Aprepitant

Last updated

Aprepitant
Aprepitant.svg
Aprepitant 3D ball.png
Clinical data
Trade names Emend, Cinvanti, Aponvie
AHFS/Drugs.com Monograph
MedlinePlus a604003
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth
Drug class NK1 receptor antagonists, antiemetics
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60–65%
Protein binding >95%
Metabolism Liver (mostly CYP3A4- mediated; some contributions by CYP2C19 & CYP1A2)
Elimination half-life 9–13 hours
Excretion Kidney (57%), feces (45%)
Identifiers
  • 5-([(2R,3S)-2-((R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.202.762 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H21F7N4O3
Molar mass 534.435 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1cc(cc(c1)C(F)(F)F)[C@H](O[C@H]4OCCN(CC/2=N/C(=O)NN\2)[C@H]4c3ccc(F)cc3)C
  • InChI=1S/C23H21F7N4O3/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)37-20-19(13-2-4-17(24)5-3-13)34(6-7-36-20)11-18-31-21(35)33-32-18/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H2,31,32,33,35)/t12-,19+,20-/m1/s1 Yes check.svgY
  • Key:ATALOFNDEOCMKK-OITMNORJSA-N Yes check.svgY
   (verify)

Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting and to prevent postoperative nausea and vomiting. [5] It may be used together with ondansetron and dexamethasone. [5] It is taken by mouth [5] or administered by intravenous injection. [3]

Contents

Common side effects include tiredness, loss of appetite, diarrhea, abdominal pain, hiccups, itchiness, pneumonia, and blood pressure changes. [5] Other severe side effects may include anaphylaxis. [5] While use in pregnancy does not appear to be harmful, such use has not been well studied. [6] Aprepitant belongs to the class of neurokinin-1 receptor antagonists medications. [5] It works by blocking substance P from attaching to the NK1 receptors. [4]

Aprepitant was approved for medical use in the European Union and the United States in 2003. [5] [4] It is made by Merck & Co. [5] It is on the World Health Organization's List of Essential Medicines. [7] [8]

Medical uses

Aprepitant is used to prevent chemotherapy-induced nausea and vomiting and to prevent postoperative nausea and vomiting. [5] It may be used together with ondansetron and dexamethasone. [5]

Mechanism of action

Aprepitant is classified as an NK1 antagonist because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients.

NK1 is a G protein-coupled receptor located in the central and peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide, composed of 11 amino acids, which sends impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain, and, when activated, it results in a vomiting reflex. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.

Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brain's neurons. Positron emission tomography (PET) studies, have demonstrated that aprepitant can cross the blood brain barrier and bind to NK1 receptors in the human brain. [9] It has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy. [10]

Pharmacokinetics

Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability is found to be around 60-65%. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered medicinal products that are metabolized through CYP3A4. Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CYP3A4 inhibition or through its NK-1 antagonist action. [11] Following IV administration of a 14C-labeled prodrug of aprepitant (L-758298), which is converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is excreted in the urine and 45% in feces. No unchanged substance is excreted in urine. [12]

Structure and properties

Aprepitant is made up of a morpholine core with two substituents attached to adjacent ring carbons. These substitute groups are trifluoromethylated 1-phenylethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen. It has three chiral centres very close together, which combine to produce an amino acetal arrangement. Its empirical formula is C23H21F7N4O3.

Synthesis

Shortly after Merck initiated research into reducing the severity and likelihood of chemotherapy-induced nausea and vomiting, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as sodium cyanide, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous byproducts such as methane. [13] The environmental concerns of the synthesis of aprepitant became so great that Merck research team decided to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant. [14]

The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.

The new process begins by enantiopure trifluoromethylated phenyl ethanol being joined to a racemic morpholine precursor. This results in the desired isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the desired isomer through a crystallization-induced asymmetric transformation. By the end of this step a secondary amine, the base of the drug, is formed.

The second step involves the fluorophenyl group being attached to the morpholine ring. Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced. [15]

This more streamlined route yields around 76% more aprepitant than the original process and reduces the operating cost by a significant amount. In addition, the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of aprepitant produced. [14]

The improvements in the synthesis process have also decreased the long-term detriment to the natural environment associated with the original procedure, due to eliminating the use of several hazardous chemicals.

History

It was approved by the US Food and Drug Administration (FDA) in 2003. [16] In 2008, fosaprepitant, an intravenous form of aprepitant was approved in the United States.

