The Efficacy of RS-25259, a Long-Acting Selective 5=HT,
`Receptor Antagonist,
`for Preventing Postoperative Nausea
`and Vomiting After Hysterectomy
`Procedures
`Jun Tang, MD*, Robert D’Angelo,
`MDt, Paul F. White, RhD, MD, FANZCA*,
`Phillip E. Scuderi, MDt
`*Department of Anesthesiology
`Dallas, Texas; and tDepartment
`North Carolina
`
`and Pain Management, University of Texas Southwestern Medical Center at Dallas,
`of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem,
`
`and
`
`We evaluated the safety and efficacy of RS-25259, a po-
`tent and long-acting selective 5-HT,
`receptor antago-
`nist, for the prevention of postoperative nausea and
`vomiting (PONV)
`in women undergoing hysterectomy
`procedures.
`In this randomized, double-blind, placebo
`controlled, dose-ranging study, 218 healthy, consent-
`ing women were assigned to one of the six treatment
`groups: placebo or RS-25259 0.1, 0.3, 1.0, 3.0, or 30
`pg/kg. All patients underwent a standardized general
`anesthetic
`technique. The study medication was ad-
`ministered
`IV 20-30 min before the end of surgery.
`During
`the initial 24-h period after surgery,
`the inci-
`dence of vomiting,
`the need for rescue antiemetics, the
`time to the first episode of emesis, and administration
`of rescue antiemetic medication, as well as a nausea vi-
`sual analog scale and verbal categorical scale scores
`were recorded. In addition, recovery times from the end
`of anesthesia and the incidences of perioperative
`side
`effects were noted. Only 30 pg/kg RS-25259 signifi-
`cantly decreased
`the incidence of vomiting and the
`
`requirement for rescue antiemetics. The largest dose of
`RS-25259 also delayed the time to the first emetic epi-
`sode and reduced the number of treatment failures.
`However, no differences were found in the severity of
`postoperative nausea (versus saline), and postopera-
`tive headaches were more common after the adminis-
`of RS-25259 0.3-30 pg/kg IV. In conclusion,
`tration
`RS-
`25259 30 pg/kg
`IV was effective in reducing the
`incidence of PONV after major gynecologic surgery,
`but the occurrence of headaches with the larger doses of
`RS-25259, a long-
`RS-25259 is a concern. Implications:
`acting 5-HT, antagonist, was effective in reducing post-
`operative vomiting only at the largest dose studied
`(30 pg/kg). However, RS-25259 had no antinausea ac-
`tivity, and the larger doses were associated with an in-
`creased incidence of headaches in the postoperative
`period.
`
`(Anesth
`
`Analg
`
`1998;87:462-7)
`
`N ausea, retching, and vomiting
`
`com-
`are common
`(l-3).
`after major gynecologic
`surgery
`plications
`Dehydration,
`electrolyte
`imbalance,
`excessive
`tension on suture
`lines, venous hypertension,
`and in-
`creased hematoma
`formation
`are secondary
`problems
`related
`to persistent
`or intractable
`postoperative
`eme-
`sis (4). Several different
`classes of prophylactic
`anti-
`emetics have been administered
`in an attempt
`to de-
`crease
`the
`incidence
`of postoperative
`nausea
`and
`vomiting
`(PONV). However,
`many of the commonly
`
`was
`
`supported,
`
`in part,
`
`by a grant
`
`from
`
`Syntex,
`
`Palo
`
`This work
`Alto, CA.
`29, 1998.
`April
`for publication
`Accepted
`F.
`to Dr. Paul
`requests
`reprint
`and
`correspondence
`Address
`and Pain Management,
`Uni-
`White,
`Department
`of Anesthesiology
`Center
`at Dallas,
`5161 Harry
`versity
`of Texas Southwestern
`Medical
`Hines
`Blvd.,
`CS2.202,
`Dallas,
`TX 75235-9068.
`Address
`e-mail
`pwhite@mednet.swmed.edu.
`
`to
`
`used antiemetics are associated with undesirable side
`effects (5,6).
