Beruflich Dokumente
Kultur Dokumente
2
-adrenergic receptor
Secretory leukocyte inhibitory protein
Clara cell protein
IL-1 receptor antagonist
IL-1R2
IB
IL-10
GILZ
MKP-1
CD163
Transrepression
Cytokines
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-12, IL-13, IL-16, IL-17, IL-18,
TNF-, GM-CSF, SCF
Chemokines
IL-8, RANTES, MIP-1, MCP-1, MCP-3, MCP-4, eotaxins
Adhesion molecules
ICAM-1, VCAM-1, E-selectin
Inammatory enzymes
Inducible nitric oxide synthase
Inducible cyclooxygenase-2
Cytoplasmic phospholipase A
2
Inammatory receptors
Tachykinin NK
1
and NK
2
receptors
Bradykinin B
2
-receptors
Peptides
Endothelin-1
a
GM-CSFgranulocyte-macrophage colony-stimulating hormone; ICAM
intercellular adhesion molecule-1; ILinterleukin; MCPmonocyte chemoattrac-
tant protein; MIPmacrophage inammatory protein; NF-Bnuclear factor-B;
GILZglucocorticoid-induced leucine zipper protein; MKP-1mitogen-activated
protein kinase phosphatase-1; RANTESregulated upon activation, normal cell
expressed and secreted; SCFstem-cell factor; TNF-tumor necrosis factor-;
VCAM-1vascular cell adhesion molecule-1.
C.-C. Chu et al. / European Journal of Pharmacology 722 (2014) 4854 50
eicosanoids (Barnes, 1998; Bray et al., 1983; Rhen and Cidlowski,
2005), may account for their antiemetic effect in patients under-
going chemotherapy and radiotherapy.
4.2. The antiemetic effect related to serotonin
Serotonin (5-HT) is a neurotransmitter that can cause emesis
(Becker, 2010; Darmani and Ray, 2009). Glucocorticoids inhibit
5-HT expression. In a study using peripheral blood mononuclear
cells, cisplatin induced the release of 5-HT, and methylpredniso-
lone attenuated that release (Mantovani et al., 1997). Both dex-
amethasone and methylprednisolone concentration-dependently
inhibited the expression of 5-HT
3A
receptors in Xenopus laevis
oocytes (Suzuki et al., 2004). In developing rats, dexamethasone
decreased the level of 5-HT in the cerebral cortex and hippocam-
pus (Slotkin et al., 2006). In central glucocorticoid receptor-
knockdown mice, the expression and function of 5-HT
2A
receptors
increased (Dennis et al., 2011; Islam et al., 2004). These mechan-
isms may also account for the antiemetic effects of glucocorticoids.
4.3. The antiemetic effect glucocorticoids related to hypofunction
of HPA-axis
Cortisol (a glucocorticoid) is the downstream hormone in the
HPA-axis. Glucocorticoids are necessary for maintaining the nor-
mal physiological functions of several organs and systems, espe-
cially under stress. Glucocorticoids may be necessary in patients
under stress and experiencing nausea and vomiting. A glucocorti-
coid deciency may cause nausea and vomiting (Hursti et al., 1993;
Kageyama, 2000; Oelkers, 1996; Sapolsky et al., 2000). It is likely
that many adverse effects commonly associated with chemo-
therapy, such as nausea and vomiting, are also characteristic of
adrenal insufciency. It is conceivable that chemotherapy drugs
may directly or indirectly affect the activity of the HPA axis. A
signicant reduction in serum cortisol was found immediately
after either cisplatin- or carboplatin-based chemotherapy for cancer
(Morrow et al., 2002). Moreover, ACTH, the hormone that stimu-
lates cortisol production in the HPA-axis, is also known to be
effective against emesis in CINV, and has a protective effect on the
nervous system: it reduces damage to the vagus and splanchnic
nerves, which leads to a more rapid recovery of normal gut
motility (Santini et al., 2001). This implies that the antiemetic
effect of glucocorticoids and ACTH may occur because it restores
normal physiological function in people in a hypocortisol state,
for instance, after a chemotherapy session. Glucocorticoids and
ACTH can also reduce nervous system damage during noxious
stimulation.
