proceedings of the Symposium on Contemporary Issues in
`Hodgkin’s Disease: Biology, Staging, and Treatment
`
`Cancer Clinical Investigation Review Committee
`National Cancer Institute
`
`Organizing Committee: Clara D. Bloomfield
`Stephen E. Jones
`Bruce A. Peterson
`
`September 9-12, 1982
`San Francisco, California
`
`HELSINN EXHIBIT 2083
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`Page 1 of 2 IPR2025-00947
`
`.
`
`
`
`
`
`
`
`
`
`Combination Antiemetics
`
`Nausea and vomiting secondary to agents such
`as cisplatin are a major cause of morbidity in cancer
`chemotherapy (1). Gastrointestinal upset occurs in
`as many as 83% of these patients and may, in fact,
`be the limiting factor in chemotherapy (2). At the
`present time, only three major drug classes have
`been considered to be effective antiemetics: anti-
`histamines, anticholinergics, and dopamine antag-
`onists. These drugs are thought to act on the chemo-
`receptor trigger zone and/or emetic center in the
`medulla oblongata (2) where recent neuropharma-
`cologic techniques have demonstrated the presence
`of histamine H, (3), muscarinic cholinergic (4), and
`dopamine (5) receptors. However, no single agent
`has yet proved to be effective in relieving severe
`nausea and vomiting. It thus follows logically that
`antiemetic efficacy might be improved by combining
`drug effects at all three proposed sites of action.
`
`Morran et al (1) reported that the combination of
`fluphenazine and nortriptyline significantly reduced
`the incidence and severity of nausea and vomiting
`during cancer chemotherapy. The effectiveness of
`nortriptyline, an antidepressant, was thought to be
`related “to the relief of psychiatric morbidity which
`is common in patients receiving chemotherapy” (1).
`More likely, nortriptyline’s antiemetic actions de-
`rive from its potent antihistamine and anticholin-
`ergic properties which have been documented in
`neurotransmitter receptor binding studies (6). In
`combination with fluphenazine, simultaneous block-
`ade of histamine H,, muscarinic cholinergic, and do-
`pamine receptors occurs.
`
`Other evidence also supports this hypothesis. Eight
`oncology patients at Stanford University Hospital
`were treated with prochlorperazine (10 mg iv every
`4 hours) and diphenhydramine (25 mg iv every 4
`hours) beginning 30 minutes prior to a 24-hour cis-
`platin infusion. Each patient had previously re-
`ceived between two and 11 cycles of cisplatin. Seven
`of the eight patients reported subjective prefer-
`ences for the drug combination over any single agent
`used during prior chemotherapy cycles. The eighth
`patient denied any significant decrease in the amount
`of nausea and vomiting experienced during the cis-
`platin infusion. As with fluphenazine and nortrip-
`tyline, the simultaneous use of prochlorperazine and
`diphenhydramine results in blockade of dopamine,
`
`LETTERS
`
`muscarinic cholinergie, and histamine H, receptors.
`In summary, dopamine, cholinergic, and hista-
`mine antagonists all display antiemetic actions which
`are mediated via different pathways (2). Current
`neuropharmacologic techniques such as receptor
`binding assays provide a rapid and accurate meas-
`ure of antiemetic effects at central nervous system
`receptor sites. It seems logical to employ these tech-
`niques to maximize antiemetic actions in the central
`emetic pathway. We are presently conducting a clin-
`ical trial to further investigate this hypothesis.
`
`REFERENCES
`
`1. MorrAN C, SmiTH DC, ANDERSON DA, ET AL. Incidence of
`nausea and vomiting with cytotoxic chemotherapy: a pro-
`spective randomised trial of antiemetics. Br Med J 1:1323—
`1324, 1979.
`
`2. SEIGEL LJ, and LoNGo DL. The control of chemotherapy
`induced emesis. Ann Intern Med 95:352-359, 1981.
`
`3. ParacrosJM, WaMsLEYJK, and KUuHAR MJ. The distribution
`of histamine-H, receptors in the rat brain: an autoradi-
`ographic study. Neuroscience 6:15-37, 1981.
`
`4. WaMmsLEY JK, LEwis MS, Younc WS, III, ET AL. Autoradi-
`ographic localization of muscarinic cholinergic receptors in rat
`brainstem. J Neurosci Res 1:176-191, 1981.
`
`5. STEFANINI E, and CLEMENT-CORMIER Y. Detection of dopa-
`mine receptors in the area postrema. EurJ Pharmacol 74:257—
`260, 1981.
`
`6. PErROUTKA SJ, and SNYDER SH. Long-term antidepressant
`treatment decreases spiroperidol-labeled serotonin receptor
`binding. Science 210:88-90, 1980.
`
`Stephen J. Peroutka
`
`Department of Neuroscience
`The Johns Hopkins University
`School of Medicine
`
`725 N Wolfe St
`
`Baltimore, MD 21205
`
`January 18, 1982
`
`Streptozocin-Induced Eosinophilia and
`Fever: A Case Report!
`
`Streptozocin, a nitrosourea compound, has been
`used alone or with 5-FU to treat pancreatic islet
`cell carcinoma and carcinoid tumors (1-4). Its major
`toxic effects are renal and gastrointestinal. Uremia
`
`!Supported by a grant from the General Clinical Research
`Centers Branch (RR-53).
`
`Cancer Treatment Reports Vol. 66, No. 6, June 1982 1449
`
`Page 2 of 2
`
`
`
`
`
`
`
`
`
`