`Ondansetron, the first 5-HT, receptor antagonist, pos-
`sesses antiemetic activity
`in women who develop intrac-
`table PONV after gynecologic surgery (7). Studies have
`confirmed the efficacy of ondansetron in both the treat-
`ment and prevention of PONV (8,9). However, a meta-
`analysis suggested that the use of ondansetron is asso-
`ciated with an increased incidence of headaches and
`transient elevations in liver enzymes (10).
`RS-25259 is a potent and highly selective 5-HT,
`receptor antagonist (11) that is more effective
`than
`ondansetron
`in preventing
`chemotherapy-induced
`emesis in animals (12). In this preliminary, double-
`blind, dose-ranging study, the efficacy and safety of
`RS-25259 were evaluated when administered prophy-
`lactically
`to women undergoing major gynecologic
`surgical procedures.
`
`462
`
`An&h
`
`Analg
`
`1998;87:462-7
`
`01998
`
`by
`
`the
`
`International
`
`Anesthesia
`
`Society
`
`Research
`0003-2999/98/$5.00
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1008
`
`Exh. 1008
`
`

`
`ANESTH
`1998;87:462-7
`
`ANALG
`
`THE ANTIEMETIC
`
`EFFICACY
`
`ET AL.
`TANG
`OF RS-25259
`
`463
`
`Methods
`placebo-controlled
`double-blind,
`This
`randomized,
`at two medical centers
`(Univer-
`study was performed
`sity of Texas Southwestern
`Medical Center
`in Dallas,
`TX and Wake Forest University
`Baptist Medical Cen-
`ter
`in Winston-Salem,
`NC). After
`obtaining
`institu-
`tional review
`board approval
`at both medical centers,
`218 ASA physical
`status
`I or
`II consenting
`women
`undergoing
`an abdominal
`or vaginal
`hysterectomy
`with a standardized
`general anesthetic
`technique were
`enrolled
`in the study. Exclusion
`criteria
`included preg-
`nancy, body weight
`>lOO% of
`the calculated
`ideal
`body weight,
`hypersensitivity
`to 5-HT,
`antagonists,
`vomiting
`or retching within
`24 h before
`the operation,
`administration
`of antiemetic
`or psychoactive medica-
`tion within
`24 h before
`the operation,
`a recent history
`of narcotic
`or alcohol abuse, and preexisting
`abnor-
`malities
`involving
`the renal, hepatic,
`cardiovascular,
`metabolic, or endocrine
`systems. Patients were asked
`to provide
`a detailed medical
`history
`and demo-
`graphic
`information
`(including
`age, weight,
`height,
`alcohol or drug consumption,
`last menstrual
`period,
`any history
`of PONV or motion
`sickness).
`an
`Because a history
`of PONV
`is associated with
`increased
`risk of PONV after a subsequent
`operation
`(l), patients were assigned
`to one of two strata based
`on
`their history
`of PONV
`after general anesthesia.
`Within each strata, patients were
`randomized
`to one
`of six prophylactic
`treatment
`groups: placebo
`(saline)
`or 0.1,0.3,1.0,3.0,
`or 30 pg/kg RS-25259. Each dose of
`study medication was prepared
`by the hospital phar-
`macy
`in a total volume
`of 15 mL of isotonic
`sodium
`chloride
`solution
`and was administered
`IV over 30 s
`approximately
`20-30 min before
`the end of surgery.
`In
`the preoperative
`holding
`area, patients
`com-
`pleted a baseline
`loo-mm
`visual analog scale (VAS)
`for
`nausea
`(0 = no nausea
`to 100 = maximal nausea) and
`a verbal categorical
`scale (VCS)
`(1 = no nausea, 2 =
`mild nausea, 3 = moderate
`nausea, or 4 = severe
`nausea). Midazolam
`2 mg IV was used to premeditate
`all patients. On arrival
`in the operating
`room,
`routine
`monitoring
`devices consisting
`of a noninvasive
`blood
`pressure
`cuff, pulse oximeter probe, and electrocardio-
`gram were placed. General anesthesia was
`induced
`with
`thiopental
`and an opioid analgesic
`(either
`fenta-
`nyl or sulfentanil)
`and was maintained
`with
`isoflu-
`rane, nitrous oxide
`(N,O)
`in oxygen, and a nondepo-
`larizing
`neuromuscular
`blocking
`drug.
