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Pharmacological Reports
Copyright © 2013
2013, 65, 279–287
by Institute of Pharmacology
ISSN 1734-1140
Polish Academy of Sciences
Review
Fever development in neuroleptic malignant
syndrome during treatment with olanzapine
and clozapine
Anna Szota1, Ewa Og³odek2, Aleksander Araszkiewicz2
1
Department of Psychiatry, University Hospital, Kurpiñskiego 19, PL 85-096 Bydgoszcz, Poland
2
Department of Psychiatry, Collegium Medicum, Nicolaus Copernicus University in Toruñ, Kurpiñskiego 19,
PL 85-096 Bydgoszcz, Poland
Correspondence: Anna Szota, e-mail: [email protected]
Abstract:
Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. It’s development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is
one of the main symptoms of this syndrome and it’s elevation is due to the activation of the immune system. Numerous studies report
that treatment with clozapine (doses 37.5–600 mg) or olanzapine (doses 10–25 mg) or the use of these drugs in polytherapy cause
pyrexia between 37.8–40.6°C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF-a were increased.
The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the
drug taken by schizophrenic patients including changes in immunological system.
Key words:
clozapine, fever, interleukins, neuroleptic malignant syndrome, olanzapine
Introduction
Neuroleptic malignant syndrome (NMS) is a dangerous and life-threatening complication, mainly occurring in cases of individuals treated with strong neuroleptic drugs (haloperidol and fluphenazine being the
most common) [43]. The frequency of cases is between 0.5–1%, of which, young males are twice as
likely to develop the disorder as young females. If left
untreated, the mortality rate can range between
5–20%. NMS may be linked to other drugs which
block dopaminergic transmission such as antidepressant drugs (clomipramine and desipramine), and lithium, amantadine, carbamazepine, L-dopa anti-cholinergic medication and metoclopramide. It may also
occur with the use of second generation atypical antipsychotic (AAP) medication such as clozapine and
olanzapine, regarded as potentially safe in antipsychotic treatment. The cause of NMS is the blockade of dopaminergic transmission (mainly in case of
receptors D2) in the nigrostriatal system [68, 70].
NMS can develop irrespective of which particular
drug is used and the duration of the therapy. It usually
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279
appears a short time after the onset of treatment, however, it may also occur later on in the further course of
treatment, and even after the withdrawal of the medication. Risk factors include having a past medical history of NMS, being of a young age, being male, dehydration, excitement, being exposed to a rapid increase
in the dose of a drug, receiving the drug intramuscularly, taking other drugs such as lithium, or there being the co-existence of neurological disorders, or affective disorders and organic changes in the central
nervous system.
The characteristic symptoms of NMS include fever, increased extrapyramidal symptoms (the occurrence of at least two of the following symptoms: an
increase in the tonicity of lead-pipe rigidity, ptyalism,
external eye muscle contraction, hyperextension of
the neck, opisthotonus, tonic facial spasm, dysphagia,
dysarthria, choreatic movements and problems affecting the posture or gait), problems with vegetative
functions (the occurrence of at least two of the following symptoms: an increase in arterial pressure by at
least 20 mmHg in comparison to the baseline recording, tachycardia – an increase in heart rate by 30 bpm,
excessive sweating and urinary and fecal incontinence) [67]. The diagnosis is still likely if less than
two of the aforementioned symptoms occur, particularly if any of the following present themselves into
the clinical picture: obnubilation or delirium, mutism,
stupor or coma, leucocytosis in excess of 15,000/mm3
and increased creatine phosphokinase (CPK) in excess of 1,000 IU/ml. An increase in the activity of
aminotransferases and mioglobinuria connected with
impaired kidney function may also appear [12].
Fever and neuroleptic malignant
syndrome
Fever is one of the main symptoms of NMS caused by
antipsychotic drugs. An elevation in body temperature
can vary from low-grade (above 37°C) to hyperpyrexial (above 41°C) and can vary depending on the
type of drug used and the dosage administered.
