Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists.
Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting
Hesketh
P J
PJ
St. Elizabeth's Medical Center; HOQ-2, Room 225, 736 Cambridge Street, Boston, MA 02135, USA.
Van Belle
S
S
Aapro
M
M
Tattersall
F D
FD
Naylor
R J
RJ
Hargreaves
R
R
Carides
A D
AD
Evans
J K
JK
Horgan
K J
KJ
D000932:Antiemetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000077608:Aprepitant; D002945:Cisplatin / Q000009:adverse effects*; D017322:Clinical Trials, Phase II as Topic; D004359:Drug Therapy, Combination; D017829:Granisetron / Q000627:therapeutic use; D006801:Humans; D009025:Morpholines / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents / Q000502:physiology*; D017294:Ondansetron / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000627:therapeutic use; D013373:Substance P / Q000502:physiology; D014839:Vomiting / Q000139:chemically induced*
D000932:Antiemetics; D000970:Antineoplastic Agents; D000077608:Aprepitant; D002945:Cisplatin; D017829:Granisetron; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D017294:Ondansetron; D011355:Prodrugs; D012701:Serotonin; D012702:Serotonin Antagonists; D013373:Substance P; C400262:L 758298