A kemoterápia okozta hányinger/hányás (CINV) kórélettana

Az előadások a következő témára: "A kemoterápia okozta hányinger/hányás (CINV) kórélettana"— Előadás másolata:

1 A kemoterápia okozta hányinger/hányás (CINV) kórélettana
Slide 1 References: 1 Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94 2 Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880 3 Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796 4 Gralla RJ, Osoba D, Kris MG et al, for the American Society of Clinical Oncology. Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. J Clin Oncol 1999;17:2971–2994 5 Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 1998;9:811–819 6 Endo T, Minami M, Hirafuji M et al. Neurochemistry and neuropharmacology of emesis—the role of serotonin. Toxicology 2000;153:189–201 7 Hesketh PJ, Van Belle S, Aapro M et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003;39:1074–1080 8 Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs 2000;60:533–546 9 Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060 10 Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy. Support Care Cancer 1998;6:197–203 11 DeVane CL. Substance P: A new era, a new role. Pharmacotherapy 2001;21:1061–1069 12 Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002;63(suppl 11):18–24 13 Saria A. The tachykinin NK1 receptor in the brain: Pharmacology and putative functions. Eur J Pharmacol 1999;375:51–60. 14 Hesketh PJ. Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 2001;9:350–354 15 Tattersall FD, Rycroft W, Francis B et al. Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 1996;35:1121–1129 16 Pisters KM, Kris MG. Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman JE, eds. Principles and Practice of Supportive Oncology. Philadelphia, PA: Lippincott-Raven; 1998:165–177 17 Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985;3:1379–1384 18 Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996;52:639–648 19 Janes RJ, Muhonen T, Karjalainen UP et al. Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy. Eur J Cancer 1998;34:196–198 20 Wilder-Smith OH, Borgeat A, Chappuis P et al. Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 1993;72:2239–2241 21 Cocquyt V, Van Belle S, Reinhardt RR et al. Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis. Eur J Cancer 2001;37:835–84 22 Campos D, Pereira JR, Reinhardt RR et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001;19:1759–1767

2 A kemoterápia okozta hányinger/hányás (CINV) kialakulásának mechanizmusa
R. Berger p. 2869 Par. 5 L. 6 Par. 6 L. 1 Központi folyamat A kemoterápiás szer aktiválja a kemoreceptor-triggerzónát (CTZ) Az aktivált CTZ különféle neurotranszmittereket felszabadítva ingerli a hányásközpontot Perifériás folyamat A kemoterápiás szer irritálja és károsítja a gasztrointesztinális (GI) nyálkahártyát, ami neurotranszmitter-felszabadulást eredményez Az így aktiválódott receptorok jelzéseket küldenek a hányásközpontnak a vagus afferensein keresztül R. Berger p. 2871 Par. 1 L. 1 Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 R. 1 p. 87 Par. 1 L. 1 R. 2 p. 2869 Par. 5 L. 1 R. 2 p. 2869 Par. 5 L. 6 Par. 6 L. 1 R. 3 p. 1790 Par. 7 L. 5 R. 2 p. 2871 Par. 1 L. 5 Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869–2880. R. 2 p. 2869 Par. 6 L. 5 p. 2871 Par. 1 L. 6 References 1. Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. 2. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. 3. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

3 A kemoterápia okozta hányinger/hányás (CINV) feltételezett útvonalai
Grunberg SM et al N Engl J Med 1993;329:1790–1796.

