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- Ondansetron
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/01/06 10:35:36」(JST)
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| Systematic (IUPAC) name | |
|---|---|
| (RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one | |
| Clinical data | |
| Trade names | Zofran Ondisolv |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a601209 |
| Pregnancy cat. |
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| Legal status |
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| Routes | Oral, rectal, IV, IM |
| Pharmacokinetic data | |
| Bioavailability | ~60% |
| Protein binding | 70%-76% |
| Metabolism | Hepatic (CYP3A4, CYP1A2, CYP2D6) |
| Half-life | 5.7 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 99614-02-5 Y |
| ATC code | A04AA01 |
| PubChem | CID 4595 |
| IUPHAR ligand | 2290 |
| DrugBank | DB00904 |
| ChemSpider | 4434 Y |
| UNII | 4AF302ESOS Y |
| KEGG | D00456 Y |
| ChEMBL | CHEMBL46 Y |
| Chemical data | |
| Formula | C18H19N3O |
| Molecular mass | 293.4 g/mol |
|
SMILES
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InChI
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| Y (what is this?) (verify) | |
Ondansetron (INN), originally marketed under the brand name Zofran, is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.
It has little effect on vomiting caused by motion sickness,[1][2] and does not have any effect on dopamine receptors or muscarinic receptors[2]
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]
Contents
- 1 Medical uses
- 1.1 Cancer treatment
- 1.2 Postoperative
- 1.3 Pregnancy
- 1.4 Cyclic vomiting syndrome
- 1.5 Gastroenteritis
- 2 Special populations
- 2.1 Pregnancy and breast feeding
- 2.2 Children
- 2.3 Elderly
- 2.4 Poor liver function
- 3 Adverse effects
- 3.1 QT prolongation
- 3.2 Overdose
- 4 Pharmacodynamics
- 5 History
- 6 Society and culture
- 6.1 Publication bias
- 6.2 Brand names[21]
- 7 Research
- 7.1 Psychiatric disorders
- 7.2 Substance use
- 7.3 Postanesthetic shivering
- 8 References
- 9 External links
Medical uses
Although an effective antiemetic agent, the high cost of brand-name ondansetron initially limited its use to controlling postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting.[4]
Cancer treatment
The 5-HT3 receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting.
Postoperative
A number of medications including ondansetron appear to be effective in controlling postoperative nausea and vomiting. It is unclear if it is better than or worse than other agents like droperidol, metoclopramide, or cyclizine.[5]
Pregnancy
Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. It is typically used after trials of other drugs have failed.[6]
Cyclic vomiting syndrome
Ondansetron is one of several antiemetic agents used during the vomiting phase of cyclic vomiting syndrome.[7]
Gastroenteritis
Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration.[8] A retrospective review found it was used commonly for this purpose, being administered in over 58% of cases. Its use reduced hospital admissions, but was also associated with higher rates of return visits to the ED. Furthermore, patients who had initially received ondansetron were more likely to be admitted on the return visit than patients who had not received the drug. However, this effect may simply be due to the agent being used more frequently in patients who present with more severe illness. Its use was not found to mask serious diagnoses.[9]
Special populations
Pregnancy and breast feeding
Animal reproduction studies have not shown evidence of harm to the fetus or impairment of fertility with use of high daily doses of ondansetron. Additionally, a cohort study of over 600,000 pregnancies in Denmark found that ondansetron administration during pregnancy was not associated with a significantly increased risk of spontaneous abortion, stillbirth, major birth defect, preterm birth, low birth weight, or small for gestational age.[10] Ondansetron is in pregnancy category B in the US.[11] It is not known if ondansetron is excreted in breast milk.[11]
Children
Ondansetron has rarely been studied in patients under 4 years of age. As such, little data are available to guide dosage recommendations.[11]
Elderly
It is not necessary to adjust the dosage for elderly patients under 75 years of age. The use of Zofran has not been studied in patients older than 75 years of age, and it is not known if dosage should be adjusted for these patients.[11]
Poor liver function
The maximum recommended dose for patients with severe liver function impairment is 8 mg/day. In these patients, Zofran is cleared from the body at half to one-third the rate as in healthy patients. The concentration of Zofran in body tissues as opposed to plasma is also higher than in healthy patients.[11]
Adverse effects
Ondansetron is a well-tolerated drug with few side effects. Constipation, dizziness, and headache are the most commonly reported side effects associated with its use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system. Anecdotally, ototoxicity has also been reported if injected too quickly.
