Cancer Chemother Pharmacol (1989) 24:307-310
`
`ancer
`hemotherapy and
`harmacology
`© Springer-Verlag 1989
`Differential interactions of traditional and novel antiemetics
`with dopamine D z and 5-hydroxytryptamine 3 receptors
`Anne Hamik and Stephen J. Peroutka
`Department of Neurology, Stanford University Medical Center, Stanford, CA 94305, USA
`Summary. The affinities of 11 drugs for both dopamine D2
`and 5-hydroxytryptamine3 (5-HT3) receptor sites were de-
`termined in brain membranes. The five "traditional" anti-
`emetics (chlorpromazine, prochlorperazine, droperidol,
`fluphenazine, and domperidone) displayed high affinity
`(< 20 nM) for dopamine D2 receptors in corpus striatum
`but were inactive at 5-HT3 receptors. In contrast, five re-
`cently developed 5-HT3 antagonists (BRL 43694,
`ICS 205-930, zacopride, Lilly 278584, and MDL 72222)
`displayed nanomolar affinity for the 5-HT3 site but were
`inactive (> 10,000 nM) at the dopamine D 2 receptor. Meto-
`clopramide was unique among these agents in that it was
`similarly potent at dopamine D2 (240+_60 nM) and 5-HT3
`(120 +_ 30 nM) receptors.
`Introduction
`Nausea and vomiting resulting from cancer chemotherapy
`are common side effects that can cause patients to refuse
`subsequent chemotherapeutic sessions [19]. However,
`against certain types of chemotherapy- or radiation-in-
`duced nausea and vomiting, traditional antiemetics such
`as dopamine D2 receptor antagonists [27, 30, 33] are only
`minimally effective. Moreover, dopamine D2 antagonists
`often cause side effects such as extrapyramidal symptoms,
`which further restrict their usefulness [3, 17, 21].
`A new class of pharmacological agents has recently
`been developed that appears to possess uniquely potent
`and effective antiemetic activity [24]. These drugs have
`been designated 5-hydroxytryptamine3 (5-HT3) receptor
`antagonists and include drugs such as ICS 205-930 and
`MDL 72222 [12, 28]. Metoclopramide, traditionally con-
`sidered to be a dopaminergic antagonist, has also been re-
`ported to have 5-HT3 receptor antagonist properties
`[13, 22]. In animals, 5-HT3 antagonists block both cytotox-
`ic drug- and radiation-induced emesis [1, 6, 11, 22-24, 31].
`These drugs also appear to abolish nausea and vomiting in
`patients receiving cytotoxic drugs [4, 10, 20]. In the present
`study, a series of five traditional dopamine D2 antagonists,
`five recently developed 5-HT3 antagonists, and metoclo-
`pramide were analyzed at both dopamine D2 and 5-HT3 re-
`ceptor binding sites in brain membranes.
`Offprint requests to: S. J. Peroutka
`Material and methods
`Radioligand-binding studies were carried out according to
`the methods of Ison and Peroutka [18] and Peroutka and
`Hamik [26]. Frozen rat brains (Pel Freez Biologicals; Ro-
`gers, Ark) were thawed from - 20 ° C and dissected. Tissue
`was homogenized in 20 vol. 50 mMTRIS (pH 7.7 at 25 ° C)
`for [3H]-spiperone binding or Krebs-HEPES buffer for
`[3H]-quipazine assays and centrifuged at 49,000g for
`10 min. Cortical tissue was used for [3H]-quipazine binding
`and corpus striatum, for [3H]-spiperone binding. The su-
`pernatant was discarded and the pellet resuspended in the
`same volume of buffer. After a 10-min incubation at 37 ° C,
`the tissue was again centrifuged. The final pellet was resu-
`spended in 80 vol. assay buffer. For dopamine binding
`([3H]-spiperone +40 nM ketanserin [25]), the assay buffer
`consisted of lO-SM pargyline, 4 mM CaC12, and 0.1% as-
`corbate in 50 mM TRIS. [3H]-Quipazine binding was car-
`ried out in a Krebs-HEPES buffer that consisted of 25 mM
`HEPES, 120 mM NaC1, 2.5 mM CaCI2, 4.8 mM KC1, and
`1.2 mM MgCI2 (pH adjusted to 7.4).
`Binding assays consisted of 0.1 ml [3H]-ligand, 0.1 ml
`buffer or displacing drug, and 0.8 ml tissue homogenate.