4 A szerotonin és az 5-HT3-receptor útvonal
R. Berger p. 2870 Par. 5 L. 6 A szerotonin és az 5-HT3-receptor útvonal R. Gralla p. 2978 Par. 6 L. 1 p. 2980 Par. 7 pp Par. Cont. L. 6 R. MASCC p. 812 p. 813 Par. 5 T. 2 R. Gralla p. 2974 Par. 9 L. 5 R. MASCC P. 816 Par. 10 L. 1 Elsőként a nagy dózisú metoclopramid adásánál figyeltek fel rá A szerotoninreceptor-antagonisták kifejlesztése nagy hatást gyakorolt a CINV kezelésére Különösen hatásosak a heveny szakaszban, hatásuk gyenge a késői szakaszban Hatásukat főként szteroiddal kombinálva fejtik ki Ez az út főként a perifériásan felszabaduló szerotonin kötődésének gátlásával kezelhető R. Endo p. 198 Par. 1 L. 11 R. Hesketh p. 1075 Par. 5 L. 1 Slide 4 The role of serotonin in chemotherapy-induced nausea and vomiting (CINV) was first recognized by investigating the mechanism of action of high-dose metoclopramide. Unlike other dopamine-receptor antagonists, metoclopramide showed significant efficacy against cisplatin-induced emesis. Recognition of the antiserotonergic effects of high-dose metoclopramide led to the development of agents that are selective for 5-HT3 receptors.2 The introduction of this class of antiemetic agents has dramatically reduced CINV in clinical practice.4,5 As reflected in practice guidelines for highly emetogenic chemotherapy, a 5-HT3 receptor antagonist combined with a corticosteroid significantly reduces acute CINV. For preventing delayed symptoms, 5-HT3 receptor antagonists are less effective.4,5 Based on the vast accumulated literature to date, the primary mechanism of action for 5-HT3 receptor antagonists is thought to be antagonism of peripherally released serotonin.6,7 R. 2 p. 2870 Par. 5 L. 6 p. 2873 Par. 3 L. 1 p. 2874 R. 4 p. 2974 Par. 9 L. 5 R. 5 P. 816 Par. 10 L. 1 R. 4 p. 2978 Par. 6 L. 1 p. 2980 Par. 7 pp Par. Cont. L. 6 p. 2982 T. 4A L. 15 R. 5 p. 812 Par. 5 p. 813 T. 2 R. 6 p. 198 Par. 1 L. 11 R. 7 p. 1075 Par. 5 L. 1 Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869–2880. Gralla RJ et al J Clin Oncol 1999;17:2971–2994. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811–819. Endo T et al Toxicology 2000;153:189–201. Hesketh PJ et al Eur J Cancer 2003;39:1074–1080. References 2. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. 4. Gralla RJ, Osoba D, Kris MG et al, for the American Society of Clinical Oncology. Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. J Clin Oncol 1999;17:2971–2994. 5. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 1998;9:811–819. 6. Endo T, Minami M, Hirafuji M et al. Neurochemistry and neuropharmacology of emesis—the role of serotonin. Toxicology 2000;153:189–201. 7. Hesketh PJ, Van Belle S, Aapro M et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003;39:1074–1080.

5 A kemoterápia okozta hányinger/hányás (CINV) kialakulásában több neurotranszmitter játszik szerepet
R. Diemunsch p. 534 Fig. 1 p. 535 Par. 3 L. 1 R. Grunberg p. 1791 Par. 1 L. 1 Par. 2 p. 1792 P-anyag Acetil-kolin Hisztamin Endorfinok Dopamin Szerotonin GABA* Hányinger- reflex R. Hornby p. G1057 Fig. 2 Slide 5 This slide depicts our current understanding of the neurotransmitters involved in chemotherapy-induced nausea and vomiting (CINV), including the most recently identified emetic neurotransmitter, substance P.3,8,9 Peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, substance P, dopamine, histamine, and other endogenous neurotransmitters. When these receptors are activated, emesis is induced.3,8 In the past 15 years or so, enormous advances have been made in our understanding of the neurochemical pathways involved in CINV. The advent of selective 5-HT3 receptor antagonists has served as a pharmacologic tool for studying the emetic pathways associated with CINV. The introduction of this class of drugs stimulated considerable clinical research and improved our understanding of CINV.10 Where the original preclinical efficacy trials of 5-HT3 receptor antagonists once involved an observation period of 4 hours,10 today we have a better appreciation of delayed symptoms, which can span several days following chemotherapy. The discovery of substance P was first reported in Some 70 years later, we now understand that this neurotransmitter plays an integral role in relaying noxious sensory information to the brain. As a modulator of nociception, it is involved in several physiologic activities, including the vomiting reflex.11 R. 8 p. 534 Fig. 1 p. 535 Par. 3 L. 1 R. 3 p. 1791 Par. 1 Par. 2 p. 1792 R. 9 p. G1057 Fig. 2 R. 10 p. 197 Par. 1 L. 1 Par. 2 L. 15 L. 5 * γ-amino-vajsav (gamma-aminobutyric acid) Diemunsch P, Grélot L Drugs 2000;60:533–546. Grunberg SM, Hesketh PJ N Engl J Med 1993;329:1790–1796. Hornby PJ Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060. R. 11 p. 1061 Par. 1 L. 1 p. 1068 Par. 4 L. 4 p. 1062 References 8. Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs 2000;60:533–546. 3. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796. 9. Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060. 10. Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy. Support Care Cancer 1998;6:197–203. 11. DeVane CL. Substance P: A new era, a new role. Pharmacotherapy 2001;21:1061–1069.

