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Paul J Hesketh - One of the best experts on this subject based on the ideXlab platform.
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aprepitant as salvage antiemetic therapy in breast cancer patients receiving doxorubicin and cyclophosphamide
Supportive Care in Cancer, 2009Co-Authors: Paul J Hesketh, Jerry Younger, Pedro Sanzaltamira, Melissa Hayden, Julie Bushey, Brian Trainor, Michael Krentzin, Peter Nowd, Konstantinos Arnaoutakis, Ann M HeskethAbstract:Goals of work To assess the efficacy of adding aprepitant to a 5-HT3 Antagonist and dexamethasone as salvage antiemetic therapy for breast cancer patients receiving their initial cycle of an anthracycline and cyclophosphamide (AC) and failing to achieve complete control of emesis.
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drug insight new antiemetics in the management of chemotherapy induced nausea and vomiting
Nature Reviews Clinical Oncology, 2005Co-Authors: Paul J HeskethAbstract:Recent improvements in the development of antiemetics have helped to minimize chemotherapy-induced nausea and vomiting. Oo and Hesketh review the latest clinical trial data and discuss how the introduction of two new antiemetics, palonosetron, a 5-HT3 Antagonist, and aprepitant, a NK-1 Antagonist, have demonstrated significant advances for patients inadequately controlled with conventional antiemetic regimens. Nausea and vomiting remain among the most feared side effects of chemotherapy for cancer patients. Significant progress has been made in the last 15 years in developing more effective and better-tolerated measures to minimize chemotherapy-induced nausea and vomiting (CINV). During the 1990s, the selective 5-hydroxytryptamine receptor Antagonists were first introduced for the treatment of CINV, and resulted in more effective and better tolerated treatment of CINV. Despite recent progress, however, a significant number of patients still develop CINV, particularly during the 2–5 day period (delayed emesis) following chemotherapy. There is evidence that this may be an underappreciated problem on the part of some caregivers. Recently, two new antiemetics, aprepitant, the first member of the neurokinin-1 Antagonists, and palonosetron, a second-generation 5-hydroxytryptamine receptor Antagonist, received regulatory approval in the US. Both represent useful additions to the therapeutic armamentarium for the management of CINV.
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differential involvement of neurotransmitters through the time course of cisplatin induced emesis as revealed by therapy with specific receptor Antagonists
European Journal of Cancer, 2003Co-Authors: Paul J Hesketh, S Van Belle, Matti Aapro, F Tattersall, R Naylor, Richard Hargreaves, Alexandra D Carides, Judith K Evans, Kevin J HorganAbstract:Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT3) Antagonist and a corticosteroid. The neurokinin-1 (NK1) Antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT3 Antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK1 Antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT3 Antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK1 Antagonist occurred within the first 8–12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT3 Antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor Antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8–12 h following cisplatin-based chemotherapy, after which time substance P acting at NK1 receptors becomes the dominant mediator of vomiting
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treatment of chemotherapy induced emesis in the 1990s impact of the 5 ht3 receptor Antagonists
Supportive Care in Cancer, 1994Co-Authors: Paul J HeskethAbstract:Considerable progress has been made in the development of means to limit nausea and vomiting arising from cancer chemotherapy. A number of key conceptual advances in the last decade have been critically important. These include recognition of the value of combination antiemetic therapy, identification of important patient- and treatment-related factors predictive of emesis, and appreciation of the importance of serotonin (5-HT) in the pathophysiology of emesis and the value of selective Antagonists of the type-3 serotonin receptor. Comparative trials of the 5-HT3 receptor Antagonists and classic antiemetic agents have helped define optimal antiemetic approaches in a number of settings. A combination of a 5-HT3 Antagonist and dexamethasone is the treatment of choice for patients receiving single- and multiple-day cisplatin. The 5-HT3 Antagonists are also effective agents with noncisplatin chemotherapy. Clear-cut superiority to classic antiemetics such as dexamethasone has not been consistently demonstrated, however. Results with the 5-HT3 Antagonists in cisplatin-induced delayed emesis have been disappointing to date. The results of ongoing prospective trials should define their role more clearly. At present a combination of metoclopramide and dexamethasone is the treatment of choice in this setting. Results of trials comparing 5-HT3 Antagonists are beginning to emerge. Available information suggests no clinically relevant differences in antiemetic efficacy between these agents. Many questions regarding the optimal use of the 5-HT3 Antagonists and their integration into clinical practice remain unanswered and are the appropriate focus for additional study.
Prabashni Reddy - One of the best experts on this subject based on the ideXlab platform.