`Following a 30-rain incubation at 25 ° C, the assays were
`rapidly filtered under vacuum through ~¢ 32 glass-fiber fil-
`ters (Schleicher and Schuell; Keene, NH) with two 5-ml
`washes using 50 mM TRIS buffer. Radioactivity was mea-
`sured by liquid scintillation spectroscopy in 2.5 ml scintil-
`lation cocktail (Research Products International; Mr.
`Prospect, Ill) at 61% efficiency. All experiments were car-
`ried out in triplicate and repeated 3-6 times. Specific
`binding was defined as the excess over blanks taken in the
`presence of 10-6M (+)butaclamol for [3H]-spiperone
`binding and 10 -7 M ICS 205-930 for [3H]-quipazine bind-
`ing. Generally, 75% of the [3H]-spiperone binding and 40%
`of the [3H]-quipazine binding was specific.
`Drugs were prepared for experiments as follows: endo-
`N-(9-methyl-9-azabicyclo-[3,2,1 ]non-3-yl)- 1 -methyl- 1 H-in-
`dazole-3-carboxamide (BRL43694), (3a-tropanyl)-lH-
`indole-3-carboxylic acid ester (ICS 205-930), zacopride,
`1 -methyl- N-(8-methyl-8-azabicyclo[3.2.1 ]oct-3-yl)- 1 H-
`indazole-3-carboxamide (Lilly 278584), and meto-
`clopramide were dissolved in assay buffer; laH,3a,5aH-
`tropan-3-yl-3,5-dichlorobenzoate (MDL 72222), chlorpro-
`mazine, and ketanserin were dissolved in dH20 and
`then diluted in assay buffer; (+)butaclamol, droperidol,
`and fluphenazine were dissolved in 25%-50% EtOH at
`HELSINN EXHIBIT 2078
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 4
`
`
`
`
`
`
`
`308
`10 -3 M and then diluted in buffer; and domperidone and
`prochlorperazine were dissolved in 25% 1 M acetic acid 7 ~ 100
`and diluted in assay buffer. - u_ _z 8o
`Drugs and chemicals were obtained from the following ~ m
`sources: [3H]-quipazine (52.3 Ci/mmol) and [3H]-spiperone ~ 7 w 60
`(21.4 Ci/mmol), Dupont New England Nuclear (Boston,
`Mass); BRL43694, Beecham (Betchworth, England); 7~ "~ w ___ 40
`ICS205-930, Sandoz Pharmaceuticals (East Hanover, ~
`N J); zacopride, A.H. Robins (Richmond, Va); Lilly o_ 20 -r
`278584, Lilly Research Laboratories (Indianapolis, Ind);
`metoclopramide, chlorpromazine, TRIS-HC1, HEPES, o 11
`and pargyline, Sigma Chemical Co. (St. Louis, Mo); pro-
`chlorperazine, Smith Kline and French (Philadelphia, Pa);
`droperidol, domperidone, and ketanserin, Janssen Phar-
`maceutica (New Brunswick, N J); (+)butaclamol, Re-
`search Biochemicals Inc. (Wayland, Mass); CaC12, Fisher
`Scientific (Phillipsburg, N J); ascorbic acid and NaC1,
`Mallinckrodt (Paris, Ky); and MgC12 and KC1, J. T. Baker
`Chemical Co. (Phillipsburg, N J).
`Results
`Drug interaction with 1)2 receptors
`The results of drug competition studies are given in Table 1. Drug
`The traditional antiemetics were, as previously reported
`[18], quite potent at the dopamine D2 site; K i values ranged
`from 2.4+0.6nM for droperidol to 18_+5 nM for chlor-
`promazine. Metoclopramide demonstrated a K i value of
`240_+ 60 nM (n = 10). By contrast, putative 5-HT3 antago-
`nists were inactive at the dopamine D2 site in the rat cor-
`pus striatum. BRL43694, ICS 205-930, zacopride, Lilly
`278584, and MDL 72222 all demonstrated K i values of
`> 10,000 nM. Representative drug competition curves for
`ICS 205-930, metoclopramide, and domperidone against
`specific dopamine D2 receptors are shown in Fig. 1 A.