Fever is a rise in body temperature to a level which
exceeds it’s normal circadian changes, but with a normal functional thermoregulatory system. Fever is an
important part of the nonspecific host defense response to infection or inflammation [41]. Fever is also
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defined as a strictly controlled, well-regulated pathophysiological reaction, which is responsible for the
restoration of homeostasis disturbed by inflammatory
factors [41].
Thermoregulatory conception of fever
The control centre of the thermoregulatory system is
located in the anterior hypothalamus, which is responsible for the maintenance of the body’s thermal homeostasis [42]. Sensory signals from thermoreceptors are
sent to the anterior hypothalamus where they are compared with the ‘set-point’. Effector mechanisms of
thermoregulation (behavioral and physical) are activated accordingly and body temperature is compensated in line with the thermoregulatory ‘set-point’, by
means of heat-production and heat-dispersion. Fever is
therefore defined as a rise in body temperature when
the regulatory ‘set-point’ has been elevated [39].
An elevation in core temperature is triggered by
substances known as pyrogens. Pyrogens can be either endogenous and exogenous. It is currently
thought that the factors which activate the synthesis of
endogenous pyrogens in immunocompetent cells of
the body are exogenous pyrogens [64]. Several studies looking at fever mechanisms show that exogenous
pyrogens include bacteria, viruses, protozoans, fungi,
alkaloids or lectins [17, 72]. Taking into consideration
the above facts, we suggest that AAPs which activate
the release of endogenous pyrogens also act as exogenous pyrogens and can therefore cause fever in NMS.
Exogenous pyrogens activate immune system cells
to produce endogenous pyrogens such as:
• interleukins: IL-1, IL-6, IL-8, IL-11, IL-12, IL-18
• interferons: INF-g, INF-b, INF-a
• tumor necrosis factor: TNF-a, TNF-b
• other cytokines: MIP-1, AFGF [40].
These proteins are produced by monocytes, granulocytes, macrophages and T lymphocytes. As well as
increasing body temperature, pyrogens can also induce anorexia, somnolence, stimulate the production
of acute-phase proteins, activate the neurohumoral
axis or have a sedative effect [6, 10, 40]. Endogenous
pyrogens produced peripherally are released into the
blood. Their main role is to activate mechanisms in
the central nervous system, responsible for altering
the ‘set-point’ to a higher level, consequently causing
fever [8].
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Anna Szota et al.
Clozapine and olanzapine and fever
development in NMS
According to current available studies regarding the
occurrence of NMS with associated fever in patients
treated with AAPs, it is clear that fever can be induced by clozapine and olanzapine.
Clozapine (dibenzodiazepine derivative) is an AAP
which can give substantial improvement in the treatment of schizophrenia [48], especially in patients
refractory to the classic neuroleptic drugs or in those
experiencing intense extrapyramidal symptoms. Moreover, this drug reduces suicide in high risk schizophrenic patients [48]. However, clozapine is also
known for its toxic effects, which can cause acute
agranulocytosis and leucopenia [49]. This drug has low
affinity for D2 receptors, relatively high affinity for D4
receptors and a high affinity for serotonin receptor subtypes (5HT2A, 5HT2c, 5HT6, 5HT7), histamine H1
receptors and muscarinic acetylcholine receptors [34].
Clozapine is metabolized in the liver by the cytochrome (CYP) 450 enzymes mainly into four metabolites. It is a very efficacious drug, however, it can cause
NMS with fever. For the first time, NMS with fever
caused by clozapine was noticed by Blum and Mauruschat [9]. Further publications of cases of NMS
development with fever in clozapine therapy support
the earlier findings of Blum and Mauruschat [9].
It was reported that clozapine doses of 37.5–600 mg/d
(mean 153 mg/d) caused NMS with fever in 13 of 52
patients after 14 days of treatment [53]. Temperatures of
38°C were recorded and lasted 2.6 days. Hinze-Selch et
al. [31] noticed that clozapine at doses of 250 mg/d induced fever up to 39°C 14 days after treatment. However, in this case the onset of the fever was not connected with NMS and extrapyramidal symptoms, but it
was due to systemic host response [31].
Lower levels of fever were found by Kluge et al.
[38], and Yacoub and Francist [71].
NMS with fever developed in 5 of 15 patients and
temperatures were recorded above 38°C [38], in relation to the dosage of 25–200 mg/d [38]. Also in 2 patients described by Yacoub and Francist [71] NMS
with fever appeared. Temperatures were recorded at
38.1°C and 38.3°C in relations to the dose of the drug
100 mg/d and 175 mg/d [71], respectively. Interesting
results connected with clozapine treatment of schizophrenic patients were obtained by Hinze-Selch et al.
[30]. Fever developed in 8 of 17 patients, however,
the authors did not define precisely that it was NMS
with fever despite of the symptoms of NMS. They excluded that infection was a reason of fever. Temperatures ranged from 38°C to 39°C (mean 38.8°C) starting between the 2nd and 25th day (mean 14 days) and
the administered dose was 178 ± 57 mg/d (first week
of treatment), 281 ± 111 mg/d (second week of treatment) and 325 ± 152 mg/d (sixth week of treatment),
respectively [30]. Because clozapine had not reached
the therapeutic level (300 mg/d) in the patients’ blood,
the question of the origin of fever was raised.
Another group of patients took clozapine at therapeutic doses between 300–450 mg/d and up to 600 mg/d.
Fever developed after a few months with the higher
dose (600 mg/d), not after 2 weeks with the low dose
(less than 300 mg/d), however, temperatures did not
rise in line with the increase of the dosage. What is
more, elevations in body temperature were similar to
those measured in patients taking low doses [25].
Haack et al. [26] described cases of 3 patients who developed NMS with fever after a year of clozapine administration. Two patients were taking 600 mg/d and
had fever above 38°C. In one of the patients treatment
with clozapine was discontinued and replaced with
oxazepam (doses ranging from 100–200 mg/d). What
is more, the doctors decreased the dose of clozapine
(to 500 mg/d) for the second patient, but against expectation the temperature rose to 39.8°C (treatment
was discontinued). Additionally, a third patient had
a higher fever after changing the dose of clozapine
from 300 mg/d to 400 mg/d. Temperature exceeded
40°C and further treatment was discontinued because
of a toxic clozapine level (1824 µg/l) in the patients’
blood. The last patient described by Haack et al. [26]
was taking clozapine at a dose of 400 mg/d. The drug
dose was increased to 500 mg/d after 2.5 months. Clozapine was discontinued because of a toxic plasma
level (2349 µg/l) [26]. When considering the influence of clozapine on the development of fever and
NMS, it is worth highlighting that temperatures did
not increase in line with drug dosage. This was confirmed by the findings of 21 patients who were taking
clozapine at a dose of 318 mg/d for 218 days, who experienced NMS with fever of up to 38.7°C [4, 15, 32,
33, 37, 59]. Similar fever was observed when patients
were treated with clozapine (600 mg/d). No matter
what dose was used the value of the fever was the
same. The mechanism responsible for this is unknown, therefore, further research is required.
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281
Whilst considering how clozapine influences NMS
development, we should also take into account its use
in polytherapy, such as when it is used with aripiprazole. In contrast to clozapine causing fever, using both
of these drugs did not induce fever at all. One exception is the case of a patient who took clozapine
(300 mg/d) and aripiprazole (30 mg/d), which increased the temperature to 38.5°C after 12 days [16].
However, after 12 days, the patient suddenly became
confused, displayed a moderate degree of fever
(38.5°C), and a slight extrapyramidal rigidity [16].
Englisch and Zink [21] described 94 patients treated
with clozapine (average dose 476.7 mg/d) and aripiprazole (average dose 20.5 mg/d) for 9 weeks. None of the
patients had fever, but 12 of them were diagnosed with
NMS. It is possible that the absence of fever my be due
to the pharmacodynamic interactions between these
two drugs but further research is required.
Another AAP similar to clozapine both in structure
and in its effects on neurotransmission is olanzapine
[66, 70]. Olanzapine (thienobenzodiazapine derivative)
has affinity for dopamine receptors (D4, D3, D1, D2),
serotonin receptors (5-HT2A, 5-HT2C, 5-HT3, 5-HT6),
histamine receptor H1, muscarinic receptor M1 and
adrenergic receptor a1. Several clinical studies have
revealed that olanzapine causes relatively few extrapyramidal effects in comparison to conventional antipsychotic drugs, but like clozapine can cause NMS
[47, 69]. The first such case being recorded in 1998
[22, 28, 36, 50].