6 A P-anyag és a neurokinin­1 (NK1)-receptor útvonal
R. Hesketh p. 351 Par. 2 L. 23 L. 34 p. 352 T. 2 L. All p. 353 Par. 1 L. 24 R. Hargreaves p. 18 Par. 1 L. 14 pp 21-23 Par. Cont. L. 7 R. Saria p. 52 L. 11 Az NK1-receptorok nagy mennyiségben találhatók az agy hányingerreflex (hányás)-központjában Ez az út főként centrálisan, a nyúltagyi NK1-receptorok gátlásával kezelhető. Hatása kiterjed mind a heveny, mind a késői szakaszra is Felerősíti a szetronok és a szteroidok hányás- és hányingercsillapító hatását R. 12 p. 18 Par. 1 L. 1 L. 14 pp 21-23 Par. Cont. L. 7 R. 13 p. 52 L. 11 Slide 6 Substance P, which belongs to the group of peptides known as neurokinins (NK), exerts its effect by binding to the NK1 receptor.12 High concentrations of substance P/NK1 receptors are located in brain regions implicated in the emetic reflex, such as the nucleus tractus solitarius and area postrema.12,13 Unlike 5-HT3 receptor antagonists, which work primarily at a peripheral site, the primary mechanism of NK1 receptor antagonists appears to be central.14 Interesting preclinical research in ferrets by Tattersall et al demonstrated that, in order for an NK1 receptor antagonist to provide antiemetic efficacy, it must be able to penetrate the central nervous system.15 In addition, animal and human studies show that NK1 receptor antagonists inhibit both acute and delayed emetic events. Several clinical trials have demonstrated that the optimal use of an NK1 receptor antagonist is with a 5-HT3 receptor antagonist and corticosteroid.14 R. 14 p. 351 Par. 2 L. 23 R. 15 p. 1127 Par. 1 L. 1 R. 14 p. 351 L. 34 p. 352 T. 2 L. All p. 353 Par. 1 L. 24 Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18–24. Saria A Eur J Pharmacol 1999;375:51–60. Hesketh PJ Support Care Cancer 2001;9:350–354. References 12. Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002;63(suppl 11):18–24. 13. Saria A. The tachykinin NK1 receptor in the brain: Pharmacology and putative functions. Eur J Pharmacol 1999;375:51–60. 14. Hesketh PJ. Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 2001;9:350–354. 15. Tattersall FD, Rycroft W, Francis B et al. Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 1996;35:1121–1129.

7 A neurokinin­1 (NK1)-receptorok elhelyezkedése emberben
Az NK1-receptorokhoz kötődött jelzőanyag képe PET-tel megjelenítve R. Hargreaves, p. 19 Par. 1 L. 8 p. 22 Fig. 5 (100 mg) p. 23 Par. 2 L. 1 Slide 7 Positron emission tomography (PET), a minimally invasive imaging technique, is the leading in vivo receptor imaging technique available for use in humans. PET images are created from the decay of low-dose positron-emitting radionuclides that contain tracer molecules with high selectivity for specific neuroreceptors. This dynamic brain imaging modality is especially useful for providing important information about a drug’s blood-brain penetration and its degree and duration of receptor occupancy.12 Researchers developed a specific tracer, called [18F]SPA-RQ, for PET imaging of NK1 receptors, and verified its suitability in studies with rhesus monkeys and humans. This tracer has a high affinity for the NK1 receptor, with low nonspecific binding and good blood-brain barrier penetration.12 This image shows the tracer binding to NK1 receptors in the brain of a healthy male volunteer, indicating high NK1 receptor expression in the striatum.12 R. 12 p. 19 Par. 1 L. 8 pp 19-20 Par. Cont. L. 1 Nagy NK1-receptor- sűrűség a striatum-ban látható R. 12 p. 24 Par. 1 L. 1 Kicsi Nagy Jelzőanyag koncentrációja R. 12 p. 23 Par. 2 L. 1 Átvéve: Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18–24. Reference 12. Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002;63(suppl 11):18–24.