QT prolongation
Use of ondansetron has been associated with prolongation of the QT interval, which can lead to the potentially fatal heart rhythm known as torsades de pointes. Although this may happen in any patient with any formulation, the risk is most salient with the injectable (intravenous) form of the drug, and increases with dose. The risk is also higher in patients taking other medicines that prolong the QT interval, as well as in patients with congenital long QT syndrome, congestive heart failure, and/or bradyarrhythmias. As such, single doses of injectable ondansetron should not exceed 16 mg at one time. (Oral dosing recommendations remain intact, including the recommendation of a single 24-mg oral dose when indicated.) Electrolyte imbalances should be corrected before the use of injectable ondansetron. Patients are cautioned to seek immediate medical care if symptoms such as irregular heartbeat/palpitations, shortness of breath, dizziness, or fainting occur while taking ondansetron.[12]
Overdose
No specific treatment is available for ondansetron overdose; patients are managed with supportive measures. An antidote to ondansetron is not known.[11]
Pharmacodynamics
Ondansetron is a highly specific and selective serotonin 5-HT3 receptor antagonist and with low affinity for dopamine receptors. The 5-HT3 receptors are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. It is not certain whether ondansetron's antiemetic action is mediated centrally, peripherally, or in both sites.
History
A vial of Zofran 4 mg containing ondansetron for intravenous injection
Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s by GlaxoSmithKline in London. It was granted US patent protection in September 1987,[13] received a use patent June 1988,[14] and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996.[15] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.[16] By this final year of its patent (2006), Zofran had become the 20th highest-selling brand-name drug in the United States, with sales of US$1.3 billion in the first 9 months of 2006 (80% from the US).[17] The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.[18]
Society and culture
Publication bias
In 1997, ondansetron was the subject of a meta-analysis case study published in the British Medical Journal. Researchers examined 84 trials, with 11,980 patients receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports and three further reports which had been duplicated six times. The number needed to treat (NNT) to prevent vomiting within 24 hours was 9.5, with 95% confidence interval 6.9 to 15, in the 16 nonduplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8). When all 25 reports were combined, the apparent NNT reat improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetron's antiemetic efficacy.[19]
In addition, the authors found the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and reports containing duplicate findings were cited in eight reviews of the drug.[19] Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.[20]
Brand names[21]
Australia
- Onsetron
- Zofran
Bangladesh
- Emizof
- Anset
- Emetron
- Emistat
- Emiston
- Ofran
- Onaserone
- Onasia
- Oncodex
- Onsat
- Osetron
- Seton
- Zofra
- Zofra ODT
Brazil
- Ansentron
- Modifical
- Nausedron
- Ontrax
- Vonau
- Zofran
Canada
- Zofran
- Zofran ODT
China
- Aoyimai
- An Si Xin
- Di Li Xin
- En Fu De
- En Nuo Ping
- Fu Mi Ting
- Kang Da Li Te
- Lu Wei Sen
- Ou Bei
- Shi Tai
- Wei Ze
- Yi Feng
- Yi Shu Ning
- Zofran
Germany
- Axisetron
- Axisetron lingual
- Cellondan
- Cellondan lingual
- Sigondan
- Zofran
- Zofran Zydis Lingual
India
- Adom-O
- Afon
- Domi-UP
- Doran-O
- Emeset
- Emigo
- Emitus
- Emtron
- Flatron
- Glendan
- Lupisetron
- Lupisetron Plus
- Naucid
- Novatron
- Nuset
- Ond
- Ond-R
- Ondai
- Ondanz
- Ondar
- Onsett
- Onstal
- Onstar
- Oset
- Osetron
- Periset
- Rulcer-ON
- Speronden
- Supracetron
- Vomikind
- Vomipra
- Vomiven
- Vomiven-P
- Vomiz
- Vona
- Vorast
- Zondan
- Zordil
Indonesia
- Cedantron
- Dantroxal
- Entron
Iran
- Demitron
Ireland
- Emizof
- Ondran
- Zofran
Japan
- Emizof
- Zofran
- Zofran Zydis
Mexico
- Amal
- Dosartron
- Frynyvom
- Lartron
- Nalisen
- Zofran
New Zealand
- Zofran
- Zofran Zydis
Philippines
- Emistop
- Emodan
- Nozuca
- Zofan
Russia
- Emizof
- Emetron
- Osetron
- Setronon
- Zofran
United Kingdom
- Ondemet
- Zofran
United States
- Zofran
- Zofran ODT
- Zuplenz
Vietnam
- Emeset
- Prezinton 8
- Onfran
Research
Psychiatric disorders
A 2006 double-blind, randomized controlled trial indicated ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. The study found the combination to significantly improve negative schizophrenia symptoms, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.[22] An earlier, smaller, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia, and the study patients also showed significant improvement in the disease's symptoms.[23][24]
Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease.[25] Its apparent benefits despite a lack of any significant antagonistic properties at dopamine receptors or the 5-HT2A receptor raises interesting questions about the etiology of psychosis.
