Early clinical trial of MDL 73.147 EF: A new 5-HT3-receptors antagonist for the prevention of chemotherapy-induced nausea and vomiting

Kirchner, V.; Aapro, Matti; Alberto, P.; O'Grady, P.; Busch, Bonnie L.; Boyce, Malcom

doi:10.1093/oxfordjournals.annonc.a058558

Cited by 17 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During this time and following the original abstract highlighting the anti-emetic activity of renzapride (Miner et al, 1986 ), experiments to demonstrate the anti-emetic activity of the 5-HT 3 receptor antagonist ICS 205-930 (Costall et al, 1986 ) were swiftly sponsored by Sandoz, the manufacturer of ICS 205-930 (see Christie and Tansey 2007 ). With respect to ondansetron and tropisetron, these can therefore be regarded as examples of “re-purposing” (bemesetron was not progressed for treatment of emesis, the company preferring its follow-up molecule MDL73147 or dolasetron; see Kirchner et al, 1993 ).…”

Section: The 1980s: a New Era In Control Of Nausea And Vomiting Prompmentioning

confidence: 99%

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Sanger

Andrews

2018

Front. Pharmacol.

View full text Add to dashboard Cite

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists–originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists–searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists–investigations of their pharmacology as “sedatives” (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonists–metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1 receptor antagonists–antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

show abstract

Section: The 1980s: a New Era In Control Of Nausea And Vomiting Prompmentioning

confidence: 99%

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Sanger

Andrews

2018

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…The development of the NK 1 -receptor antagonists also provides the opportunity for more patients to have good control of emesis in the delayed phase [48,49]. Recent trials have indicated that the addition of aprepitant to standard dual-therapy regimens of ondansetron or granisetron plus dexamethasone improves the control of delayed CINV [29][30][31].…”

Section: Delayed Onsetmentioning

confidence: 99%

Granisetron: An Update on its Clinical Use in the Management of Nausea and Vomiting

Aapro

2004

The Oncologist

View full text Add to dashboard Cite

ABSTRACTchemotherapy-induced, radiation-induced, and postoperative nausea and vomiting, and also reviews its use in special patient populations. Granisetron is a potent and highly selective 5-HT 3 -receptor antagonist that has little or no affinity for other receptors, a characteristic that is thought to underlie the favorable side-effect and safety profiles of this agent. Extensive clinical trial data have shown granisetron to be an effective and well-tolerated agent for the treatment of nausea and vomiting in the oncology and surgical settings. Granisetron has also been shown to be effective and well tolerated in special populations, such as patients refractory to antiemetic treatment, patients with hepatic or renal impairment, and children. Data also suggest that its safety profile and minimal potential for drug-drug interactions would make it an antiemetic agent of choice for elderly cancer patients. The Oncologist 2004;9:673-686

show abstract

“…flex, an accepted model for the characterization of the in vivo potency and duration of action of 5-HT, receptor antagonists [Fozard, 19841. In addition, MDL 72,222 was effective in inhibiting cisplatin-induced vomiting in fcrrets [Miner and Sanger, 19861, an es-tablished model for defining antiemetic activity induced by cisplatin and other highly emetogenic chemotherapeutic agents [ Florczyk et al, 19821. Dolasetron mesylate (MDL 73,147EF) is a novel 5-HT, receptor antagonist [Gittos and Fatmi, 19891 that has shown significant antiemetic activity in the ferret model for chemotherapy-induced nausea and vomiting [Miller et al, 19931 aci well as in patients receiving emetogenic chemotherapy [ Kirchner et al, 1993;Conroy et al, 1994;Kris et al, 19941. Pharmacokinetic studies have shown that dolasetron is rapidly and extensively reduced at the ketone group to form a major metabolite, MDL 74,156, which has a long plasma half-life [Boxenbaum et al, 1992, 19931.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT₃ receptor antagonist

Bigaud¹,

Elands²,

Kastner³

et al. 1995

Drug Development Research

View full text Add to dashboard Cite

Dolasetron mesylate (MDL 73,147EF) i s a novel 5-HT3 receptor antagonist under development as an anti-emetic. Dolasetron undergoes rapid and extensive metabolism to form a major metabolite, MDL 74,156; the metabolism is stereoselective, with the [ + 1-enantiomer (MDL 73,405) predominant. MDL 74,156 is also hydroxylated to form MDL 102,382 (5'-OH metabolite) and MDL 73,492 (6'-OH metabolite). The present study evaluated the pharmacological properties of dolasetron and its human metabolites in vitro and following oral and intravenous administration in rats and compared the antiemetic effects of dolasetron and ondansetron in dogs. Each of the metabolites had high affinity at and was selective for 5-HT3 receptors. In anesthetized rats, the 5-HT-mediated von Bezold-Jarisch reflex was inhibited by 1 mglkg oral doses of either dolasetron (3.1 pmol/kg), ondansetron (3.4 bmol/kg), granisetron (3.2 pmol/kg), or tropisetron (3.5 pmol/kg) and by intravenous doses of dolasetron and ondansetron. Dolasetron had a significantly longer duration of action than ondansetron. In addition, the metabolites MDL 73,405, MDL 102,382, and MDL 73,492 exhibited significant 5-HT3 receptor antagonist activity following intravenous administration, but only MDL 73,405 exhibited significant activity following oral administration. Both dolasetron mesylate and ondansetron reduced the number of emetic episodes and increased the time to first emetic event in cisplatin-treated dogs. The clinical effects and duration of action observed following administration of dolasetron mesylate to humans are likely due mainly to MDL 73,405 (the [ t 1-enantiomer of MDL 74,156). o 1995 Wiley-Liss, Inc.

show abstract

Early clinical trial of MDL 73.147 EF: A new 5-HT3-receptors antagonist for the prevention of chemotherapy-induced nausea and vomiting

Abstract: We conclude that MDL 73.147 EF is a well tolerated and possibly effective antiemetic.

Cited by 17 publications

References 5 publications

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Granisetron: An Update on its Clinical Use in the Management of Nausea and Vomiting

Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT₃ receptor antagonist

Contact Info

Product

Resources

About

Early clinical trial of MDL 73.147 EF: A new 5-HT3-receptors antagonist for the prevention of chemotherapy-induced nausea and vomiting

Abstract: We conclude that MDL 73.147 EF is a well tolerated and possibly effective antiemetic.

Cited by 17 publications

References 5 publications

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Granisetron: An Update on its Clinical Use in the Management of Nausea and Vomiting

Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT3 receptor antagonist

Contact Info

Product

Resources

About

Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT₃ receptor antagonist