8 A kemoterápia okozta hányinger/hányás (CINV) heveny szakasza
R. Pisters p. 165 Par. 2 L. 1 p. 168 A kemoterápia beadását követő első 24 órát jelenti A kemoterápiás szerek többsége a beadást követő 1-3 órában okoz hányingert Ez a fázis a kemoterápia okozta hányás és hányinger legtöbbet kutatott szakasza Annak ellenére, hogy a gyógyszeres megelőzés sokat fejlődött, a hányás/hányinger még mindig gyakori jelenség ebben a szakaszban R. MASCC p. 812 Par. 4 L. 1 Slide 8 Nausea and vomiting occurring within the first 24 hours after chemotherapy administration is defined as acute. Most, but not all, chemotherapy agents induce emesis approximately 1–3 hours following administration.16 Considerable research has focused on acute chemotherapy-induced nausea and vomiting (CINV) compared with other types of CINV, such as delayed, anticipatory, breakthrough, and refractory CINV; consequently, the greatest strides in antiemetic treatment have occurred in the control of acute emesis.5,16 While current therapy has dramatically improved protection, acute CINV remains common among patients undergoing chemotherapy.5 R. 16 p. 165 Par. 2 L. 1 p. 168 R. 16 p. 165 Par. 2-6 L. 1 R. 5 p. 812 Par. 4 Pisters KMW, Kris MG. In: Principles and Practice of Supportive Oncology. Lippincott-Raven; Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811–819. References 16. Pisters KM, Kris MG. Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman JE, eds. Principles and Practice of Supportive Oncology. Philadelphia, PA: Lippincott-Raven; 1998:165–177. 5. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 1998;9:811–819.

9 A kemoterápia okozta hányinger/hányás (CINV) késői szakasza
R. Berger p. 2871 Par. 7 L. 7 p. 2875 Par. 1 L. 10 R. MASCC p. 812 L. 3 p. 813 Par. 4 L. 1 p. 814 R. Kris p Par. 2 A kemoterápia okozta hányinger/hányás (CINV) késői szakasza 24 órával a kemoterápia beadása után kezdődik Elsősorban nagydózisú cisplatin esetén jelentkezik, de ismert más kemoterápiás szerek esetén is: Carboplatin Ciklofoszfamid Doxorubicin Epirubicin Antraciklinek A teljes mechanizmus nem ismert, de a heveny szakasztól eltérőnek tűnik R. Berger p. 2875 Par. 4 L. 11 R. MASCC p. 812 Par. 1 L. 10 Slide 9 Delayed chemotherapy-induced nausea and vomiting (CINV) has been arbitrarily defined as nausea and vomiting occurring 24 hours after chemotherapy administration.2,5 It was first described by Kris et al in a study published in 1985 that involved patients receiving high doses of cisplatin.5,17 Additional studies have since determined that delayed CINV can occur with other chemotherapy agents, including carboplatin, cyclophosphamide, doxorubicin, epirubicin, and anthracyclines.2,5 While the mechanism of action for delayed CINV is unclear, it is likely that it is different from the mechanism of action for acute CINV.2,5 R. 5 p. 813 Par. 4 L. 1 R. 17 p. 1379 Par. 2 L. 10 R.2 p. 2871 Par. 7 L. 7 p. 2875 Par. 1 L. 10 R. 5 p. 812 L. 3 p. 813 Par. 4 L. 1 p. 814 R. 2 p. 2875 Par. 4 L. 11 p. 812 Par. 1 L. 10 Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins, 2001:2869–2880. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811–819. References 2. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. 5. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 1998;9:811–819. 17. Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985;3:1379–1384.

10 Hányinger/hányás erőssége
A cisplatin-kemoterápia okozta hányinger/hányás (CINV) erőssége kettős csúcs képét mutatja Heveny szakasz Késői szakasz Hányinger/hányás erőssége Erős R. Tavorath p. 640 Fig. 1 Legend Slide 10 The time course and intensity of CINV seen with cisplatin administration have been well characterized. Traditionally, the pattern of CINV as shown in this graph displays an initial peak in the intensity of cisplatin-induced nausea and vomiting within the first 24 hours after administration, followed by a second, more prolonged phase of lesser intensity occurring during Days 2 to 4.18 Closer examination of the data demonstrates that maximal emetic intensity occurs within 8 to 12 hours after chemotherapy.18 This corresponds with data from other studies documenting the release of serotonin following cisplatin in this same time frame.19,20 A time course study demonstrated a peak of urinary serotonin metabolite excretion at 6 hours following chemotherapy, with levels returning to baseline by 16 hours20 Investigators in a second study also observed a peak of urinary serotonin metabolite excretion at 6 hours as well19 Gyenge R. 18 p. 640 Fig. 1 Legend Time (Days) Kezelés utáni idő (nap) R.20 p. 2240 Par. 3 L. 3 R. 19 p. 197 L. 1 A legerősebb hányinger a kemoterápia utáni első 24 órában tapasztalható Az elsőtől jól elkülönülő második szakasz a 2-5 napon észlelhető Átvéve: Tavorath R, Hesketh PJ Drugs 1996;52:639–648. © Used with permission from Adis International Limited. References 18. Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996;52:639–648. 19. Janes RJ, Muhonen T, Karjalainen UP et al. Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy. Eur J Cancer 1998;34:196–198. 20. Wilder-Smith OH, Borgeat A, Chappuis P et al. Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 1993;72:2239–2241.