`Drug interactions with 5-HT3 receptors
`Drug affinities were determined at 5-HT3 membrane-rec-
`ognition sites labeled by [3H]-quipazine. Of the 11 drugs
`analyzed, 4 demonstrated less than nanomolar affinity for
`the 5-HT3 site. These drugs (BRL 43694, ICS 205-930, za-
`z
`~ loo
`m ~
`E = ~ 60
`n +
`03
`~ 40
`Z 0
`W c,~
`~ 20
`w E
`n
`L
`11
`A , • ' , , , , ,
`• metoclopramide ~ I1~
`o ics 205-930 --~ "~
`i i i i 1 i i
`10 9 8 7 6 5 4
`-log[DRUG]
`Fig. 1A. Drug competition studies vs specific [3H]-spiperone
`+40 M ketanserin binding in rat corpus striatum. Radioligand-
`binding assays were carried out as described in Materials and
`methods. Nonspecific binding was determined in the presence of
`1 l-tM (+) butaclamol. Data shown are the results of a single ex-
`periment carried out in triplicate. Each experiment was repeated
`3-6 times
`0
`I I I 0 ~
`10 9 8 7 6
`0 ICS 205--930
`• metocloprarnide
`• dompeHdone
`t r
`5 4 3
`log[DRUG]
`Fig. 1B. Drug competition studies vs specific [3H]-quipazine bind-
`ing in rat cortical membranes. Radioligand-binding assays were
`carried out as described in Materials and methods. Nonspecific
`binding was determined in the presence of 100 nM ICS 205-930.
`Data shown are the results of a single experiment carried out in
`triplicate. Each experiment was repeated 3-6 times
`Table 1. Drug affinities for 5-HT3- and dopamine D2-1abeled sites
`in rat brain membranes
`Potency at Potency at Ratio
`5-HT3 Receptors D2 Receptors 5-HT3/D 2
`K, (nM) K, (nM)
`Dopamine drugs:
`Prochlorperazine 1,800 + 300 7.3 + 1 200
`Chlorpromazine 1,900+200 18 ___5 100
`Droperidol 4,200_ 30 2.4 + 0.6 2,000
`Fluphenazine > 10,000 4.8 + 3 > 2,000
`Domperidone > 10,000 12 +3 >800
`5-HT3 drugs:
`BRL 43694 0.30___ 0.04 > 10,000 < 0.001
`ICS 205-930 0.38___0.02 > 10,000 <0.001
`Zacopride 0.42 ___ 0.2 > 10,000 < 0.001
`Lilly 278584 0.52 _ 0.2 > 10,000 < 0.001
`MDL 72222 9.20 _ 1.0 > 10,000 < 0.002
`Mixed drug:
`Metoclopramide 120 + 30 240 _ 60 0.5
`Radioligand-binding studies were carried out as described in Mat-
`erials and methods. Values represent the mean + SE of 3 - 6 expe-
`riments carried out in triplicate
`copride, and Lilly 278584) were essentially equipotent at
`the 5-HT3 site, with Ki values ranging from 0.30 to
`0.52 nM. MDL 72222 was slightly less potent, with a K i
`value of 9.2 + 1 nM. Metoclopramide was the only tradi-
`tional antiemetic that displayed less than micromolar af-
`finity for the 5-HT3 site, with a K, value of 120+30 nM. In
`contrast, the remainder of the traditional antiemetics were
`significantly less potent, with K, values ranging from
`1,800+300 nM for prochlorperazine to > 10,000 nM for
`fluphenazine and domperidone. Representative drug com-
`petition curves are shown in Fig. 1 B.
`Discussion
`The major finding of the present study is that the 11 drugs
`tested showed differential interactions with dopamine D2
`and 5-HT3 receptor sites. The 5-HT3 antagonists, although
`showing nanomolar affinity for central 5-HT3 recognition
`sites, were inactive at dopamine D2 receptor sites. Conver-
`Page 2 of 4
`
`
`
`
`
`
`
`309
`sely, the traditional antiemetics showed high affinity for
`the dopamine D2 site. With the exception of metoclopra-
`mide, these drugs were approximately 100-2,000 times
`more potent at the D2 site than at the 5-HT 3 site. Metoclo-
`pramide appeared to be similarly potent at D2 and 5-HT3
`sites, a unique finding among the 11 drugs tested.
`The antiemetic efficacy of various drugs, including do-
`pamine D2 antagonists, antihistamines, anticholinergics,
`and corticosteroids has been well documented [14, 15, 30,
`32-34]. Unfortunately, these traditional antiemetics pro-
`vide only modest relief from nausea and vomiting in pa-
`tients undergoing therapy with most chemotherapeutic
`drugs; they are of extremely limited value with agents such
`as cisplatin, doxorubicin, and dacarbazine, which induce
`severe nausea and vomiting. Of particular interest is the
`claim that high-dose metoclopramide is the most effective
`agent currently available for the treatment of adverse ef-
`fects caused by these regimens [33].