The treatment of obsessive–compulsive disorder with ondansetron 1 mg three times daily was associated with a significant decrease in the Yale Brown obsessive-compulsive scores in a small (n=8), 8-week, open-label study.[26]
Substance use
Ondansetron lowers the cravings for alcohol, especially in early-onset alcoholics. In one cognitive-behavioral therapy study, ondansetron patients with early-onset alcoholism had fewer drinks per day and reported more days without drinking at all, as compared to the other groups in the study. Also of note, individuals with the LL genotype show significant improvements in alcohol misuse when treated with ondansetron, compared with individuals with the other genotypes of the 5HTTLPR polymorphism, who showed no improvement over placebo.[27][28][29]
Ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions.[30] Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid.[30] Additionally, it does not require continued supervision like treatment with clonidine.[30]
The original experiment used mice that were injected with increasing doses of morphine, assayed with naloxone, and then underwent haplotypic analysis to isolate a gene candidate.[31] HTR3A which codes for the 5-HT3 receptor emerged as the primary candidate, which suggested 5-HT3 antagonist ondansetron as a possible treatment.[31] The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.[31]
Postanesthetic shivering
Two small, placebo-controlled trials have been conducted to assess the efficacy of ondansetron for postanesthetic shivering, a common occurrence after surgery. Ondansetron was found to be as effective as pethidine (meperidine, Demerol) when given as a single intravenous dose before anesthesia.[32]
References
- ^ Muth, E. R.; Elkins, A. N. (2006). "27 High dose ondansetron is not effective for reducing motion sickness in highly susceptible subjects". Neurogastroenterology and Motility 18 (6): 488. doi:10.1111/j.1365-2982.2006.00789_27.x. edit
- ^ a b "Metabocard for Ondansetron". Retrieved 29 April 2004.
- ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ Cooke, C. E.; Mehra, I. V. (1994). "Oral ondansetron for preventing nausea and vomiting". American journal of hospital pharmacy 51 (6): 762–771. PMID 8010314. edit
- ^ Carlisle JB, Stevenson CA (2006). "Drugs for preventing postoperative nausea and vomiting". Cochrane Database Syst Rev (3): CD004125. doi:10.1002/14651858.CD004125.pub2. PMID 16856030.
- ^ Smith JA, Refuerzo JS, Ramin SM. "Treatment and outcome of nausea and vomiting of pregnancy". UpToDate.
- ^ Abell TL, Adams KA, Boles RG, Bousvaros A, Chong SK, Fleisher DR, Hasler WL, Hyman PE, Issenman RM, Li BU, Linder SL, Mayer EA, McCallum RW, Olden K, Parkman HP, Rudolph CD, Taché Y, Tarbell S, Vakil N (April 2008). "Cyclic vomiting syndrome in adults". Neurogastroenterol. Motil. 20 (4): 269–84. doi:10.1111/j.1365-2982.2008.01113.x. PMID 18371009.
- ^ Freedman SB, Adler M, Seshadri R, Powell EC (April 2006). "Oral ondansetron for gastroenteritis in a pediatric emergency department". N. Engl. J. Med. 354 (16): 1698–705. doi:10.1056/NEJMoa055119. PMID 16625009.
- ^ Sturm JJ, Hirsh DA, Schweickert A, Massey R, Simon HK (May 2010). "Ondansetron use in the pediatric emergency department and effects on hospitalization and return rates: are we masking alternative diagnoses?". Ann Emerg Med 55 (5): 415–22. doi:10.1016/j.annemergmed.2009.11.011. PMID 20031265.
- ^ Pasternak B, Svanström H, Hviid A (February 2013). "Ondansetron in pregnancy and risk of adverse fetal outcomes". N. Engl. J. Med. 368 (9): 814–23. doi:10.1056/NEJMoa1211035. PMID 23445092.
- ^ a b c d e f GlaxoSmithKline. "Zofran". Prescribing Information. U.S. Food and Drug Administration.
- ^ US Food and Drug Administration. (2012). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm
- ^ US patent 4695578, Coates IH, Bell JA, Humber DC, Ewan GB, "1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances", issued 1987-09-22, assigned to Glaxo Group Limited
- ^ US patent 4753789, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Method for treating nausea and vomiting", issued 1988-06-28, assigned to Glaxo Group Limited
- ^ US patent 5578628, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Medicaments for the treatment of nausea and vomiting", issued 1996-11-26, assigned to Glaxo Group Limited
- ^ "One Year Post-Pediatric Exclusivity Post-marketing Adverse Event Review: Drug Use Data Zofran". Memorandum. U.S. Food and Drug Administration. 2006-03-07.