Several publications on this topic point to the fact
that olanzapine used in mono and polytherapy has
both a pyretic and antipyretic influence in NMS. The
pyretic influence in patients treated with olanzapine
was observed by Burkchard et al. [11] and García
López et al. [23]. They reported that olanzapine
10 mg/d caused fever (37.5–38.2°C) after 14 days of
treatment [11, 23]. Ananth et al. [3] also observed
NMS fever in 19 patients using the same dose of the
drug. Fever began after 123 days of treatment. It was
also noticed that a higher dose of olanzapine
(12.5 mg/d) caused NMS with a higher fever
(40.6°C), which is found to be life-threatening for the
patient [46].
Olanzapine used in monotherapy rarely causes
NMS with fever, than clozapine. Hickney et al. [29]
and Hanel et al. [28] noticed that NMS without fever
appear in any patients taking olanzapine at doses of
7.5 mg/d and 10 mg/d, respectively. However, the
authors did not mention how this drug can influence
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interleukin levels in the blood. This is important because interleukins are involved in the mechanism of
fever pathogenesis. Therefore, the measurement of interleukins levels might be a starting point in explaining the twofold influence of olanzapine on body temperature.
As seen with clozapine, when used in polytherapy
olanzapine (e.g., with clozapine, levopromazine or
nefazodone) caused NMS with fever among large
groups of patients after 14 days of treatment. Regardless of the combination of polytherapy, temperatures
did not differ that significantly. Olanzapine (10 mg/d)
[50] or 25 mg/d [20] taken with clozapine (300 mg/d)
induced fevers of 38.6°C and 38.8°C, respectively.
Whereas, olanzapine (10 mg/d) taken with levopromazine [35] or haloperidol and nefazodone [54] raised
temperatures up to 38.1°C and 38.5°C, respectively.
There have been reports about olanzapine (5 mg/d)
used in conjunction with lithium or fluoxetine [63] or
valproic acid [36]. In all cases patients suffered from
NMS and fever and temperatures recorded were
above 38°C. Significantly much higher temperatures
(39.9°C) were induced by olanzapine (10 mg/d) when
taken with valproic acid [65]. Whilst considering the
influence of olanzapine in polytherapy, it is worth
pointing out that not all patients experienced fever,
but they had NMS. Gheorghiu et al. [24] noticed that
when olanzapine (10 mg/d) is taken with carbamazepine, there was no significant rise in body temperature above 37°C. Taking olanzapine at the same
dose with lithium, also did not increase body temperature [36].
In all cases described in this article so far, curing
with clozapine or olanzapine caused typical NMS
with fever or without fever. However, it should be
noted that atypical antipsychotics may cause atypical
NMS with fever as a dominant feature, but without
clear extrapyramidal symptoms. Atypical NMS
caused by clozapine (550–700 mg/d) was described
by Corallo and Ernest [14]. A patient cured with this
drug did not reveal extrapyramidal symptoms, but had
a very high fever (38.6°C), diaphoresis, tachycardia
and altered conscious state. Laboratory test revealed
leukocytosis with neutrophilia and increased creatinine kinase CK (63,328 IU/l). Also, Ahmadkhaniha et
al. [2] described a patient who was taking clozapine at
a dose of 400 mg/d for 3.5 months. After that time,
NMS with a very high fever (38.2°C) developed. On
the basis of symptoms which were observed in this
patient a diagnose of atypical NMS was made. There
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Anna Szota et al.
were observed symptoms such as mild muscular rigidity, the rigidity was only in extremities instead of
general muscular rigidity and mild extra pyramidal
symptoms [2].
