Metopimazine

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Metopimazine
Metopimazine.svg
Clinical data
Trade names Vogalen, Vogalene
Other namesEXP-999; RP-9965; NG-101
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.034.367 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H27N3O3S2
Molar mass 445.60 g·mol−1
3D model (JSmol)
  • O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C
  • InChI=1S/C22H27N3O3S2/c1-30(27,28)17-7-8-21-19(15-17)25(18-5-2-3-6-20(18)29-21)12-4-11-24-13-9-16(10-14-24)22(23)26/h2-3,5-8,15-16H,4,9-14H2,1H3,(H2,23,26) Yes check.svgY
  • Key:BQDBKDMTIJBJLA-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Metopimazine (INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name), sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. [1] [2] [3] [4] [5] [6] It is marketed in Europe, Canada, and South America. [2] [5] As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis. [6] [5]

Contents

Metopimazine has antidopaminergic, antihistamine, and anticholinergic activity. [7] However, it has also been described as a highly potent and selective dopamine D2 and D3 receptor antagonist. [5] The D2 receptor antagonism of metopimazine is thought to underlie its antiemetic and gastroprokinetic effects. [5] It is said to not readily cross the blood–brain barrier and hence to have peripheral selectivity, in contrast to metoclopramide but similarly to domperidone. [5] Unlike domperidone however, metopimazine shows no hERG inhibition and hence is expected to have a more favorable cardiovascular profile. [5] In contrast to metoclopramide, metopimazine does not interact with serotonin 5-HT3 and 5-HT4 receptors. [5]

Medical uses

Metopimazine is an approved prescription drug in France under the brand name Vogalene® [8] that has been used for the treatment of nausea and vomiting. [9] Vogalene® is available under different forms, including 15 mg capsules, 7.5 mg orally disintegrating tablets, 5 mg suppository, 0.1% oral liquid, and a 10 mg/mL intravenous (IV) solution approved for the prevention of chemotherapy-induced nausea and vomiting. [10] Metopimazine is also an over-the-counter medication available in pharmacies in France (Vogalib®, 7.5 mg orally disintegrating tablets). [11] The approved dose is 30 mg per day. Most adult prescriptions are for seasonal gastroenteritis or acute nausea and vomiting of various etiologies. The IV formulation is almost exclusively used to treat chemotherapy-induced nausea and vomiting in adults and children. [12]

Adverse effects

Generally, studies in chemotherapy-induced nausea and vomiting suggest that doses of metopimazine higher than approved for common nausea and vomiting conditions tend to be more efficacious while remaining safe and well tolerated. Numerous open-label and randomized, placebo-controlled efficacy studies involving oral administration (ranging from 7.5 mg/day for 4 days, to up to 45 mg/day for ~7–30 days, to 120 mg/day for 4 days) or IV administration (10 mg to 40 mg) of metopimazine have concluded that metopimazine is safe and well tolerated with no report of severe adverse events. [13] [14] [15] [16] [17] [18] [19] [20] [21] In a dose-ranging, open-label study in patients undergoing chemotherapy, metopimazine administered orally at 20, 30, 40, 50, or 60 mg every 4 hours (q4h) for 48 hours was used to determine its safety and tolerability. Metopimazine was determined to be safe at a dose of 30 mg administered 6 times daily (180 mg/day). The dose-limiting toxicity to metopimazine was moderate-to-severe dizziness caused by orthostatic hypotension, which was observed beginning at 40 mg every 4 hours for 48 hours. Other side effects were few and mild in severity. A single possibly drug-related extrapyramidal adverse event was observed in a patient in the 60 mg q4h or 360 mg daily dose group. [22] In a randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as an antiemetic prophylaxis during platinum-based chemotherapy, metopimazine was administered by IV (24-hour continuous infusion) at 35 mg/m2 followed by 30 mg per orally (PO) 4 times a day (120 mg/day) for 4 days. Metopimazine plus ondansetron was more efficacious than ondansetron alone, and adverse reactions were mild and without significant differences between the two treatment groups. However, there was an asymptomatic decrease in standing blood pressure when patients received the combination antiemetic therapy. [19] In a randomized, double-blind study assessing the efficacy and safety of sublingual metopimazine compared to ondansetron in chemotherapy-induced delayed emesis, patients received either 45 mg/day of metopimazine (7.5 mg x 2 every 8 hours) or 16 mg/day of ondansetron (8 mg every 12 hours). Results showed that metopimazine was comparable in efficacy to ondansetron; however, the incidence of gastrointestinal disorders was significantly lower in the metopimazine group, particularly abdominal pain and constipation. [23]