Research

Major depression

Plans to develop aprepitant as an antidepressant have been withdrawn. [17] Subsequently, other trials with NK1 receptor antagonists, casopitant and orvepitant, have shown promising results. [18] [19] [20]

Beyond suggestions that PET receptor occupancy must not be used routinely to cap dosing for new medical indications for this class, [21] or that > 99% human receptor occupancy might be required for consistent psycho-pharmacological or other therapeutic effects, [20] critical scientific dissection and debate of the above data might be needed to enable aprepitant, and the class of NK1 antagonists as a whole, to fulfill preclinically predicted utilities beyond chemotherapy-induced nausea and vomiting (i.e., for other psychiatric disorders, addictions, neuropathic pain, migraine, osteoarthritis, overactive bladder, inflammatory bowel disease and other disorders with suspected inflammatory or immunological components. However, most data remain proprietary and thus reviews on the expanded clinical potential for drugs like aprepitant range from optimistic [22] to poor. [23]

Cannabinoid Hyperemesis Syndrome

Aprepitant has been identified as having strong potential in treating protracted vomiting episodes in individuals with cannabinoid hyperemesis syndrome. [24] This syndrome is characterized by nausea, cyclical vomiting, and cramping abdominal pain resulting from prolonged, frequent cannabis use.

Standard first-line anti-emetics such as ondansetron and prochlorperazine are often ineffective in treating cannabinoid hyperemesis syndrome. [25]

Related Research Articles

An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

<span class="mw-page-title-main">Substance P</span> Chemical compound (polypeptide neurotransmitter)

Substance P (SP) is an undecapeptide and a type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator. Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

<span class="mw-page-title-main">Granisetron</span> Serotonin 5-HT3 antiemetic

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. 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 effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the post-anesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

<span class="mw-page-title-main">Ondansetron</span> Medication to prevent nausea and vomiting

Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, migraines or surgery. It is also effective for treating gastroenteritis. It can be given orally, intramuscularly, or intravenously.

<span class="mw-page-title-main">Dolasetron</span> Pharmaceutical drug

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.

<span class="mw-page-title-main">Tachykinin peptides</span>

Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an Aromatic or an Aliphatic amino acid. The genes that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptides by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.

<span class="mw-page-title-main">Vomiting</span> Involuntary, forceful expulsion of stomach contents, typically via the mouth

Vomiting is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.

Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

<span class="mw-page-title-main">Tachykinin receptor 1</span> Protein-coding gene in the species Homo sapiens

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

<span class="mw-page-title-main">Metopimazine</span> Chemical compound

Metopimazine, sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.

<span class="mw-page-title-main">Nausea</span> Medical symptom or condition

Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.

<span class="mw-page-title-main">L-733,060</span> Chemical compound

L-733,060 is a drug developed by Merck which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08 nM. Only one enantiomer is active which has made it the subject of several asymmetric synthesis efforts.

<span class="mw-page-title-main">Vestipitant</span> Chemical compound

Vestipitant (INN) is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus and insomnia.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

<span class="mw-page-title-main">Cancer and nausea</span>

Cancer and nausea are associated in about fifty percent of people affected by cancer. This may be as a result of the cancer itself, or as an effect of the treatment such as chemotherapy, radiation therapy, or other medication such as opiates used for pain relief. About 70–80% of people undergoing chemotherapy experience nausea or vomiting. Nausea and vomiting may also occur in people not receiving treatment, often as a result of the disease involving the gastrointestinal tract, electrolyte imbalance, or as a result of anxiety. Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs and may result in patients delaying or refusing further radiotherapy or chemotherapy.

<span class="mw-page-title-main">Netupitant</span> Chemical compound

Netupitant is an antiemetic medication. In the United States, the combinations of netupitant/palonosetron and the prodrug fosnetupitant/palonosetron are approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin. In the European Union, the combinations are approved by the European Medicines Agency (EMA) for the same indication.

<span class="mw-page-title-main">Rolapitant</span> Pharmaceutical drug

Rolapitant (INN, trade name Varubivə-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.

Paul L. R. Andrews is a British physiologist whose basic research on the mechanisms of action and efficacy of antiemetic substances contributed to development of treatments for anti-cancer chemotherapy-induced nausea and vomiting.