Similar to clozapine, olanzapine also may induce
atypical NMS. Hall et al. [27] reported that olanzapine
10 mg/d caused atypical neuroleptic malignant syndrome with a very high fever (40.8°C). Additionally,
autonomic disturbances and mental status changes
arised. The patient did not have muscular rigidity, or
tremors, which are usually considered along with fever, to be the cardinal features of NMS. Atypical
NMS was also described by Reevers et al. [57]. In this
case olanzapine (10 mg/d) induced several symptoms
of NMS such as: a very high fever (39.4°C), increased
level of CPK (1,388 IU/l) and autonomic dysfunction.
However, there was no severe muscular rigidity or increased muscle tone [57].
Clozapine and olanzapine – mechanisms
of fever
As it was mentioned before, fever is one of the main
symptoms of NMS caused by antipsychotic drugs and
is connected with the influence of the drugs on dopaminergic transmission in the brain. Both clozapine
and olanzapine bind to dopamine receptors (D2, D4)
with different affinity and they block these receptors
[34, 47]. The dopaminergic receptors antagonism
caused by neuroleptics may interfere with dopamine’s
normal role in central thermoregulation. The blockade
of dopamine receptors within the nigrostratial, hypothalamic and mesolimbic/cortical pathways seems to
be responsible for development of some clinical features of NMS including fever, rigidity and altered
mental status [1]. This theory is supported by an earlier observation that the primary cause of NMS was
the use of antipsychotic drugs that specifically block
dopamine D2 receptors and that the syndrome can also
be induced by abrupt dopamine withdrawal. Additionally, support comes from another study showing low
levels of the dopamine metabolite, homovanillic acid,
in the cerebro-spinal fluid (CSF) of patients with
acute NMS [52]. Therefore, the blockade of dopaminergic receptors in preoptic area (POA), where thermoregulatory center can be found [58] leads to elevation
of the thermoregulatory ‘set-point’ to a higher level
and as a result initiating fever. Production of the heat
is also connected with stimulating effect of serotonin
in hypothalamus, dopamine blockades this process
[73]. Consequently, dopaminergic blockade leads to
less inhibition of serotonin stimulation and contributes to heat production and fever develops [5].
However, development of fever is not only connected with the influence of antipsychotic drugs on
dopaminergic and serotonergic receptors. It is also associated with activation of immunologic system and
interleukins production. As already outlined, endogenic pyrogens are involved in fever development
by crucially elevating the thermoregulatory ‘set-point’
[7]. Studies so far have concentrated on the influence
of clozapine or olanzapine and have looked closely at
the efficiency of these drugs according to the doses.
Nevertheless, the influence of clozapine and olanzapine on interleukins levels in the blood seems to be
a very important point. The influence of antipsychotic
drugs on inflammatory interleukins levels such as
IL-1, IL-6 and TNF-a is particularly important because it would help to explain the origin of fever in
NMS. From available studies we can clearly see that
levels of fever in NMS were very high (38–41°C)
after treatment with AAPs (clozapine, olanzapine
both in mono and polytherapy). Such high temperatures may not only damage neurons in brain, but may
also be life-threatening if medication is not discontinued. Therefore, understanding how a particular type
and dose of AAP can effect interleukin levels seems
to be pivotal when choosing a patients drug regime.
From previous studies we know that treatment with
clozapine, similar to when using typical neuroleptic
drugs, may lead to NMS with fever regardless of the
dosage. It is worth highlighting that fever was noticed
in patients, even when the drug had not reached therapeutic levels in the blood [30, 56]. So, the question
naturally rises as to the cause of fever. This is most
likely connected to the increase of interleukin levels
in the blood of treated patients. Pollmächer et al. [56],
Maes et al. [45] and Hinze-Selch et al. [30] established that the level of IL-6 becomes raised after clozapine treatment. It is well documented that IL-6, as
well as IL-1 are the major cytokines responsible for
the development of fever [8, 18, 40, 72].
IL-6 is lyophobic and quite a large protein which is
produced by a variety of immunocompetent cells before being released into the blood. For many years it
has been considered that cytokines (IL-6 and IL-1)
circumvent the blood-brain barrier, especially in the
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283
circumventricular organ known as the organum vasculosum of the lamina terminalis (OVLT) where the
barrier is incomplete. This area is situated very
closely to the POA, where the thermoregulatory center can be found [58]. However, cytokines synthesized
peripherally, cross the brain so slowly that this process is not fundamental in the pathogenesis of fever.