`In contrast, 5-HT3 antagonists (MDL 72222,
`ICS 205-930, BRL 24924, and GR38032F) are a recently
`developed group of drugs that have been shown to be po-
`tent antiemetics in ferrets receiving cisplatin and total-
`body radiation [6, 7, 8, 22-24, 31]. In recent human trials,
`the 5-HT 3 antagonists GR38032F [101, ICS 205-930 [20],
`and BRL 43694 [4] provided excellent relief from chemo-
`therapy-induced nausea and vomiting. For example, 14 of
`15 patients did not experience nausea or vomiting when
`given GR38032F along with cytotoxic drugs [10]. The only
`adverse effects were headache and mild sedation with
`ICS205-930 and dry mouth and mild sedation with
`GR38032F. Therefore, 5-HT3 antagonists appear to be ex-
`tremely effective antiemetics when given with strongly
`emetic anticancer agents.
`The mechanism(s) by which the drugs examined in this
`study relieve nausea and vomiting are not completely
`known [2]. Specific dopamine D2 antagonists are thought
`to act via central dopamine antagonism in the chemore-
`ceptor trigger zone [15]. Metoclopramide is thought to act
`at the cortex as well as with receptors in the periphery,
`where it induces gastric motility and emptying [16, 29].
`This peripheral action may be explained in part by antag-
`onism of dopamine D2 receptors. However, since the role
`of dopamine in the control of gut motility seems minor,
`other mechanisms must exist through which metoclopra-
`mide exerts these effects [29]. It seems likely that this drug
`interacts with 5-HT3 receptors located in the enteric sys-
`tem, and it may mediate gastric effects through this mecha-
`nism. In addition, since metoclopramide has relatively
`high affinity for 5-HT3 recognition sites in rat brain tissues,
`some of its antiemetic effects may be due to its interactions
`with these CNS sites.
`The antiemetic effects of the 5-HT3 antagonists appear
`to be a consequence of 5-HT 3 blockade; however, whether
`this is due to largely peripheral actions or to both periph-
`eral and central interaction with the receptor remains un-
`clarified. For example, at small doses BRL 24924 (a potent
`stimulant of gastric motility [51) mimics abdominal vagot-
`omy in total-body-irradiated ferrets; that is, retching and
`vomiting is delayed by 30 min. Higher doses of BRL 24924
`almost eliminate retching and vomiting for the entire
`90-min test period [1]. These results were interpreted as in-
`dicating that BRL 24924 may, in addition to its probable
`action at the abdominal vagi, have an important effect in
`another area of the body.
`In addition to their direct effect on 5-HT transmission,
`the 5-HT3 antagonists may also have some modulatory ef-
`fects on the dopaminergic system. A potent and highly se-
`lective 5-HT3 antagonist, GR38032F, has been shown to
`modulate hyperactivity resulting from dopamine adminis-
`tration to rats and marmosets [9]. GR38032F was hypo-
`thesized to work by interrupting a 5-HT-dopamine-5-HT
`loop by which 5-HT serves to facilitate dopaminergic
`transmission. Perhaps a similar interaction between 5-HT
`and dopamine transmission is involved in the reduction of
`nausea and vomiting by 5-HT3 antagonists.
`However, the direct antagonism of dopamine D2 recep-
`tors does not appear to be necessary for effective anti-
`emetic treatment. Metoclopramide, which is significantly
`less potent at dopamine D2 receptors than are the other
`traditional dopamine D 2 antiemetic agents, has also been
`shown to be the most effective antiemetic of the group [33].
`Recent trials suggest that the 5-HT3 antagonists are at least
`as effective as metoclopramide in reducing or eliminating
`nausea and vomiting resulting from chemotherapy. Thus,
`it is not apparent that the dopamine D2 antiemetic effects
`of metoclopramide are a necessary component of its anti-
`emetic efficacy; its 5-HT3 antagonism alone may be suffi-
`cient to control emesis effectively.
`Finally, radioligand-binding studies may be used as a
`screening tool for the selection of clinically useful drugs.