Mechanism of action

Metopimazine, a phenothiazine derivative, is a potent D2/D3 dopamine receptor antagonist. Metopimazine has also shown adrenergic alpha1, histamine H1, serotonin 5HT2a antagonism. [10]

Pharmacokinetics

The pharmacokinetics (PK) profile of metopimazine has been reported as comparable between adults and children. The maximum plasma concentration (Cmax) of metopimazine is reached approximately 60 minutes after oral administration, and the elimination half-life is approximately two hours. [24] Metopimazine is rapidly metabolized to metopimazine acid (Tmax ~2 hours), its major metabolite in humans. Metopimazine is primarily metabolized by a liver amidase in humans and therefore present a low risk on drug-drug interaction. [25] Exposure is reduced by ~30% and 50% (area under the curve (AUC) and Cmax, respectively) when metopimazine is administered with food. [26] [10]

The bioavailability of metopimazine in humans is low. A 10 mg dose of metopimazine was reported to have an absolute bioavailability under 20%. [26]

Research

Metopimazine mesylate (NG101), a novel formulation of metopimazine, is under clinical development for idiopathic gastroparesis in the United States. [27] Gastroparesis is a debilitating chronic gastrointestinal disorder characterized by delayed gastric emptying without evidence of mechanical obstruction. Symptoms include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain. [28] [29] [30]

Synthesis

Thieme Patent: Revised: Metopimazine synthesis.svg
Thieme Patent: Revised:

For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide and acetic anhydride to give 1-[2-(Methylthio)-10H-phenothiazin-10-yl]ethanone [23503-69-7] (2). Oxidation with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone. Upon hydrolysis of the acetate this affords 2-(methylsulfonyl)-10h-phenothiazine [23503-68-6] (3). Alkylation with 1-Bromo-3-chloropropane (4) gives 10-(3-chloropropyl)-2-methylsulfonylphenothiazine [40051-30-7] (5). Alkylation with piperidine-4-carboxamide (Isonipecotamide) [39546-32-2] (6) affords metopimazine (7).

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">Metoclopramide</span> Medication

Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

<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">Domperidone</span> Peripheral D2 receptor antagonist

Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis. It raises the level of prolactin in the human body and is used to induce and promote breast milk production off label. It may be taken by mouth or rectally.

<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, or surgery. It is also effective for treating gastroenteritis. It can be given orally, intramuscularly, or intravenously.

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

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

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<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">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.

<span class="mw-page-title-main">Droperidol</span> Antidopaminergic drug

Droperidol is an antidopaminergic drug used as an antiemetic and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.

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">Azasetron</span> Chemical compound

Azasetron is an antiemetic which acts as a 5-HT3 receptor antagonist, pKi = 9.27 It is used in the management of nausea and vomiting induced by cancer chemotherapy (such as cisplatin chemotherapy). Azasetron hydrochloride is given in a usual dose of 10 mg once daily by mouth or intravenously. It is approved for marketing in Japan, and marketed exclusively by Torii Pharmaceutical Co., Ltd. under the trade names "Serotone I.V. Injection 10 mg" and "Serotone Tablets 10 mg". Pharmacokinetics data from S. Tsukagoshi.