`Residual
`neuromuscular
`block was antagonized
`with
`neostig-
`mine and glycopyrrolate.
`After
`tracheal
`extubation,
`the patients were
`transported
`to
`the postanesthesia
`care unit (PACU) where morphine
`or meperidine was
`administered
`as needed
`for postoperative
`analgesia.
`to
`The anesthetic
`time (from
`induction
`of anesthesia
`discontinuation
`of N,O) and the operating
`time (from
`surgical
`incision
`to completion
`of the last suture) were
`
`patients were able to
`times at which
`The
`recorded.
`follow
`commands
`(e.g., squeeze
`the
`investigator’s
`hand) and were discharged
`from
`the PACU were also
`noted. Episodes
`of PONV
`and administration
`of res-
`cue antiemetics
`were
`recorded
`during
`the
`first 24-h
`period after surgery.
`An emetic episode was defined
`as a single vomiting
`or retching
`event or any combi-
`nation of these events separated by less than 1 min.
`Rescue antiemetic medication was administered
`af-
`ter a repeat emetic episode or at the request
`of the
`patient.
`In addition,
`the time
`interval
`to first experi-
`encing an emetic episode
`or
`to receiving
`a rescue
`antiemetic,
`as well as treatment
`failures
`(defined as a
`situation
`in which
`the patient experienced
`a single
`emetic episode or required
`rescue antiemetic medica-
`tion), were noted. On arrival
`in the PACU and 1,2,4,
`8, 12, 16, 20, and 24 h after
`the end of anesthesia,
`patients were asked
`to assess
`their degree of nausea
`using
`the VAS and VCS. At the end of the 24-h obser-
`vation period, a VCS was also used
`to evaluate
`the
`overall degree of nausea during
`the postoperative
`pe-
`riod. Overall
`patient
`satisfaction
`with
`the control
`of
`their PONV was assessed using a VCS (1 = very good,
`2 = good, 3 = fair, and 4 = poor). Finally, all patients
`were
`contacted
`24 h, 3 days, and 14 days after
`the
`operation and asked
`the nonspecific
`question,
`“Is any-
`thing bothering
`you?”
`anal-
`of a one-way
`consisted
`The statistical
`analysis
`to compare
`the continuous
`ysis of variance
`(ANOVA)
`variables
`among
`the six treatment
`groups.
`If a signif-
`icant difference was noted, Scheffe’s multiple
`compar-
`ison
`test was performed
`to determine
`intergroup
`dif-
`ferences. A two-way
`ANOVA
`was used to analyze
`the
`repeated measures.
`Categorical
`variables
`were
`ana-
`lyzed by using
`the 2
`test or Fisher’s
`exact
`test as
`appropriate.
`All
`tests were
`two-sided,
`and a P value
`co.05 was
`considered
`statistically
`significant.
`Data
`are presented
`as mean
`values
`numbers,
`or
`+SD,
`percentages.
`
`Results
`data for the six treatment groups are
`The demographic
`summarized
`in Table 1. The six groups were
`compa-
`rable with
`respect
`to age, weight,
`height, number
`of
`days since
`the start of their
`last menstrual
`cycle, per-
`centage of patients with
`a history
`of PONV and mo-
`tion sickness,
`and
`type of hysterectomy
`procedure
`(i.e., transabdominal
`versus
`vaginal). The dosages of
`anesthetic
`and analgesic
`drugs
`administered
`during
`the intraoperative
`and postoperative
`period,
`the dura-
`tion of anesthesia and surgery,
`and the time to follow-
`ing verbal commands,
`and the duration
`of the PACU
`stay were also similar among all six groups.
`Within
`the first 2 h after surgery,
`the incidence of
`vomiting was significantly
`reduced
`in patients
`receiv-
`ing RS-25259 30 pg/kg
`IV compared with
`the groups
`
`Exh. 1008
`
`

`
`464
`
`ET AL.