`For example, in the present study, two of the 5-HT3 antag-
`onists (zacopride and Lilly 278584) were not shown to
`have antiemetic effects. These drugs showed a binding pat-
`tern similar to those of the demonstrated antiemetics
`ICS 205-930, MDL 72222, and BRL 43694; that is, high af-
`finity for the 5-HT3 site in cortical tissue and inactivity at
`the dopamine D2 site in corpus striatum. Zacopride shows
`an affinity for the 5-HT3 site similar to that of BRL 43694.
`Lilly 278584 is more potent at the site than is MDL 72222.
`Thus, we would predict that both of these drugs would be
`effective in reducing emesis caused by agents such as cis-
`platin or by total-body radiation.
`In summary, this study demonstrates that affinities of
`drugs to 5-HT3 and dopamine D 2 sites correlates with their
`efficacy as antiemetics. Metoclopramide is superior to the
`other traditional agents in its antiemetic action and is also
`the only traditional agent that displays moderate affinity
`for 5-HT3 receptors. Clinical trials with the 5-HT3 antago-
`nists MDL 72222, ICS 205-930, BRL 43694, and
`GR38032F have shown them to be at least equal to, and
`probably superior to, metoclopramide in antiemetic effi-
`cacy. These data indicate that the 5-HT3 receptor plays a
`novel and important role in the pathophysiology of nausea
`and vomiting.
`References
`1. Andrews PLR, Hawthorn J (1987) Evidence for an extra-ab-
`dominal site of action for the 5-HT 3 receptor antagonist
`BRL24924 in the inhibition of radiation-evoked emesis in the
`ferret. Neuropharmacology 26:1367
`2. Andrews PLR, Rapeport WG, Sanger GJ (1988) Neurophar-
`macology of emesis induced by anti-cancer therapy. TIPS 9:
`334
`3. Arrowsmith J, Gams RA (1981) Dystonia with droperidol
`therapy. New Engl J Med 305 : 227
`4. Carmichael J, Cantwell BMJ, Edwards CM, Rapeport WG,
`Harris AL (1988) The serotonin type 3 receptor antagonist
`BRL 43694 and nausea and vomiting induced by cisplatin. Br
`MedJ 297:110
`Page 3 of 4
`
`
`
`
`
`
`
`310
`5. Cooper SM, McClelland CM, McRitchie B, Turner DH
`(1986) BRL 24924: a new and potent gastric motility stimu-
`lant. Br J Pharmacol [Suppl]: 383, volume 88
`6. Costall B, Domeney AM, Naylor RJ, Tattersall FD (1986)
`5-Hydroxytryptamine M-receptor antagonism to prevent cis-
`platin-induced emesis. Neuropharmacology 25:959
`7. Costall B, Kelly ME, Naylor RJ, Tan CCW, Tattersall FD
`(1986) 5-Hydroxytryptamine M-Receptor antagonism in the
`hypothalamus facilitates gastric emptying in the guinea-pig.
`Neuropharmacology 25 : 1293
`8. Costall B, Domeney AM, Gunning S J, Naylor R J, Tattersall
`FD, Tyers MB (1987) GR38032F: a potent and novel inhibi-
`tor of cisplatin-induced emesis in the ferret. Br J Pharmacol
`[Suppl]: 90, volume 90
`9. Costall B, Domeney AM, Naylor RJ, Tyers MB (1987) Effects
`of the 5-HT 3 receptor antagonist, GR38032F, on raised dopa-
`minergic activity in the mesolimbic system of the rat and mar-
`moset brain. Br J Pharmacol 92:881
`10. Cunningham D, Pople A, Ford HT, Hawthorn J, Gazet JC,
`Challoner T, Coombes RC (1987) Prevention of emesis in pa-
`tients receiving cytotoxic drugs by GR38032F, a selective
`5-HT 3 receptor antagonist. Lancet I: 1461
`11. De Haan LD, De Mulder PHM, Beex LVAM, Debruyne
`FMJ, Challoner T, De Pauw BE (1988) The efficacy of
`GR38032F, an antagonist of 5-hydroxytryptamine-3 (5-HT3)
`in the prophylaxis of cisplatin (CDDP)-induced nausea and
`vomiting. Eur J Clin Oncol 8:1383
`12. Fozard JR (1984) MDL 72222: a potent and highly selective
`antagonist at neuronal 5-hydroxytryptamine receptors. Nau-
