Two Decades of Progress in Treating
C h e m ot h e r a p y I n d u c e d E m e s i s
particularly when extrapyramidal reactions prevent the use of prochloperazine and metoclopramide7. Even cannabinoids were tried because of anecdotal reports from young patients who smoked marijuana that it alleviated their vomiting after chemotherapy. Delta-9-tetrahydrocannabinol was less activethan high-dose intravenous metoclopramide in controlling The use of cytotoxic drugs such as cisplatin, which caused cisplatin-induced emesis, but is better with chemotherapy of severe nausea and vomiting unresponsive to standard moderate emetic potential as are the synthetic cannabinoids antiemetics, stimulated research into the mechanisms of nausea levonantradol and nabilone8. They are, however, more toxic than and vomiting. Cisplatin was associated with both an acute other antiemetics with the somnolence and dysphoric reactions emesis in the first 24 hours and a delayed emesis which could tolerated poorly, particularly in older patients9. last for a week. The discovery of that 5 hydroxytrytamine3 receptors in the small intestine and brain were responsible foracute chemotherapy induced vomiting and the introduction of The empiric observation that chemotherapy cycles including a 5-HT3 receptor antagonists revolutionised the treatment of corticosteroid were associated with less emesis than those acute chemotherapy induced emesis, but had only minor without led to these agents being investigated as antiemetics10.
impact on delayed emesis, which was thought to be mediated Although they have some efficacy as single agents their greatest by a different mechanism. Now aprepitant a new drug that is a role has been as part of antiemetic combinations11. neurokinin1 receptor antagonist, which is centrally acting andgiven orally, has improved the control of acute emesis when Benzodiazepines such as lorazepam have been used in addition to antiemetics, particularly metoclopramide and proclorperazine12,13.
importantly has made a major advance in the control of delayed Lorazepam has an amnesic anxiolytic effect and is a sedative. This emesis when continued for two further days in combination can improve the patients’ tolerance of chemotherapy and can with dexamethasone. This control of nausea and vomiting reduce the risk of extrapyramidal reactions from associated with chemotherapy has translated into improved metoclopramide.14 Trials of benzodiazepines have been directed at quality of life of the patients receiving chemotherapy. Nausea and vomiting have been listed by patients as amongst the most distressing side effects of chemotherapy1. Much of the It was the discovery that cisplatin-induced acute emesis could knowledge gained over the last two decades about the be ameliorated by specifically blocking one of the seven 5- mechanisms of emesis has resulted from the need to control hydroxytryptamine (5-HT) receptors, the 5-HT3 receptor, that chemotherapy induced emesis following the introduction of allowed a great stride in our understanding of the pathways of cytotoxic drugs of high emetic potential, such as cisplatin. the emetic response.16 The 5-HT3 receptors are found centrally There are three phases of emesis associated with chemotherapy.
and peripherally where the main site of activity is in the small Following cisplatin, which is the cytotoxic used in trials of new intestine. The 5-HT3 receptors have allowed identification of antiemetics because without antiemetics it causes emesis in the role of the vagal afferent-enterochromaffin cell unit in the most patients, there is an acute phase of emesis starting a few emetic response.17 Cytotoxic drugs cause a calcium dependent hours after chemotherapy and lasting until 18 to 24 hours, then release of hydroxytryptamine from enterochromaffin cells in a delayed phase, which follows and can last for up to a week.
the upper gastrointestinal mucosa. This is reflected by the fact Finally there is anticipatory nausea and vomiting which is a that cisplatin-induced emesis is associated with increases in conditioned response prior to the chemotherapy in subsequent urine and plasma 5-hydroxyindoleacetic acid (5 HIAA), a cycles when emesis has occurred with previous doses2. This metabolite of 5-HT supposedly released from the provides the rationale for prophylactically trying to prevent post enterochromaffin cells.18 It is an anomaly, however, that chemotherapy emesis so there can be no learned response. cyclophosphamide induced emesis which responds to 5-HT3antagonists fails to induce these changes to 5-HT release and so the precise mechanism of emesis remains undefined.19 The initial anti-emetic drugs used for chemotherapy induced The recognition of the role of the 5-HT3 receptor in acute post emesis were dopamine antagonists, particularly chemotherapy emesis and the development of selective metoclopramide, which blocked the D2 receptor thought to antagonists including ondansetron, granisetron, tropisetron and mediate emesis3. At conventional doses this drug was not very dolasetron has revolutionised the management of this effective, however a breakthrough came when, based on complication of anti-cancer chemotherapy.20,21 They are not broad animal studies, clinical trials established that high doses of spectrum antiemetics, their major uses being confined to post metoclopramide, up to 3mg/kg were more effective for chemotherapy and post anaesthetic emesis. Despite preclinical preventing cisplatin induced emesis and were tolerated with differences, there is little difference clinically between the drugs.
