dolasetron

Dolasetron
Systematic (IUPAC) name
	(3R)-10-oxo-8-azatricyclo[5.3.1.03,8]undec-5-yl 1H-indole-3-carboxylate
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a601001
Pregnancy; category	B (US);
Legal status	℞ (Prescription only);
Routes of; administration	Intravenous, oral
Pharmacokinetic data
Protein binding	69 to 77%
Biological half-life	8.1 hours
Identifiers
CAS Number	115956-12-2
ATC code	A04AA04
PubChem	CID 60654
DrugBank	DB00757
ChemSpider	16736416
UNII	82WI2L7Q6E
KEGG	D07867
ChEMBL	CHEMBL1201240
Chemical data
Formula	C19H20N2O3
Molar mass	324.374 g/mol
	SMILES O=C5CN4[C@@H]1C[C@H]5C[C@H]4C[C@H](C1)OC(=O)c3cnc2ccccc23 ;
	InChI InChI=1S/C19H20N2O3/c22-18-10-21-12-5-11(18)6-13(21)8-14(7-12)24-19(23)16-9-20-17-4-2-1-3-15(16)17/h1-4,9,11-14,20H,5-8,10H2/t11-,12+,13-,14- ; Key:UKTAZPQNNNJVKR-YXSUXZIUSA-N ;
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/26 18:58:05」(JST)

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Dolasetron (trade name Anzemet) is a serotonin 5-HT₃ receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Dolasetron breaks down slowly, staying in the body for a long time. One dose usually lasts 4 to 9 hours and is usually administered once or twice daily. This drug is removed from the body by the liver and kidneys.

Clinical uses

Chemotherapy-induced nausea and vomiting
- 5-HT₃ receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting. Many times they are given intravenously about 30 minutes before beginning therapy.
Post-operative and post-radiation nausea and vomiting
Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis
Unlike most other 5HT3 antagonists, data is lacking for use of dolasetron with aprepitant in chemotherapy-induced nausea and vomiting (CINV).
It is also sometimes used as an antiemetic (anti-vomiting medication) in veterinary medicine for dogs and cats.

Adverse effects

Dolasetron is a well-tolerated drug with few side effects. Headache, dizziness, and constipation are the most commonly reported side effects associated with its use. There is a potential for prolonging of the QT interval to occur as well. There have been no significant drug interactions reported with this drug's use. It is broken down by the liver's cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system. Intravenous dolasetron is contraindicated in Chemotherapy-induced nausea and vomiting (CINV). Doxorubicin and cyclophosphamide are as emetogenic as cisplatin, and preventive drugs should always be considered. The 5HT3 agonists are the mainstays of prevention and are frequently used in combination with other drugs such as corticosteroids and the NK1 receptor antagonist aprepitant. However, the FDA recently issued a drug communication stating that the injection form of dolasetron, a 5HT3 agonist, should no longer be used in adult or pediatric patients with CINV. Dolasetron injection can increase the risk of developing torsade de pointes, a potentially fatal abnormal heart rhythm. Patients with underlying heart conditions or existing heart rate or rhythm problems are at increased risk. Although the oral form of this agent can still be used, careful monitoring and correction of potassium and magnesium levels should be initiated prior to and during treatment. In addition, in older patients and in patients with heart failure, a slow heart rate, underlying cardiac disease, and those with renal impairment, monitoring with electrocardiography is indicated when this drug is used. Congenital long-QT syndrome and drugs that prolong the PR or QRS interval are contraindications to dolasetron therapy. Dolasetron injection may still be used for the prevention and treatment of postoperative nausea and vomiting. As per Food and Drug Administration.

References

http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm
Katzung, Bertram G. Basic and Clinical Pharmacology, 9th ed. (2004). ISBN 0-07-141092-9

UpToDate Contents

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1. 化学療法誘発性悪心および嘔吐の予防および治療 prevention and treatment of chemotherapy induced nausea and vomiting
2. 制吐剤の特性 characteristics of antiemetic drugs
3. 放射線療法による悪心および嘔吐：予防と治療 radiotherapy induced nausea and vomiting prophylaxis and treatment
4. 麻酔後ケア病棟における合併症発生の概要 overview of complications occurring in the post anesthesia care unit
5. アントラサイクリン系以外の癌化学療法剤の心毒性 cardiotoxicity of nonanthracycline cancer chemotherapy agents

English Journal

Safety of an Oral Fixed Combination of Netupitant and Palonosetron (NEPA): Pooled Data From the Phase II/III Clinical Program.

Aapro M1, Hesketh PJ2, Jordan K3, Gralla RJ4, Rossi G5, Rizzi G5, Palmas M5.
The oncologist.Oncologist.2016 Apr;21(4):494-502. doi: 10.1634/theoncologist.2015-0301. Epub 2016 Mar 21.
BACKGROUND: Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 receptor antagonist (NK1RA), and corticosteroid therapy. NEPA is a fi
PMID 27000465

The prospective IQ-CSRC trial: A prototype early clinical proarrhythmia assessment investigation for replacing the ICH E14 thorough QTc (TQT) study.

Cavero I1, Holzgrefe H2, Clements M3.
Journal of pharmacological and toxicological methods.J Pharmacol Toxicol Methods.2016 Mar 9;80:1-8. doi: 10.1016/j.vascn.2016.02.181. [Epub ahead of print]
INTRODUCTION: Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiP
PMID 26903171

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14.

Darpo B1, Garnett C, Keirns J, Stockbridge N.
Drug safety.Drug Saf.2015 Sep;38(9):773-80. doi: 10.1007/s40264-015-0325-5.
Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as
PMID 26162419

Japanese Journal

A Practical and Direct Comparison of Intrinsic Metabolic Clearance of Several Non-CYP Enzyme Substrates in Freshly Isolated and Cryopreserved Hepatocytes

AKABANE Takafumi,GERST Nicolas,NARITOMI Yoichi,MASTERS Jeffrey N.,TAMURA Kouichi
Drug Metabolism and Pharmacokinetics 27(2), 181-191, 2012
… However, the number of compounds with >20% CLint reduction decreased to 3 on comparing average of CLint values including un-matched donors (dolasetron: −27%, naltorexone: −32%, and phthalazine: −48%; …
NAID 130004463242

Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol

BREYER-PFAFF U.
J. Pharm. Pharmacol. 56, 1601-1606, 2004
NAID 30023106409

Dolasetron decreases postoperative nausea and vomiting after breast surgery

ZEID HA
Breast J 4, 216-221, 2002
NAID 30014924021

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