`TANG
`THE ANTIEMETIC
`
`EFFICACY
`
`OF RS-25259
`
`ANALG
`ANESTH
`1998;87:462-7
`
`Table
`
`1. Demographic Characteristics and Surgical and Recovery Times
`
`Saline
`36
`41 +- 8
`70 2 14
`162 f 10
`
`0.1
`27
`43 ? 9
`76 5 18
`164 t 7
`
`-
`
`RS-25259 (&kg)
`1.0
`35
`39 -c- 9
`74 f 17
`164 2 9
`
`0.3
`41
`39 ? 7
`70 + 16
`163 -c 7
`
`7
`5
`14
`1
`12
`4
`
`12
`6
`23
`0
`14
`3
`
`12
`5
`16
`2
`13
`6
`
`40
`42 2 8
`73 + 14
`164 -c 7
`
`10
`8
`21
`1
`15
`5
`
`30
`39
`42 k 8
`71 2 13
`162 f 7
`
`11
`8
`20
`0
`12
`2
`
`he (yr)
`Weight (kg)
`Height (cm)
`Last menstrual period
`O-8 d
`9-16 d
`>16 d
`Unknown
`Previous PONV
`Previous motion
`sickness
`Intraoperative opioid
`analgesics (pg)
`Fentanyl
`Sufentanil
`Postoperative opioid
`analgesics (mg)
`Morphine
`Meperidine
`Anesthetic time (min)
`Operative time (min)
`Respond to
`commands (min)
`Duration of PACU
`stay (min)
`are means
`-c SD or n.
`= postoperative
`nausea
`
`Values
`POIW
`
`7
`4
`24
`1
`14
`5
`
`271 2 140
`89 2 30
`
`47 -c 35
`283 + 173
`132 + 46
`108 c 39
`10 ? 7
`
`102 t 34
`
`304 + 129
`88 + 27
`
`305 + 92
`86 I! 29
`
`262 t 94
`78 2 27
`
`242 + 103
`92 t 33
`
`277 St 113
`86 ? 32
`
`56 C 31
`273 2 102
`147 + 73
`121 ? 61
`11 -c 6
`
`101 ? 30
`
`46 t 21
`243 k 151
`148 t 64
`122 It 57
`11 2 11
`
`102 + 33
`
`59 -c 25
`221 ? 180
`146 k 76
`122 -c 72
`12 2 10
`
`101 2 40
`
`60 ? 31
`217 t 152
`138 t 57
`117 ? 53
`11 +6
`
`106 + 33
`
`56 -c 26
`334 ? 118
`148 -t 71
`120 t 66
`9t6
`
`87 2 38
`
`and
`
`vomiting,
`
`PACU
`
`= postanesthesia
`
`care unit
`
`IV
`receiving saline or RS-25259 0.1 or 1.0 &kg
`(Table 2). Similarly, RS-25259 30 &kg
`IV was signif-
`icantly more effective
`in preventing vomiting within
`the first 12 h after surgery than either the saline or
`RS-25259 0.1 pg/kg
`IV. RS-25259 30 pg/kg
`IV also
`marginally decreased the number of emetic episodes
`within
`the first 24 h postoperatively compared with
`placebo treatment (P = 0.05). Although
`the need for
`rescue antiemetics within
`the first 2 h was similar
`among all groups, RS-25259 1.0,3.0, and 30 pg/kg
`IV
`significantly decreased the antiemetic
`requirement
`compared with saline within
`the first 12 h after sur-
`gery. Within
`the first 24 h after surgery, only
`the
`30 Fg/kg
`IV dose of RS-25259 significantly
`reduced
`the antiemetic requirement compared with the saline
`group. In addition, the time to the first emetic episode
`was significantly shorter in patients receiving saline or
`RS-25259 0.1 pg/kg
`IV compared with those receiving
`30 pg/kg
`IV RS-25259. Similarly, the mean time to the
`first episode of vomiting was significantly shorter in
`the patients receiving RS-25259 0.1 pg/kg
`IV than in
`those receiving RS-25259 0.3 pg/kg
`IV. The percent-
`age of treatment
`failures was significantly higher in
`the saline group than in the RS-25259 30 Fg/kg
`IV
`group during the first 24 h after surgery (Table 2).