- ^ IHS. (2006). Generics firms line up to enter Zofran market. Retrieved from http://www.ihs.com/products/global-insight/industry-economic-report.aspx?id=106598562
- ^ "FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution". News Release. U.S. Food and Drug Administration. 2006-12-17.
- ^ a b Tramèr MR, Reynolds DJ, Moore RA, McQuay HJ (September 1997). "Impact of covert duplicate publication on meta-analysis: a case study". BMJ 315 (7109): 635–40. doi:10.1136/bmj.315.7109.635. PMC 2127450. PMID 9310564.
- ^ Rennie D (November 1999). "Fair conduct and fair reporting of clinical trials". JAMA 282 (18): 1766–8. doi:10.1001/jama.282.18.1766. PMID 10568651.
- ^ Drugs.com. (n.d.). Ondansetron. Retrieved February 2, 2014, from http://www.drugs.com/international/ondansetron.html
- ^ Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006). "Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study". Schizophrenia Research 88 (1–3): 102–10. doi:10.1016/j.schres.2006.07.010. PMID 16959472.
- ^ Zullino DF, Eap CB, Voirol P (2001). "Ondansetron for tardive dyskinesia". Am J Psychiatry 158 (4): 657–8. doi:10.1176/appi.ajp.158.4.657-a. PMID 11282718.
- ^ Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD (February 2000). "Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia". Am J Psychiatry 157 (2): 287–9. doi:10.1176/appi.ajp.157.2.287. PMID 10671405.
- ^ Zoldan J, Friedberg G, Livneh M, Melamed E (1995). "Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist". Neurology 45 (7): 1305–8. doi:10.1212/WNL.45.7.1305. PMID 7617188.
- ^ Hewlett WA, Schmid SP, Salomon RM (2003). "Pilot trial of ondansetron in the treatment of 8 patients with obsessive compulsive disorder". J Clin Psychiatry 64 (9): 1025–30. doi:10.4088/JCP.v64n0907. PMID 14628977.
- ^ "Ondansetron can prevent alcohol craving". June 11, 2006. Retrieved 2007-11-05.
- ^ Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994). "Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence". Alcohol Clin Exp Res 18 (4): 879–85. doi:10.1111/j.1530-0277.1994.tb00054.x. PMID 7978099.
- ^ "Genes Predict Success of Ondansetron Treatment for Alcoholism". January 25, 2011. Retrieved 2011-01-25.
- ^ a b c "Stanford scientists identify drug to treat opioid addiction". 17 Feb 2009. Retrieved 19 Feb 2009.
- ^ a b c Chu LF, Liang DY, Li X, Sahbaie P, D'arcy N, Liao G, Peltz G, David Clark J (March 2009). "From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics". Pharmacogenet. Genomics 19 (3): 193–205. doi:10.1097/FPC.0b013e328322e73d. PMC 2730361. PMID 19214139.
- ^ Generali JA, Cada DJ (August 2009). "Ondansetron: postanesthetic shivering". Hospital Pharmacy 44 (8): 670–1. doi:10.1310/hpj4408-670.
External links
- U.S. National Library of Medicine: Drug Information Portal - Ondansetron
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UpToDate Contents
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English Journal
- Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP).
- Thanacoody HK, Gray A, Dear JW, Coyle J, Sandilands EA, Webb DJ, Lewis S, Eddleston M, Thomas SH, Bateman DN.AbstractBACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
- BMC pharmacology & toxicology.BMC Pharmacol Toxicol.2013 Apr 4;14(1):20. [Epub ahead of print]
- BACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time
- PMID 23556549
- A pilot study of full-dose ondansetron to treat heavy-drinking men withdrawing from alcohol in Brazil.
- Corrêa Filho JM, Baltieri DA.SourceDepartment of Psychiatry of the University of São Paulo, Brazil.
- Addictive behaviors.Addict Behav.2013 Apr;38(4):2044-51. doi: 10.1016/j.addbeh.2012.12.018. Epub 2013 Jan 4.
- Ondansetron has emerged as a promising medication for the treatment of alcohol dependence, mainly among early-onset alcoholics. This research primarily aimed to evaluate the efficacy and safety of ondansetron at a 16mg/day dosage to treat alcohol-dependent outpatients. A double-blind, placebo-contro
- PMID 23396176
Related Links
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