`nyn-Schmiedeberg Arch Pharmacol 326:36
`13. Fozard JR (1987) 5-HT 3 receptors and cytotoxic drug-induced
`vomiting. TIPS 8:44
`14. Gralla RJ, Itri LM, Pisko SE, Squillante AE, Kelsen DP,
`Braun DW, Bordin LA, Braun TJ, Young CW (1981) Anti-
`emetic efficacy of high-dose metoclopramide: randomized
`trials with placebo and prochlorperazine in patients with
`chemotherapy-induced nausea and vomiting. New Engl J
`I Med 305:905
`15. Gralla RJ, Tyson LB, Bordin LA, Clark RA, Kelsen DP, Kris
`MG, Kalman LB, Groshen S (1984) Antiemetic therapy: a re-
`view of recent studies and a report of a random assignment
`trial comparing metoclopramide with delta-9-tetrahydrocan-
`nabinol. Cancer Treat Rep 68:163
`16. Harrington RA, Hamilton CW, Brogden RN, Linkewich JA,
`Romankiewicz JA, Heel RC (1983) Metoclopramide: an up-
`dated review of its pharmacological properties and clinical
`use. Drugs 25 : 451
`17. Indo T, Ando K (1982) Metoclopramide-induced parkinson-
`ism: clinical characteristics of ten cases. Arch Neurol 39:494
`18. Ison PJ, Peroutka SJ (1986) Neurotransmitter receptor bind-
`ing studies predict antiemetic efficacy and side effects. Cancer
`Treat Rep 70:637
`19. Laszlo J, Lucas VS Jr (1981) Emesis as a critical problem in
`chemotherapy. New Engl J Med 305 : 948
`20. Leibundgut U, Lancranjan I (1987) First results with
`ICS 205-930 (5-HT 3 receptor antagonist) in prevention of che-
`motherapy-induced emesis. Lancet I: 1198
`21. Leopold NA (1984) Prolonged metoclopramide-induced dys-
`kinetic reaction. Neurology 34:238
`22. Miner WD, Sanger GJ (1986) Inhibition of cisplatin-induced
`vomiting by selective 5-hydroxytryptamine M-receptor antag-
`onism. Br J Pharmacol 88:497
`23. Miner WD, Sanger GJ, Turner DH (1986) Comparison of the
`effect of BRL 24924, metoclopramide and domperidone on
`cisplatin-induced emesis in the ferret. Br J Cancer [Suppl 1]:
`374
`24. Miner WD, Sanger GJ, Turner DH (1987) Evidence that
`5-hydroxytryptamine receptors mediate cytotoxic drug- and
`radiation-evoked emesis. Br J Cancer 56:159
`25. Norman AB, Battaglia G, Creese I (1987) Differential recov-
`ery rates of rat D 2 dopamine receptors as a function of aging
`and chronic reserpine treatment following irreversible modifi-
`cation: a key to receptor regulatory mechanisms. J Neuro-
`sci 7:1484
`26. Peroutka SJ, Hamik A (1988) [3H]Quipazine labels 5-HT 3
`recognition sites in rat cortical membranes. Eur J Pharma-
`col 148:297
`27. Peroutka S J, Snyder SH (1982) Antiemetics: neurotransmitter
`receptor binding predicts therapeutic actions. Lancet I: 658
`28. Richardson BP, Engel G (1986) The pharmacology and func-
`tion of 5-HT 3 receptors. Trends Neurosci 7: 424
`29. Schulze-Delrieu K (1981) Metoclopramide. New Engl J
`Med 305 : 28
`30. Seigel LJ, Longo DL (1981) The control of chemotherapy-
`induced emesis. Ann Intern Med 95:352
`31. Stables R, Andrews PLR, Bailey HE, Costall B, Gunning S J,
`Hawthorn J, Naylor RJ, Tyers MB (1987) Antiemetic proper-
`ties of the 5HT3-receptor antagonist GR38032F. Cancer Treat
`Rev 14:333
`32. Strum SB, McDermed JE, Opfell RW, Riech LP (1982) In-
`travenous metoclopramide: an effective antiemetic in cancer
`chemotherapy. JAMA 247: 2683
`33. Triozzi PL, Laszlo J (1987) Optimum management of nausea
`and vomiting in cancer chemotherapy. Drugs 34:136
`34. Wampler G (1983) The pharmacology and clinical effective-
`ness of phenothiazines and related drugs for managing che-
`motherapy-induced emesis. Drugs 25 [Suppl 1]: 35
`Received 15 November 1989/Accepted 10 March 1989
`Page 4 of 4
`
`
`
`
`
`
`
`