon R, Hsiao J, Taaffe W, Hahn E, Tuttle R. Nalmefene. Radioimmunoassay for a
`new opioid antagonist. J Pharm Sci
`l984;73:1645—l646.
`24. Dixon R, Howes J, Gentile J, et al. Nalmefene. Intravenous safety and kinetics ofa new
`opioid antagonist. Clin Pharmacol Ther l986;39:49—53.
`25. Michel ME, Bolger G, Weissman B. Binding of a new opiate antagonist, nalmefene,
`to rat brain membranes. Methods Find Exp C/in Pharmacol
`l985;7: 175—177.
`
`Metabolism of Technetium-99m-L,L-Ethyl Cysteinate
`Dimer in Rat and Cynomolgus Monkey Tissue
`
`Yusuke Inoue, Toshimitsu Momose, Tohru Ohtake, Junichi Nishikawa, Yasuhito Sasaki, Takaki Waritani and Minoru Inoue
`Department
`ofRadiology,
`University
`of Tokyo, and Daiichi Radioisotope
`Laboratories,
`Ltd., Tokyo, Japan
`
`Technetium-99m-LL-ethyl cysteinatedimer (@Tc-ECD) is thought
`to be hydrolyzed in the brain by an enzyme and to be trapped as a
`hydrophilicproduct. We investigatedthe characteristicsof the
`enzymaticsystemthat metabolizes @Tc-ECD.Methods In 50
`mM phosphatebuffer (pH 7.4), @°‘Tc-ECDwas incubatedwith
`various concentrations of homogenates of rat tissues (blood,
`liver
`and brain)or cynomolgus monkeytissues (blood, liver,cerebralgray
`matter, cerebral white matter and cerebellar gray matter), and the
`metabolic rates were assessed. Inhibition studies were performed
`using diisopropylfluorophosphate,eserineand p-chloromercu
`ribenzoate as inhibitors. The metabolic rates in the brain homoge
`nates of rat and monkey were measured at various levels of pH,
`rangingfrom 6.6 to 7.6. Technetium-99m-L,L-ethylcysteinatedimer
`metabolismwas also examinedinthe presenceof purified enzymes.
`Results: In both species,the metabolic rate was high in livertissue,
`intermediatein braintissueand low in blood.Theratein cerebral
`
`Jan. 28, 1997.
`revision accepted
`Received Jul. 8, 1996;
`For correspondence or reprints contact: Yusuke Inoue, MD, Department of Radiol
`ogy, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
`
`gray matterof cynomolgusmonkeywas higherthan those in rat
`brain,monkeycerebralwhite matterand monkeycerebellargray
`matter. All substances used as inhibitors depressed @°‘Tc-ECD
`metabolism,and the responsewas different among tissues. Reduc
`tion in pH inducedslightdecreasesin metabolicrate.Hydrophilic
`conversion of @°°@Tc-ECDwas observed after incubation with per
`cinelivercarboxylesterase.Conclusion:Theseresuttssupportthe
`hypothesis that the hydrophilic conversion of °@Tc-ECDis medi
`atedbyenzymes.Itisalsosuggestedthatvariousenzymescatalyze
`the hydrolysisof @Tc-ECDand that the enzymaticsystemthat
`metabolizes @rc-ECDis different between tissues and between
`species.
`Key Words technetium-99m-ECD; metabolism; in vftro
`J Nuci Med 1997;38I733-1737
`
`
`
`Technetium-99m-L,L-ethylcysteinatedimer(99mTc@ECD),a
`
`is widely used in various
`brain perfusion agent for SPECT,
`clinical
`situations (1). After its intravenous injection, 99mTc..
`
`METABOLISM OF TECi@ETIuM-99m-ECD
`
`•Inoue
`
`et al.
`
`1731
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 6 of 7
`
`

`

`Downloaded from
`
`jnm.snmjournals.org
`
`by on January 17, 2020. For personal use only.
`
`Longer Occupancy of Opioid Receptors by Nalmefene Compared to Naloxone as
`Measured In Vivo by a Dual-Detector System
` 
`Stanley Kim, Henry N. Wagner, Jr., Victor L. Villemagne, Pan-Fu Kao, Robert F. Dannals, Hayden T. Ravert, Tenshang
`Joh, Rosina B. Dixon and A. Cahid Civelek
`J Nucl Med.  
`
`1997;38:1726-1731.
`
`This article and updated information are available at:
`http://jnm.snmjournals.org/content/38/11/1726
`
`
`Information about reproducing figures, tables, or other portions of this article can be found online at:
`http://jnm.snmjournals.org/site/misc/permission.xhtml
`
` 
`Information about subscriptions to JNM can be found at:
`http://jnm.snmjournals.org/site/subscriptions/online.xhtml
` 
`
`
`
` is published monthly.
`The Journal of Nuclear Medicine
`SNMMI | Society of Nuclear Medicine and Molecular Imaging
`1850 Samuel Morse Drive, Reston, VA 20190.
`(Print ISSN: 0161-5505, Online ISSN: 2159-662X)
`
`© Copyright 1997 SNMMI; all rights reserved.
`
`Nalox1224
`Nalox-1 Pharmaceuticals, LLC
`Page 7 of 7
`
`