References

  1. ↑ "Emend- aprepitant capsule Emend- aprepitant kit Emend- aprepitant powder, for suspension". DailyMed. 6 May 2022. Archived from the original on 9 March 2022. Retrieved 27 September 2022.
  2. ↑ "Cinvanti- aprepitant injection, emulsion". DailyMed. 24 March 2022. Archived from the original on 31 August 2022. Retrieved 27 September 2022.
  3. 1 2 "Aponvie (aprepitant) injectable emulsion, for intravenous use Initial U.S. Approval: 2003" (PDF). Archived (PDF) from the original on 28 September 2022. Retrieved 28 September 2022.
  4. 1 2 3 "Emend EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 12 November 2020. Retrieved 13 October 2019.
  5. 1 2 3 4 5 6 7 8 9 10 "Aprepitant/Fosaprepitant Dimeglumine Monograph for Professionals". Drugs.com. Archived from the original on 13 August 2020. Retrieved 13 October 2019.
  6. ↑ "Aprepitant Use During Pregnancy". Drugs.com. Archived from the original on 28 October 2020. Retrieved 13 October 2019.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  9. ↑ Bergström M, Hargreaves RJ, Burns HD, Goldberg MR, Sciberras D, Reines SA, et al. (May 2004). "Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant". Biological Psychiatry. 55 (10): 1007–1012. doi:10.1016/j.biopsych.2004.02.007. PMID   15121485. S2CID   21071199.
  10. ↑ Gralla RJ, de Wit R, Herrstedt J, Carides AD, Ianus J, Guoguang-Ma J, et al. (August 2005). "Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials". Cancer. 104 (4): 864–868. doi: 10.1002/cncr.21222 . PMID   15973669. S2CID   24860776.
  11. ↑ Walsh SL, Heilig M, Nuzzo PA, Henderson P, Lofwall MR (March 2013). "Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers". Addiction Biology. 18 (2): 332–343. doi:10.1111/j.1369-1600.2011.00419.x. PMC   4354863 . PMID   22260216.
  12. ↑ "FDA Advisory Committee Background Package" (PDF). Food and Drug Administration . Archived (PDF) from the original on 16 May 2017. Retrieved 16 December 2019.
  13. ↑ Hale JJ, Mills SG, MacCoss M, Finke PE, Cascieri MA, Sadowski S, et al. (November 1998). "Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist". Journal of Medicinal Chemistry. 41 (23): 4607–4614. doi:10.1021/jm980299k. PMID   9804700.
  14. 1 2 Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, et al. (March 2011). "Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting". Annals of the New York Academy of Sciences. 1222 (1): 40–48. Bibcode:2011NYASA1222...40H. doi:10.1111/j.1749-6632.2011.05961.x. PMID   21434941. S2CID   21202644.
  15. ↑ Brands KM, Payack JF, Rosen JD, Nelson TD, Candelario A, Huffman MA, et al. (February 2003). "Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation". Journal of the American Chemical Society. 125 (8): 2129–2135. doi:10.1021/ja027458g. PMID   12590540.
  16. ↑ "Drug Approval Package: Emend (Aprepitant) NDA #21-549". Archived from the original on 24 March 2017. Retrieved 19 April 2011.
  17. ↑ Rupniak NM, Kramer MS (December 2017). "NK1 receptor antagonists for depression: Why a validated concept was abandoned". Journal of Affective Disorders. 223: 121–125. doi:10.1016/j.jad.2017.07.042. PMID   28753469.
  18. ↑ Ratti E, Bellew K, Bettica P, Bryson H, Zamuner S, Archer G, et al. (December 2011). "Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder". Journal of Clinical Psychopharmacology. 31 (6): 727–733. doi:10.1097/JCP.0b013e31823608ca. PMID   22020354. S2CID   24609826.
  19. ↑ Trist DG, Ratti E, Bye A (December 2013). "Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists". Journal of Receptor and Signal Transduction Research. 33 (6): 333–337. doi:10.3109/10799893.2013.843194. PMID   24106886. S2CID   21799710.
  20. 1 2 Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, et al. (May 2013). "Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies". Journal of Psychopharmacology. 27 (5): 424–434. doi:10.1177/0269881113480990. PMID   23539641. S2CID   6523822.
  21. ↑ Barrett JS, McGuire J, Vezina H, Spitsin S, Douglas SD (December 2013). "PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions?". Journal of Clinical Psychopharmacology. 33 (6): 725–728. doi:10.1097/JCP.0b013e3182a88654. PMID   24100788.
  22. ↑ Herpfer I, Lieb K (2005). "Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential". CNS Drugs. 19 (4): 275–293. doi:10.2165/00023210-200519040-00001. PMID   15813642. S2CID   25497814.
  23. ↑ Griebel G, Holsboer F (May 2012). "Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?". Nature Reviews. Drug Discovery. 11 (6): 462–478. doi:10.1038/nrd3702. PMID   22596253. S2CID   10721248. Archived from the original on 5 March 2021. Retrieved 1 July 2019.
  24. ↑ Parvataneni S, Varela L, Vemuri-Reddy SM, Maneval ML (June 2019). "Emerging Role of Aprepitant in Cannabis Hyperemesis Syndrome". Cureus. 11 (6): e4825. doi: 10.7759/cureus.4825 . PMC   6682377 . PMID   31403013.
  25. ↑ Ruberto AJ, Sivilotti ML, Forrester S, Hall AK, Crawford FM, Day AG (June 2021). "Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial". Annals of Emergency Medicine. 77 (6): 613–619. doi:10.1016/j.annemergmed.2020.08.021. PMID   33160719. S2CID   226287931.
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