`Among patients with a history of PONV, there were
`no differences in the incidence of vomiting or in the
`
`need for rescue antiemetic medication among the six
`groups (Table 3). However, among patients with no
`history of PONV, RS-25259 30 pg/kg
`IV was signifi-
`cantly more effective in the prevention of emetic epi-
`sodes within the first 2,12, and 24 h after surgery, and
`it decreased the need for rescue antiemetic therapy
`within 12 and 24 h after surgery compared with saline.
`RS-25259 1.0 pg/kg
`IV was also effective in reducing
`the number of emetic episodes and the need for anti-
`emetic rescue medication within 12 h compared with
`saline (Table 4). Of interest, the VAS and VCS scores
`for nausea did not differ among the six groups (data
`not shown). The overall satisfaction with the control of
`PONV
`in the first 24 h after surgery was also similar
`(data not presented).
`Finally, the overall incidences of adverse side effects
`were similar among all treatment groups (Table 5).
`However, more postoperative headaches were noted
`in patients who received
`larger doses of RS-25259
`compared with
`those who received
`W-30
`pg/kg)
`saline and the smallest dose of RS-25259 (0.1 &kg)
`(P < 0.02).
`
`Discussion
`This clinical study demonstrated that the IV adminis-
`tration of RS-25259 30 pg/kg 20-30 min before the
`
`Exh. 1008
`
`

`
`ANESTH
`1998;87:462-7
`
`ANALG
`
`THE ANTIEMETIC
`
`EFFICACY
`
`ET AL.
`TANG
`OF Rs-25259
`
`465
`
`Table 2. Patients Experiencing
`Vomiting,
`in the First 24 Hours After Surgery
`
`Receiving Antiemetic
`
`(Rescue) Medication,
`
`and Reported
`
`as Treatment
`
`Failures
`
`Saline
`36
`
`17
`39
`47
`
`0.1
`27
`
`15
`41
`44
`
`(pg/ kg)
`RS-25259
`1.0
`35
`
`14
`23
`34
`
`3.0
`40
`
`13
`23
`30
`
`0.3
`41
`
`10
`24
`32
`
`30
`39
`
`o*-l$
`13*t
`26
`
`31
`72
`75
`339 2 319
`234 2 211
`78
`
`22
`63
`67
`213 rt 189
`314 ? 308
`70
`
`22
`56
`61
`637 + 530t
`326 t 264
`63
`
`23
`43”
`54
`428 + 507
`381 + 447
`60
`
`20
`43*
`53
`475 c 544
`430 + 473
`58
`
`23
`46”
`49*
`795 2 416*-t
`474 k 330”
`51”
`
`(min)
`
`*
`
`sD.
`
`tomiting
`
`(%)
`
`(%)
`
`O-2 h
`O-12 h
`O-24 h
`Rescue antiemetics
`O-2 h
`O-12 h
`O-24 h
`(min)
`Time
`to first emesis
`Time
`to rescue antiemetic
`Treatment
`failures
`(%)
`
`are percentages
`Values
`* P < 0.05 versus
`saline.
`t P < 0.05 versus
`RS-25259
`$ P < 0.05 versus
`RS-25259
`
`or means
`
`0.1 &kg.
`1.0 &kg.
`
`Table 3. Patients with a History of PONV Who
`Experienced
`Vomiting
`or Required Rescue Antiemetic
`Therapy Within
`24 Hours After Surgery
`
`Table 4. Patients with No History
`of PONV Who
`Experienced
`Emesis or Required Rescue Antiemetics
`Within
`24 Hours After Surgery
`
`(pg / kg)
`RS-25259
`0.1 0.3 1.0 3.0 30
`12
`14
`13
`15 12
`
`25
`50
`58
`
`33
`75
`75
`
`14
`43
`50
`
`29
`79
`86
`
`31
`46
`54
`
`46
`62
`62
`
`20
`27
`33
`
`0
`25
`42
`
`33
`20
`67
`47
`67 67
`
`Saline
`14
`
`14
`36
`43
`
`(%)
`
`29
`79
`79
`vomiting.