only sporadic extrapyramidal reactions4. It is now believed that The 5-HT3 receptor antagonists were shown to be superior to high-dose metoclopramide affects the 5 hydroxtryptamine3 high dose metoclopramide regimens for preventing chemotherapy-induced emesis and they have a favorable toxicity Other drugs available at the time included prochlorperazine, profile with reversible headache, constipation and mild elevations where again low doses were minimally effective and higher in liver transaminases being the most common side effects.22,23 A doses more so, but at the expense of toxicities such as 5-HT3 receptor antagonist combined with dexamethasone had hypotension and extrpyramidal reactions6. Of the become the gold standard given prophylactially to prevent acute butyrophenones, oral domperidone has been most used, post chemotherapy induced emesis.2 This results in complete Cancer Forum ■ Volume 28 Number 3 ■ November 2004 protection from cisplatin-induced emesis ranging from 70-90 per cisplatin induced emesis, which suggested additive activity in cent.24 These drugs are also active for radiation induced emesis.20 controlling acute emesis and good control of delayed emesis if As a class of drugs, clinically, there is a threshold effect for the three drugs were given on day one (either granisetron or efficacy, only a modest dose response curve and a plateau in ondansetron with dexamethasone and aprepitant) and the therapeutic efficacy21. Failure of response or breakthrough of dexamethasone and aprepitant on days 2 and 3.37-39 emesis on these agents may not be remedied by larger or more The first phase III placebo controlled trials were performed in frequent dosing because other receptor mechanisms may be South America (Poli-Bigelli et al) and in centers from North responsible.25,26 Currently single daily dosage regimens are most America, Europe and Australia (Hesketh et al)24,25. Both studies commonly used. Oral doses when adjusted for their bioavailability included patients receiving their first cycles of cisplatin seem as effective as intravenous dosing if there are no barriers to >70mg/m2. The patients on the standard arms of both studies absorption.21 Mainly used intravenously and orally, other received intravenous ondansetron 32mg 30 minutes before formulations such as ondansetron wafers, which dissolve in the cisplatin with oral dexamethasone 20 mg on day one followed mouth and suppositories have been trialed.27, 28 by oral dexamethasone 8mg twice daily from days two to four.
The aprepitant groups received oral aprepitant 125mg onehour before cisplatin, then intravenous ondansetron 32mg 30 The 5-HT3 receptor antagonists were very effective for acute minutes before cisplatin with oral dexamethasone 12mg on emesis, but a second mechanism of emesis was responsible for day one. On days two and three oral aprepitant 80mg and oral delayed emesis which begins towards the end of the first day dexamethasone 8mg only once daily (because of the and can continue for a week. If a 5-HT3 antagonist and interaction with dexamethasone) was given and then day four dexamethasone was continued the control of the delayed phase oral dexamethasone 8mg. An extension phase of the study of emesis rarely exceeded 50 per cent29,30. Here dexamethasone appeared to be the key drug and combining it withmetoclopramide yielded similar results to studies combining it Combining trials 1099 patients were enrolled. The complete response rate for the days of the first cycle in the Poli-Bigelli trial 3 antagonists31. It is now known that the centrally located neurokinin1(NK1) receptors are important mediators of was 62.7 per cent for the aprepitant group versus 43.3 per cent for control (p<0.001) and for the Hesketh trial 72.7 per centaprepitant versus 52.3 per cent control (p<0.001). For acute emesis the results were aprepitant 82.8 per cent versus control68.4 per cent (p<0.001), for Poli-Bigelli and aprepitant 89.2 per Substance P is an 11 amino acid neurotransmitter which cent versus controls 78.1 per cent (p<0.001) for Hesketh. The displays a strong affinity for the NK1 receptor.32 There are high biggest differences were seen in delayed emesis; 67.7 per cent concentrations of substance P, which can be imaged by versus 46.8 per cent (p<0.001) and 74.4 per cent versus 55.8 per positron emission tomography, in areas of the brain responsible cent (p<0.001) respectively. Similar results were seen with for emesis such as the nucleus tractus solitarus and area nausea. The efficacy of aprepitant was maintained over six postrema33. NK1 receptor antagonists are highly selective for courses as was consistent with the result of a study designed to NK1 receptors and they act centrally, inhibiting the binding of specifically test protection over multiple cycles42. substance P. In the ferret model they show activity against bothacute and delayed cisplatin-induced emesis34. In the two phase III trials logistic regression analyses of theFunctional Living Index Emesis (FLIE) quality of life scale showed The first of the NK1 antagonists available clinically is aprepitant.