<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. While not painful, 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">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand names Vraylar,Reagila and Symvenu among others, is an atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

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 to 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.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<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

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  6. 1 2 "Metopimazine - Neurogastrx - AdisInsight".
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  8. ↑ "Vogalene®". www.rxreasoner.com.
  9. ↑ "Accueil - ANSM". ansm.sante.fr (in French). Retrieved 26 March 2023.
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  11. ↑ "Vogalib". www.rxreasoner.com.
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  13. ↑ Paradis B, Brault R (December 1967). "[A new antiemetic: vogalen (metopimazine or 9965 RP)]". Laval Medical. 38 (10): 901–907. PMID   5596819.
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  16. ↑ Berry GH, Duncan W, Bowman CM (October 1971). "The prevention of radiation sickness. Report of a double blind random clinical trial using prochlorperazine and metopimazine". Clinical Radiology. 22 (4): 534–537. doi:10.1016/s0009-9260(71)80130-7. PMID   4944444.
  17. ↑ Arnaud B, Sportouch M (January 1972). "[Value of metopimazine (Vogalene) in the prevention and treatment of postoperative vomiting in ocular surgery. (Apropos of 100 cases)]". Archives d'Ophtalmologie et Revue Generale d'Ophtalmologie. 32 (1): 63–68. PMID   4261213.
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  19. 1 2 Herrstedt J, Sigsgaard T, Handberg J, Schousboe BM, Hansen M, Dombernowsky P (April 1997). "Randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as antiemetic prophylaxis during platinum-based chemotherapy in patients with cancer". Journal of Clinical Oncology. 15 (4): 1690–1696. doi:10.1200/JCO.1997.15.4.1690. PMID   9193370.
  20. ↑ Lebeau B, Depierre A, Giovannini M, Rivière A, Kaluzinski L, Votan B, et al. (September 1997). "The efficacy of a combination of ondansetron, methylprednisolone and metopimazine in patients previously uncontrolled with a dual antiemetic treatment in cisplatin-based chemotherapy. The French Ondansetron Study Group". Annals of Oncology. 8 (9): 887–892. doi: 10.1023/a:1008276412559 . PMID   9358940.
  21. ↑ Sigsgaard T, Herrstedt J, Handberg J, Kjaer M, Dombernowsky P (April 2001). "Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy". Journal of Clinical Oncology. 19 (7): 2091–2097. doi:10.1200/JCO.2001.19.7.2091. PMID   11283143.
  22. ↑ Herrstedt J, Sigsgaard T, Angelo HR, Kampmann JP, Hansen M (January 1997). "Dose-finding study of oral metopimazine". Supportive Care in Cancer. 5 (1): 38–43. doi:10.1007/BF01681960. PMID   9010988. S2CID   24370010.
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  26. 1 2 Herrstedt J, Jørgensen M, Angelo HR (August 1990). "The effect of food on serum concentrations of metopimazine". British Journal of Clinical Pharmacology. 30 (2): 237–243. doi:10.1111/j.1365-2125.1990.tb03770.x. PMC   1368223 . PMID   2206785.
  27. ↑ "A Phase 2 Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study, of the Safety and Efficacy of NG101 Administered Orally to Patients With Gastroparesis". clinicaltrials.gov. 4 November 2022.
  28. ↑ Camilleri M, Kuo B, Nguyen L, Vaughn VM, Petrey J, Greer K, et al. (August 2022). "ACG Clinical Guideline: Gastroparesis". The American Journal of Gastroenterology. 117 (8): 1197–1220. doi:10.14309/ajg.0000000000001874. PMC   9373497 . PMID   35926490.
  29. ↑ De Colle C, van der Hart M, Chen J, Rassoulpour A, Pasricha PJ (2016). "1079 NG101: A potent and selective dopamine D2 receptor antagonist as a potential alternative to metoclopramide and domperidone for the treatment of gastroparesis". Gastroenterology. 150 (4): S214. doi:10.1016/S0016-5085(16)30794-6.
  30. ↑ Stein B, Everhart KK, Lacy BE (August 2015). "Gastroparesis: A Review of Current Diagnosis and Treatment Options". Journal of Clinical Gastroenterology. 49 (7): 550–558. doi:10.1097/MCG.0000000000000320. PMID   25874755.
  31. ↑ DE 1092476,Jacob RM, Robert JG,issued 1960, assigned to Rhone Poulenc SA.
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