11 Szerotonin-kiválasztódás cisplatin-kemoterápia esetén
mol/mmol R. Wilder-Smith p. 2240 Fig. 1 Caption p. 2239 Par. 2 L. 1 Ratio, 5­HIAA*/Creatinine Slide 11 To gauge serotonin release during the time frame associated with both acute and delayed chemotherapy-induced nausea and vomiting (CINV), urinary levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured during the 48 hours after induction of chemotherapy. Ten women who experienced nausea and vomiting refractory to a 5-HT3 receptor antagonist and dexamethasone in their first cisplatin cycle were included in the study. All patients received cisplatin chemotherapy (80 mg/m2) and antiemetic prophylaxis with propofol (1 mg/kg/hr from 4 hours before chemotherapy to 48 hours after chemotherapy), ondansetron hydrochloride (8 mg intravenous [IV] at 30 minutes before chemotherapy and 4 hours after chemotherapy), and dexamethasone (10 mg IV at 30 minutes before chemotherapy). The values depicted in the graph are the means of 30 cycles.20 A single, large peak in 5-HIAA occurred 6 hours after the induction of cisplatin chemotherapy, which coincides with the usual time of acute-phase CINV. 5-HIAA returned to baseline levels 16 hours after chemotherapy induction. Thus, cisplatin is associated with serotonin release in the acute phase but not in the delayed phase. These results suggest different underlying mechanisms for CINV in the acute and delayed phases.20 R. 20 p. 2240 Par. 1 L. 4 Fig. 1 Caption R. 20 p. 2239 Par. 2 L. 1 Idő (óra) Kemoterápia kezdete Vizelettel kiválasztott 5-HIAA szint, cisplatin-kemoterápia mellett alkalmazott ondansetron-hidroklorid, dexametazon és propofol antiemetikus védelem esetén. Az értékek 10 nő-nél alkalmazott 30 cisplatin-ciklus átlagát mutatják, akik az ondansetron-hidroklorid és a dexametazon védelem ellenére az első ciklusnál erős hányingertől szenvedtek. R. 20 p. 2240 Par. 3 L. 3 Par. 7 L. 1 *5-HIAA (5-hydroxyindoleacetic acid) = 5-hidroxi-indolecetsav. Átvéve: Wilder-Smith OH et al Cancer 1993;72:2240. Reference 20. Wilder-Smith OH, Borgeat A, Chappuis P et al. Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 1993;72:2239–2241.

12 A cisplatin-kezelés után: A hányinger/hányás kiváltásában különböző neurotranszmitterek vesznek részt az idő függvényében Heveny szakasz (Első Nap) Késői szakasz (Második naptól) R. Hesketh p. 1079 Par. 3 L. 1 p. 1076 Fig. 1 p. 1078 Fig. 3 Szerotonin kiváltotta mechanizmus (perifériás folyamat) P-anyag kiváltotta mechanizmus (központi folyamat) R. 7 p. 1076 Par. 4 L. 1 p. 1077 Par. 2 Slide 12 Hesketh et al recently evaluated the time course of the antiemetic effect of a 5-HT3 receptor antagonist and a neurokinin-1 (NK1) receptor antagonist.7 Data from two Phase II clinical trials of cancer patients who received either an NK1 receptor antagonist (aprepitant), a 5-HT3 receptor antagonist, or a combination of both agents served as the basis for the time course analysis.21,22 Patients in one of the trials also received dexamethasone.22 Clinical data (i.e., rate of no emesis) suggest that serotonin-dependent mechanisms predominate early during the initial time interval postcisplatin therapy, specifically in the first 8 to 12 hours (early acute). It is likely that the early acute events responsive to 5-HT3 receptor antagonists are mediated by peripheral serotonin release.7 After the first 8 to 12 hours of serotonin-mediated events, it appears that NK1-dependent mechanisms have greater importance. Emetic events in the “late” acute phase (8 to 24 hours after chemotherapy) and in the delayed phase (24 hours to 120 hours after chemotherapy) are likely mediated by substance P acting centrally at NK1 receptors.7 The different patterns of emesis blockade produced by the two classes of drugs, each targeting a different neurotransmitter receptor, provide substantial evidence for separate neurophysiologic mechanisms in chemotherapy-induced vomiting. Confirmation of the differential involvement of neurotransmitters also supports the rationale for combination therapy to enhance prevention of emesis following cisplatin administration.7 R. 21 p. 837 Fig. 2 R. 22 p. 1760 T. 1 L. All R. 7 p. 1079 Par. 3 L. 1 p. 1076 Fig. 1 p. 1078 Fig. 3 8 12 24 120 Cisplatin-kezelés után eltelt idő (óra) R. 7 p. 1075 Par. 1 L. 1 p. 1079 Par. 3 L. 12 Hesketh PJ et al Eur J Cancer 2003;39:1074–1080. References 7. Hesketh PJ, Van Belle S, Aapro M et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003;39:1074–1080. 21. Cocquyt V, Van Belle S, Reinhardt RR et al. Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis. Eur J Cancer 2001;37:835–842. 22. Campos D, Pereira JR, Reinhardt RR et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001;19:1759–1767.

13 Összefoglaló a kemoterápia okozta hányinger/hányás (CINV) kórélettanáról
R. Berger p. 2875 Par. 4 L. 11 R. Hesketh p. 1075 Par. 6 L. 1 p. 1079 Par. 3 R. Hesketh p. 1075 Par. 1 L. 1 p. 1079 Par. 3 L. 12 pp Par. Cont. L. 11 R. Grunberg p. 1792 Par. 4 A kemoterápia okozta hányinger/hányás (CINV) heveny és késői szakaszában eltérő kórélettani mechanizmusok játszanak szerepet A heveny szakaszt főként a szerotonin okozza, ellenben a késői szakaszban a P-anyag a jelentős A különféle neurotranszmitterek szerepe miatt indokolt a kombinációs terápia alkalmazása A neurokinin-1 (NK1)-receptor gátlása – kombinációs terápiában – jelentős védelmet nyújt a hányinger/hányás kialakulásával szemben Slide 13 Different pathophysiologic mechanisms appear to contribute to different phases of chemotherapy-induced nausea and vomiting (CINV), such as acute (Day 1) versus delayed (Days 2 to 5):2,7 Serotonin-dependent mechanisms appear to occur in the first 8 to 12 hours post-cisplatin therapy; afterward, substance P and neurokinin-1 (NK1)–dependent mechanisms have greater importance7 Unlike acute events, delayed CINV appears to be mediated by nonserotonin mechanisms2,7 The role of multiple neurotransmitters continues to support the rationale for combination regimens3,7 and the addition of NK1 receptor antagonists for improved emetic protection.7 R. 2 p. 2875 Par. 4 L. 11 R. 7 p. 1075 Par. 6 L. 1 p. 1079 Par. 3 R. 7 p. 1075 Par. 1 L. 1 p. 1079 Par. 3 L. 12 pp Par. Cont. L. 11 R. 3 p. 1792 Par. 4 Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869–2880. Hesketh PJ et al Eur J Cancer 2003;39:1074–1080. Grunberg SM, Hesketh PJ N Engl J Med 1993;329:1790–1796. References 2. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. 3. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796. 7. Hesketh PJ, Van Belle S, Aapro M et al. Differential involvment of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003;39:1074–1080.

14 A kemoterápia okozta hányinger/hányás (CINV) kórélettana
Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturers’ prescribing information. MSD Magyarország Kft.* 1123 Budapest, Alkotás u. 50. Telefon: Fax: Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA. Minden jog fenntartva. *A MERCK & CO., INC., Whitehouse Station, N.J., U.S.A. leányvállalata. EMD-2008-HU-2012-SS Lezárva: Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. EMD-2008-HU-2012-SS VISIT US ON THE WORLD WIDE WEB AT