that more patients in the aprepitant groups reported minimal or Aprepitant has a pro-drug L-758298, which is an intravenous no impact of chemotherapy induced nausea and vomiting on preparation, but itself is an oral formulation with 60 to 65 per their daily life compared to those on the standard treatments cent being absorbed and that absorption not affected by food.
(74.7 per cent versus 63.5 per cent in Poli-Bigelli and 70.4 per It is recommended for once a day administration. It crosses the cent versus 64.3 per cent in Hesketh). Moreover this result was blood brain barrier which is necessary for its antiemetic effect.
independent of the gender of the patients. In the Hesketh study, Its main pathway of elimination is by the cytochrome P450 the percentage of males (69.8 per cent) and females (77.6 per CYP3A4 isozyme of which it is a moderate inhibitor. This creates cent) with complete response overall were similar in the the potential for drug interactions. Of significance, when given aprepitant treated group, but in the standard arm complete with dexamethasone there was a two fold increase in responses were less for females (38.8 per cent) than males (60.5 dexamethasone AUC (area under the dose/time curve)35. The per cent), which is the more usual result since females don’t AUC of ethinyl estradiol is decreased by 40 per cent and the respond to other antiemetics as well as males43. manufacturer recommends alternate methods ofcontraception. No significant interactions have been found with Aprepitant added to a 5 HT3 receptor antagonist and 5-HT3 receptor antagonists or cytotoxics such as docetaxel36. No dexamethasone was effective in both the older and younger age dosage adjustments are necessary for mild to moderate hepatic groups, whereas other antiemetics tend to be less effective in or renal insufficiency, age race or gender. Based on negligible younger patients. The overall complete response in patients pharmacokinetic differences, there are no dosage adjustments aged 65 and over was 76 per cent for the aprepitant arm and 54 recommended on the basis of age, race or gender. PET studies per cent for the standard arm (p<0.001). Similar results are seen have shown correlations between receptor occupancy and for both the acute and delayed phases of emesis and safety plasma concentration and efficacy. Antiemetic efficacy increases comparisons between older and younger patients showed no with increased receptor occupancy up until a dose of 125mg difference44. The FLIE analysis also showed that the addition of but no additional benefit is seen with higher doses33. aprepitant to standard therapy reduced the impact of postchemotherapy emesis on both older and younger patients45.
The single agent activity of these agents was disappointingagainst acute cisplatin-induced emesis and therefore the NK1 Aprepitant was well tolerated. The incidence of drug related receptor antagonists have been trialed added to 5-HT3 receptor adverse events was 19.5 per cent for aprepitant versus 14.4 per antagonists and steroids. Following phase I studies there were five cent controls on Poli-Bigelli and 14.6 per cent versus 11.0 per phase II trials (two with the prodrug and three with aprepitant) in cent on Hesketh. Anorexia, asthenia and hiccoughs were more Cancer Forum ■ Volume 28 Number 3 ■ November 2004 frequent with aprepitant; the other side effects were similar to 14. Kris MG, Gralla RJ, Clarke RA, Tyson LB, Groshen S. Antiemetic control the 5HT3 antagonists with which they were combined. and prevention of side effects of anticancer therapy with lorazepam ordiphenhydramine when used in combination with metoclopramide plusdexamethasone. Cancer 1987;69:2816-22.
15. Greenberg DB, Surman OS, Clarke J, Baer L. Alprazolam for phobic The new standard for antiemetic prophylaxis for drugs of high nausea and vomiting related to cancer chemotherapy. Cancer1987;71:549-60.
emetic potential will be a 5HT3 receptor antagonist, 16. Andrews PRL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its dexamethasone and aprepitant for the acute phase followed relevance to anti-emetic therapy. Consensus and controversies. Support by aprepitant and dexamethasone for two days of the delayed 17. Andrews PL, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Science 1988;9:334-41.