Nevertheless, this is not equal to the lack of involvement of the OVLT in fever, because this area is sensitive and possesses many receptors for endogenous pyrogens [7]. Nowadays, it is thought that proinflammatory cytokines produced peripherally induce the
production of prostaglandin E2 (PGE2 ) in the brain
[13]. Prostaglandins produced in the neural or glial
cells of the POA and prostaglandins produced in microglial cells in area of the OVLT are extremely influential [62]. These prostaglandins diffuse into the anterior hypothalamus, induce the local production of pyrogenic cytokines, which then act on neurons of the
thermoregulatory center to elevate the thermoregulatory ‘set-point’ to a higher level, therefore, initiating
fever [18]. Clozapine as an atypical antipsychotic
drug, not only stimulates the synthesis of IL-6, but
also significantly increases levels of TNF-a and activates receptors for this cytokine (sTNF-Rs) [25, 56].
In contrast to IL-6, TNF-a is a cytokine which has
a two-sided influence on the human body, both pyretic
and antipyretic. Associated with very high temperatures in patients treated with clozapine, we may assume that TNF-a has a pyretic influence in such cases
[51]. On the basis of the above facts we may suggest
that the development of fever in patients taking clozapine is strongly connected to the activation of the
immune system and the increase in the levels of IL-6
and TNF-a. In view of this fact, it seems vital to
measure the levels of these cytokines in the cerebrospinal fluid. It would allow verification and specification of the mechanisms responsible for development
of fever in patients treated with clozapine.
Whilst considering fever mechanisms we must take
into account how peripherally induced fever alerts the
central nervous system. It is not only via humoral
pathways, but also within neuronal tracts. Pyrogenic
cytokines released peripherally activate the subdiaphragmatic vagal afferent fibers, through which information is transferred to the nucleus of the solitary
tract (NTS), and then via adrenergic fibres to the hypothalamus. Catecholamines are released in the hypothalamus in turn stimulating the local release of PGE2
and fever develops [61].
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Pharmacological Reports, 2013, 65, 279–287
In contrast to clozapine, olanzapine may reveal
both pyretic and antipyretic effects in mono and polytherapy. It has been reported that olanzapine used in
monotherapy does not increase the level of IL-6 [55]
and TNF-a [19]. Moreover, Lü et al. [44] and Schuld
et al. [60] found that cytokine levels were actually decreased. These findings allow us to formulate the hypothesis that the lack of pyrogenic influence of olanzapine is directly connected to suppression of the immune system. Nevertheless, the mechanism of fever
induced by olanzapine is still unclear because the levels of the proinflammatory cytokines (IL-6 and
TNF-a) are not increased [19].
Olanzapine used in polytherapy causes fever above
38°C regardless of the dose. Using olanzapine with
clozapine or olanzapine with valproic acid trigger fever
as high as 38.8°C and 39.9°C, respectively. Taking into
account that clozapine in contrast to olanzapine stimulates the production of proinflammatory interleukins,
we may suggest that clozapine used in polytherapy is
responsible for the development of fever.
Conclusions
The scientific reports presented in this article make it
possible to arrive at the conclusion that olanzapine,
when used in mono or polytherapy, is a drug with
a safer pharmacological profile than clozapine. Treatment with olanzapine, similar to that with clozapine,
is connected with the risk of developing neuroleptic
malignant syndrome. Nevertheless, the development
of this syndrome is seen less with olanzapine, which
does not induce fever that can become severe enough
to threaten the lives of many patients. When choosing
medication-based therapy, one should pay particular
attention to the risk of such life-threatening side effects, the pharmacological reactions that can take
place, and consider monitoring drug (serum) levels as
a matter of routine.
Acknowledgment:
The authors would like to thank Peter Koœmider-Jones for checking
an English version of the article.
Disclosure of conflict of interest:
The authors have no conflicts interest that are directly relevant
to the content of this review.
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Anna Szota et al.
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Received: April 26, 2012; in the revised form: November 17, 2012;
accepted: November 26, 2012.
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