Italian pharmacy online: cialis senza ricetta medica in farmacia.
wo 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-
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21. Gandara DR, Roila F, Warr D, Edelman MJ, Perez EA, Gralla RJ.
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Consensus proposal for 5HT3 antagonists in the prevention of acute
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route of administration. Support Care Cancer 1998;6:237-43.
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rational selection of antiemetic regimens for patients. For
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Cancer Forum ■ Volume 28 Number 3 ■ November 2004
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