Traditionally, with cytotoxics of moderate emetic potential, 18. Cubeddu LX, Hoffman IS, Fuenmayor NT, Malave JJ. Changes in serotonin similar antiemetic regimens are used to those used with drugs of metabolism in cancer patients: its relationship to nausea and vomiting high emetic potential, although one of the newer HT3 receptor induced by chemotherapy agents. Brit J Cancer 1992;66:198-203.
antagonists, palonosetron, has been specifically given an 19. Cubeddu LX, O’Connor DT, Hoffmann I, Palmer RJ. Plasma indication for use for delayed emesis in this setting46. Studies are chromogranin A marks emesis and serotonin release associated withdacarbazine and nitrogen mustard but not with cyclophosphamide- ongoing to evaluate combinations including the NK1 receptor based chemotherapies. Brit J Cancer 1995;72:1033-8.
antagonists for cytotoxics of moderate emetic potential and see 20. Gralla RJ, Osoba D, Kris MG et al for the American Society of Clinical whether delayed emesis will be as well controlled in this setting Oncology. Recommendations for the use of antiemetics: Evidence-based as it is when used with cytotoxics of high emetic potential.
clinical practice guidelines. J Clin Oncol 1999;17:2971-94.
21. Gandara DR, Roila F, Warr D, Edelman MJ, Perez EA, Gralla RJ.
Finally in the era of more targeted therapy, the emergence of Consensus proposal for 5HT3 antagonists in the prevention of acute gene array technology identifying the genes coding for the 5- emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration. Support Care Cancer 1998;6:237-43.
3 and NK1 receptors may allow clinical correlations and more rational selection of antiemetic regimens for patients. For 22. Marty M, Pouillart P, Scholl S. Comparison of the 5-hydroxytryptamine (serotonin) antagonist ondansetron (GR 38032F) with high-dose example, patients with genetic variations in the 5-HT3B metoclopramide in the control of cisplatin-induced emesis. New Engl J receptor gene might respond differently to antiemetic treatments including the 5-HT3 receptor antagonists.47 23. de Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron (GR38032F) versus high dose metoclopramide in the prophylaxis of acute and delayed cisplatin-induce nausea and vomiting. Annals ofInternal Medicine 1990; 113: 834-40.
1. Coates A, Abraham S, Kaye SB et al. On the receiving end - patient 24. Roila F, Tonato M, Ballatori E et al. Comparative studies of various perception of the side-effects of cancer chemotherapy Eur J Cancer Clin antiemetic regimens. Support Care in Cancer 1996;4:270-80.
25. Herstedt J. New perspectives in antiemetic treatment. Support Care 2. Antiemetic Subcommittee of the Multinational Association of supportive care in Cancer (MASCC). Prevention of chemotherapy- and 26. Tattersall FD, Rycroft W, Hill RG, Hargreaves RJ. Enatioselective inhibition radiotherapy-induced emesis: Results of the Perugia Consensus of apomorphine-induced emesis in the ferret by the neurokinin1 Conference. Ann Oncol 1998;9:1022-9.
receptor antagonist CP-99,994. Neuropharmacology 1994;33:259-60.
3. Sibley D, Monsma F. Molecular biology and dopamine receptors. Trends 27. Seager H. Drug delivery products and the Zydis fast-dissolving dosage- form. J Pharm Pharmacol 1998;50:375-82.
4. Gralla RJ, Itri LM, Pisko SE et al. Antiemetic efficacy of high-dose 28. Davidson NG, Paska W, Van Belle S, Goedhals L, McQuade B, McRae J.
metoclopramide: randomized trials with placebo and prochlorperazine Ondansetron suppository: a randomized double-blind, double-dummy, in patients with chemotherapy-induced vomiting. England Journal of parallel group comparison with oral ondansetron for the prevention of cyclophosphamide induced emesis and nausea. The Ondansetron 5. Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by Suppository emesis study group. Oncology 1997;54:380-6.
selective 5-hydroxytryptamine M-receptor antagonism. Brit J Cancer 29. Olver I, Paska W, Depierre A et al. A multicentre, double-blind study comparing placebo, ondansetron and ondansetron plus dexamethasone 6. Olver IN, Wolf M, Laidlaw C et al. A randomized double-blind study of for the control of cisplatin-induced delayed emesis. Ann Oncol high-dose intravenous prochlorperazine versus high-dose metoclopramide as antiemetics for cancer chemotherapy. Eur J Cancer 30. Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose 7. Cunningham D, Evans C, Gazet J-C et al. Comparison of antiemetic cisplatin. J Clin Oncol 1985;3:1379-84.
