In vivo assessment of antiemetic drugs and mechanism of lycorine-induced nausea and emesis (original) (raw)
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Frontiers in Pharmacology
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 (H 1) 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 (D 2) 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-hydroxytryptamine 3 (5-HT 3) receptor antagonists-metoclopramide was initially assumed to act only via D 2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine 4 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-HT 3 receptors. The latter led to identification of selective 5-HT 3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin 1 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 Sanger and Andrews History of Anti-emetic Drug Discovery 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.
Treatment of nausea and vomiting: Gaps in our knowledge
Autonomic Neuroscience, 2006
The past 20 years have seen notable advances in our understanding of the physiology and pharmacology of the emetic reflex leading to the identification of the anti-emetic effects of 5-hydroxytryptamine 3 (5-HT 3) and neurokinin 1 receptor (NK 1) antagonists. The introduction of 5-HT 3 and NK 1 receptor antagonists into the clinic has had a major impact in alleviating the nausea and vomiting associated with the treatment of cancer and the sequelae to anaesthesia and surgery (post-operative nausea and vomiting, PONV). Despite these advances there are major gaps in our understanding. Interestingly, one of these is the relatively poor ability to treat nausea. Additional gaps in our knowledge are highlighted to provide a framework within which directions for research can be proposed. Particular attention is drawn to: lacunae in knowledge of some currently used anti-emetics such as the source of dopamine required to initiate emesis; the theoretical assumptions and mechanisms underlying the concept of a "universal anti-emetic"; the variety of receptors at which agonists act to have anti-emetic effects (GABA B , CB 1 , 5-HT 1A , ghrelin, opioid); issues of translation from animals to humans and the relationship between the pathways involved in emesis and certain gastrointestinal disorders such as dyspepsia and gastroesophageal reflux, with the latter being of particular interest as some agents affecting reflux are also anti-emetic. Together, the unmet clinical need to adequately control nausea, possibly by new drugs acting within the brainstem, and the significant gaps in understanding key aspects of the emetic reflex, suggest an important need to focus and redirect research into the distressing and sometimes life-threatening symptoms of nausea and vomiting.
The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694
British Journal of Cancer, 1988
In ferrets, the selective 5-hydroxytryptamine (5-HT) 5-HT3 receptor antagonist BRL 43694 given as a single injection (0.05-0.5 mg kg-1 i.v.) before cisplatin, or by divided dose (2 x 0.005-2 x 0.5 mg kg-I i.v.) before and after cisplatin dramatically reduced or abolished the severe cisplatin-induced vomiting. BRL 43694 also substantially reduced the vomiting induced by cyclophosphamide: doxorubicin, and prevented the trimelamol-induced emesis. The severe emesis caused by whole body exposure to X-irradiation was prevented by intravenous or oral BRL 43694. A single i.v. dose of BRL 43694 given during an emetic episode or within the peak emetic period, abolished the vomiting induced by the cytotoxic drugs and by X-irradiation, usually within 30s. Where the induction of emesis was prevented or subsequently abolished by BRL 43694, the associated behaviour (subjectively assessed as nausea) was also absent or greatly attenuated. BRL 43694 (0.1 mg kg-1 i.v.) did not affect the emesis evoked in dogs by the dopamine agonist apomorphine. The potent anti-emetic activity of BRL 43694 is discussed in terms of potential clinical use, and of the fundamental role that 5-HT3 receptors may play in the mechanisms of nausea and vomiting.
Ondansetron in the treatment of antidepressant-induced nausea
Journal of the American Psychiatric Nurses Association, 2001
In the next two issues of the journal, Psychobiology Perspectives will feature content in a somewhat different area than previously covered here. We will examine the underlying biology of two sets of problematic side effects from one class of antidepressants, namely those with strong 5-HT2 antagonist properties. Although the mechanism of action of 5-HT2 antagonism has many benefits, it may also yield some untoward effects. Two of these
BMC Veterinary Research
Background: Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m 2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT 3 antagonist), maropitant (1 mg/kg; NK 1 antagonist) or metoclopramide (0.5 mg/kg; D 2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations. Results: The placebo treated group vomited an average number of 7 times (range 2-13). None of the dogs in either the ondansetron or maropitant treated groups vomited during the observation period. The onset of nausealike behaviour in the placebo-treated group occurred at t 3.5h and peaked at t 4.75h with nausea behaviour score of 58.5 ± 4.6 mm. Ondansetron and maropitant reduced overall the area under the curve of nausea behaviour score by 90% and 25%, respectively. Metoclopramide had no effect on either vomiting or nausea. Cisplatin-induced nausea and vomiting caused concomitant increases in AVP and cortisol. In the placebo-treated group, AVP and cortisol increased from t 2.5h , peaked at t 5h (11.3 ± 2.9 pmol L −1 and 334.0 ± 46.7 nmol/L, respectively) and returned to baseline by t 8h. AVP and cortisol increases were completely prevented by ondansetron and only partially by maropitant, while metoclopramide had no effect. The terminal half-lives (harmonic mean ± pseudo SD) for ondansetron, maropitant and metoclopramide were 1.21 ± 0.51, 5.62 ± 0.77 and 0.87 ± 0.17 h respectively. Conclusions: 5-HT 3 receptor antagonist ondansetron demonstrates the greatest anti-emetic and anti-nausea efficacy of the three drugs. AVP and cortisol appear to be selective biomarkers of nausea rather than emesis, providing a means of objectively measuring of nausea in the dog.
Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists
Supportive Care in Cancer, 2017
Chemotherapy-induced nausea (CIN) has a significant negative impact on the quality of life of cancer patients. The use of 5-hydroxytryptamine-3 (5-HT 3) receptor antagonists (RAs) has reduced the risk of vomiting, but (except for palonosetron) their effect on nausea, especially delayed nausea, is limited. This article reviews the role of NK 1 RAs when combined with 5-HT 3 RA-dexamethasone in CIN prophylaxis. Aprepitant has not shown consistent superiority over a twodrug (ondansetron-dexamethasone) combination in nausea control after cisplatin-or anthracycline-cyclophosphamide (AC)-based highly emetogenic chemotherapy (HEC). R e c e n t l y, d e x a m e t h a s o n e a n d d e x a m e t h a s o n emetoclopramide were demonstrated to be non-inferior to aprepitant and aprepitant-dexamethasone, respectively, for the control of delayed nausea after HEC (AC/cisplatin), and are now recognized in the guidelines. The potential impact of the new NK 1 RAs rolapitant and netupitant (oral fixed combination with palonosetron, as NEPA) in CIN prophylaxis is discussed. While the clinical significance of the effect on nausea of the rolapitant-granisetron-dexamethasone combination after cisplatin is not conclusive, rolapitant addition showed no improvement in nausea prophylaxis after AC or moderately emetogenic chemotherapy (MEC). NEPA was superior to palonosetron in the control of nausea after HEC (AC/cisplatin). Moreover, the efficacy of NEPA in nausea control was maintained over multiple cycles of HEC/MEC. Recently, NK 1 RAs have been challenged by olanzapine, with olanzapine showing superior efficacy in nausea prevention after HEC. Fixed antiemetic combinations (such as NEPA) or new antiemetics with a long half-life that may be given once per chemotherapy cycle (rolapitant or NEPA) may improve patient compliance with antiemetic treatment. Keywords NK 1 receptor antagonist. Chemotherapy-induced nausea (CIN). Chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines * Snežana M. Bošnjak
The Oncologist, 2002
Learning Objectives After completing this course, the reader will be able to: List the differences in side-effect profiles of the 5-HT3-receptor antagonists.Explain the potential issues of each 5-HT3-receptor antagonist in patients with cardiovascular disease.Understand the potential issues of each 5-HT3-receptor antagonist in patients with hepatic or renal impairment. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents exist to combat these side effects, though the 5-HT3-receptor antagonists have become the first-line treatment choice for many cancer patients and are considered the “gold standard” in antiemetic therapy. Compared with the older generation antiemetic drugs, 5-HT3-receptor antagonists are effective, well tolerated, and associated with few side ef...
Therapeutics and Clinical Risk Management, 2009
Chemotherapy-induced nausea and vomiting (CINV) are among the most feared and distressing symptoms experienced by patients with cancer. The knowledge of the pathogenesis and neuropharmacology of CINV has expanded enormously over the last decades, the most significant discoveries being the role of 5-hydroxytryptamine (5-HT) 3 -and neurokinin (NK) 1 receptors in the emetic reflex arch. This has led to the development of two new classes of antiemetics acting as highly selective antagonists at one of these receptors. These drugs have had a huge impact in the protection from chemotherapy-induced vomiting, whereas the effect on nausea seems to be limited. The first NK 1 receptor antagonist, aprepitant, became clinically available in 2003, and casopitant, the second in this class of antiemetics, has now completed phase III trials. This review delineates the properties and clinical use of casopitant in the prevention of CINV.
Potential of Substance P Antagonists as Antiemetics
Drugs, 2000
The introduction of serotonin 5-HT3 receptor antagonists into clinical practice allowed for a dramatic improvement in the management of nausea and vomiting. Despite this, postoperative and chemotherapy-induced emesis remains a significant, unresolved issue in many patients even when a combination of antiemetic drugs is used. Numerous neurotransmitters have been implicated in triggering emesis; however, the tachykinin substance P, by virtue of its localisation within both the gastrointestinal vagal afferent nerve fibres and brainstem emetic circuitry, and its ability to induce vomiting when administered intravenously, is thought to play a key role in emetic responses. Because substance P is the most likely endogenous ligand for the neurokinin-1 (NK1) receptor, the development of nonpeptide NK1 receptor antagonists led scientists to evaluate these compounds as antiemetics. The five NK1 receptor inhibitors that have been studied initially in humans are: vofopitant (GR-205171), CP-122721, ezlopitant (CJ-11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy in acute cisplatin-induced emesis, this new class of drugs has proven to be highly effective in the control of both chemotherapy-induced nausea and vomiting, and postoperative nausea and vomiting. No major adverse event was reported in the preliminary trials. Further investigation is mandatory in order to assess the optimal treatment regimen and to make sure the wide spectrum activity of the NK1 receptor inhibitors does not cause significant adverse effects in the context of the treatment of nausea and vomiting.