4.4. Glucocorticoids on glucocorticoid receptors or
adrenergic receptors
Central adrenergic receptors are also involved in the development
of emesis in many conditions. Intracerebroventricular injections of
noradrenaline produced dose-dependent emesis in cats (Beleslin and
Strbac, 1987). A Swedish study (Fredrikson et al., 1994) reported the
involvement of the endogenous adrenergic system in CINV in humans
as well. In their study, pretreatment nighttime adrenaline and
noradrenaline levels were measured in patients receiving chemother-
apy. Excretion of noradrenaline, but not adrenaline, correlated with
the severity of nausea 2472 h after chemotherapy. The activation of
adrenoceptors, especially the alpha-2 subtype receptor, was also an
important mechanism for xylazine-induced emesis in cats and dogs
(Hikasa et al., 1989, 1986). Alpha-2, but not alpha-1, adrenoceptor
blockers can antagonize the emetic action of xylazine (Hikasa et al.,
1986). In contrast, dexamethasone also signicantly reduced the
frequency of xylazine-induced emetic episodes when it was injected
into the bilateral STN of the medulla of cats (Ho et al., 2004). When
injected into the area postrema, it had no effect. This central
antiemetic effect also acted on the glucocorticoid receptors in the STN.
In many brain areas, such as the amygdala and hippocampus,
corticosteroids interact with adrenoceptors to regulate memory
function (Kukolja et al., 2011; Schutsky et al., 2011). Moreover,
corticosteroids and noradrenalin can act together to synergistically
increase hippocampal activity during the encoding of emotional
stimuli (Kukolja et al., 2011). Taking these ndings together, we
hypothesize that glucocorticoid act directly on glucocorticoid recep-
tors or interact with adrenoceptors to regulate emesis. However,
more specic studies are needed to verify this hypothesis.
4.5. Some other effects
Glucocorticoids reduce tissue inammation by inhibiting the
release of inammatory mediators, e.g., prostaglandins and sub-
stance P, which cause pain (Barnes, 1998; Rhen and Cidlowski,
2005). Glucocorticoids may also reduce the use of opioids used as
analgesics, which in turn reduces opioid-related nausea and vomiting
(Diakos et al., 2011; Korman and McKay, 1985; Lunn et al., 2013).
5. Chemotherapy-induced nausea and vomiting
Nausea and vomiting are common in chemotherapy and may
severely reduce the quality of life of patients with cancer (Glare
et al., 2008; Hesketh, 2008). Several risk factors are suggested to
be associated with the development of CINV. Some are related to
patient characteristics, and others are related to chemotherapeutic
agents. The intrinsic emetogenicity of chemotherapeutic agents is
the major known risk factor and should serve as the primary
consideration in guiding antiemetic treatment (Basch et al., 2011;
Hesketh, 2008).
The mechanisms for CINV caused by chemotherapeutic drugs
are complex and not yet fully understood. However, they can be
simplied as follows. First, after chemotherapy, the enterochro-
mafn cells in the gastrointestinal tract will be stimulated
by drugs alone, or by other toxic substances arising during
chemotherapy, to release neurotransmitters, primarily 5-HT, sub-
stance P, cholecystokinin, prostaglandins, etc. These neurotrans-
mitters will bind to the appropriate receptors on the vagal afferent
terminals in the wall of the gastrointestinal (GI) tract. These
bindings will induce an afferent impulse primarily to the STN,
and, to a lesser extent, the CTZ, and then trigger vomiting. Second,
chemotherapeutic drugs, or the neurotransmitters and toxic sub-
stances generated during chemotherapy, may be directly delivered
to the CTZ via a blood-borne pathway and then trigger vomiting
(Darmani and Ray, 2009; Hesketh, 2008).
A wide variety of antiemetic drugs, including 5-HT
3
receptor
antagonists, tachykinin NK
1
receptor antagonists, and glucocorti-
coids, are used to prevent and treat CINV (Basch et al., 2011).
According to the MASCC/ESMO, ASCO, and NCCN guidelines,
dexamethasone is effective when used alone for patients under-
going low-emetogenic chemotherapy (Basch et al., 2011; Feyer
et al., 2011; Jordan et al., 2007). For patients undergoing moder-
ately emetogenic chemotherapy, a two-drug regimen of a 5-HT
3
antagonist and dexamethasone is suggested. For patients under-
going highly emetogenic chemotherapy, a three-drug regimen
of a 5-HT
3
antagonist, an NK
1
antagonist, and dexamethasone is
recommended.
The mechanisms through which glucocorticoids prevent CINV
are not clear, but some possibilities have been suggested. First,
glucocorticoids reduce the inammatory response through com-
plex actions during chemotherapy by inhibiting the production of
inammatory mediators, which reduces the severity of CINV
C.-C. Chu et al. / European Journal of Pharmacology 722 (2014) 4854 51
(Girod et al., 2002; Hesketh, 2008; Rudd et al., 1996; Tanihata
et al., 2004). Second, glucocorticoids act directly on the STN, which
reduces the severity of CINV (Ho et al., 2004). Third, glucocorti-
coids may reduce the severity of CINV by acting on the neuro-
transmitter 5-HT, and on receptor proteins NK1, NK2, etc. (Barnes,
1998; Ihara and Nakanishi, 1990; Mantovani et al., 1997; Suzuki
et al., 2004). Fourth, glucocorticoids may reduce the severity
of CINV if patients undergoing chemotherapy are under great
stress and need a glucocorticoid to maintain their normal physio-
logical functions (Hursti et al., 1993; Kageyama, 2000).
6. Radiotherapy-induced nausea and vomiting
As many as 5080% of patients undergoing radiotherapy
experience RINV (Abdelsayed, 2007; Dennis et al., 2011). The risk
factors related to RINV depends primarily on the site and dose of
radiation (Dennis et al., 2011; Maranzano, 2001). Patients under-
going total body irradiation are at the highest risk; those under-
going upper abdominal, upper body, or lower body irradiation are
at moderate risk; and those undergoing cranial, craniospinal, head
and neck, lower thorax, or pelvic irradiation are at the lowest risk
(Dennis et al., 2011).
The mechanisms for RINV after irradiation have not been
thoroughly investigated. However, they may be related to inam-
mation in the local tissue (Carpenter et al., 1986, 1988; Pausescu
et al., 1976; Stryker et al., 1979). Patients undergoing total body
irradiation are at the highest risk, and those undergoing half-body
irradiation are at moderate risk. These ndings suggest that the
risk of RINV is highly correlated with the amount of tissue injured.
Moreover, patients undergoing upper abdominal irradiation are at
moderate risk. In these patients, activation of the enterochromaf-
n cells and the vagal nervous system may be important for
triggering RINV (Dennis et al., 2011). Like CINV, RINV may cause
tissue destruction and inammation (Carpenter et al., 1988;
Pausescu et al., 1976; Steel et al., 1983; Stryker et al., 1979). Toxic
substances and inammatory neurotransmitters that appear after
radiotherapy may also be directly transmitted to the CTZ via
a blood-borne pathway and then trigger a vomiting response
(Dennis et al., 2011).
A regimen of a 5-HT
3
receptor antagonist plus dexamethasone
is suggested to prevent RINV in patients at high risk. For patients
at moderate risk, it is suggested that a 5-HT
3
antagonist be used
alone or combined with dexamethasone. For patients at low risk, it
is suggested that a 5-HT
3
receptor antagonist prophylactic or
rescue therapy be used (Basch et al., 2011; Roila et al., 2010).
The mechanisms through which glucocorticoids prevent RINV
have not been thoroughly investigated. However, their anti-inam-
matory effect may be involved (Carpenter et al., 1986; Pausescu et al.,
1976; Steel et al., 1983; Stryker et al., 1979). Glucocorticoids may
prevent RINV through their anti-inammatory actions or some other
mechanisms, such as those described in the CINV section above
(Dennis et al., 2011; Hesketh, 2008).
7. Postoperative nausea and vomiting
PONV is a common and distressing postoperative complication.
Several risk factors have been linked to its development (Apfel et al.,
2012). Some are related to patient characteristics, others to the
anesthetics used, and still others to the surgical sites. All three groups
of risk factors contribute substantially to the occurrence of PONV.
However, only the risk factor of anesthetic drugs can be altered when
attempting to reduce the risk of PONV. Many anesthetic drugs,
whether used for induction, maintenance, or reversal, can trigger
PONV (Apfel et al., 2012; Gan, 2007; Kenny, 1994). The strongest
emetogenic drugs are inhaled anesthetics and opioids (Kenny, 1994).
In general, inhaled anesthetics, such as halothane, enurane,
isourane, desurane, and sevourane, are thought to cause emesis
because they act on the CTZ via the blood (Apfel et al., 2002). The
longer a patient is exposed to inhaled anesthetics, the higher the
incidence of PONV (Apfel et al., 2002). Perioperative opioids, regard-
less of the route of administration, cause PONV (Coluzzi et al., 2012;
Kenny, 1994; Roberts et al., 2005). Opioids may cause emesis through
the following mechanisms: (i) increased vestibular sensitivity,
(ii) direct effects on the CTZ, and (iii) delayed gastric emptying (ileus)
(Coluzzi et al., 2012).
Patients who undergo laparoscopy, strabismus surgery, middle
ear surgery, or eye surgery have a higher incidence of PONV (Gan,
2006). It is hypothesized that local tissue irritation of the visceral
vagal afferent system, trigeminal nervous system, or vestibular
system in these surgical procedures trigger PONV (Gan, 2007;
Stadler et al., 2003). Many drugs have been used to prevent or
treat PONV. Two equally effective therapeutics are 5-HT
3
antago-
nists and dexamethasone, which are often used for severe PONV
(Gan, 2007).
The exact mechanisms through which glucocorticoids prevent
PONV are unclear. However, they may correlate highly with those
used in CINV. In patients given inhaled anesthetics or opioids,
which can directly trigger PONV in the CTZ, the central antiemetic
action of glucocorticoids on the STN may be involved (Apfel et al.,
2002; Roberts et al., 2005). Additionally, the prophylactic effect
of corticosteroids on PONV may be secondary to their anti-
inammatory effect, which reduces pain and lowers the required
opioid dose, which in turn causes both less ileus and less PONV
(Diakos et al., 2011; Korman and McKay, 1985; Lunn et al., 2013;
Rhen and Cidlowski, 2005; Thomas and Beevi, 2006).
8. Limitations of this review
This review has the following limitations. First, because there
are only a few studies focused on the mechanisms of the
antiemetic effects of glucocorticoids, we are unable to clearly
and completely describe these mechanisms. Second, the conclu-
sion about the association between inammation and emesis is
sometimes challenged because no elevation of plasma levels of
prostanoids was found in patients undergoing cisplatin anticancer
therapy (Curry et al., 1981). However, that prostanoids in tissue
alone may be strong enough to directly trigger an emetic response
through a local mechanism, e.g., in the GI tract through the vagal
nervous system, explains this seeming contradiction (Darmani and
Ray, 2009; Hesketh, 2008). Third, unlike in the study on piglets
(Girod et al., 2002), indomethacin did not prevent cisplatin-
induced emesis in the study on pigeons (Tanihata et al., 2004).
These conicting ndings may be due to different physiological
functions in different species (Tanihata et al., 2004). Moreover,
indomethacin was found to be intrinsically emesis-inducing,
possibly because indomethacin inhibits the enzyme
cyclooxygenase-1 (Girod et al., 2002). In contrast, meloxicam, a
cyclooxygenase-2 inhibitor, did not induce emesis; rather, it
inhibited emesis (Girod et al., 2002). Fourth, we do not discuss
in detail the interactions between glucocorticoids and neurotrans-
mitters, such as dopamine and substance P, because we have
insufcient data to do so. Fifth, we do not discuss in detail the
characteristics of CINV, RINV, and PONV, because many studies on
these conditions have been published. Sixth, although we do not
discuss the antiemetic mechanisms of 5-HT
3
antagonists and NK
1
receptor antagonists, the antiemetic mechanisms of glucocorti-
coids are not similar to those of these two antiemetics. Combined
use of these antiemetics yields the most benet (Basch et al., 2011;
C.-C. Chu et al. / European Journal of Pharmacology 722 (2014) 4854 52
Feyer et al., 2011; Gan et al., 2007; Jordan et al., 2007). Seventh,
emesis occurs in many contexts. We use only CINV, RINV, and
PONV as examples in this review because these three subcate-
gories of emesis are often a serious quality-of-life problem for
patients being treated for cancer or surgical procedures.
9. Conclusions
The mechanisms that glucocorticoids use to prevent emesis are not
clearly understood. These mechanisms might include the following:
[1] anti-inammatory effect; [2] direct central action at the solitary
tract nucleus, [3] interaction with the neurotransmitter serotonin, and
receptor proteins tachykinin NK
1
and NK
2
, alpha-adrenaline, etc.; [4]
maintaining the normal physiological functions of organs and systems;
[5] regulation of the hypothalamic-pituitary-adrenal axis; and [6]
reducing pain and the concomitant use of opioids, which in turn
reduces opioid-related nausea and vomiting.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.ejphar.2013.10.008.
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