efficacy of domperidone, metoclopramide and dexamethasone in 31. Kris MG, Gralla RJ, Tyson LB et al. Controlling delayed vomiting: double- patients receiving outpatient chemotherapy regimens. BMJ blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J 8. Gralla RJ, Tyson LB, Bordin LA et al. Antiemetic therapy: a review of recent studies and a report of a random assignment trial comparing 32. Diemunsch P, Grelot L. Potential of substance P antagonists as metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treatment 33. Hargreaves R. Imaging substance P receptors (NK1) in the living human 9. Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG.
brain using positron emission tomography. J Clin Psychiatry Recent clinical experience with dronabinol. Pharmacol Biochem 34. Tattersall FD, Rycroft W, Cumberbatch M et al. The novel NK1 receptor 10. Winokur SH, Baker JJ, Lokey JL, Price NA, Bowen J. Dexamethasone in antagonist MK-0869 (L-754,030) and its water soluble phosphoryl the treatment of nausea and vomiting from cancer chemotherapy. J prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in the ferret. Neurophamacology 2000;39:652-63.
11. Herrstedt J, Aapro MS, Smyth JF, Del Favero A. Corticosteroids, 35. McCrea JB, Majumbdar AK, Goldberg MR et al. Effects of the neurokinin dopamine antagonists and other drugs. Support Care Cancer 1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharm Ther 2003;74:17-24.
12. Gordon CJ, Pazdur R, Zicarelli A, Cunningham G, Al-Sarraf M.
36. Blum RA, Majumdar AK, McCrea JB et al. Effects of aprepitant on the Metoclopramide versus metoclopramide and lorazepam: superiority of pharmacokinetics of ondansetron and granisetron in healthy subjects.
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dexamethasone alone. J Clin Oncol 2001:19(6):1759-67.
Cancer Forum ■ Volume 28 Number 3 ■ November 2004 38. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced 43. Martin AR, Ma JG, Carides AD et al. The oral NK1 antagonist, emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med aprepitant, was effective in maintaining patients’ daily life activities in both male and female patients receiving highly emetogenicchemotherapy. Proc Am Soc Clin Oncol 2003;22:750 39. Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy- 44. Bauwens G, Aapro MS, Pendergrass K et al. The oral NK1 receptor induced nausea and vomiting. Cancer 2003;97(9):2290-300.
antagonist aprepitant is effective for the prevention of chemotherapy induced nausea and vomiting in elderly patients receiving high-dose 40. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the cisplatin. Proc Am Soc Clin Oncol 2003;22:786.
neurokinin 1 receptor antagonist aprepitant to standard antiemetic 45. Ma JG, Martin AR, Carides AD et al. The oral NK1 antagonist, therapy improves control of chemotherapy-induced nausea and aprepitant, is effective in reducing impact of chemotherapy-induced vomiting: results from a randomized, double-blind, placebo-controlled nausea and vomiting on daily life in both younger and older patients trial in Latin America. Cancer 2003;97(12):3090-8.
receiving highly emetogenic chemotherapy. Proc Am Soc Clin Oncol 41. Hesketh PJ, Grunberg SM, Gralla RJ et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced 46. Aapro E, Selak M, Lichinitser D et al. Palonosetron (PALO) is more nausea and vomiting: a multinational, randomized, double-blind, effective that ondansetron (OND) in preventing chemotherapy-induced placebo-controlled trial in patient receiving high-dose cisplatin.-The nausea and vomiting (CINV) in patients receiving moderately aprepitant protocol 052 study group. J Clin Oncol 2003;21:4112-9.
emetogenic chemotherapy (MEC): Results of a phase III trial. Proc Am 42. de Wit R, Herrstedt J, Rapoport B et al. Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection 47. Tremblay PB, Kaiser R, Sezer O et al. (2003) Variations in the 5- against nausea and vomiting during multiple cycles of cisplatin-based hydroxytryptamine type 3B receptor gene as predictors of the efficacy of chemotherapy. J Clin Oncol 2003;21:4105-19.
antiemetic treatment in cancer. J Clin Oncol 21:2147-55.
Cancer Forum ■ Volume 28 Number 3 ■ November 2004

Source: http://cancerforum.org.au/File/2004/November/CF04Nov_140-143.pdf

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