`
`nausea
`
`and
`
`(%)
`
`tomiting
`2h
`12 h
`24 h
`Rescue antiemetics
`2h
`12 h
`24 h
`PONV
`= postoperative
`
`RS-25259 @g/kg)
`0.1 0.3 1.0 3.0 30
`15 27 22
`25 27
`
`Saline
`22
`
`18
`41
`50
`
`8 O*
`5
`7
`7
`9* 20
`7*
`15
`33
`33 22 23
`28 19*
`
`6
`19
`13
`32
`53 44 32*
`68
`60 48 50
`73
`vomiting.
`
`20 19
`40 37%
`44 41*
`
`(%)
`
`nausea
`
`and
`
`(%)
`
`tomiting
`2h
`12 h
`24 h
`Rescue antiemetics
`2h
`12 h
`24 h
`PONV
`= postoperative
`* P < 0.05 versus
`saline.
`
`in decreasing emesis in
`end of surgery was effective
`women undergoing major gynecologic surgery. How-
`ever, analogous to the recent findings of Tramer et al.
`(10) with ondansetron, larger doses of RS-25250 were
`associated with more headaches. Although
`the length
`of stay in the PACU was slightly shorter in the large-
`dose RS-25259 group, this difference was not statisti-
`cally significant. Moreover,
`the patients’ overall satis-
`faction with the control of the PONV symptoms was
`not improved by the administration of RS-25259. Con-
`sidering the more meaningful outcome measures (e.g.,
`recovery
`times, patient satisfaction), RS-25259 seems
`to be of
`limited benefit
`in
`this high-risk patient
`population.
`in re-
`The 5-HT, receptor antagonists are effective
`ducing emesis by acting on both the central and pe-
`ripheral nervous systems (13). Ondansetron has been
`successfully used for both prophylaxis and treatment
`of PONV with few clinically significant adverse effects
`
`free of activity at histamin-
`(7-9). Although apparently
`ergic, dopaminergic, or cholinergic receptors (14), side
`effects such as chest pain, headaches, and extrapyra-
`midal symptoms have been reported with ondanse-
`tron (15,16) and other 5-HT, antagonists. Granisetron
`and tropisetron,
`two more recently introduced 5-HT,
`receptor antagonists that have also been reported to
`decrease emesis after surgical procedures (17,18), pos-
`sess longer elimination half-life values than ondanse-
`tron [9-11 h (19) and 6-7 h (20) versus 2.8 2 0.6 h (21),
`respectively]. However,
`the long-lasting antiemetic ac-
`tivity associated with granisetron is allegedly due to
`its high affinity
`for the 5-HT,
`receptor (22,23). Of
`interest, Naguib et al. (24) reported that the prophy-
`lactic administration of ondansetron was as effective
`as granisetron and tropisetron
`in reducing
`the inci-
`dence of PONV during the first 24 h after laparoscopic
`cholecystectomy. Unfortunately, none of the currently
`
`Exh. 1008
`
`

`
`466
`
`ET AL.
`TANG
`THE ANTIEMETIC
`
`EFFICACY
`
`OF RS-25259
`
`ANALG
`ANESTH
`1998;87:462-7
`
`Table
`
`5. Perioperative
`
`Eide effects (%)
`Pain
`Anxiety
`Constipation
`Dizziness
`Drowsiness
`Headache
`Insomnia
`Itching
`Rash
`* P < 0.05
`
`versus
`
`saline
`
`Side Effects
`(pg/ kg)
`RS-25259
`0.3
`1.0
`3.0
`41
`35
`40
`
`0.1
`27
`
`Saline
`36
`
`14
`0
`39
`0
`3
`6
`11
`8
`6
`and RS-25259
`
`15
`
`32
`
`17*
`7
`17
`
`7
`45
`37
`45
`45
`7
`19
`22
`75
`0.1 pg/kg.
`
`9
`0
`31
`3
`3
`23*
`14
`14
`6
`
`13
`55
`33
`58
`00
`15*
`18
`15
`30
`
`30
`39
`
`10
`
`23
`
`21*
`8
`8
`
`available 5-HT, receptor antagonists are completely
`effective in preventing PONV.
`RS-25259 is a highly potent and selective 5-HT,
`receptor antagonist (11) that decreases chemotherapy-
`induced emesis (12). The dose range chosen for this
`preliminary study was based on the single-dose safety
`and tolerability studies performed
`in healthy male
`volunteers (Robert Smith, PhD, personal communica-
`tion, 1993). After
`IV doses of 0.3-90 pg/kg, RS-
`25259 has an elimination half-life of 30-40 h in hu-
`(data on file at Syntex/Roche, Palo Alto, CA).
`mans
`For this preliminary dose-ranging study, a female sur-
`gical population undergoing major gynecologic pro-
`cedures was chosen because it is at high-risk of devel-
`oping PONV. These results suggest that smaller doses
`of RS-25259 are ineffective
`in preventing of PONV.
`Only the largest dose of RS-25259, 30 pg/kg
`IV, was
`effective in decreasing vomiting and the need for res-
`cue antiemetic drugs during the first 24 h after major
`gynecologic surgical procedures. Unfortunately, even
`the largest dose of RS-25259 did not reduce the sever-
`ity of nausea during
`the early postoperative period.
`Like other 5-HT,
`receptor antagonists (17,25), RS-
`25259 also seems to increase postoperative headaches.
`Although oral RS-25259 1 pg/kg
`is effective
`in pre-
`venting PONV
`in outpatients undergoing
`laparo-
`scopic surgery (26), it was less effective in this inpa-
`tient population
`undergoing major gynecologic
`procedures.
`to their
`When patients were stratified according
`history of PONV, RS-25259 was ineffective
`in the pre-
`vention of PONV in the high-risk subpopulation.
`It is
`possible that the failure
`to demonstrate a beneficial
`effect in patients with a history of PONV was related
`to the small number of subjects in these subgroups.
`The lack of an active comparative drug also limits the
`clinical implications of this study. However, before
`initiating comparative clinical trials with a new anti-
`emetic drug, it is necessary to determine the effective
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`References
`of
`SM, et al. The efficacy
`AH, McDonald
`Darvish
`1.
`Desilva
`PHDP,
`perphenazine,
`and met-
`droperidol,
`ondansetron,
`prophylactic
`in
`the prevention
`of nausea
`and
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`after
`oclopramide
`major
`gynecologic
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`Anesth
`Analg
`1995;81:139-43.
`Leeser
`J, Lip H. Prevention
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`nausea
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`a new,
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`5-HT,
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`Analg
`1991;72:751-5.
`Madej
`TH, Simpson
`KH. Comparison
`done,
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`and metoclopramide
`sea and
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`Anaesth
`1986;58:884-7.
`Watcha MF, White
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`JE. Promethazine-induced
`T, Simon
`DeGrandi
`Care
`1987;3:91-2.
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`R, Karambelkar
`Melnick
`B, Sawyer
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`1989;69:748-51.
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`PF. Antiemetic
`Bodner
`M, White
`Analg
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`laparoscopy.
`Anesth
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`T, et al. Comparison
`McKenzie
`R, Kovac
`A, O’Connor
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`and
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`versus
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`to prevent
`vomiting
`in women
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`ambulatory
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`-
`gery. Anesthesiology
`1993;%:21-8.
`-.
`Scuderi
`I’. Wetchler
`B. SunPr Y, et al. Treatment
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`w&h
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`Anesthesiology
`1993;78:15-20.
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`DJ, Moore
`RA, McQuay
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`J Clin Oncol
`
`dose range and the side effect profile using a placebo-
`controlled, dose-ranging study design.
`In conclusion, RS-25259 30 &kg
`IV was effective
`in preventing PONV
`in women undergoing major
`gynecologic surgery. However,
`it did not decrease
`postoperative nausea or improve patient satisfaction.
`Of concern, postoperative headaches were increased
`in patients who received larger doses of RS-25259.
`
`the use of domperi-
`of
`in the prevention
`of nau-
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`Br J
`
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`Pharmacol
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`after
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`
`I/II
`C, Fine S, et al. Phase
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`for
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`
`Exh. 1008
`
`

`
`ANESTH
`1998;87:462-7
`
`ANALG
`
`THE ANTIEMETIC
`
`EFFICACY
`
`ET AL.
`TANG
`OF R’S25259
`
`467
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`the 24-hour
`Anaesthesia
`
`for
`
`Exh. 1008