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evidence to support use of palonosetron over generic serotonin type 3 receptor Antagonists for chemotherapy induced nausea and vomiting
American Journal of Health-system Pharmacy, 2014Co-Authors: Gayle C Blouin, Prabashni ReddyAbstract:Palonosetron, a serotonin type 3–receptor (5-HT3) Antagonist, was approved by the Food and Drug Administration (FDA) in 2003 for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately
Miodrag Radulovacki - One of the best experts on this subject based on the ideXlab platform.
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r zacopride a 5 ht3 Antagonist 5 ht4 agonist reduces sleep apneas in rats
Pharmacology Biochemistry and Behavior, 2001Co-Authors: David W Carley, Henri Depoortere, Miodrag RadulovackiAbstract:The effects of R-zacopride, a benzamide with potent 5-HT3 receptor Antagonist and 5-HT4 receptor agonist properties, on spontaneous apneas were studied in 10 Sprague-Dawley rats by monitoring respiration and sleep for 6 h. R-zacopride (0.5, 1.0 and 10.0 mg/kg) suppressed spontaneous central apneas during non-rapid-eye-movement (NREM) sleep by 50% (P=.05 for 0.5 mg/kg, P=.02 for 1.0 mg/kg and P=.001 for 10.0 mg/kg dose vs. control), and during rapid-eye-movement (REM) sleep by 80% by all doses tested (P<.0007) for at least 2 h after intraperitoneal injection. We conclude that R-zacopride, over a 20-fold dose range, significantly reduces central apnea expression during NREM and REM sleep in the rat. The efficacy of this compound to suppress central apneas most probably arises from its Antagonist actions at 5-HT3 receptors or from its mixed agonist/Antagonist profile at 5-HT4/5-HT3 receptors.
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mirtazapine a mixed profile serotonin agonist Antagonist suppresses sleep apnea in the rat
American Journal of Respiratory and Critical Care Medicine, 1999Co-Authors: David W Carley, Miodrag RadulovackiAbstract:Serotonin enhancing drugs, including l-tryptophan and, more recently, fluoxetine and paroxetine, have been tested as pharmacologic treatments for sleep apnea syndrome. Although some patients have demonstrated reduced apnea expression after treatment with these compounds, this improvement has been restricted to nonrapid eye movement (NREM) sleep, with some patients showing no improvement. This study reports the effects of mirtazapine, an antidepressant with 5-HT1 agonist as well as 5-HT2 and 5-HT3 Antagonist effects, on sleep and respiration in an established animal model of central apnea. We studied nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded after intraperitoneal injection of: (1) saline, (2) 0.1 mg/kg + / − mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all three doses reduced apnea index during NREM sleep by more than 50% (p ...
Michael Camilleri - One of the best experts on this subject based on the ideXlab platform.
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is there an experimental basis for the development of ischaemic colitis as a result of 5 ht3 Antagonist treatment
Neurogastroenterology and Motility, 2007Co-Authors: Michael CamilleriAbstract:5-HT(3) Antagonists are effective treatments for chemotherapy-induced emesis and diarrhoea and urgency and pain associated with irritable bowel syndrome. Reports of ischaemic colitis led to restricted use of the approved drug, alosetron. This article briefly reviews the controversial information from epidemiology and adverse reaction reports and addresses the experimental basis for the development of ischaemic colitis as a result of 5-HT(3) Antagonist treatment. The author reviews the potential factors based involved in the ischaemic colitis and ways in which this class of compound may influence those factors based on experimental evidence, including the literature on any vascular effects of these agents. Finally, the article addresses the theoretical basis for the constipation as a predisposing factor for the development of ischaemic colitis. The evidence reviewed suggests that further studies are needed to explore the principles to prove or disprove the association.
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management of the irritable bowel syndrome
Gastroenterology, 2001Co-Authors: Michael CamilleriAbstract:Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT3 Antagonist, tegaserod, a partial 5-HT4 agonist, k-opioid agonists, and neurokinin Antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain— gut axis is key to the eventual development of effective therapies for IBS.
Gayle C Blouin - One of the best experts on this subject based on the ideXlab platform.
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evidence to support use of palonosetron over generic serotonin type 3 receptor Antagonists for chemotherapy induced nausea and vomiting
American Journal of Health-system Pharmacy, 2014Co-Authors: Gayle C Blouin, Prabashni ReddyAbstract:Palonosetron, a serotonin type 3–receptor (5-HT3) Antagonist, was approved by the Food and Drug Administration (FDA) in 2003 for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately