FIZIOLOGIA
physiology
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Fiziologia - Physiology • 2014.24.4(84)FIZIOLOGIA

physiology
CONTENTS
1. Assessment of the Cardiotoxicity Induced by Chemotherapy. Correlations with the Cardiovascular Risk Factors ....... 4
Valcovici M, Buleu F, Luca C, Drăgan S
2. Therapeutic Options in Allergic Rhinitis .................................................................................................................... 15Goanță CM, Mihalcea R, Tusaliu M
3. Keratinized Mucosa – Predictive Factor for the Health of Peri-Implant Tissues ....................................................... 19Cărămidă M, Sîrbu I, Ciortea C, Dumitrache MA, Gălușcan A
4. Leukotrienes and Pain-New Therapeutic Perspectives ............................................................................................ 24
Nechifor M, Gales C, Petrescu D
5. The Influence of Intracoronary Verapamil Administration on Left Ventricular Function in Patients with Previous
Myocardial Infarction Treated with Direct Stenting ..................................................................................................... 30
Pascalau L, Valcovici M, Turi V, Drăgan S
6. Antibiotic Consumption Data in an Intensive Care Unit ............................................................................................. 36
Axente C, Baditoiu L, Muntean D, Horhat F, Bedreag O, Hogea E, Moldovan R, Licker M

CUPRINS
1. Evaluarea cardiotoxicității indusă de chimioterapie. Corelații cu factorii de risc cardio-vasculari ............................... 4
Valcovici M, Buleu F, Luca C, Dragan S
2. Opțiuni terapeutice în rinita alergică ......................................................................................................................... 15
Goanta CM, Mihalcea R, Tusaliu M
3. Mucoasa keratinizată – factor de predicție pentru sănătatea țesuturilor peri-implantare .......................................... 19Cărămidă M, Sîrbu I, Ciortea C, Dumitrache MA, Gălușcan A
4. Leukotrienele și durerea – noi perspective terapeutice ............................................................................................ 24
Nechifor M, Gales C, Petrescu D
5. Influența verapamilului administrat intracoronarian asupra funcției ventriculului stâng la pacienții
cu infarct miocardic acut anterior tratați prin stentare directă .................................................................................... 30
Pascalau L, Valcovici M, Turi V, Drăgan S
6. Consumul de antibiotice într-o secție de terapie intensivă ........................................................................................ 36
Axente C, Baditoiu L, Muntean D, Horhat F, Bedreag O, Hogea E, Moldovan R, Licker M

Fiziologia - Physiology • 2014.24.4(84)3ASSESSMENT OF THE CARDIOTOXICITY INDUCED BY
CHEMOTHERAPY. CORRELATIONS WITH THE CARDIOVASCULARRISK FACTORSMIHAELA VALCOVICI1,2, FLORINA BULEU1, CONSTANTIN LUCA1,2, SIMONA DRAGAN1,2
1University of Medicine and Pharmacy Victor Babes Timisoara
2Institute of Cardiovascular Diseases Timisoara

ABSTRACT
Objective/Purpose: Knowing the risk factors for chemotherapy-induced cardiovascular complication can help to focus
preventive efforts to reduce cardiotoxicity. We assessed the association of cardiovascular risk factors with the appearance of
cardiotoxicity in breast cancer patients.
Design and Method: A prospective study was carried out on 72 women with HER2-positive breast cancer. Inclusion criteria
were: age > 18 year, normal sinus rhythm, left ventricular ejection fraction (LVEF) > 50%, HER2 overexpression andtrastuzumab therapy. In all patients cardiovascular risk factors were quantified. For the SCORE risk assessment, were used
the SCORE chart for the European zone with high risk of cardiovascular mortality. Metabolic syndrome was diagnosed
according to the International Diabetes Federation criteria. According to the Seidman criteria recommended by the 2012
ESMO guidelines the patients were examined at baseline and then at 3, 6 and 12 months and the cardiotoxicity wasdiagnosed by decrease of LVEF.
Results: The mean age at baseline was 55.4 ± 11.80 years. Hypertension was present in 43.1% (n=31) patients andincreased with 4.9% at 12 months (χ2 test, p <0.001). The analysis of cardiovascular risk factors shows that metabolic
syndrome was present in 33.3% of patients (n = 24), 12.5% of patients were diabetic, 37.5% were obese. The Spearman test
revealed significant correlations between the decrease of LVEF with 5-10% and >10% and the total number of chemotherapy
cycles. There was a significant correlation between SCORE risk and decrease of LVEF < 55% at 12 months (test χ2, p=0,001).
Severe cardiotoxicity occurred in 3 patients with very high SCORE risk.
Conclusion: Assessment of cardiovascular risk factors for trastuzumab induced cardiotoxicity and appropriate patientmonitoring during trastuzumab treatment allows for safe and effective use of this important adjuvant therapy.
Keywords: cardiotoxicity, chemotherapy, trastuzumab, risk factors, breast cancer

INTRODUCTION

Cardiovascular disease (CVD) and cancer are themost common diseases in our times, and continue to rise.
Treatment for cancer has become more efficient, butinstead, cardiac damage in these patients has become
more frequent. CVD can affect the quality of patients life
and the course of cancer treatment (1).
The frequency of breast cancer increases with age
and has a higher incidence especially in premenopausal(between 45-49 years) and postmenopausal (> 60 years)
according to European Society of Medical Oncology(ESMO) (2). Recently concerns have focused on
identifying patients at risk of cardiac events due tochemiotherapy. So far, only a few risk factors have been
identified among patients enrolled in clinical trials
because most of them were in optimal health (3-5).
Cardiotoxicity may be the dose limiting factor incancer treatment and appears during therapy withseveral cytotoxic agents. In addition, cardiotoxicity may

also be responsible for the long-term side effects andmay cause severe morbidity of surviving cancer patients(6).
Cardiotoxicity from chemotherapy is known to have ahigh prevalence (7) and more than 2 million breast
cancer survivors in the United States are at risk (1).
More recently, the National Cancer Institute in the
United States defined cardiotoxicity as the ‘toxicity that
affects the heart’. This includes the direct effect oftherapy on the heart and also indirectly through changes
in haemodynamic flow alterations or due to thrombotic
events (8).
However, now that progress in terms of early
diagnosis, therapy, and survival has been made, specificdrugs and combinations of two or three different agents
have emerged, and intervention is more and more more
frequently used in the early stage; subsequentcardiotoxicity is a central problem (2), becoming a risingconcern, for both cardiologists and oncologists (9).

Received 14th of September 2014. Accepted 20th of October 2014. Address for correspondence: Valcovici Mihaela, MD, PhD student, „Victor Babes”
University of Medicine and Pharmacy Timisoara, Institute of Cardiovascular Diseases Timisoara, Eftimie Murgu Square No. 2A, RO-300041, Romania;
phone/fax: +40256207355; e-mail: mihaeladanielacardio@gmail.com

4

Fiziologia - Physiology • 2014.24.4(84)Cardiotoxicity remains the limiting factor for many
type of oncology therapy and represents the focus ofincreased clinical research (10).
The incidence of cardiotoxicity dependens on various
risk factors (eg, patient age,sex, the total dose ofanti-neoplastic drugs, time of follow-up, family/personal
history of cardiovascular disease, and mediastinal
irradiation), as well as the criteria used to define thecardiotoxicity, ranging in studies from 5% to 65% of
patients (11,12).
The cardiac dysfunction is defined as the onset of
cardiac symptoms or an asymptomatic decrease in left
ventricular ejection fraction (LVEF) of 10% or more (13).
Several approaches can be made in order to identify
cardiac dysfunction such as clinical examination,
echocardiography
and measurement of cardiac
biomarkers, as troponins and natriuretic peptides, (as anindicators of myocardial injury) (5).
The cardiotoxicity of trastuzumab did not appear
immediately and was only evident in Phase III clinical
trials (14). The first clinical trials have shown little or no
indication of increased risk of cardiotoxicity in patientstreated with trastuzumab (15,16). For example, in a
Phase II study in women with refractory metastatic breast
carcinoma, has been reported that no grade 3 or 4 ofcardiotoxicity appears following the National Cancer
Institute criteria common in patients treated withtrastuzumab plus cisplatin for 8 weeks (16). One of thenineteen patients treated (5%) showed cardiomyopathy
during the same phase of the study. However, the patient,in particular, have a number of risk factors for arrhythmia,
including prior cumulative dose of anthracyclines (ANT)
to 420mg/m2, mediastinal irradiation, high blood pressure(hypertension) and diabetes (16).
The delay in identifying the cardiotoxic effects due tothe fact that heart problems were not initially anticipated,
cardiac monitoring was not performed in most studies,and even if it was performed, the results wereinconsistent from one study to another. As such, it is very
difficult to compare results across studies to identify risk
factors that predispose to the occurrence CIT.
Furthermore, it is difficult to compare cardiotoxicity
induced by trastuzumab with cardiotoxicity related toother chemotherapeutic agents as the nature of cardiac
dysfunction associated with all these agents has notbeen yet characterized comprehensively (15).
The potential for cardiotoxicity should be recognised
before before initiating chemotherapy. The probability ofcardiotoxicity should be recognized before initiating
chemotherapy. Furthermore, the initial assessment ofthese patients should include: cumulative dose
(especially for anthracyclines, mitomycin); the total dose
administered during the day or cycle (cyclophosphamide,
ifosfamide, 5-fluorouracil); the rate of administration(anthracyclines, 5-fluorouracil); administration schedule(anthracyclines); mediastinal irradiation; age; female
Fiziologia - Physiology • 2014.24.4(84)gender; coadministration with other cardiotoxic agents;
previous anthracycline chemotherapy; history or
pre-existing cardiovascular disorders; electrolyte
imbalance (hypokalemia and hypomagnesemia) (17).
As a result, we conduct this study to investigate theincidence and risk of cardiotoxicity in patients treatedwith trastuzumab. The objectives of the study was
identification and quantification of cardiovascular risk
factors in a group of patients with HER-2 positive breast
cancer, the evaluation at 3, 6 and 12 months after the
inclusion in the study, of the systolic and diastolic
function parameters of the left ventricle using 2Dtransthoracic echocardiography (2D-TTE) in order toassess an early diagnosis of cardiotoxicity and thecorrelation between the risk factors taken separately(hypertension, metabolic syndrome) and SCORE risk, asa measure of cardiovascular risk accumulation and theprogression of the ejection fraction as a measure ofsystolic function, framed by Seidman criteria,
recommended by ESMO guidelines.

PATIENTS AND METHODS

Study Population
All consecutive women with breast cancer
undergoing trastuzumab therapy, from January, 2010, toNovember, 2014, were considered. The study was
conducted over a period of 12 months for each patient.
Indication for trastuzumab therapy were early-stage andadvanced or metastatic breast cancer, with HER2
overexpression. The patients were in records ofOncology Clinic, Surgical Oncology Clinic and
Department of Radiotherapy of Municipal Hospital,
Timisoara. The patients had different numbers ofchemotherapy cycles with trastuzumab during the study.
The inclusion criteria were: age > 18 year, normal
sinus rhythm, left ventricular ejection fraction (LVEF) >50%, HER2 overexpression and trastuzumab therapy.
The local ethics committee approved the protocol, andwritten informed consent was obtained from all patientsin accordance with the Helsinki Declaration.
Study Protocol
The breast cancer was diagnosed and orderedaccording to the receptors status (estrogen receptor (ER),progesterone receptor (PR), and human epidermal
growth factor receptor 2 (HER2)) and the TNM
classification for staging breast cancer.
In all patients cardiovascular risk factors were
quantified. Hypertension was defined as systolicblood pressure (SBP) ≥140 mmHg and/or diastolicblood pressure (DBP) ≥ 90 mmHg, taking into
account the average obtained from three
determinations or already present antihypertensive
treatment according to the European Guidelines on
Cardiovascular Disease Prevention in Clinical
Practice 2012 (18). For smoking condition were noted5the number of cigarettes per day or non-smoker inthe last 4 weeks. Type 2 diabetes was definedaccording to the fasting plasma glucose ≥ 126 mg/dL
on two different determinations or treatment with oral
antidiabetic agents based on World HealthOrganization (WHO) criteria and those of the American
Society of Diabetology (19). Hypercholesterolemia,
another cardiovascular risk factor, is defined by the valuesof total cholesterol over 200 mg/dl according to National
Cholesterol Education Program Adult The Treatment PanelIII (NCEP ATP III). Recommended target level in primaryprevention is <190 mg / dl and the values that exceeded
this limit were considered to be a major risk factor. The useof normolipidemic medication was retained as a criterion
for diagnosis (20). Hypertriglyceridemia was definedaccording to ACC/AHA guidelines. HDL cholesterol was
also detected, which also was used to calculate LDLcholesterol by Friedewald formula.
For the SCORE risk assessment, were used the
SCORE chart for the European zone with high risk ofcardiovascular mortality. Based on the results, breast
cancer patients were included in the four categories:
SCORE risk<5%, 5-10%, 10-15% or > 15% (21).
Evaluation of metabolic syndrome was definedaccording to National Cholesterol Education Program
criteria Adult Treatment Panel III (NCEP ATP III, 2001) andthe ones developed by International Diabetes Federation(IDF, 2005) (22).
The patients were cardiologically examined atbaseline and then at 3, 6 and 12 months, evaluations that
includedclinicalexamination,
ECG
andechocardiography, as ESMO guidelines recommend (5).
A standard 12-lead ECG was performed at each
evaluation. The QT time was corrected for heart rate
(QTc) with Bazett’s formula (QTc = QT/√RR).
2D echocardiography was performed on ultrasoundsystem (Vivid 4 General Electric, C5-multidisciplinary
ultrasound, Vivid 9, General Electric Milwaukee) and themeasurements were made in 2D M - mode, Colour
Doppler, and to the special cases, Tissue Doppler and3D measurements were applied.
Left ventricular diastolic function was evaluated bymeasuring Doppler transmitral flow: the maximal velocityof the E and A waves (rapid filling and atrial filling), theratio of early peak flow velocity to atrial peak flow velocity(E/A ratio; normal value >1), left ventricular end-diastolic
diameter (normal value, 47 ± 4 mm), left ventricularejection fraction (LVEF) and the isovolumic relaxation
time (IVRT; normal value <100 ms).
Cardiotoxicity was defined according to the Seidman
et al. criteria issued by 2012 ESMO guidlines (5) and ischaracterized by ‘1) decrease in cardiac LVEF that waseither global or more severe in the septum; (2) symptomsof congestive heart failure (CHF); (3) associated signs of
CHF, including but not limited to S3 gallop, tachycardia,
or both; and (4) decline in LVEF of at least 5% to less6than 55% with accompanying signs or symptoms of CHF,
or a decline in LVEF of at least 10% to below 55%
without accompanying signs or symptoms.
Statistical analysis
Statistical processing was performed using Excel
software packages, SPSSv.17 and Epi Info 7. In all cases
we used the significance threshold of 0.05 (5%),
corresponding to a 95% confidence level.

RESULTS

In total, 72 women (mean age, 55.4±11.80 years)
were enrolled. Characteristics of the study group atbaseline showed that the age of the breast cancer
patients included was between 27 and 78 years. The
measured values of the parameters of the lipid profile
revealed a slight hypercholesterolemia, total cholesterol
with mean values of 208.7 ± 45.60 mg / dl, the extreme
values of 120 mg/dl and 350 mg/dl andhypertriglyceridemia, with means of 161.8 ± 51.82 mg/dl,
extremes included between 63 mg/dl and 382 mg/dl. The
mean HDL-C was 43.3 ± 13.47 mg/dl, the extremes
being at 26 mg/dl and 85 mg/dl. The mean LDL-C was
calculated according to the Friedewald formula and was132.1 ± 44.70 mg/dl, with ranges between 27 mg/dl and294 mg/dl. The other metabolic parameters were within
normal limits with an average of 0.9 ± 0.35 mg/dl for
creatinine and 4.8 ± 3.65 mg/dl for uric acid (Table I).
Table I. Characteristics of the study group at baseline (n=72)
CHARACTERISTIC
AGE, YEARSTOTALCHOLESTEROL(mg/dl)TRIGLYCERIDES(mg/dl)HDL-C (mg/dl)
LDL-C (mg/dl)
CREATININE(mg/dl)URIC ACID (mg/dl)
GLYCEMIA (mg/dl)
SBP (mmHG)
DBP (mmHG)
BMI (Kg/m2)
WAIST
CIRCUMFERENCE
(cm)

MEAN
±
DEV.STD.
55.4±11.80

MINIMUM
VALUE
27

MAXIMUM
VALUE
78

208.7±45.60

120

350

161.8±51.82

63

382

43.3±13.47
132.1±44.70

26
27

85
294

0.9±0.35

0.5

2.5

4.8±3.6587±18.93
129.2±17.14
75.8±14.30
32.8±5.23

2.7
72
90
50
28.1

8.5
197
180
105
41.93

89±15.74

75

127

Blood pressure (BP) values were between 129.2 ±17.14 mmHg for SBP and 75.8 ± 14.30 mmHg for DBP,
with extreme values of 180 mmHg and 105 mmHg.
Most patients were overweight or obese, and this isreflected in the mean values of the BMI between 32.8 ±5.23 kg/m2, extreme 28.1 kg/m2 and 41.93 kg/m2 and in
the mean values of the waist circumference of 89 ±15.74 cm, extreme 75 cm and 127 cm, 25% of patients
Fiziologia - Physiology • 2014.24.4(84)were with stage I obesity (n = 18), 8.3% with stage II (n =6), and 4.2% with stage III (n = 3) (Table II).
Table II. The percentage distribution of degrees of obesity
at baseline (n = 72)%(n=25), 5-10% (considered to be increased) in 16.7%(n=12), 10-15% in 5.6% (n=4), and very high> 15% in
43.1% (n=31)(Table IV).
Table IV. The percentage representation of the SCORE risk inthe study group (n = 72)

OBESITY

FREQUENCY

normal weight

45

62.5

SCORE RISK FREQUENCY%

class I obesity

18

25.0

< 5%

25

34.7

class II obesity

6

8.3

5-10%

12

16.7

class III obesity3

4.2

10-15%

4

5.6

Total

72

100.0

>15%

31

43.1

Total

72

100.0

Most of the patients had stage II breast cancer(36.9%) and III (37.6%), and in terms of TNM, most ofthem were classified as forms of advanced neoplasia,
19.4% T3 and 25%T4, with positive lymph nodes in a
proportion of 37.5% N1 and 26.4% N2. Distantmetastasis rate was positive in 15.3%. 40.3% of patients(n = 29) had right breast cancer and 59.7% of patients (n= 43) left breast cancer.
Determination of hormone dependent on tumor
blocks or biopsy revealed fragments ER sensitivity over
15% to 75% of patients (n = 54) and PR over 20% in
63.9% of patients (n = 46). Ki-67 proliferative index wasover 20 in 81.9% of the patients (n = 59). HER2
overexpression as determined by immunohistochemistry,
was positive in all patients, representing an inclusion
criteria. 50% were HER2+2 patients and 50% of patientswere HER2+3 (n = 36 per share).
The analysis of the types of chemotherapies applied tothe study group, found that cyclophosphamide was used in a
proportion of 80.6% (n = 58), anthracyclines in 98.6% (n =71), taxanes in 75% (n=54) and anti-metabolites at a rate of
5.6% (n = 4). All patients received trastuzumab, this being acriterion for inclusion in the study.
The analysis of cardiovascular risk factors in thestudied group
The analysis of cardiovascular risk factors in thestudied group shows a prevalence of metabolic syndromein the majority of patients, with a ratio of 33.3% (n=24) andalso high BP, rating 43.1%. (n=31). Obesity was present in
37.5% (n=27), and smoking in 26.4% (n=9). Diabetes
mellitus was present at 12.5% (n=9)(Table III).
Table III. The percentage representation of risk factors in the
study group at baseline (n = 72)
RISK FACTORS
Smoking
Diabetes Type 2
Hypertension
Obesity
Metabolic Syndrome

No.
19
9
31
27
24

%
26.4
12.5
43.1
37.5
33.3

The percentage distribution of the SCORE risk was<5% (considered to be low) in a proportion of 34.7%
Fiziologia - Physiology • 2014.24.4(84)The analysis of ejection fraction in the studied group
Analysing the evolution of the echocardiographic
parameters in the studied group, was found that themean ejection fraction (EF) was 58.1 ± 5.22% atbaseline and 54.5 ± 6.37% at 12 months. At the time ofchemotherapy initiation, the extreme values of the EF
were set between 49% minimum and 75% maximum,and 25% minimum and 68% maximum 67% at 3 and 6
months, so that after 12 months, the minimum value ofEF returned to the value of 40% and maximum 66%(Table V).
Table V. The evolution of LVEF in the 4 time points in thestudied group (mean ± dev.std.)
VARIABLES
EF at baseline (n = 72)
EF at 3 months (n = 71)
EF at 6 months (n = 69)
EF at 12 months (n =69)

MEAN ±
DEV.STD.
58.1±5.22
55.0±7.19
54.4±7.46
54.5±6.37

MINIMUM
VALUE
49
25
25
40

MAXIMUM
VALUE
75
68
67
66

Analysis of the EF values at 12 months are
represented in Table VI. There were recorded 3 deaths(4.2% of patients). These occurred in 2 patients who
presented to the evaluation of 3 and 6 months, 25%
decreased EF that was associated with cardiovascularpathology. A third death occurred at 6 months, with apreserved EF of 52%. Consequently, echocardiographymeasurements at 3 months were performed on 71
patients, and at 6 and 12 months were performed on 69
patients. A proportion of 5.6% of the patients (n=4)
showed EF of between 40-44%, 19.4% (n=14) had an EF
between 45-50%, and 70.8% of the patients (n=51) were
presented with EF> 50%.
All three deaths occurred in patients who have EF
decreased between 5-10% and over 10% from EF
baseline, respectively, all the three patients were part ofthe subgroup of patients with EF <55% (Table VI). The
heart failure in the first two cases and the malignant
ventricular rhythm disturbances in the third case were thecauses of death installed on the merits of cardiotoxicity.

7

Table VI. The percentage and numerical representation ofdeaths according to the categories of EF decrease
DEATHS

EF

NO

YES
33

EF>55%

Decrease <5%

Decrease between 5-10%

Decrease >10%

NUMBER OF THERAPIES /PATIENTEF<50

100.0%

0%17

0

100.0%

0%

8

2

83.3%

16.7%

11

1

94.1%

5.9%

The analysis of the ejection fraction following
Seidman criteria recommended in the 2012 ESMO
guidelines
EF evolution analysis after the Seidman criteria
recommended in the 2012 ESMO guidelines, showedthat the subgroup of patients with EF>55% was 47.8%(n=33) of all 69 patients remaining in the study, due tothe 3 deaths. In the subgroup of patients with EF <55%,
24.6% (n=17) showed a decreased LVEF <5% frombaseline, 11.5% (n=8) showed EF 5-10% decrease frombaseline, and 15.9% (n=11) showed decreased EF>10%
from baseline (Table VII).
Table VII. The percentage and numerical distribution of EF
evolution at 12 months from baseline (n = 69) according tocriteria recommended by ESMO 2012 guidlines
EF
EF>55%

Table VIII. The percentage and numerical distribution of EF
evolution at 12 months from baseline and number of cytostatic
preparations (n=69)

FREQUENCY

%

33

47.8

EF>55%
Decrease <5%
Decrease between 5-10%
Decrease > 10%

>5

18

15

54.5%

45.5%

5

11

31.3%

68.8%

4

6

40.0%

60.0%

0

10

0.0%

100.0%

The association between the percentage of decreasein EF and the number of therapies was significant (χ2test, p = 0.018).
The analysis of shortening fraction
The rank values of diastolic dysfunction weresignificantly lower at 12 months (Wilcoxon test for paired
values, p <0.001)(Table IX). Shortening fraction (SF)decreased from 35.6 ± 5.38% to 32.5± 7.9% (p <0.001).
SF evolution compared at baseline and at 12 months isrepresented graphically in Figure 1.
Table IX. The analysis of the rank values of shortening fraction
at baseline and at 12 months (n = 69). Wilcoxon test for paired
valuesMEAN

STANDARD
DEVIATION

STANDARD
ERROR

SF at baseline

35.6

5.38

0.63

SF 12 months

32.5

7.90

0.93

PAIRED VALUES

percentage decreased of the patients with
EF at endpoint < 55%
Decrease <5%

17

24.6

Decrease between

8

11.5

11

15.9

5-10%
Decrease > 10%

The correlation between the number of cytostatic
preparations and percentage of decrease in EF at 12
months
The association between the number of cytostatic
preparations and percentage of decrease in EF at 12
months were performed for each patient. The results arepresented in Table VIII for n = 69 patients.

8

Fig.1. The graphical representation of SF values comparison atbaseline and at 12 months. Wilcoxon test for paired values (n = 69)

The echocardiographic parameters of diastolic
function in the studied group
In table X is represented the evolution of LV
end-diastolic volume (EDV) in the study group (n = 72)
during the four examinations: at baseline, at 3, 6 and 12
Fiziologia - Physiology • 2014.24.4(84)months (the endpoint of the study) as mean ± standard
deviation. EDV average values were 71.6 ± 11.72 ml atbaseline and 77.9 ± 19.96 ml at 12 months. EDV
extreme values ranged between 42 ml initially (minimum)and 175 ml at 3 months (maximum). Due to the threedeaths in the studied group. 3 months measurements
were performed on 71 patients, and at 6 and 12 months
on 69 patients.
Table X. The evolution of LV end-diastolic volume (EDV)in the study group (n = 72) during the 4 time points(mean ± dev.std.)
VARIABLESEDV at baseline(n = 72)
EDV at 3 months(n = 71)
EDV at 6 months(n = 69)
EDV
at
12
months (n = 69)

MEAN ±
DEV.STD.

MINIMUM
VALUE

MAXIMUM
VALUE

71.6±11.72

42

138

76.9±22.70

55

175

78.0±20.57

55

163

77.9±19.96

51

157

EDV evolution from baseline to 12 months wasobserved by applying Friedmann non-parametric test ofsignificance which showed significant differences between
the values of EDV at the 4 time points (p = 0.002).
Comparisons of the 2 by 2 points in time were performed
with Wilcoxon Signed Ranks non-parametric test ofsignificance and revealed the following results: at 3 months,
EDV values significantly increased compared to the start(p = 0.001), at 6 months significantly raised from the ones
at 3 months (p = 0.004) and to start (p <0.001) and at 12
months decreased slightly compared to the ones at 6
months (p = 0.421). EDV evolution compared at the 4 time
points is represented graphically in Figure 2.

Fig.3. The graphical representation of IVRT values comparison atbaseline and at 12 months. Wilcoxon test for paired values (n = 69)

Applying χ2 test to these data, significant differences
between the proportions of patients after initial and final
IVRT group were observed (χ2 test, p <0.001)(Figure 4).

Fig.4. The graphical representation of the percentage
differences between the distribution of patients after initial andfinal IVRT group (n = 69). χ2 Test

To analyze group differences for diastolic dysfunction
were used ordinal variables: 0 = absence of diastolic
dysfunction, 1 = Class I diastolic dysfunction, 2 = Class IIdiastolic dysfunction and 3 for Class III diastolic
dysfunction.
Rank values of diastolic dysfunction weresignificantly increased at 12 months (Wilcoxon test for
paired values)(Table XI). Comparison of diastolic
dysfunction is represented in Figure 5.
Table XI. The analysis of the rank values of diastolic function
parameters at baseline and at 12 months (n = 69). Wilcoxon
test for paired values

MEAN

STANDARD
DEVIATION

STANDARD
ERROR

0.2

0.43

0.05

IVRT at 12 months

0.3

0.58

0.07

Diastolic dysfunction atbaseline

0.39

0.49

0.02

Diastolic dysfunction at
12 months

0.56

0.80

0.17

PAIRED VALUES

Fig.2. The graphical representation of mean values of EDV
comparison at the 4 time points

For IVRT were used ordinal variables: 0 = 60-100 ms
range values, 1 = values over the 100 ms and 2 = valuesof less than 60 ms. At 12 months the IVRT values weresignificantly increased (Wilcoxon test for paired values, p= 0.020) (Figure 3).

Fiziologia - Physiology • 2014.24.4(84)

IVRT at baseline

9DBP at baselinemonths

DBP at 12

Fig.5. The graphical representation of the comparison of rank
values between the parameters of diastolic function at baseline
and at 12 months (n = 69). Wilcoxon test for paired values

The analysis of cardiovascular risk factors evolution
The blood pressure values at baseline were between
129.2 ± 17.14 mmHg for SBP, and 75.8 ± 14.30 mmHg
for DBP, with extreme values of 180 mmHg for SBP and
105 mmHg for DBP. At 12 months, blood pressure values
were between 130.0 ± 17.26 mmHg for SBP and 79.4 ±12.29 mmHg for DBP, with extreme values of 170 mmHg
for SBP and 105 mmHg for DBP (Table XII).

Fig.7. The comparison between the proportion of hypertension
at baseline (n=72) and at 12 months (n = 69). χ2 Test

There was a significant correlation, reverse, between
systolic blood pressure and EF at 12 months (r = - 0.364,
p = 0.002)(Figure 8).

Table XII. The evolution of blood pressure in the study group atbaseline and at 12 months. Mean and standard deviation
CHARACTERISTIC
DBP at baseline(n = 72)
SBP at baseline(n = 72)
DBP at 12 months(n = 69)
SBP at 12months (n = 69)

MEAN ±
DEV.STD.
129.2±17.14

MINIMUM
VALUE
90

MAXIMUM
VALUE
18075.8±14.30

50

105

130.0±17.26

90

170

79.4±12.29

60

105

Wilcoxon test for paired values showed that the valuesof SBP were not significantly raised at 12 months
compared to baseline (p = 0.537). DBP values weresignificantly increased at 12 months (p = 0.019)(Figure 6).

Fig.6. The comparison between DBP values at baseline (n=72)
and at 12 months (n = 69). Wilcoxon test for paired values

At inclusion, hypertension was present in 43.1%(n=31) of all patients. Between the number of patientswith hypertension present at baseline and at 12 months,
there were significant differences; 4.9% of patients had
higher blood pressure values at the end of chemotherapy(χ2 test, p <0.001)(Figure 7).
10

Fig.8. The correlation between systolic blood pressure and EF
at 12 months (n = 69)

Diastolic blood pressure at 12 months was significant
inverse and medium correlated with EF at 12 months (r =-0.400, p = 0.001)(Figure 9).

Fig. 9. The correlation between diastolic blood pressure and EF
at 12 months (n = 69)

At first examination the metabolic syndrome (MS)was present in 33.3% of patients (n = 24). Obesity
prevalence was of 37.5% (n = 27). Table XIII shows thepercentage distribution of MS according to the Seidman
Fiziologia - Physiology • 2014.24.4(84)criteria for EF recommended by the ESMO 2012
guidlines. The differences were not significant, there wasno association between the presence of MS anddecreased EF (χ2 test, p = 0.387).
Table XIII. The percentage distribution of MS according to the
Seidman criteria for EF
Metabolic syndrome

EF

No

EF>55%
Decrease <5%
Decrease between 5-10%
Decrease >10%

Yes

3

30

9.1%

90.9%

1

16

5.9%

94.1%

2

6

25%

75%

0

11

0%

100.0%SCORE risk correlation at 12 moths with decreased
EF according to the Seidman classification, showed asignificant correlation between SCORE risk anddecreased EF for the women who had at 12 months an
EF less than 55% (χ2 test, p = 0.001), is represented inTable XIV and Figure 10.
Table XIV. The percentage representation of the correlation
between SCORE risk and decreased EF according to the
Seidman criteria at 12 months (n = 69)
EF
EF>55%
Decrease <5%
Decrease
between 5-10%
Decrease > 10%

<5%
1
3.0%
1
10.0%
1
8.3%
1
5.9%

SCORE risk
5-10%
10-15%
5
6
15.2%
18.2%
7
1
66.7%
10.0%
8
1
70.0%
8.3%
8
4
64.7%
23.5%

>15%
21
63.6%
1
10.0%
2
16.7%
1
5.9%

Fig.10. The graphical representation of the correlation between
SCORE risk categories and EF according to the Seidman
criteria at 12 months (n = 69). χ2 Test

Fiziologia - Physiology • 2014.24.4(84)DISCUSSION

In total, 72 women (mean age, 55.4±11.80 years)
were enrolled. This study was conducted over a period of
12 months for each patient, from January, 2010, toNovember, 2014. The patients had different numbers ofchemotherapy cycles with trastuzumab during the study.
The inclusion criteria were: age > 18 years, normal sinus
rhythm, LVEF > 50%, HER2 overexpression andtrastuzumab therapy.
In this study were evaluated the cardiac performance
expressed by left ventricular ejection fraction anddiastolic function parameters (end-diastolic volume, IVRT
and E/A ratio) in patients with HER-2 positive breast
cancer under chemotherapy treatment with trastuzumab.
SCORE risk correlation at 12 moths with decreased
EF, according to the Seidman classification (14) showeda significant correlation between SCORE risk anddecreased EF for the women who had at 12 months an
EF less than 55% (χ2 test, p = 0.001).
This correlation explains the deaths of the 3 patients,
two with the advent of cardiotoxicity after 6 months ofenrollment, with a marked decrease in EF from 55% to
25% and from 60% to 25%, both overlapping risk factors.
The first patient died 3 months after enrollment, was
57 years old, with right breast cancer, presented the
SCORE risk 21%, being hypertensive, dyslipidemic andobese with BMI 31.4 kg / m2, total cholesterol = 290
mg/dl and triglycerides = 200 mg/dl.
The second patient died at 6 months from baseline,
65 years old, with left breast cancer classified T3N1M0,
presented the SCORE risk 28%, with uncontrolled valuesof BP under antihypertensive therapy (HT=160/100
mmHg), dyslipidemia, obesity (BMI=33.22 kg/m2), totalcholesterol = 230 mg / dl and with lipid-lowering therapy.
The third death occurred suddenly in a 67 years oldpatient, with left breast cancer classified T2N0M0 andpreserved EF at 52% at 6 months from baseline. The causeof death was probably malignant arrhythmia, because thepreviously 24 Hour Holter ECG performed documented
recurrent episodes of sustained ventricular tachycardia. The
patient had the SCORE risk 24%, being hypertensive,
dyslipidemic and diabetic (BMI= 21.88 kg / m2).
The entire risk spectrum gender-specific andpathophysiology of cardiac ischemia, extends beyond
obstructive coronary disease to include other causes, suchas microvascular dysfunction that is not included in thestandard definition of coronary artery disease, which should
include and other forms of ischemic heart disease.
The diagnosis and evolution is further challenged by
sex/gender differences in variable sensitivity andpresentation of cardiac biomarkers, imaging parameters,
and risk SCORE (23).
The first two deaths confirm the observation ofliterature according to which women diagnosed withobesity and breast cancer have an increased risk ofdeath. The relationship between obesity as a risk factor
11and breast cancer is complex, having a protective role inyoung women and increase the risk to the elderly.
According to Biglia et al in a study on 2148 patients(592 premenopausal, 1556 postmenopausal), high BMI
was significantly associated with larger size tumor both in
pre (p = 0.01) and postmenopausal women (p = 0.00).
Premenopausal women with obesity showed worse
histopathologic features (presence of vascular invasion
and more metastatic axillary lymphnodes) compared tounder/normal weight women (24).
The metabolic syndrome is characterized by insulin
resistance/hyperglycemia and subacute chronic
inflammation, two conditions that associated is offering aplausible link with breast cancer. Thus, in addition to theincreased risk of cardiovascular morbidity and mortality,
women with MS is also in a high risk group of developing
breast cancer, more often with poor prognosis (25).
Colonna et al. conducted a retrospective study on
860 patients with breast cancer to determine therelationship between the individual components of themetabolic syndrome and this type of cancer. The data
showed the incidence of metabolic syndrome in 15% of
women, 16% had elevated blood glucose levels, 26%
were obese, 54% had hypertension and 30% had
dyslipidemia. According to the study, presence of MS has
not contributed to a more aggressive evolution of thedisease (26). In the present study, the incidence of MS
was 33.3%, 12.5% of patients were diabetic, 37.5% wereobese and 43.1% hypertensive.
Unexpectedly, active smoking has not been proved
so far to be a risk factor in breast cancer. However,existing data have raised serious doubts regarding
passive smoking but also in this case, the evidence is stillinsufficiently clarified (27). In the present study, 19
patients was smoking (26.4%).
Imaging monitoring of the heart function isrecommended during and after chemotherapy for early
diagnosis of heart dysfunction (5). However, the validity of
the 2-dimensional echocardiography in detecting cardiac
dysfunction in this population has not been tested.
Thavendiranathan et al. observed in a study on 56
patients undergoing chemotherapy (all women), the best
echocardiographic method for sequential quantification of
EF and cardiac volumes. A temporal variability of 0.06
might occur in EF with noncontrast 3DE due tomeasurement variability and physiological differences,whereas this might be > 0.10 with 2D methods. 3DE also
had the best intra- and inter-observer as well as
test-retest variability (28).
3D Echocardiography is the one that determines
most accurately left ventricular function, with the lowest
rate of estimation, but this determination is not frequently
available for clinical use (29).
Geisbergb et al. examined Tissue Doppler imaging
techniques in studies with anthracycline cardiotoxicity. In
small studies, these techniques which also investigates12

the strain, appear to be promising for the detection ofearly subclinical changes in cardiac performance and to
anticipates a decrease in EF. Are not yet available
long-term data performed on large populations ofpatients, to confirm the clinical relevance of thesemeasurements (30).

CONCLUSIONS It is necessary to explore the cardiovascularsystem both clinical and paraclinical carefully
before initiating chemotherapy which is known to
be associated with significant cardiotoxicity.
 The presence of cardiovascular risk factors inoncology patients on cytostatic therapy requires
special attention.
 The presence of an accumulation of risk factors
prior to cytostatic therapy contributes to theemergence of cardiotoxicity, especially after
cumulative doses of anthracyclines or combinationof several chemotherapeutics.
 In this study, there was a significant correlation
between the SCORE risk and decreased EF inpatients who at 12 months had an EF less than
55%. Increased SCORE risk> 5% requires
therapeutic and prophylactic interventions forprevention of cardiotoxicity.
 Echocardiography is the standard procedure for
evaluating basal structure, performance andcardiac hemodynamic. LVEF assessment is
mandatory to investigate cardiac function prior toinitiation of treatment with potentially cardiotoxic.
 Observe the ESMO guidelines, where the necessityof the cardiac performance evaluation before
treatment with cytostatic that can lead to a potential
irreversible cardiotoxicity (type I) or reverse (type II)
is class I of evidence and recommendation level A.
 Seidman criteria, recommended by ESMO indicatethat 2D echocardiography for measure decrease ofEF, represents an optimum solution for theevaluation of cardiotoxicity, although variability
intra- and inter-observer limits its usefulness.
 Assessment of diastolic dysfunction revealed
significant differences between the proportions ofpatients classified initially and finally with diastolic
dysfunction at 12 months and may be an optimal
criterion for tracking cardiotoxicity installation.
 3D echocardiography assess the most accurate the
LV function, with the lowest rate of estimate, but
this measurement is not frequently available forclinical use.

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13

30. Geisberg CA, Sawyer DB. Mechanisms of anthracycline
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Current Hypertension Reports. 2010;12(6):404-10.

EVALUAREA CARDIOTOXICITĂȚII INDUSĂ DE CHIMIOTERAPIE.
CORELAȚII CU FACTORII DE RISC CARDIO-VASCULARIREZUMAT
Scop: Identificarea factorilor de risc ce determina complicații cardiovasculare în timpul tratamentului chimioterapic poate ajutala prevenirea și reducere toxicității cardiace. Acest studiul iși propune evaluarea implicării factorilor de risc cardiovasculari în
apariția cardiotoxicității la pacientele cu cancer de sân.
Materiale si metode: Un studiu prospectiv a fost efectuat pe 72 de femei cu cancer de sân HER2-pozitive. Criteriile deincludere au fost: vârsta> 18 ani, ritm sinusal regulat, fracție de ejectie (FEVS)> 50%, HER2 pozitive și tratament cu
trastuzumab. La toate pacientele au fost cuantificați factorii de risc cardiovasculari. Pentru evaluarea riscului SCORE, a fostutilizată diagrama pentru populaţiile cu risc înalt de mortalitate cardiovasculară. Sindromul metabolic a fost diagnosticat în
conformitate cu criteriile Federației Internaționale de Diabet. Conform criteriilor Seidman și recomandărilor din ghidul ESMO2012 pacientele au fost examinate la momentul inițial și la 3, 6 și 12 luni de intrarea în studiu, iar cardiotoxicitatea fiind definită
ca scăderea FEVS.
Rezultate: Vârsta medie la momentul includeri în studiu a fost de 55.4 ± 11.80 ani. Hipertensiunea a fost prezentă la 43,1% (n= 31) din paciente și a crescut procentual cu 4,9% la 12 luni (test χ2, p <0,001). Analiza factorilor de risc cardiovasculari arată
că sindromul metabolic a fost prezent la 33,3% dintre paciente (n = 24), 12,5% dintre paciente fiind diabetice iar 37,5% fiindobeze. Testul Spearman a relevat corelații semnificative între scăderea FEVS cu 5-10% și > 10%, și numărul total de cicluri
chimioterapice. Nu s-a realizat o corelație semnificativă între risc SCORE și scăderea FEVS <55% la 12 luni (test χ2, p =0,001). Cardiotoxicitatea severă a apărut la 3 paciente care au prezentat valori ale riscului SCORE foarte crescute.
Concluzii: Evaluarea factorilor de risc cardiovasculari implicați în cardiotoxicitatea indusă de trastuzumab și monitorizarea
adecvată a pacientelor în timpul chimioterapiei permite utilizarea sigură și eficientă a acestui tratament adjuvant.
Cuvinte cheie: cardiotoxicitate, chimioterapie, trastuzumab, factori de risc, cancer de sân

14

Fiziologia - Physiology • 2014.24.4(84)THERAPEUTIC OPTIONS IN ALLERGIC RHINITIS
CRISTINA-MARIA GOANTA1, R. MIHALCEA1, M. TUSALIU1,2
1University of Medicine and Pharmacy “Carol Davila” Bucharest
2Institute of Phonoaudiology and Functional ENT Surgery ”Prof Dr D. Hociota”, Bucharest, Romania

ABSTRACT
Allergic rhinitis is a type I allergic disease of the nasal mucosa, characterized by paroxysmal repetitive sneezing, wateryrhinorrhea, and nasal blockage. The symptoms are often ignored by patients and physicians, and most affected individuals do
not report their complaints or seek treatments. In Europe, AR affects at least 21-23% of the population.
Rhinitis can be classified in infectious (acute and chronic) and non-infectious (allergic and non-allergic).
Treatment options are a very difficult to assess for the medical doctor because of the various options and because of the factthat allergic rhinitis is a very common disease with a tendency to reoccur.
The current paper aims to asses a clear classification of the allergic rhinitis and to point out the main treatment courses for the
disease.
Key words: allergic rhinitis, treatment, rhinorrhea, nasal obstruction.

INTRODUCTION

Allergic rhinitis is a type I allergic disease of the nasal
mucosa, characterized by paroxysmal repetitive sneezing,watery rhinorrhea, and nasal blockage. The symptoms
are often ignored by patients and physicians, and mostaffected individuals do not report their complaints or seek
treatments. In Europe, AR affects at least 21-23% of the
population (1).
Allergic rhinitis is classified into perennial andseasonal. The term rhinitis is usually used to define nasal
mucosal inflammation, which, from a histopatological pointof view it is an exudative inflammation but suppurative andallergic inflammation are particularly common (4). Bothare characterized by leakage of serum components fromvessels, edema, cell infiltration, and hypersecretion.

CLASSIFICATION OF RHINITIS

Rhinitis can be basically classified as infectious andnon-infectious, both types with different subdivisions(Table I):

Medicament rhinitis is usually caused by the long-term
administration of a variety of pills like antidepressants,
sympathomimetics, β-stimulatory antihypertensives,
bronchodilators, contraceptive pills or vasodilatory
antihypertensives but the most common cause is theoveruse and overdose of sympathomimetic nose drops
prescribed for nasal blockage.
There are numerous theories that try to explain themechanism of appearance allergic rhinitis, but theirmechanisms remain largely unknown (7). The mostimportant ones are the ones based on IgE antibody
production. In response to antigen entry into the mucous
membrane, IgE antibodies are produced in the nasal
mucosa and regional lymphatic tissues. This type ofreaction has two phases: an early phase and a late phaseseen at 6-10 hours after the exposure. Most causative
antigens are inhalation antigens, such as
Dermatophagoides (a major antigen in house dust),
pollens (trees, grasses, and weeds), fungi, and pets (11).

Table I. Classification of rhinitis
Infectious
Acute Chronic

RhinitisNon-infectious
Allergic
Non-allergic
Vasomotor rhinitis =Rhinitis with Rhinorrhea type,
Congestive Type (medicament rhinitissymptomatically similar toeosinophilia including gustatory and psychogenic rhinitis, pregnant
allergic rhinitis, but it cannot syndromerhinitisrhinopathy, hormonal rhinitis, and cold
be identified as an allergy byrhinitis)
tests

Dry
type

Received 1th of October 2014. Accepted 21th of October 2014. Address for correspondence: Dr. Goanta CM, Division of Physiology and Neuroscience,
University of Medicine and Pharmacy “Carol Davila”, Eroii Sanitari Street No. 8, Bucharest, RO-050474, Romania, phone/fax: +40213180762, e-mail:cristina.goanta@gmail.com

Fiziologia - Physiology • 2014.24.4(84)15COMMON SYMPTOMS
Table II. Common symptoms of rhinitis.
Sneezing

Watery Rhinorrhea

Nasal Mucosal Swelling

Caused by

Most rhinorrhea is

Caused by interstitial

histaminesecreted from theedema in the nasal

irritation of thenasal glands;

mucosa, due to plasma

sensory nerve

10% sensory nerve

leakage, and congestion(trigeminal

irritation in the nasalof the nasal mucosal

nerve) in themucosa =>vessels

nasal mucosa,

parasympathetic nerve

The direct actions oftransmitted toexcitement =>chemical mediators, suchthe sneezing

sneezing reflex.

as histamine, PAF,

center of theAcetylcholine isprostaglandin D2, kinin,

medullareleased from,and particularly

oblongatahistamine acts directly

leukotriene, are essential

on the nasal mucosal

Continuous antigen

vessels to cause

irritation cause chronic

plasma leakage.

lesions.

DIAGNOSISTo establish the diagnosis of allergic rhinitis isrequired a series of tests. The most common are the nasal
eosinophil staining in the nasal secretion and serum IgE
antibody measurement. We can use o series of tests thatare based on skin reactions or serum allergen-specific IgE
antibody measurements. A nasal mucosa provocation test
can be conducted for house dust and ragweed, but theirassessments may be difficult. Rhinoscopy and x-ray
examinations can be performed for differential diagnosis,
but usually the definite diagnosis is clinical and it is madebased on three symptoms: sneezing and nasal itch,watery rhinorrhea, and nasal blockade (9).

TREATMENT

Usually, allergic rhinitis is manageable when treated,but resists cure so the treatment is aimed at improving thequality of life, its aim being to alleviate symptoms andremove difficulties with everyday life (5).
The first rule in a successful treatment plan is
educating the patient. The patient has to avoid theantigens, keep humidity at 50% and room temperature at
20-25°C, improve ventilation and clean rooms, avoid
using textile sofa, carpet wherever possible, prevent
pollen inhalation or avoid contact with pets.
There are also a few other new methods of treating theallergic rhinitis and among that are:- Specific immunotherapy which is indicated for patientsthat are over 6 years old and the therapy should be
administrated for at least 3 years and its therapeutic
effects often continue for several years after
discontinuation of administration (12);16Sublingual immunotherapy (SLIT)-it is not used on alarge scale; SLIT has been established as
evidence-based treatment for AR. It was introducedin latest update of ARIA guidelines in 2010 with weakrecommendation and moderate quality of evidence
for patient sensitive to pollen and low quality ofevidence for house dust mite according to the
GRADE system. Beside its efficacy in reducing thesymptoms and medication scores recorded inmeta-analyses, the unique advantages of long-lastingand preventive actions are due to profound andpersistent modifications in the immune system (2).
- Probiotics - Preliminary data exist providing beneficial
results in using probiotics in the treatment of allergic
rhinitis and probiotics could emerge as a novel,
complementary treatment option for AR.
In some cases the surgical treatment is proved to beeffective. Nasal blockage in allergic rhinitis is often caused
by nasal deformities, such as deviated septum,
hypertrophic rhinitis, and nasal polyps. In this case,perform corrective surgery of nasal cavity to improve nasal
ventilation. The main purpose is to alleviate nasal
blockage (8).
Sometimes complications can occur. The mostcommon are acute and chronic sinusitis, eosinophilic
sinusitis, allergic conjunctivitis, and sometimes evenasthma can occur (4).
Pregnant women should be approached with caution
because during pregnancy, congestive and allergic rhinitis
often occurs, and symptoms are exacerbated. If
medication is required after the fourth month of pregnancy,
minimize the use of local agents, such as DSCG, nasal
spray mast cell stabilizer, nasal spray antihistamine, andnasal topical steroids.
In children allergic rhinitis is common among maleinfants, often complicated by atopic dermatitis andsometimes it may heal spontaneously.
-

CONCLUSION

Allergic rhinitis is one of the most prevalent diseases
in young people and is responsible for a significant
impairment in quality of life but its control is usually far
from satisfactory (3). Medications provide some relief, but
improvement is only partial. Recent evidence fromdouble-blind, placebo-controlled, randomized clinical
trials suggests that the more severe the disease, thegreater the treatment effect. Anti-IgE shots show better
efficacy, but are still very expensive. Anti-allergic
immunotherapy is promising but new, well designed,long-term clinical trials are needed. Most patientsseeking treatment for allergic rhinitis are polysensitized,
and allergen immunotherapy has proven efficacy.
Avoidance procedures could lead to improvement if they
are designed as multi-trigger, multi-component
interventions (14).

Fiziologia - Physiology • 2014.24.4(84)Table III. Therapeutic agents for allergic rhinitis
Therapeutic agents
Alpha-sympathomimetics (vasoconstrictor nose
drops)

Effects- temporarily alleviate nasal blockage

Mast cell stabilizer (local agents (eye drops an nasal
spray) and oral agents)- mild effects- 2-week prolonged administration is required.
- amelioration rates are increased bycontinuous administration- often cause adverse effects(sleepiness,
impaired performance, dry mouth)- have immediate effects on sneezing andwatery rhinorrhea.

Chemicalmediator
receptor
antagonists

Histamine H1
receptor
antagonists(antihistamine)First-generation
antihistamine

Second-generation
antihistamine

Leukotriene receptor antagonists(antileukotrienes)

Prostaglandin D2 and thromboxane A2
receptor antagonist

Th2 cytokine inhibitors

Steroids

Nasal steroids

Steroids forinternal use

Alpha-sympathomimetics

Fiziologia - Physiology • 2014.24.4(84)- are effective to some extent for nasal
blockage aside from sneezing and wateryrhinorrhea- priority indications are mild to moderatesneezing and rhinorrhea type
- potent relaxing effects on the vascularsmooth muscles of the nasal mucosa- enhancing effects on vascular permeability- stimulating effects on eosinophil migration.
-effective for nasal blockage.
- their effects are increased by prolonged
administration.
- enhances vascular permeability in the nasal
mucosa and suppresses eosinophil
migration by blocking thromboxane
receptors, and suppresses eosinophil
migration by blocking CRTh2- they have strong delayed effects on nasal
blockage- IPD inhibits the production of Th2 cytokines,
such as IL-4 and IL-5, in T lymphocytes toalleviate allergic inflammation- strong local effects in small amounts,- are poorly absorbed and readily degraded- they have few systemic adverse effects- exert their effects within 1-3 days
- only for intractable cases with severe nasal
blockage and laryngopharynx symptoms
uncontrollable with nasal spray steroids,- prednisolone (20-40 mg/day) can beadministered for 4-7 days at the start oftreatment- act on the α-receptors of vascular smoothmuscles to cause vasoconstriction andtemporarily alleviate nasal mucosal swelling.
-Long-term continuous administration
causes medicament rhinitis

Contraindications
Transsphenoidal Hypophysectomy
High Blood Pressure
Overactive Thyroid Gland,
Diabetes
Paradoxical bronchospasm
Liver disease
Kidney disease
Patients with glaucoma, prostatic
hyperplasia, and asthma because of
their potent anticholinergic effects [6]They have less central nervous
system depressant actions in children
than in adults.
Caution should be exercised for
excitatory effects, such as
convulsions.
Severe hepatic disorders

Asthma attacks
Major liver diseases

17

Acknowledgement
This work recived financial support through the project entitled"CERO-career profile: Romanian Researcher" grant number
POSDRU/159/1.5/135760 cofinanced by the European Social
Fund for Sectoral Operational Programme Human Resources
Development 2007-2013.

REFERENCES
1. Yu YI, Cho JS, Lee KH, Kim KH, Hong SM, Kim SW.
Clinical statistical study on offending allergens of patients withallergic rhinitis: prevalence of multiple sensitization. Korean J
Otolaryngol-Head Neck Surg. 2003;46:48-53.
2. Bahceciler
NN,
Galip
N,
Cobanoglu
N.
Multiallergen-specific immunotherapy in polysensitized patients:
where are we? Immunotherapy. 2013;5:183-190.
3. Veling MC, Trevino RJ. The treatment of allergic rhinitis
with immunotherapy: a review of 1,000 cases. Ear Nose Throat
J. 2001;80:542-543.
4. Asher MI, Montefort S, Bjorksten B, et al. ISAAC Phase
Three Study Group. Worldwide time trends in the prevalence ofsymptoms of asthma, allergic rhinoconjunctivitis, and eczema inchildhood: ISAAC Phases One and Three repeat multicountry
cross-sectional surveys. Lancet. 2006;368:733-43.
5. Schwindt CD, Settipane R. Allergic rhinitis (AR) is now
estimated to affect some 1.4 billion people globally andcontinues to be on the rise. Editorial. Am J Rhinol Allergy.
2012;26(Suppl 1):S1
6. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis
and its Impact on Asthma (ARIA) 2008 Update (in collaboration

with the World Health Organization, GA2LEN and AllerGen).
Allergy. 2008;63(Suppl 86):8-160.
7. Incorvaia C, Di Rienzo A, Celani C, Makri E, Frati F.
Treating allergic rhinitis by sublingual immunotherapy: a review.
Ann Ist Super Sanita. 2012;48(2):172-176.
8. Pichler CE, Helbling A, Pichler WJ. Three years of specificimmunotherapy with house-dust-mite extracts in patients withrhinitis and asthma: significant improvement of allergen-specificparameters and of nonspecific bronchial hyperreactivity. Allergy.
2001;56:301-306.
9. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy:
therapeutic vaccines for allergic diseases. A WHO position
paper. J Allergy Clin Immunol. 1998;102: 558-562.
10. Durham S, Birk AO, Andersen JS. Days with severe
symptoms: an additional efficacy endpoint in immunotherapy
trials. Allergy. 2011;11:120-123.
11. Xiao JZ, Kondo S, Yanagisawa N, Takahashi N, Odamaki T,
Iwabuchi N, et al. Probiotics in the treatment of Japanese cedar
pollinosis: A double-blind placebo-controlled trial. Clin Exp
Allergy. 2006;36:1425-35.
12. Till SJ, Francis JN, Nouri-Aria K, et al. Mechanisms of
immunotherapy. J. Allergy Clin. Immunol. 2004;113(6):1025-34.
13. Cox L, Nelson H, Lockey R. Allergen immunotherapy: A
practical parameter third update. J. Allergy Clin. Immunol.
2001;1(suppl):S1-S55.
14. Shedden A. Impact of nasal congestion on quality of life
and work productivity in allergic rhinitis. Treat Respir. Med.
2005;4(6):439-446.

OPTIUNI TERAPEUTICE IN RINITA ALERGICA
REZUMAT
Rinita alergica este o reactive alergica de tipul I a mucoasei nazale, caracterizata prin episoade de stranut repetitive, rinoreeapoasa si obstructive nazala. Simptomatologia este adesea ignorata de pacienti si chiar si de medici , iar cel mai mult s,unt
afectati indivizii ce aleg sa ignore simtomatologia si sa nu se prezinte la medic. In Europa rinita alergica afecteaza 21-23% din
populatie.
Rinita se poate clasifica in infectioasa (acuta si cronica ) si non-infectioasa (alergica si non-alergica).
Optiunile terapeutice sunt multiple si greu de ales deoarece rinita alergica este o boala foarte frecventa in populatie si are
tendinta de a recadea.
Cuvinte cheie: rinita alergica, tratament, rinoree, obstructive nazala.

18

Fiziologia - Physiology • 2014.24.4(84)KERATINIZED MUCOSA – PREDICTIVE FACTOR FOR THE HEALTH
OF PERI-IMPLANT TISSUESCĂRĂMIDĂ MARIANA1, SÎRBU IOAN1, CIORTEA CLAUDIU1, DUMITRACHE MIHAELAADINA2, GĂLUȘCAN ATENA3
1Implantology Department, Faculty of Dentistry, “Carol Davila” Medicine and Pharmacy University, Bucharest, România
2Oral Health and Community Dentistry Department,“Carol Davila” Medicine and Pharmacy University, Bucharest, România
of Preventive, Community Dentisty and Oral Health, “Victor Babeș” Medicine and Pharmacy University,Timișoara, România
3Department

ABSTRACTDue to the enhanced proprieties of the oral implants and advanced surgical techniques in the recent years, prosthetic
treatments using dental implants are recommended and performed on large scale. In order to raise even more thepredictability of this type of oral implants treatments, there must be evaluated and corrected their present complications.
The inflammatory complications were found with the highest frequency compared to the other two categories - surgical andprosthetic. Among local risk factors for this type of complication are implant surface characteristics, history of periodontal
disease and decrease width of keratinized mucosa around implants.
The role of the keratinized mucosa played in the peri-implant health is an controversial subject in the literature due to the lackof consensus regarding the conclusions of the studies developed in time with the aim to assess the effects of the absence of
this type of mucosa on the tissues around dental implants. The width of the keratinized mucosa considered sufficient tomaintain the health of the peri-implant tissue is considered at least 2 mm – of which 1 mm should be attached mucosa.
On the other hand, there are authors that consider that as long as the oral hygiene is properly performed, there are not sign ofperi-implant inflammation irrespective the width of the keratinized mucosa.
This review aimed to assess the correlation between the changes on the peri-implant tissues and the width of keratinizedmucosa. The inconsistency of the results of these studies do not establish an consensus regarding this clinical aspect. The
limits are given, among others, by the different study designs used and there is recommended onward research.
The recommendation is that the prognosis for the oral implants surrounded by a narrow keratinized mucosa is good but it iscompulsory for oral hygiene procedures to be rigorous. In addition, in areas that are hard to be accessed for cleaning or inesthetic areas, there are recommended additional therapeutic procedures to offer sufficient quantity of keratinized mucosa
Keywords: periimplantitis, keratinized mucosa, soft tissue management

INTRODUCTION

Due to the enhanced proprieties of the oral implants
and advanced surgical techniques in the recent years,
prosthetic treatments using dental implants arerecommended and performed on large scale. In order toraise even more the predictability of this type of oral
implants treatments, there must be evaluated andcorrected their present complications.
A retrospective study made at the Faculty of Dentistryof the Harvard University, Boston, USA, and published in2003 aimed to identify different types of complication of
the oral implants. These complications were classified inthree groups: inflammatory, surgical and prosthetic. The
inflammatory complications were found with the highest
frequency compared to the other two categories – 10.2 %of the patients treated presenting specific signs (1).
Among the inflammatory complications, those
localized on the peri-implant tissues and induced by thedental plaque is found with a prevalence ranging
between 25% and 45% (2). According to the conclusionsof the Peri-implantitis Workshop of Periodontology, heldin 2008, based on the analyzed studies, the inflammationof the peri-implant tissues prevalence varies as it follows:
peri-implant mucositis – 80% and peri-implantitis –28-53% of the total number of the patients with dental
implants (3,4).
Inflammation localized on the tissues around
implants that have been successfully osseointedrated, iscaused by the microbial colonization and multiplication towhich human body give an immune response. During thefirst phase, the inflammation affects only the soft tissue –pathology known as peri-implant mucositis, and then as aconsequence of the evolution of the pathological process
in absence of any therapeutic procedure, theinflammation extends to the hard tissue, causing theperi-implantitis (5-7).

Received 12th of September 2014. Accepted 25th of October 2014. Address for correspondence: Assoc. Prof. Atena Galuscan, Department of Preventive,
Community Dentisty and Oral Health, ”Victor Babes” University of Medicine and Pharmacy Timisoara, Spl.T. Vladimirescu no.14A, Timisoara, Romania;
phone/fax: + 0040-256-204950; e-mail: atedent@yahoo.com

Fiziologia - Physiology • 2014.24.4(84)19Peri-implant mucositis is defined as the reversible
inflammation of the soft tissue around the implant, which
is diagnosed by the following signs: bleeding on probing,increased depth of the peri-impant sulcus (4-5 mm) andno bone alteration (5,6,8,9). These clinical signs develop
as a consequence of the inflammatory response of thehost tissue that release cytokines, in a similar way as
noticed in natural dentition tissues (10,11). In presence ofa persistent local microbial colonization, the level ofthese cytokines significantly increases which has
destructive effects on host tissues. The first destroyed iscollagen fibers and next – the bone 7. In this phase, thepathology has turned to peri-implantitis which isrecognized by bleeding on probing, peri-implant pockets
deeper than 5 mm, and the most important – peri-implantbone resorption (3,5-8,10).
Microbial colonization is developed because of thepersistent dental plaque as a consequence of theunproper oral hygiene. Thus, dental implants inserted inareas hard to be cleaned are prone to development ofperi-implantitis. Among local risk factors for this type ofcomplication are implant surface characteristics, historyof periodontal disease and decrease width of keratinizedmucosa around implants (7).
Peri-implant keratinized mucosa is represented bykeratinized epithelium that covers a dense connective
tissue with no elastic fibers, that lays between freegingival margin and muco-gingival junction with a freecomponent – external wall of the peri-implantsulcus/pocket, and an attached component – firmly
connected to the periosteum. The width varies dependent
to the location in the dental arch, the frenulum insertionand patient age (12-14). When it comes to edentulous
areas, the width of the keratinized mucosa decreases asa consequence of the bone resorption which also leads
to higher insertion of the mobile mucosa. Mobile mucosa
has an increased number of elastic fibers and isconnected to the peri-oral muscles and thus could cause
traction of the soft tissue around the implant during themuscular activity (12,13).
The role of the keratinized mucosa played in theperi-implant health is an controversial subject in theliterature due to the lack of consensus regarding theconclusions of the studies developed in time with the aim
to assess the effects of the absence of this type of mucosa
on the tissues around dental implants (12,14-20).
In the literature, the authors that support theimportance of the presence of keratnized mucosa, use
the following reasons (14-16,18-21):
the traction forces caused by the mobile mucosa
generate the movement of the external wall of theperi-implant sulcus during the mastication, thus
accumulation of the dental plaque subgingivally
the ease in oral hygiene procedures, decreasing thetrauma and pain caused by the dental cleaning inareas where the bone resorption is advanced and the20

position of tongue, lips and chicks impede the accessfor the toothbrush
mobile mucosa is unproper to form a good quality
peri-implant sealing
moreover, frequent traction caused by the mobile
mucosa will jeopardize the peri-implant sealing
the movement of the mobile mucoasa around
implants could cause soft tissue recession and dental
exposureperi-implant mucosa could collapse during theattachment/detachment of the prosthetic accessories
The width of the keratinized mucosa consideredsufficient to maintain the health of the peri-implant tissue
is considered at least 2 mm – of which 1 mm should be
attached mucosa (19,20).
On the other hand, there are authors that consider
that as long as the oral hygiene is properly performed,
there are not sign of peri-implant inflammation
irrespective the width of the keratinized mucosa(9,14,19,20).

RESULTS

The studies that aimed to assess the correlation
between the changes on the peri-implant tissues and thewidth of keratinized mucosa showed contradictory
results.
Analyzing the articles with this focus published till thepresent accessible on the PubMed database, wecollected the results and distributed them into to majorgroups: supporting and denying the necessity of thekeratinized mucosa for the peri-implant tissues health.
We compared them using as parameters: efficacy of theoral hygiene, inflammation of the soft tissue, tissue
recession, bone resorption and implant loss.
A study (8) developed in 2006 in Kristianstad –Sweeden, on 218 patients restored using 999 two stage
oral implants, had a following time of 9-14 years. All thesubjects enrolled in the study received oral hygiene
instructions. Results revealed that plaque index, pocket
depth and also quantity of pus increased with thedecreasing of the width of the keratinized mucosa (using
one or multi variable tests).
A study (22) published in 2006, developed inMichigan – USA on 69 patients restored using a total
number of 339 dental implants, aimed to assess theinfluence of the keratinizemucosa and examined inaddition to other studies the width of attached mucosa.
Results obtained showed that plaque index and gingivalindex had significant higher values in peri-implant sitswith keratinized mucosa narrower than 2 mm andattached mucosa narrower than 1 mm. Yet, regarding theannual bone resorption, no significant differences were
noticed depending on the quantity of keratinized mucosa.
A study (18) developed in 2003-2007 in Seoul –South Korea, on a sample of 100 patients who wereinserted 273 two-stage oral implants, monitored the
Fiziologia - Physiology • 2014.24.4(84)evolution on an average period of 13 months (6-26
months). Restored areas were posterior areas (premolar
and molar, maxillary and mandibular areas). Dependingon the quantity of the keratinized mucosa, there were
186 implants withing sufficient category and 90 –insufficient. The results regarding the oral hygiene
efficacy (plaque index), inflammatory signs (bleeding on
probing, pocket depth) did not show significant
differences between the two categories. However,regarding the soft tissue recession and the bone
resorption, implants with insufficient keratinized mucosa
being significantly more affected.
A retrospective study (12) published in 2008 anddeveloped in Haifa-Israel on 32 patients who wererestaured using single or multi unit fixed restorations on
63 implants. Results established a negative correlation
between tissue recession and reduction of the level of
peri-implant tissue ring and the width of the keratinizedmucosa. Surprisingly, a positive correlation wasdetermined between the width of keratinized mucosa andthe pocket depth but the researchers consider thedecrease of sulcus depth a consequence if tissue
recession. In this study, the inflammation was analyzed
also using test to reveal the level of inflammation
markers and the results showed that the PgE2 had asignificant increase in cases with insufficient keratinizedmucosa.
In 2008 there have been published a cross-sectional
study (23) applied in Cleveland – USA on 76 patients
restored with fixed dentures on 200 oral implants. The
researcher found significant higher values for plaqueindex, gingival index, bleeding on probing index for sites
with less than 2 mm of keratinized mucosa than thosewider than that. In addition, significant more bone
resorption (assessed using radiographs) and regarding
this parameter, the results remained unchanged
irrespective the variables used in the analysis.
A multicentric study (19) (applied in 5 dental schools
in USA and an private dental office in Great Britain)
published in 2009, included 73 patients with completely
edentulous arches who were restored using a total
number of 386 stage two dental implants. They weremonitored for 5 years, and only 58 patients with 307
implants were maintained in the study until the final point.
All the patients were given proper oral hygiene
instructions. Results showed that plaque index andbleeding on probing index were correlated with the widthof keratinize mucosa on lingual areas but no significant
differences were obtained for buccal areas. Again, tissue
recession and width of keratinized mucosa were found innegative correlation. Based on these results, theresearchers determined the quantity of keratinizedmucosa necessary for the maintenance of theperi-implant tissue health: 1-2 mm for efficient oral
hygiene, 0-1 mm for absence of the inflammation, 1-2mm for resistance to soft tissue recessions.
Fiziologia - Physiology • 2014.24.4(84)A cross-sectional study (20) published in 2009,
applied in Isfahan – Iran, examined 27 patients withcompletely edentulous arches and restored using a
total number of 66 oral implants. Patients enrolled were
distributed into two groups: with a width keratinizedmucosa higher or less than 2 mm. Results revealed
significant differences between the two groups, withhigher plaque index, gingival index, bleeding on probing
index at patient in the second group. The samenegative correlation was found also for the tissue
recession parameter. Still, no significant differenceswere found for the pocket depth. Also, although thevalues of the bone resorption were higher in sites withless than 2 mm of keratinized mucosa, the differences
between groups were not statistically significant.
A longitudinal study (24) published in 2013, appliedin Istanbul – Turkey, included 15 completely edentulous
arch patients using a total number of 60 implants who
were not only clinically and but also biochemicallyassessed and followed up for 12 months, taking into
consideration for examination the quantity of keratinizedmucosa. Plaque index and gingival index had
significant higher values at sites with narrower than 2
mm of keratinized mucosa. Moreover, when it comes toinflammation markers assessed after harvesting
sulcular fluid, the results revealed that TNF alpha value
were significantly higher at this group, and the values
increased at 12 months after the first assessment.
A study (25) published in 1994 was developed in
Goteborg – Sweeden on 39 completely or partiallyedentulous arch patients who were restored on 171 oral
implants. The results show that there are no significant
changes in clinical signs at patients who do not benefitof a sufficient keratinized mucosa compared to thosepatients who have an adequate quantity of this type ofmucosa. Plaque index and bleeding on probing index
did not reveal significant differences. Thus, the authors
do not support the concept of the necessity for a widthof 2 mm of keratinized mucosa around oral implants.
Another study (26) published in 2012 developed in
Sao Paolo – Brasil, in 109 patients with palatal cleft who
were restored using 202 two stage dental implants andfollowed up for 1 year after the implant insertion. The
subjects were divided in two groups depending on thewidth of keratinized mucosa: more or less that 2 mm.
Only the buccal sites were examined this time. The
results obtained revealed that plaque index and gingivalindex did not have significant differences between thetwo groups. Moreover, the bigger the width of thekeratinized mucosa, the deeper the peri-implant pockets.
Conclusion of this study on special category of patientswas that plaque accumulation around the dental implants
next to the cleft area is not influence of the keratinizedmucosa.

21

CONCLUSION

The inconsistency of the results of these studies
does not establish a consensus regarding this clinicalaspect. The limits are given, among others, by thedifferent study designs used and there are recommended
onward research.
The conclusion and recommendation of the 6th
European Workshop on Periodontology focused on
Peri-implantitis are that the prognosis for the oral
implants surrounded by a narrow keratinized mucosa isgood but it is compulsory for oral hygiene procedures tobe rigorous. In addition, in areas which are hard to beaccessed for cleaning or in esthetic areas, there arerecommended additional therapeutic procedures to offer
sufficient quantity of keratinized mucosa (14).

REFERENCES



McDermott NE, Chuang SK, Woo VV, Dodson TB.
Coplications of dental implants: identification, frequency, andassociated risk factors. Int J Oral Maxillofac Implants.
2003;18(6):848-855.
 Lindhe J, Karring T, Lang NP - Clinical periodontology andimplant dentistry. Oxford: Blackwell Munksgaard, 2011;534.
 Lindhe J, Meyle J. Peri-implant diseases:Consensus Reportof the Sixth European Workshop on Periodontology. J Clin
Periodontol. 2008;35 (Suppl. 8): 282-285.
 Salvi GE, Aglietta M, Eick S, Sculean A, Lang NP,
Ramseier CA. Reversibility of experimental peri-implant mucositis
compared with experimental gingivitis in humans. Clin. Oral Impl.
Res. 2012; 23: 182–190.
 Ata-Ali J, Flichy-Fernández AJ, Ata-Ali F, Peńarrocha-Diago
M, Peńarrocha-Diago M - Clinical, Microbiologic, and Host
Response Characteristics in Patients with Peri-implant Mucositis.
J Oral Maxillofac Implants. 2013;23(8):883-890.
 Heitz-Mayfield LJA. Diagnosis and management ofperi-implant diseases. Australian Dental Journal. 2008; 53(1Suppl): 43-48.
 Nguyen-Hieu1 T, Borghetti A, Aboudharam G. Peri-implantitis:from diagnosis to therapeutics. J Investig Clin Dent. 2012;
3:79-94.
 Roos-Jansaker AM, Renvert H, Lindahl Ch, Renvert S.
Nine-to fourteen-year followup of implant treatment. Part III:factors associated with peri-implant lesions. J Clin Periodontol.
2006; 33: 296-301.
 Heitz-Mayfield LJA. Peri-implant diseases: diagnosis and risk
indicators. J Clin Periodontol. 2008; 35 (Suppl. 8):292-304.
 Eriesson I, Persson LG, Berglundh T, Marinello CP, Lindhe J,
Klinge B. Different types of infiammatory reactions in peri-implant
soft tissues. J Clin Periodontol. 1995; 22:255-261.
 Kozlovsky A, Tal H, Laufer BZ, Leshem R, Rohrer MD,
Weinreb M, Artzi Z. Impact of implant overloading on theperi-implant bone in inflamed and noninflamed peri-implantmucosa. Clin. Oral Impl. Res. 2007; 18:601-610.
 Zigdon H, Machtei EE. The dimensions of keratinizedmucosa around implants affect clinical and immunological

22

parameters. Clin. Oral Impl. Res. 2008; 19:387-392.
 Wennstrom JL, Derks J. Is there a need for keratinizedmucosa around implants to maintain health and tissue stability?
Clin. Oral Implants Res. 2012; 23 (Suppl. 6):136-146.
 Basegmez C, Ersanli S, Demirel K, Bölükbasi N, Yalcin S.
The comparison of two techniques to increase the amount ofperi-implant attached mucosa: free gingival grafts versus
vestibuloplasty.One-year results from a randomised controlled
trial. Eur J Oral Implantol. 2012; 5(2):139-45.
 Mehta P, Peng LL. The width of the attached gingiva-Muchado about nothing? J Dent. 2010; 38:517-525.
 Park JC, Yang KB, Choi Y, Kim YT, Jung W, Kim CS,
Cho KS, Chai JK, Kim CK, Choi SH. A simple approach topreserve keratinized mucosa around implants using a
pre-fabricated implantretained stent: a report of two cases. J
Periodontal Implant Sci. 2010; 40:194-200.
 Lorenzo R, Garcı´a V , Orsini M, Martin C, Sanz M. Clinicalefficacy of a xenogeneic collagen matrix in augmenting
keratinized mucosa around implants: a randomized controlled
prospective clinical trial. Clin. Oral Impl. Res. 2012; 23:316-324.
 Kim BS, Kim YK, Yun PY, Yi YJ, Lee HJ, Kim SG, Son JS.
Evaluation of peri-implant tissue response according to thepresence of keratinized mucosa. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod. 2009; 107(3):24-8.
 Schrott AR, Jimenez M, Hwang JW, Fiorellini J, Weber HP.
Five-year evaluation of the influence of keratinized mucosa on
peri-implant soft-tissue health and stability around implants
supporting full-arch mandibular fixed prostheses. Clin. Oral Impl.
Res. 2009; 20:1170-77.
 Adibrad M, DDS, Shahabuei M, Sahabi M. Significance of
the width of kertinized mucosa on the health status of the
supporting tissue around implants supporting overdentures. J
Oral Implantol. 2009; 5(5):232-7.
 Krygier G, Glick PL, Versman KJ, Dahlin CJ, Cochran DL. To
minimize complications, is it essential that implant abutments besurrounded by keratinized tissue? Int J Oral Maxillofac
Implants. 1997; 12(1):127.
 Chung DM, Oh TJ, Shotwell JL, Misch CE, Wang HL.
Significance of keratinized mucosa in maintenance of dental
implants with different surfaces. J Periodontol. 2006;
77(8):1410-20.
 Bouri A Jr, Bissada N, Al-Zahrani MS, Faddoul F, Nouneh I.
Width of keratinized gingiva and the health status of the
supporting tissues around dentalimplants. Int J Oral
Maxillofac Implants. 2008; 23(2):323-6.
 Boynueğri D, Nemli SK, Kasko YA. Significance of
keratinized mucosa around dental implants: a prospective
comparative study. Clin Oral Implants Res. 2013; 24(8):928-33.
 Wennström JL, Bengazi F, Lekholm U. The influence of themasticatory mucosa on the peri-implant soft tissue condition. Clin
Oral Implants Res. 1994; 5(1):1-8.
 Esper LA, Ferreira SB Jr, de Oliveira Fortes Kaizer R, deAlmeida AL. The role of keratinized mucosa in peri-implant health.
Cleft Palate Craniofac J. 2012; 49(2):167-70.

Fiziologia - Physiology • 2014.24.4(84)MUCOASA KERATINIZATĂ – FACTOR DE PREDICȚIE PENTRU SĂNĂTATEAȚESUTURILOR PERI-IMPLANTAREREZUMAT
Datorită îmbunătățirii proprietăților implanturilor orale și tehnicilor chirurgicale avansate în ultimii ani, restaurarea protetică pe
implanturi sunt recomandate și utilizate pe scară largă. Pentru creșterea predictibilității acestui tip de tratament, este necesar
să fie evaluate și minimalizate potențialele complicații.
Complicațiile inflamatorii ale tratamentului prin implanturi dentare a fost întâlnit cu frecvența cea mai mare, prin comparație cu
celelalte două tipuri de complicații asociate tratamentului implantar: chirurgicale și protetice. Printre factorii de risc locali seregăsesc caracteristicile de suprafață, istoricul de boală parodontală și lățimea scăzută a mucoasei keratinizate
periimplantare.
Rolul mucoasei keratinizate din jurul implanturilor în statusul țesuturilor periimplantare este un subiect controversat în
literature, datorită lipsei unei consecvențe în ceea ce privește concluziile studiilor efectuate, care au urmărit evaluarea
consecințelor pe care le are lipsa mucoasei keratinizate atașate de os în jurul implanturilor orale. Lățimea mucoasei
keratinizate, considerate a fi suficientă pentru menținerea sănătății țesuturilor periimplanare, este de minim 2 mm, din care 1
mm trebuie să fie mucoasă atașată.
Pe de altă parte, sunt autori care consideră că dacă igiena orală este realizată adecvat, nu apar semne de inflamație
periimplantară, indiferent de lățimea mucoasei keratinizate.
Review-ul de față are ca scop evaluarea corelației dintre modificările la nivelul țesuturilor periimplantare și lățimea mucoasei
keratinizate. Rezultatele studiilor analizate nu a dus la un consens în ceea ce privește acest aspect clinic. Limitele s-au
datorat designului diferit al acestor studii, de unde necesitatea unor studii suplimentare.
Recomandarea este ca, pentru un prognostic bun al implanturilor dentare care prezintă o mucoasă keratinizată îngustă,igiena orală este obligatoriu să fie riguroasă. Totuși, se recomandă ca, în zonele în care accesul este îngreunat pentru
igienizare sau în zonele frontale ce implică cerințe estetice, să fie realizate intervenții de augmentare a mucoasei keratinizate.
Cuvinte cheie: periimplantită, mucoasă keratinizată, management țesut moale

Fiziologia - Physiology • 2014.24.4(84)23LEUKOTRIENES AND PAIN-NEW THERAPEUTIC PERSPECTIVESMIHAI NECHIFOR1, CRISTINA GALES 2, DIANA PETRESCU1
1 Department of Pharmacology
2 Department of Histology“Gr.T.Popa” University of Medicine and Pharmacy, Iasi 700115, Romania

ABSTRACT
Leukotrienes (LTs) are an important eicosanoids group involved in the mechanism of inflammatory and non-inflammatory pain.
The involvement of LTs in the peripheral mechanism of nociception is supported by data which show that many inflammation
mediators (TNF, some interleukines and others) stimulate LTB4 and peptidoleukotrienes synthesis. LTB4 antagonists and5-lipoxygenase inhibitors decrease the peripheral inflammatory nociception. LTs are also involved in the neurophatic pain. The
activation of cysLT2 receptor from dorsal root neurons can modulate TRPV1 receptor activity. Our experimental data show thatmontelukast (cysLT1 receptor antagonist) increased the mechanical nociceptive threshold in rats. The inhibition of LTs
synthesis, as well as BLT1, BLT2, cysLT1 and cysLT2 receptors blockade could be in the future a new way in pain therapy.
Key words: leukotrienes,inflammarory pain, neuropatic pain, 5-LOX inhibitors, montelukast, risedronate, licofelone

GENERAL CONSIDERATIONSThis group of active lipids are an important part ofeicosanoids derived by arachidonic and eicosapentaenoic
acids under the influence of 5-lipooxygenase (5-LOX).TheLTs are oxygenated metabolites of arachidonic andeicosapentaenoic acids with an important biological activity
and a lot of involvements in normal functions of the cells
but also in the pathogenesis of various diseases (1).LTs
synthesis is present in different cells and tissues fromhuman and animal body The LTs derived from arachidonic
acid are the most important group of leukotrienes. The
arachidonic acid is released from membrane phospholipids
by phospholipase A2. The first step in the synthesis of LTs
is the transformation of arachidonic acid into LTA4. This is
an inactive compound but is rapidly metabolized in two
important groups of LTs: i) LTB4 (which doesn’t contain in
its molecule aminoacids rests); ii) Peptidoleukotrienes
LTC4, LTD4, LTE4 (which have an aminoacid sequence inthe molecule: peptide-containing LTs)
The LTA4 is metabolized to LTC4 by LTC synthase.
The LTC4 is metabolized in LTD4 by agamma-glutamyltransferase
andbygamma-glutamilleukotienase (2). The metabolism of
LTD4 in LTE4 is produced for about 40% by adipeptidase but now is not clear what is the enzyme
involved for other 60% from LTE4 synthesis (3).
All of the leukotrienes above mentioned are derived
from arachidonic acid. There are also leukotrienes which
derive from eicosapentaenoic acid (EPA). For example,
LTB5 derived from EPA was shown to be approximately
30 times less active than LTB4 (derived from arachidonicacid). The potency of LTB5 in potentiating

bradikinine-induced plasma exudation was ten times
lower than that of LTB4 (4).
Besides the most active leukotriene-producing cells
are the leukocytes, but also lung, kidney and liver
parenchyma which actively synthesize these eicosanoids.
In leukotriene’s case, an important role plays also thetranscelullar synthesis. Although endothelial cells can’t
generate LTs from arachidonic acid it has been shown thatpolymorphonuclear leukocytes can transfer to endothelial
cells LTA4 (an intermediary compound) as substrate for
peptidoleukotrienes synthesis. All leukotrienes act onmembrane receptors. There are four types of membrane
G-protein coupled receptors for LTs.BLT1 and BLT2 arereceptors for LTB4 and LTB5 and cysLT1 and cysLT2 arereceptors for peptidoleukotrienes (5,6).
The most known involvements of the leukotrienes indifferent pathogenic processes are those from bronchialasthma, allergic rhinitis, atherosclerotic lesions, idiopathic
pulmonary fibrosis, inflammation, anaphylaxia, but also in
psoriasis, ulcerative colitis,nasal polyposis, chronic
urticaria, allergic conjunctivitis, migraine, atopic
dermatitis and reumathoid arthritis pathogeny (7-9).
LTs are involved in inflammatory and non-inflammatory
pain. LTs are eicosanoids with a pro-inflammatory profile
involved in pathogenesis of several types of inflammation(10,11). Several studies have demonstrated that LTs are
involved in pathogenesis of inflammatory pain.
Cysteinyl-LTs are potent inflammatory mediators but
are involved also in central nociception and peripheral
nociception.
There are clinical and experimental data which show
the involvement of LTs in nociception and pain.

Received 15th of September 2014. Accepted 10th of October 2014. Address for correspondence: Mihai Nechifor, MD, PhD, Department of Pharmacology,
Gr.T.Popa” University of Medicine and Pharmacy, Iasi 700115, Romania; e-mail: mnechif@yahoo.com

24

Fiziologia - Physiology • 2014.24.4(84)Inflammatory pain
Several studies have demonstrated that LTs are
involved in pathogenesis of inflammatory pain. There aredata that showed that leukotrienes are a part of theactive pro-nociceptive factors. Previous studies reported
that some lipoxygenase metabolites are involved in
hyperalgesia in peripheral inflammation. In these cases,
LTs were released from infiltrated immune cells, such as
neutrophils, and may have an effect on nociceptors inperipheral inflamed tissues. The blocking agents of theboth LTB4 receptors and cys- LT1 and cys-LT2 receptors
influence the nociception (12,13).
Several studies have demonstrated that LTs are
involved in pathogenesis of inflammatory pain.
Intraplantar LTs receptor agonist administrationinduces a powerful hyperalgesic response anddecreases the mechanical and thermal pain threshold of
C-fibers nociceptors (14). The administration of a BLT
receptor antagonist suppresses this hyperalgesia andalso blocks the painful response after experimental
carrageenin administration in rats (15).
There are data that showed that leukotrienes are apart of the active pro-nociceptive factors.The blocking
agents of the both LTB4 receptors and cys- LT1 andcys-LT2 receptors influence the nociception.
Zafirlukast (a cysLT1 antagonist) 2.5-20 mg/kg per os
produce a significant dose-dependent antinociceptive
effect against the experimental acid-acetic induced
chemonociception in mice and attenuated thecarrageenan-induced peripheral hyperalgesia, but thesame antagonist of cysLT1 receptors does not change
the pain threshold in central nociception (11).
LTB4 which mediates different inflammatory
processes is involved also in the mechanism ofhypernociception and inflammatory pain. Intraarticularexperimental administration of LTB4 by joint injection
induced a dose dependent hypernociception (13). A partof hypernociception induced by intrajoint LTB4
administration of zymosan was reduced by celecoxib(COX-2 inhibitor) or indomethacin 5mg/kg. This factshows that LTB4 effect in nociception is partially mediatedby the increased prostaglandin’s synthesis.
The sensitization of nociceptors is an essential
phenomenon of inflammatory pain. The up-regulation of
nociceptors is involved in hyperalgesia.LTB 4
participates at the genesis of inflammatory hyperalgesia(16). In the pain produced in the rat paw subsequent to
the intraplantar injection with ovalbumin the level ofinterleukines IL-1ß and IL-8 but also TNFα is higher.
TNFα and some interleukines stimulate the LTB 4synthesis. The administration of MK886 (an LTB 4synthesis inhibitor) and a LTB4 selective receptor
antagonist CP105696 reduced LTB4 mediatedovalbumin induced hypersensibility. The main source
for LTB4 synthesis in these situations are the

Fiziologia - Physiology • 2014.24.4(84)polymorphonuclear neutrophils. A very selective
non-redox 5-LOX inhibitor, PL-4191834 is very efficient
in reduction of acute experimental inflammation andpain (17).
The endothelin-1(ET-1) involved in inflammatory
events including pain, stimulates the LTB4 synthesis,
BQ-123 and BQ-788 (two endothelin receptors
antagonists) decreased the LTB4 level in a murine modelof zymosan-induced arthritis (18). Risedronate has animportant anti-inflammatory and anti-nociceptive activity
in rats receiving zymosan intraarticulary. This effect was
associated to a reduction of LTB4 joint synthesis (19).
Risedronate action is not mediated or by endogenous
opioid synthesis. The interleukins involved in the
inflammation modulate cys-LT receptors expression at
the level of cell membrane. The IL-4 increases the cellsurface expression for cys-LT1 and cys-LT2 Interferon
receptors (IFN gamma) stimulate cys-LT1, cys-LT2 andBLT1 receptor mRNA production and also the surface
expression (20). Il-5 increases only cys-LT1 receptor
surface expression (21).
The same involvement of LTB4 in pain mechanism
exists also in carrageenan and LPS-induced
inflammation. The ratio between different groups ofeicosanoids plays an important role in roles inphysiologic and pathophysiologic processes.
New groups of lipid mediators stimulate theresolution of acute inflammation. These include theresolvins (E-series and D-series), protectins(neuroprotectin D1/protectin D1), and maresins
biosynthesized from omega-3 essential fatty acids.
The existing data involve more the leukotrienes inperipheral nociception. Others eicosanoids synthesizedfrom arachidonic acid-like lipoxins are involved in themodulation of pain intensity. Chronic morphine
experimental administration induced the development ofhyperalgesia and the expression of spinalanti-nociceptive tolerance to morphine. LXA4ME, ananalogue of LXA4 (lipoxin A4) treatment significantly
attenuated the development of the expression of spinal
antinociceptive tolerance to morphine in bothmechanical and thermal experimental induced pain in
rats. LXA4ME inhibited the activation of microglia andastrocytes, and reduced the expression of
pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6,
and tumour necrosis factor-α (TNF-α). At this moment,
it is unclear which is the relationship between
leukotrienes and resolvins in the field of nociception.
The lipids mediators derived from ω-3 fatty acids suchas docosahexaenoic acid and eicosapentaenoic acidcalled resolvins and protectins (22) which displayedanti-inflammatory actions could be also important for
nociception (23). Docosahexaenoic acid (DHA) (22:6)
which generates a part of resolvins and protectins isabundant in the brain and plays a neuroprotector role atthis level (24).
25

Resolvins control the evolution of the inflammatory
process and protect against the oxidative stress inexperimental induced inflammation (25).
Transient receptor potential subtype vanilloid 1(TRPV1) and TRP ankyryn 1 (TRPA1) are important for
the inflammatory pain genesis via both peripheral
mechanisms and spinal cord mechanisms (central
sensitization). The resolvins are potent endogenous
inhibitors for TRPV1/TRPA1 and inflammatory pain (26).
The ratio between pro-inflammatory leukotrienes andanti-inflammatory (pro-resolving) lipids is important not
only for the development of inflammation, but also in themodulation of the hypernociception. Resolvins reduced
inflammatory pain via central and peripheral actions (27).
It is possible that the ratio between leukotrienes andprostaglandins as enhancing hypernociception eicosanoids
and other eicosanoids as lipoxins, resolvins and protectins
play a role in the modulation of nociception both at thecentral and peripheral level in our body.
Neuropathic pain
The neurophatic pain is produced by nerve injury or bydiseases which damage the nerves. In the neuropathic
pain, the peripheral nerve terminals sensitization is an
important step. The molecules resulted after tissue injury
act as pro-nociceptive mediators and produce peripheral
nerve sensitization. Many types of trauma increased thetissues and the neutrophile leukotrienes synthesis. The
level of cys- LTs increased in the dorsal spinal horn after
peripheral nerve injury. The expression in CysLT1 mRNA in
the spinal cord increased in the dorsal horn after peripheral
nerve trauma. The CysLT2 mRNA was expressed in thewhite matter of the spinal cord, and this expression was
not changed after nerve injury (28).
In the neuropathic pain, the peripheral nerve
terminals sensitization is an important step. The
molecules resulted after tissue injury act as
pro-nociceptive mediators and produce peripheral nerve
sensitization. Eicosanoids play important roles at thelevel of the central and peripheral nervous system. Many
types of trauma increased the LTs synthesis in manytissues and in leukocytes. Leukotrienes are produced in
nervous system so in neurons as well as in nevroglia.
The LTs synthesis is mainly regulated by the activity ofphospholipase A2 (which release arachidonic acid from
phospholipids) and 5-LOX (29).
We tested the influence of montelukast (MK), a
cysLT1 antagonist in mechano-nociception in rats. It wastested the MK effect for 10mg/kg p. o.
Our data (30) showed that the association of MK withmorphine significantly increased the threshold of
mechanoalgesia compared to the group which received
only morphine. These data are consistent with the idea of
peptidoleukotriene involvement in mechano-nociceptive
mechanism.

26

In this way, the research showed that MK can
influence the morphine action. The results show that MK
raised the mechanical nociceptive threshold in rats which
received morphine. These data suggest that is possiblethat montelukast facilitates the morphine action on µ
receptors or that cysLT1 receptors are involved in
reduction of morphine analgesic effect after stimulation ofµ receptors. The increase of LT synthesis in spinal
microglia produced via p38 mitogen-activated protein
kinase (MAPK) has a role in the generation ofneuropathic pain (28).
By blocking cysLT1, montelukast reduced theimprovement of nociception by peptide-LTs. Probably, thecysLT1 receptor stimulation interferes in central
nociception mechanism in a different way thanstimulating cysLT2 receptors from the level of ganglionicroots. In our study, MK administrated as single
medication
didn’tincreasesignificantly
themechano-nociception threshold, but induced a significant
anti-nociceptive
effectinexperimental-induced
thermoalgesia (30).
The expression of leukotriene receptors in the rat
dorsal root ganglion (15) showed a pathway for the
involvement of leukotrienes in neuropathic pain: neurons
containing CysLT2 receptors are co-localized with TRPV1
neurons and P2x3 positive neurons. CysLT2 receptor
stimulation at the level of dorsal root of ganglion itself did
not induce hyperalgesia or spontaneous pain behaviour
but the treatment with LTC4 enhanced the painful
behavior produced by P2x3 receptor agonists (asbeta-methylene adenosine 5´triphosphate) (31). By
cysLT2 receptor way peptidoleukotrienes can be involvedin the augmentation of the pain behavior. On the otherpart the activation of both cysLT2 receptors and EP(receptors for prostaglandin E) in the unmyelinatednociceptive fibers from the dorsal root neurons canmodulate TRPV1 receptor activity and play a role inneuronal sensitization.
The peripheral nerve injury increased the spinal cord
prostaglandins and LTs synthesis. Because both PGE2
and peptidoleukotrienes potentiate the P2x3 receptor
activity in dorsal root ganglion neurons and modulate the
TRPV1 receptor activity is possible to be a complex
modulator action of the eicosanoids system in theneuropathic pain. The BLT1 is expressed also in thedorsal root ganglion neurons in mice (32). There is also a
direct activation of capsaicin receptors by 5-LOX
metabolites as leukotrienes (33).
LTB4 acts as intracellular mediator at the level ofvanilloid type 1 receptor (34). This receptor type isinvolved in nociception. 5-HPETEs and LTB4 act as
endovanilloids receptors modulator (35).
Some data indicate the possibility of trascellular
biosynthesis of cysteinyl-leukotrienes in neural and glial
cells (36). The release of spinal glutamate byinflammatory stimuli causes hyperalgesia by NMDA
Fiziologia - Physiology • 2014.24.4(84)receptor activation and by sensitization of primarysensory neurons (37). The leukotrienes from CNS could
be involved in this process.
The systemic administration of kainate (an agonist of
NMDA receptors) in rats induced upregulation of thebrain 5-LOX. By this mechanism endogenous glutamate
can increase the 5-LOX activity in the CNS (38). NMDA
receptors stimulation activates 5-LOX in rats’ central
neurons (39). By this way the synthesized leukotrienes
have a modulating action at TRPV central receptors level.
We believe that the eicosanoids system would play acomplex modulator role not only in inflammation but also
in nociception.

CLINICAL DATA
A strong argues for the involvement of LTs in thisprocess is the increased urinary release of LTs during thepain produced in different diseases. Urinary
concentration of cysteinyl-leukotrienes (especially LTE4)
significantly increased in pain, in cases of the patientswith sickle cell disease (40). There is an important
increase in the urinary clearance of LTE4, from82.34pg/mg creatinine in sick but painful patient, up to
162.8 pg/mg during a pain episode. The measurement of
the urinary LTE4 is a non-invasive method. The urinary
LTE4 measurements can be used as a marker for asthma
evolution and a susceptibility to the treatment with cysLT1
receptors antagonists, but we consider that the rapid
variations of this leukotriene’s urinary level can be abiological marker of pain intensity (at least for some
types of pain)(and of course of treatment efficacy) (41).
The leukotrienes urine levels are increased inpatients with Printzmetal angina. Compared to control
healthy group, the urine level of LTE4 increases from51.1±21.3pg/mg creatinine (in control group) to
122.7±37pg/mg creatinine in the Printzmetal angina
group (p<0.01) (42). The level is not increased in patientswith chronic stable angina. In experimental model ofcardiac ischemia in animals, and also in acute chest painin patients with the myocardial infarction, the level ofurinary LTE4 excretion increased (43). Because theelevated rates of urinary LTE4 excretion were measured
shortly after the onset of the chest pain, we think that thehigh level of leukotrienes overlap the highest intensity of
the ischemic pain. In experimental ischemia someinhibitors of 5-LOX showed an important reduction in
infarct size (44). The ischemia enhances the 5-LOX
activity and synthesis of LTs involved in nociception. It is
possible that leukotrienes act in this situation by two
different ways:
1. involvement in the production of ischemic
myocardial damages and the nociceptive
production consecutive to synthesis andrelease of different compounds in the infractedarea;
2. direct action at the level of nervous endings.
Fiziologia - Physiology • 2014.24.4(84)We suggest that 5-LOX expression in brain is
possible to be higher in chronic pain. It is not clear thecorrelation between the chronic pain and theneurodegeneration, but the 5-LOX expressed in the CNS
neurons and nevroglia may be involved also in theneurodegeneration process (45).

THERAPEUTIC PERSPECTIVES

The fact that besides the involvement in pain
generation, prostaglandins (the first group of eicosanoids
studied) and leukotrienes have an important role in thesame process opens many therapeutic ways:
1. The use of cysLT1 antagonists (alreadytherapeutically used as anti-asthma drugs) inthe therapy of some types of pain;
2. The association of leukotriene antagonists
with COX-1 or COX-2 inhibitors;
3. The production and use in the pain therapy of
the 5-LOX selective inhibitors (such as
zileuton);
4. The use for the pain treatment of dual inhibitorsof 5-LOX and COX-1/COX-2 (such as
licofelone) (46);
5. The therapeutic use of cys-LT1 receptor
antagonists is considered to be safe.
A small number of side effects were observed.
Montelukast, pranlukast and zafirlukast are well tolerated
drugs. The most common side effects are theChurg-Strauss syndrome, gastric discomfort, headache(47). Zileuton (25-100 mg/kg p.o.) and licofelone (10-100mg/kg p.o.) significantly reversed the both cold allodynia
threshold, but the effect of licofelone was stronger. These
results indicate that the dual inhibition of these two key
enzymes involved in the eicosanoids synthesis could
represent a beneficial way in the treatment ofhyperalgesia from postoperative pain.
The association between zileuton and zafirlukast
inhibited acid acetic-induced writhing in mice. In this case
it is interesting that ED50 of zileuton (inhibitor of 5-LOX)
was 31,81mg/kg p.o. compared to ED50 of zafirlukast(antagonist of receptors) 6,15mg/kg p.o (48). Zileuton
wasalso
efficientagainstexperimental
carrageenan-induced hyperalgesia. This inhibitor of
5-LOX is also well tolerated and increases the hepatictransaminases level (only in 4.4% from patients receiving
3 months zileuton treatment had elevations in ALT levels)(49). Regarding the the therapeutic use of 5-LOX
inhibitors, there are data about the a possible interaction
between 5-LOX and nuclear factorNF-kB and on thecapability of 5-LOX to influence the process oftranscription (50).
Flavocoxid, a dual inhibitor of cyclooxygenase and5-LOX flavocoxid decreased MDA, TNF and nitrite levels
from LPS-stimulated macrophages, inhibits thephospholipase A2 and could be also used as an analgesic
drug (51).
27

Besides the bronchial asthma therapy, theleukotrienes synthesis inhibitors and LTs antagonists will
become important therapeutic agents in inflammatory
bowel diseases, rheumatoid arthritis, allergic rhinitis andothers. There are possibilities to associate in pain
therapeutics the anti pain action of resolvins analogs (52)to cys-LT1 receptors antagonists and to 5-LOX inhibitors.
Finally, the 5-LOX metabolites are involved also in
the toxicity of non-steroidal anti-inflammatory drugs(NSAID). NSAID are very used in the treatment of thepain. This group of substances inhibits the COX-1 andthe COX-2 and suppresses the prostaglandins and thesynthesis but but show no anti-5-LOX activity.
The 5-LOX is a new target for anti-inflammatory
drugs and there have perspectives to be also a target forthe pain therapy.

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LEUKOTRIENELE SI DUREREA – NOI PERSPECTIVE TERAPEUTICEREZUMAT
Leukotrienele (LTs) sunt un important grup de icosanoizi implicaţi în mecanismul durerii inflamatorii şi
neinflamatorii.Implicarea LTs în mecanismul durerii inflamatorii este susţinută de datele ce arată că multi mediatori ai
inflamatiei cum sunt TNF, unele interleukine şi alţii stimulează sinteza de LTB 4 şi de peptidoleukotriene.Antagonistii LTB4 si
inhibitorii de 5-lipoxigenază reduc nociceptia inflamatorie de cauză periferică. LTs sunt implicate de asemenea în durerea
neuropatică. Activarea receptorilor cys LT1 din neuronii din cornul dorsal al măduvii poate modula activitate receptorilor
TRPV1. Datele noastre experimentale arată că montelukastl (un cysLT1 antagonist) creşte pragul mecanoalageziei la sobolan.
Inhibarea sintezei LTs precum şi blocarea receptorilor BLT1, BLT2, cysLT1 şi cys LT2 ar putea constitui in viitor o noua caleîn terapia durerii.
Cuvinte cheie: leukotriene, durere inflamatorie, durere neuropatică, inhibitori ai 5-LOX, montelukast, risedronat, licofelon

Fiziologia - Physiology • 2014.24.4(84)29THE INFLUENCE OF INTRACORONARY VERAPAMIL
ADMINISTRATION ON LEFT VENTRICULAR FUNCTION
IN PATIENTS WITH PREVIOUS MYOCARDIAL INFARCTION
TREATED WITH DIRECT STENTINGLAURENTIU PASCALAU1,2, MIHAELA VALCOVICI 1,2, VLADIANA TURI1,2, SIMONADRAGAN1,2
1University of Medicine and Pharmacy “Victor Babes” Timisoara
2Institute for Cardiovascular Diseases Timisoara

ABSTRACT
Objectives: We evaluated the effect of intracoronary verapamil on left ventricular function and prognosis in patients withprevious myocardial infarction treated with direct stenting of the artery responsible for infarction by primary percutaneoustransluminal coronary angioplasty (PTCA) using ultrasound parameters (EDV-diastolic volume, end systolic volume-ESV;
diastolic diameter-EDD, ejection fraction, EF) at admission, 6 weeks and 1 year after.
Background: Clinical trials to date have documented verapamil’s potential to increase coronary blood flow after primary
PTCA.
Methods: We conducted a retrospective analysis of 56 consecutive patients with a first anterior AMI who underwent direct
stenting of the lesion responsible for infarction; they were randomized into verapamil group (n = 28) or control group (n = 28).
In the first group, 500ug verapamil were injected (2 ml from a dilution of 5 mg in 20ml of saline)) through guide catheter in thecoronary artery (LAD) 1 minute after direct stenting of the lesion responsible for infarction, whereas in the control group were
given 2 ml of saline. To evaluate the effect of intracoronary verapamil administration on left ventricular function, the following
ultrasound parameters were assessed (EDD, EDV, ESV, EF) on admission, at 6 weeks and 1 year.
Results: The two groups were homogeneous in terms of age, gender, systolic blood pressure, diastolic blood pressure, heart
rate and cardiovascular risk factors. No statistically significant differences were noted on EDD, EDV, ESV, EF at theechocardiography performed on admission.
6 weeks after the first echocardiographic evaluation the patients from control-group presented unfavourable evolution after
stenting with statistically significant increases of EDD (p = 0.001), EDV (p = 0.002), ESV (p = 0.004) and a statisticallysignificant decrease for EF (p = 0.0015), while in the verapamil-group they had a positive evolution with statisticallyinsignificant slow increase of EDD (p = 0.083), EDV (p = 0.9), and a statistically insignificant decrease of ESV (p = 0.52) witha highly statistically significant increase of EF (p <0.001).
1 year after the second echocardiography, patients in the control group had an negative outcome after stenting withstatistically significant increases for EDD (p <0.001), EDV (p = 0.002), ESV (p = 0.003) and a statistically insignificant
decrease of EF (p = 0.062), while in the verapamil-group had a favourable evolution with a constant growth statisticallyinsignificant of EDD (p = 0.085), EDV (p = 0.878), a statistically insignificant decrease of ESV (p = 0.379) and a highly
statistically significant increase of EF (p <0.001).
Patients from control group, at 1 year compared to 6 weeks had a highly statistically significant (p <0.001) increase of EDD
and a statistically significant increase of EDV (p = 0.007) and ESV (p = 0.022). EF was insignificantly increased (p = 0.506) at
1 year compared to 6 weeks.
In patients from verapamil-group at 1 year compared to 6 weeks no statistically significant differences regarding EDD (p =0.151), EDV (p = 0.928), ESV (p = 0.251) were found. Regarding EF, there was a statistically significant increase (p = 0.003)
at 1 year compared to 6 weeks.
Conclusions: Intracoronary administration of verapamil after primary PTCA can improve left ventricular function most likely
by reducing microvascular dysfunction and therefore, by increasing myocardial blood flow in patients with AMI, leading tobetter outcomes compared to patients treated only with PTCA. Thus, increasing myocardial blood flow in patients with AMI,
intracoronary verapamil administration prevents left ventricular negative remodelling, which could explain the positive
long-term outcomes in patients with AMI who received intracoronary verapamil.

Received 10th of September 2014. Accepted 25th of October 2014. Address for correspondence: Laurentiu Pascalau, MD, PhD student, „Victor Babes”
University of Medicine and Pharmacy Timisoara, Institute of Cardiovascular Diseases Timisoara, Eftimie Murgu Square No. 2A, RO-300041, Romania;
phone/fax: +40256207355; e-mail: pascalau_laurentiu@yahoo.com

30

Fiziologia - Physiology • 2014.24.4(84)INTRODUCTION
Heart attacks are fatal in about one third of the cases.
Because acute myocardial infarction can occur in themost productive years of activity of an individual,
significant negative consequences are possible both interms of psychosocial and economical outcomes (1).
Today there are many options for reperfusion such as
pharmacological or mechanical, which may be different interms of efficacy. The success of reperfusion therapy inacute myocardial infarction depends on the ability ofobtaining complete and rapid restoration of antegrade
blood flow in the infarction artery. In patients with acute
myocardial infarction the favourite approach is primary
PTCA (2). However, epicardial reperfusion after thisprocedure is not able to stop immediately the
myocardium impairment. The strategies are geared
toward improving myocardial perfusion on a tissue level
because that is affected in approximately 70% of thecases even after angioplasty, and therefore afflicts
prognosis.
Out of all types of acute myocardial infarction, theanterior AMI, involving the anterior descending artery anda wider territory exposed to infarction risk, has thegreatest impact on prognosis and left ventricular function.

MATERIAL AND METHODSIn this study were included 56 consecutive patientswith acute anterior myocardial infarction treated by direct
stenting of the infarction lesion, hospitalized in theInstitute of Cardiovascular Diseases Timisoara between
February 2012 and October 2013. Included patients werediagnosed with acute anterior myocardial infarction
without known history of other heart attacks, withthrombotic occlusion or stenosis with superimposed
thrombus in the proximal and middle third of the anterior
descending artery, undergoing percutaneous transluminal
coronary angioplasty with direct stenting of the lesion
responsible for infarction in the first 12 hours of thesymptomatology onset.
Patients were randomized into verapamil group (n =28) and control group (n = 28). In the first group, 500ug
verapamil (2 ml out of 5mg dilution in 20ml of saline)
were injected into the infarction artery through guidecatheter 1 minute after direct stenting. Choosing adosage of 500ug verapamil was based on findings fromother studies with intracoronary3 verapamil administration.
In the control group 2 ml of saline were administeredthrough guide catheter 1 minute after direct stenting of
the infarction lesion.
Medication management protocol: prior to PTCA, allpatients were treated with acetylsalicylic acid 250mg,
clopidogrel 600 mg and after PTCA, 100 mg / day
acetylsalicylic acid and 150 mg / day clopidogrel for one
month, then 75mg / day up to one year; all patients
received unfractionated heparin between 3 and 5 days

Fiziologia - Physiology • 2014.24.4(84)after PTCA. All patients were echocardiographic
assessed in the first 24 hours from admission and key
parameters were evaluated (end-diastolic diameter EDD, end-diastolic volume - EDV, end systolic volume ESV, ejection fraction - EF).
The study lasted over 1 year. Patients were
evaluated at 6 weeks, 3 months, 6 months, 9 months and1 year. At 6 weeks and 1 year they repeated theechocardiography. To determine the effect of
intracoronary verapamil administration on left ventricularfunction the key ultrasound parameters were assessed atadmission, at 6 weeks and 1 year.
The angiography was performed by femoral orradial approach in the day of admission. Afterdiagnostic coronary angiography by which the lesion
located in the in the proximal or medial 1/3 of theanterior descending artery responsible for infarction
was identified (hemodynamically significant stenosis
with thrombus superimposed or thrombotic occlusion)
the next step was direct stenting of the lesion. In
verapamil-group, 500ug verapamil (2 ml out of 5mg
dilution in 20ml of saline) were injected into theinfarction artery through guide catheter 1 minute after
direct stenting, whether or not "no reflow" phenomenon
was present. There was no significant change in any
variable (SBP, DBP and HR) before and afteradministration of intracoronary verapamil. No significant
hemodynamic abnormality, shock or malignant
ventricular arrhythmia was observed during or afteradministration of intracoronary verapamil.

ETHICAL CONSIDERATIONS
All patients were instructed on entrance into the study,
and each patient signed an informed consent. The study
was based on international standards of medical ethics
regarding patient’s confidentiality, established by the
Declaration of Helsinki.

STATISTICAL ANALYSIS
For numerical variables 2 by 2 for the 3 moments ofevaluation, we used t test, and for ordinal variables weutilized signed-rank Wilcoxon test. The significancethreshold was 0.05 (5%), corresponding to a 95%
confidence level. Depending on the p value, the results
were interpreted as: p≥0.05 - insignificant differences, p<0.05 - significant differences, p <0.01 – very significant
differences; p <0.001 - highly significant differences.

RESULTSTo assess the outcomes for the patients in the control
group, ultrasound parameters (EDD, ESV, EDV and EF)
were compared on admission, at 6 weeks and 1 year.
Also, ultrasound parameters were analysed at 6 weeks
compared to 1 year. The results are in Table I.

31

Table I. Echocardiography parameters in patients in control
group at admission (start), 6 weeks (6W) and 1 year.

1
2
3
4
5
6
7
8
9
10
11
12

Match

Mean

N

Std.
deviation

Meanstandard
deviation

Start-EDD cm

4.78

28

0.551

0.147

6 W EDD cm

5.02

28

0.531

0.142

6 W EDD cm

5.02

28

0.531

0.142

1year EDD cm

5.32

28

0.430

0.119

Start-EDD cm

4.78

28

0.551

0.147

1year EDD cm

5.32

28

0.430

0.119

Start-EDV ml

128.8628

33.222

8.879

6W EDV ml

151.0728

40.91210.934

6W EDV ml

151.0728

40.91210.934

1year EDV ml

166.1528

47.35313.133

Start- EDV ml

128.8628

33.2228.879

1year EDV ml

166.1528

47.35313.133

Start-ESV ml

77.21

28

22.807

6.096

6W ESV ml

93.21

28

29.652

7.925

6W ESV ml

93.21

28

29.652

7.925

1year ESV ml

102.462837.85410.499Start-ESV ml

77.21

28

22.8076.096

1year ESV ml

102.462837.85410.499EF (start)

40.14

28

6.347

1.696

EF (6W)

37.64

28

6.134

1.640

EF (6W)

37.64

28

6.134

1.640

1year EF

39.00

28

5.745

1.593

EF (start)

40.14

28

6.347

1.696

1year EF

39.00

28

5.745

1.593

p

Table II. Echocardiography parameters in patients in verapamilgroup at admission (start), 6 weeks (6W) and 1 year.

0.001<0.001

1<0.001
2
0.002
0.007

3

0.002

4

0.004

5

0.022

6

0.003

7

0.015

8

0.506
0.062

Table I shows significant increases over time for EDD(start EDD-6W EDD, p = 0.001; start EDD - 1 year EDD,
p <0.001), EDV (start EDV – 6W EDV, p = 0.002; start
EDV - 1 year EDV, p = 0.002), ESV (start ESV – 6W ESV,p = 0.004; start ESV - 1 year ESV, p = 0.003). EF at 6
weeks was significantly decreased (p = 0.015) comparedto 6 weeks; EF at 1 year compared to admission wasn’t
statistically significant decreased. At 1 year compared to
6 weeks, there was a highly statistically significant
increase of EDD (p <0.001), EDV (p = 0.007) and ESV (p= 0.022). EF didn’t have a statistically significant increase(p = 0.506) at 1 year compared to 6 weeks.
These data prove a slowly bad evolution in patientsfrom control group after stenting, heading towards
ventricular dilatation and systolic dysfunction, withsignificant changes in cardiac function with repercussions
on the patient's symptoms.
In order to track the evolution of patients in verapamilgroup, ultrasound parameters (EDD, ESV, EDV and EF)
were compared on admission, at 6 weeks and 1 year.
32

The ultrasound parameters were also interpreted at 6
weeks compared to 1 year. The findings are in Table II.

9

10
11
12

Match

Mean

Start-EDDcm

4.65

6 W EDD cm

4.78

6 W EDD cm

4.78

1year EDD
cm

4.73

Start-EDDcm

4.65

1 year EDD
cm

4.73

Standard
deviation

Meanstandard
deviation

0.392

0.105

28

0.314

0.084

28

0.314

0.084

0.367

0.098

0.392

0.105

0.367

0.098

N
28

28
28
28

0.083

Start-EDV ml 116.93

28

25.605

6.843

6W EDV ml

117.2928

20.514

5.483

6W EDV ml

117.2928

20.5145.483

1yearEDV ml 117.50

28

14.6433.914

Start-EDV ml 116.93

28

25.6056.843

14.6433.914

1year EDV
ml

117.50Start-ESV ml

67.86

28

14.411

3.851

6W ESV ml

64.64

28

11.567

3.091

6W ESV ml

64.64

28

11.5673.091

1year ESV
ml

63.93

7.869

2.103

Start-ESV ml

67.86

14.4113.851

1year ESV
ml

63.93

7.869

2.103

EF (start)

40.36

28

3.650

0.976

EF (6W)

44.64

28

4.217

1.127

EF (6W)

44.64

28

4.217

1.127

1year EF

46.43

28

4.620

1.235

EF (start)

40.36

28

3.650

0.976

1year EF

46.43

28

4.620

1.235

28

28
28
28

p

0.151

0.085

0.900
0.928

0.878

0.520

0.251

0.379

<0.001
0.003<0.001

Table II shows that were obtained statisticallyinsignificantly increases in time for EDD (start EDD-6W
EDD, p = 0.083; start EDD - 1 year EDD, p = 0.085) andEDV (start EDV – 6W EDV, p = 0.9; start EDV - 1 year
EDV, p = 0.878), a statistically insignificant decrease of
ESV (start ESV – 6W ESV, p = 0.52; start ESV - 1 year
ESV, p = 0.379), and an increased EF highly statisticallysignificant at 6 weeks and 1 year (p <0.001). At 1 year
compared to 6 weeks there weren’t statistically significant
differences for EDD (p = 0.151), EDV (p = 0.928), ESV (p= 0.251). EF had a statistically significant increase (p =0.003) at 1 year compared to 6 weeks.
These results prove that patients in verapamil group
had a slowly favourable progression after stenting,without significant changes in left ventricular end-diastolicFiziologia - Physiology • 2014.24.4(84)volume, with significant decreases in left ventricular end
systolic volume and consequently a significant increasein ejection fraction compared at 6 weeks with admission.
These results, meaning the absence of significant
changes in left ventricular end-diastolic volume,
significantly decreased end systolic volume, significantly
increased left ventricular ejection, were maintained at 1
year compared to admission. There weren’t any
significant differences in patient outcomes in verapamilgroup (EDV, ESV and EF) at 1 year compared to 6
weeks. Most likely, a possible explanation could be
intracoronary verapamil administration during angioplasty
procedure, medication with important role on left
ventricular remodelling, remodelling that occurs in thefirst month after myocardial infarction.

DISCUSSIONS

Percutaneous coronary angioplasty is the main
reperfusion strategy for acute coronary syndromes (2).
Initially, it was thought that its benefit is due to timely
restoration of blood flow to the ischemic myocardium
above. Despite current evidence in favour of PTCA, theno-reflow phenomenon can happen and is associatedwith a poor prognosis both in hospital and long term (4).
No reflow concept means hypoperfusion of the
myocardial tissue, due to coronary microcirculation
dysfunction in the presence of opened epicardial coronary
arteries. No reflow phenomenon is an independent
predictor of both short- and long-term adverse cardiac
events and mortality following PTCA (5). The existence ofno reflow phenomenon was initially a debate theme;
however, multiple experimental data and clinical studies
have clearly demonstrated that it occurs after reperfusion
with a variable prevalence ranging from 5% to 50%, in
accordance with the methods used to evaluate thephenomenon and the analysed population (6,7).
Patients who develop no-reflow have a higher
prevalence of: 1) early post-infarction complications(arrhythmias, pericardial effusion, cardiac tamponade,early congestive heart failure); 2) negative remodelling of
the left ventricle; 3) rehospitalisation for acutedecompensated heart failure; and 4) mortality.
From a pathophysiological point of view it can bedivided into two categories: reperfusion no-reflow andintervention no-reflow. Reperfusion no-reflow may occur
after opening an epicardial coronary artery that closed
suddenly, for example during thrombolysis for STEMI, but
in fact, the most common cause is PTCA performed in a
STEMI. Intervention no-reflow is defined as an impairment
or lack of perfusion of myocardial tissue after ballooning or
stenting, provided that no significant residual stenosis,
dissection, thrombus or spasm exists. It can happen during
PTCA on native vessels or, more commonly, during PTCA
on vein grafts. No-reflow phenomenon is multifactorial withmany pathological changes that eventually lead todamaged microcirculation and impaired myocardial
Fiziologia - Physiology • 2014.24.4(84)perfusion (8,9). Reperfusion no-reflow is mainly associatedwith ischemia reperfusion injury, inflammatory activity andembolization of thrombotic and atherosclerotic material.
Interventional no-reflow is triggered by local tissue damageand embolization of atherosclerotic material into
microcirculation during PTCA. The main factors
contributing to the no-reflow phenomenon are: cellular
oedema, ischemia reperfusion injury, microvascular spasm,
obstruction of capillaries with neutrophils, microemboli,
activation of the extrinsic pathway of coagulation.
Although the negative effects are well known, no
specific technique is currently recommended in
guidelines to prevent distal embolization during PTCA.
Direct stenting and avoiding thrombus fragmentation byballooning and fixing thrombotic material in the stent wall,
was suggested as a possible technique to reduce distal
embolization. One randomized study (10) showed
improvement of reperfusion in patients selected for direct
stenting compared with standard PTCA.
A promising technical approach to prevent no-reflow
during mechanical reperfusion is the use of thrombectomy
devices and distal filters. Thrombectomy suction catheter isrecommended in any STEMI with high thrombotic load as it
improves clinical outcomes compared with PTCA alone
and reduces especially the reperfusion no-reflow by 52%(11,12). Mechanical thrombectomy (with devices forfragmentation and suction of the thrombus) had
controversial results and is not generally recommended.
Distal protection devices shown good results in PTCA forsaphenous vein grafts, improving clinical and angiographic
results, but failed to enhance clinical outcomes during
PTCA for AMI on native (11,13) vessels.
Current therapy of no-reflow phenomenon includes
vasodilators, antithrombotic drugs medication andtrombolitics (14-16). Adenosine is regarded as aneffective drug for reducing the incidence of no-reflow
phenomenon; however, it may increase the risk of heart
block, hypotension, and other side effects. Moreover, thehalf-life is relatively short, and so the agent should be
repeatedly administered (17). In addition, sodium
nitroprusside improves blood flow and prevents coronary
no-reflow, but the vasodilator effect can cause adose-dependent hypotension, which limits its clinicalusefulness (18,19). In contrast to these drugs, verapamil
not only prevents the occurrence of no-reflow, but also
improves clinical outcomes on short term. However,further clinical studies on a large scale are needed toassess the broad utility of the agent and long-term
prognosis, but verapamil could be a more promising
adjunctive therapy than other agents currently available.
Vasodilator drugs can be given before (either
routinely or in selected patients) or after PTCA procedure.
In practice, these drugs are considered only in patientswith slow coronary blood flow.
In our study, intracoronary administration ofverapamil resulted in a reduction of the infarction area, a33

more favourable left ventricular remodelling, meaning theabsence of left ventricular dilatation at 6 weeks and 1
year compared to admission, and increased ejection
fraction of left ventricle at 6 weeks and 1 year comparedto admission. Intracoronary verapamil administration
exerts its effect by dilating mostly resistance arterioles
and reducing calcium influx in cells of the myocardiumwith ischemia. Our data indicate that the coronary bloodflow improvement has been associated with a decrease
in myocardial infarct size, indicating attenuation of
postischemic
microvascular
dysfunction.
Thisenhancement was noticed in the penumbra area
especially where myocardial perfusion is partiallypreserved. Thus, intracoronary verapamil administration
can alleviate microvascular dysfunction, especially in thedecreased blood flow area in patients with AMI treatedwith PTCA, and this attenuation may be associated withan increase in coronary blood flow.

CONCLUSIONS

Patients in the verapamil group had better outcomesthan patients in the control group, accordingly to results
at 6 weeks compared to admission, which remained
favourable at 1 year compared to admission in patientsfrom verapamil group. The administration of intracoronary
verapamil resulted in a more favourable left ventricularremodelling, meaning the absence of left ventricular
dilatation at 6 weeks and 1 year compared to admission,and increased left ventricular ejection fraction at 6 weeks
and 1 year compared to admission.
No significant differences in patient outcomes werenoted in verapamil group (EDV, ESV and EF) at 1 year
compared to 6 weeks. This could be explained byadministration of intracoronary verapamil during primary
PTCA procedure, a medication with an important role in
left ventricle remodelling, remodelling that occurs in thefirst month after myocardial infarction.

CLINICAL IMPLICATIONS

Success or failure of a coronary intervention should
ideally be assessed by myocardial perfusion recovery.
However, the end-point of several studies wasangiographic patency of the artery responsible for
infarction. Our results clearly indicate that a patent artery
does not necessarily guarantee the permeability ofcoronary microcirculation in patients with AMI. The
administration of intracoronary verapamil can partially
recover microcirculation integrity and enhance coronary
blood flow, leading to a better recovery of the myocardial
function. Therefore, epicardial coronary arteryrecanalization should not be the only goal.
Pharmacological adjuvant treatment (intracoronary
verapamil) may protect coronary microcirculation against
ischemic damage, realising an optimal myocardial savingfor patients with AMI.

34

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INFLUENTA VERAPAMILULUI ADMINISTRAT INTRACORONARIAN ASUPRA
FUNCTIEI VENTRICULULUI STANG LA PACIENTII CU INFARCT MIOCARDIC
ACUT ANTERIOR TRATATI PRIN STENTARE DIRECTAREZUMAT
Obiective: am evaluat efectul administarii de verapamil intracoronarian asupra prognosticului si functiei ventriculului stang lapacientii cu infarct miocardic acut anterior la care s-a efectuat stentarea directa a leziunii responsabile de infarct ca tehnicade angioplastie coronariana percutana transluminala(PTCA) primara, prin compararea parametrilor ecografici(volum
telediastolic-VTD; volul telesistolic-VTS; diametru telediastolic-DTD; fractia de ejectie-FE) la internare, 6 saptamani si 1 an.
Context: Studii clinice efectuate pana in prezent au documentat potențialul verapamilului de a crește fluxul sanguin
coronarian după PTCA primară.
Metode: In perioada februarie 2012 - octombrie 2013, 56 de pacienti consecutivi cu un prim IMA anterior la care s-a efectuat
stentarea directa a leziunii responsabile de infarct au fost repartizati aleator la grupul verapamil (n = 28), sau la grupul control(n = 28). In grupul verapamil, a fost injectat verapamil (dilutie 5mg in 20ml de ser fiziologic) 500ug (2ml din dilutie) pe categhidîn artera afectată de infarct (LAD) la 1 minut după realizarea stentarii directe a leziunii responsabile de infarct, pe cand in
grupul control s-au administrat 2 ml de ser fiziologic. Pentru a evalua efectul verapamilului administrat intracoronarian asuprafunctiei ventriculului stang s-au urmarit parametrii ecografici(DTD, VTD, VTS, FE) la internare, la 6 saptamani si la 1 an.
Rezultate: Cele doua grupuri au fost omogene din punct de vedere al varstei, sexului, tensiunii arteriale sistolice, tensiunii
arteriale diastolice, frecventei cardiace si al factorilor de risc cardiovasculari. Ecografia cardiaca efectuata la internare nu aevidentiat diferente semnificative statistic in privinta DTD, VTD, VTS si FE.
La 6 saptamani dupa prima reevaluare ecocardiografica s-a constatat o evolutie nefavorabila dupa stentare a pacientilor din
grupul control cu cresteri semnificative statistic pentru DTD (p=0.001), VTD (p=0.002), VTS (p=0.004) si o scadere
semnificativa statistic pentru FE (p=0.0015), pe cand cei din grupul verapamil au avut o evolutie lent favorabila cu cresteri
nesemnificative statistic ale DTD (p=0.083), VTD (p=0.9), o scadere nesemnificativa statistic a VTS (p=0.52) si o crestere
extrem de semnificativa statistic a FE (p<0.001).
La 1 an dupa a doua reevaluare ecocardiografica s-a constatat o evolutie nefavorabila dupa stentare a pacientilor din grupul
control cu cresteri semnificative statistic pentru DTD (p<0.001), VTD (p=0.002), VTS (p=0.003) si o scadere nesemnificativa
statistic pentru FE (p=0.062), pe cand cei din grupul verapamil au avut o evolutie constant favorabila cu cresteri
nesemnificative statistic ale DTD (p=0.085), VTD (p=0.878), o scadere nesemnificativa statistic a VTS (p=0.379) si o crestere
extrem de semnificativa statistic a FE (p<0.001).
In ceea ce priveste rezultatele la 1 an fata de 6 saptamani la pacientii din grupul control se constata o crestere extrem desemnificativa statistic a DTD (p<0.001), precum si o crestere semnificativa statistic a VTD (p=0.007) si VTS (p=0.022). In
ceea ce priveste FE se constata o crestere nesemnificativa statistic (p=0.506) la 1 an fata de 6 saptamani.
In ceea ce priveste rezultatele la 1 an fata de 6 saptamani la pacientii din grupul verapamil nu se constata diferentesemnificative statistic in privinta DTD (p=0.151), VTD (p=0.928), VTS (p=0.251). In ceea ce priveste FE se constata ocrestere semnificativa statistic (p=0.003) la 1 an fata de 6 saptamani.
Concluzii: Administrarea intracoronariana de verapamil după PTCA primară poate imbunatati functia ventriculului stang
probabil prin atenuarea disfunctiei microvasculare și, prin urmare, prin cresterea fluxului de sange miocardic la pacientii cu
IMA, ceea ce duce la rezultate mai bune decât in cazul pacientilor tratati numai cu PTCA. De asemenea, prin cresterea
fluxului de sange intramiocardic la pacientii cu IMA, administrarea intracoronariana de verapamil ajuta la remodelajul
ventriculului stang, ceea ce poate explica evolutia mai favorabila pe termen lung a pacientiilor cu IMA la care s-a administrat
verapamil intracoronarian.

Fiziologia - Physiology • 2014.24.4(84)35

ANTIBIOTIC CONSUMPTION DATA IN AN INTENSIVE CARE UNIT
AXENTE CARMEN1, BADITOIU LUMINITA 1,2, MUNTEAN DELIA1, HORHAT FLORIN 1,3,
BEDREAG OVIDIU 1,3, HOGEA ELENA1,3, MOLDOVAN ROXANA1,2, LICKER MONICA 1,3
1“Victor Babes” University of Medicine and Pharmacy Timisoara
2Timisoara Regional Centre for Public Health
3Timisoara Emergency Clinical County Hospital

ABSTRACT
Patients admitted to intensive care units (ICUs) are at a greater risk of hospital acquired infection (H.A.I.) than other hospitalized
patients and are more likely to die of that infection as a result of a multitude of compounding factors. Patients admitted to ICU’s
are usually critically ill and require frequent monitoring; rates of infections vary widely depending on the type of ICU.
The study took place in the ICU department of the Timisoara Emergency Clinical County Hospital (TECCH), Romania. Data
were recorded for 18 months, between 01.01.2012 and 30.06.2013, for all ICU admitted patients who received antibiotic
treatment. For each patient age, gender, admission diagnosis, origin, evolution, type and quantity of antimicrobial agents used
(in the ICU) as well as the number of treatment days for each type of antibiotic were recorded.
Data on the number of patients in the ICU, as well as the number of antimicrobials and administration routes were recordedfor 1186 patients, with a mean age of 61.78 years (age range between 4 months and 91 years). Based upon the WHO
classification system we obtained a total of 911.24 DDD. Out of 1186 patients treated with antimicrobials who were studied
during the 18 months period in the TECCH-ICU, 504 received prophylactic treatment, 462 were treated for the underlying
pathology and 220 for hospital acquired infection.
The most frequently used classes of chemotherapeutic drugs were third generation cephalosporins, followed by the second
generation, represented by cefuroxime alone, the fifth generation on the third position represented by ceftaroline and, finally,
the fourth generation represented by cefpirome. These were used for prophylactic purposes and for treating underlying
infectious pathology, while carbapenems were especially involved in treating HAI.
Key words: antimicrobials, intensive care units (ICUs), hospital acquired infection (HAI)INTRODUCTION

In the last decade, it has become possible to treat
many patients who could have been lost early at
intensive care units (ICU) in the past, thanks to theprogress in medical developments and improvement inpatient care services (1).
Patients admitted to intensive care units (ICUs) are ata greater risk of hospital acquired infection (H.A.I.) thanother hospitalized patients and are more likely to die ofthat infection as a result of a multitude of compounding
factors. Patients admitted to ICU’s are usually critically ill
and require frequent monitoring; rates of infections vary
widely depending on the type of ICU (2-7).
Antibiotics have contributed greatly to improvements
in health but the irrational consumption of these
preparations lead to more cases of bacterial germs
resistant to usual treatments (5-10).
Data from the Surveillance System Intensive Care
Antimicrobial Resistance Epidemiology (ICARE) and the
Antimicrobial Use and Resistance (AUR) component of
the US National Nosocomial Infections Surveillance(NNIS) System show that for most antimicrobial agents,
the rate of use was highest in the intensive care area andthat consumption ran parallel to the pattern seen forresistance (8).
The aim of this study was to observe the antibiotic
consumption in an ICU and to corroborate the above
information with a comparative analysis of patient status
upon hospital discharge.

MATERIALS AND METHODS

The study took place in the ICU department of theTimisoara Emergency Clinical County Hospital (TECCH),
Romania. Data were recorded for 18 months, between
01.01.2012 and 30.06.2013, for all ICU admitted patients
who received antibiotic treatment.
For each patient age, gender, admission diagnosis,
origin, evolution, type and quantity of antimicrobial
agents used (in the ICU) as well as the number oftreatment days for each type of antibiotic were recorded.
The amount of antimicrobial drugs was standardized
by conversion to defined daily doses (DDD) according to
the Anatomical Therapeutic Chemical Classification
system (ATC) as defined by the World HealthOrganization (WHO: www.whooc.no). A DDD is definedas the assumed average maintenance dose per day for a

Received 10th of September 2014. Accepted 25th of October 2014. Address for correspondence: Axente Carmen, MD, PhD student, „Victor Babes”
University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2A, RO-300041, Romania; phone/fax: +40256220479; e-mail:lickermonica@yahoo.com

36

Fiziologia - Physiology • 2014.24.4(84)drug used for its main indication in adults, but does notnecessarily reflect the recommended or prescribed daily
dose (11,12).
Statistics
The pooled number of grams for each antibiotic
applied by the ICU was divided by the number of grams
per DDD for a specified antibiotic, divided by the numberof patient-days of this ICU and multiplied by 1,000 to
derive the number of DDD per 1,000 patient-days or the
antimicrobial use density (AD). Consumption was
calculated separately for prophylaxis, treatment of theunderlying pathology and hospital acquired infection(HAI).

RESULTS

Data on the number of patients in the ICU, as well as
the number of antimicrobials and administration routes
were recorded for 1186 patients, with a mean age of
61.78 years (age range between 4 months and 91 years).
Based upon the WHO classification system we obtained
a total of 911.24 DDD.
Out of 1186 patients treated with antimicrobials who
were studied during the 18 months period in the
TECCH-ICU, 504 received prophylactic treatment, 462
were treated for the underlying pathology and 220 for
hospital acquired infection.
Population analysis revealed the following gender
distribution: 58.90% male and 41.10% female.
The mean age of patients receiving prophylactic
treatment was 60.11 years and, as expected, more thanhalf of the antibiotics used belonged to the class of
cephalosporins (56.48%), followed by fluoroquinolones(9.68%) and penicillins (9.05%).

was similar, cephalosporins being also the mostfrequently used, with 96.66 DDD per patient-days, but
this time closely followed by carbapenems with 88.92
DDD per patient-days as shown in the Figure 2.

Fig.2. The DDD per patient-days for the classes of
antimicrobials used for the treatment of the underlying
pathology in the ICU. Legend: “Other” antimicrobials include:
sulfonamides, oxazolidindiones, aminophenols.

For the treatment of hospital acquired infections(HAI), the main classes of antimicrobials used werecarbapenemes, cephalosporins and glycopeptides.
After comparing with the two above mentioned
circumstances, we observed that the intensively usedclass of cephalosporins was exceeded by carbapenems(Figure 3).

Fig.3. Incidence of antimicrobial classes used in the treatment
of HAI expressed as DDDs per patient-days.

Fig.1. The antimicrobial groups prescribed for prophylaxis
purposes in the ICU during the studied period.

The consumption for each antibiotic class was
defined as the proportion between the number of DDDs
and the number of patient-days.
For the treatment of the underlying pathology, themean age of the monitored patients was 63.05 years
and here the situation regarding the types of antibiotics
Fiziologia - Physiology • 2014.24.4(84)The following carbepenems were used in the studied
ICU: Meropenem, Imipenem and Ertapenem.
The next figure (Figure 4) presents the antibiotic
consumption for HAI, expressed as active substances inorder to highlight the most used molecules during the
given period. As shown below, Colistin, Ceftriaxone andMeropenem were extensively used.
We also aimed to corroborate the above information
with a comparative analysis of patient status upon
hospital discharge. Of the patients who received
prophylactic treatment, 66.30% left the ICU with an
improved status but in 29.80% the evolution was lethal,
whereas over 50% mortality was recorded in the groups
treated for underlying pathology and for HAI, respectively
37

i.e. 52.6% deaths in the group treated for underlying
pathology and, as expected, a higher percent of deathsin the HAI group (59.10%).

Fig.4. The antimicrobials used for the treatment of HAI. Legend:“Other”: Chloramphenicol, Ceftaroline, Amoxicillin/clavulanic
acid, Doxycycline, Trimethoprim/Sulfamethoxazole, Ampicillin,
Ketoconazole etc.

We further observed the frequency of prescription forthe major classes of antibiotics during the studied period
in the TECCH -ICU. The most frequently used antibiotics
were cephalosporins (236.95 DDD per 1000 patients /day), followed by carbapenems (193.58 DDD per 1000
patients / day) and glycopeptides (107.42 DDD per 1000
patients / day) (Figure 5).

Fig.5. The most frequently prescribed antimicrobial groups in
the ICU during the studied period, defined as DDDs per
patient-days. Legend: “Other” antimicrobials include:
aminophenols, macrolides, sulfonamides, tetracyclines,
oxazolidindiones, monobactams.

DISCUSSION

The antibiotic consumption in a hospital department
is correlated to the number of infections to which patientsin that department are exposed. Also, the most frequently
prescribed antibiotics depend upon the resistanceprofiles of microorganisms involved in the aetiology of
infections.
Literature data show that the highest risk foracquiring multidrug resistant (MDR) germs occurs inpatients admitted in ICUs, the risk being associated toseveral factors such as: prophylactic or curative antibiotic
38

therapy, exposure to invasive diagnostic and treatment
procedures, long term contact with healthcare personnel,
long term hospitalization, as well as limited availability ofspace in the hospital department.
A study conducted in Bulgaria in 2003 revealed anover 10 times higher prevalence of HAI in ICU as
compared to other hospital departments (13).
Numerousinterventions
addressing
theimprovement of antibiotic use have been described:
restrictive antibiotic use programmes, the use of special
forms limiting the number of therapeutic options, clinicalguides. All these aim at a restrictive antibiotic use withconsecutive reduced costs, together with decreasing
the excessive prescription of wide spectrum antibiotics.
In our study, the four most frequently prescribed were
wide spectrum antibiotic classes: cephalosporins,
carbapanems, glycopeptides and fluoroquinolones, due
to the specific ICU pathology and to the presence of
MDR germs.
For prophylactic treatments, cephalosporins wereby far the most frequently used antimicrobial class(62% second generation cephalosporins with 25.99
DDD per 1000 patient days and 38% third generation
cephalosporins). On the other hand, for the treatment ofunderlying pathology, cephalosporins are very closely
followed by carbapenems (96.66 DDD per 1000 patientdays for cephalosporins and 88.92 DDD per 1000
patient days for carbapenems), and in HAI
cephalosporins are exceeded by carbapenems whichhave the broadest antibacterial spectrum of the
β-lactam class (largely because they are so
β-lactamase stable) (14).
Due to their broad antibacterial spectrum coveringgram-positive, gram-negative, and anaerobic bacteria,
carbapenems are useful for the treatment of a wide
variety of infections (14).
In a study conducted in Germany that included 35
ICUs, the authors observed that the pooled antibiotic
usage density (AD=DDD/1000 patient days) was thehighest for penicillins with lactamase inhibitor: 338.3 AD,
followed by quinolones with 155.5 AD and second
generation cephalosporins with 124.6 AD. The otherclasses in decreasing AD order were: third generation
cephalosporins (109.5 AD), carbapenems (83.7 AD),extended spectrum penicillins (70.3 AD) andglycopeptides (42.3 AD). The ICUs that took part in thisstudy were of different profiles: non-surgical,
interdisciplinary and surgical (8).
Examining the results of a study conducted in France
and published in 2002, starting with 1998, the antibiotic
consumption in decreasing AD order may be observed:
penicillins 981, cephalosporins 484, fluoroqinolones 272,
aminoglycosides 216, glycopeptides 130, carbapenems
114, and other antibiotic classes, 114 DDD per 1000
patient-days, respectively. These results were obtained
after implementation of an antibiotic-use policy (15).
Fiziologia - Physiology • 2014.24.4(84)In another study conducted in a German surgical ICU,
that evaluated the impact of reducing the duration of
antibiotic prophylaxis, the mean antimicrobial use density(AD) of antibiotic groups with an AD>30 was reported.
Results have been compared with the pre-intervention
level (January 2002-December 2003).Total antibiotic use
was: 1035.9, cephalosporins - 423.5, amoxicillin –clavulanic acid - 129.8, penicillins with beta-lactamse
inhibitior -129.5, quinolones - 129.2, carbapenems - 75.8,
imidazoles - 72.3, piperacillin-tazobactam - 58.2,
sulfonamides + trimethoprim 46.9 (16).
In another study published in 2009 and conducted in thesame clinical department of TECCH, a marked yearlydecrease in antibiotic use was observed (2004-2005). Thiswas justified by the appointment in 2005 of the Antibiotic
Therapy Commission in TECCH, with a strict policy on
antibiotic treatments. In 2004, the most frequently used
antibiotic classes were penicillins - 578.98, third generation
cephalosporins – 280.77, penicillins with beta-lactamase
inhibitors – 139.40, aminoglycosides – 76.23,
fluoroquinolones - 20.83, carbapenems - 20.36,
glycopeptides - 13.26 etc., penicillins being reduced to
7.75 (13).

CONCLUSION

The most frequently used classes of chemotherapeutic
drugs were third generation cephalosporins, followed by
the second generation, represented by cefuroxime
alone, the fifth generation on the third position
represented by ceftaroline and, finally, the fourth
generation represented by cefpirome. These were used
for prophylactic purposes and for treating underlying
infectious pathology, while carbapenems were
especially involved in treating HAI.

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39

CONSUMUL DE ANTIBIOTICE ÎNTR-O SECȚIE DE TERAPIE INTENSIVĂREZUMAT
Pacienții internați într-o secție de terapie intensivă (ICUs) sunt expuși unui risc mai mare de a dobândi infecții intraspitalicești
(HAI) comparativ cu alți pacienți spitalizați și pot deceda dacă infecția survine în asociație cu alți factori de risc. Pacienții
internați în ICU sunt de obicei în stare critică și necesită monitorizări frecvente; rata infecțiilor variază în limite largi în funcție
de tipul ICU.
Studiul s-a desfășurat în cadrul departamentului ICU al Spitalului Județean de Urgență Timișoara (TECCH), România. Datele
au fost înregistrate pe o perioadă de 18 luni, între 01.01.2012 și 30.06.2013, pentru toți pacienții internați la ICU care au primit
tratament antibiotic. Pentru fiecare pacient au fost monitorizați următorii parametri: vârsta, sexul, diagnosticul la internare,originea, evoluția, tipul și cantitatea de agenți antimicrobieni folosită (în cadrul ICU), precum și numărul zilelor de tratament
pentru fiecare antibiotic.
Au fost colectate date referitoare la 1186 de pacienți ai ICU, cu privire la numărul și calea de administrare a agenților
antimicrobieni, pacienții având vârsta medie de 61,78 ani (între 4 luni și 91 de ani). Pe baza sistemului de clasificare WHO amobținut un total de 911,24 DDD. Dintre cei 1186 de pacienți tratați cu antimicrobiene, care au fost studiați pe o perioadă de 18
luni în TECCH-ICU, 504 au primit tratament profilactic, 462 au fost tratați pentru patologie subiacentă, iar 220 de pacienți au
fost tratați pentru infecții intraspitalicești.
Cele mai frecvent utilizate clase de medicamente chemoterapice au fost cefalosporinele de generația a treia, urmate de celede generația a doua, reprezentate de monoterapie cu cefuroxima; generația a cincea s-a clasat pe locul trei și a fost
reprezentată de ceftarolina, iar în final, generația a patra a fost reprezentată de cefpiroma. Aceste antibiotice au fost folosite
în scop profilactic și pentru tratarea patologieie infecțioase subiacente, în timp ce carbapenemii au fost utilizați în special
pentru tratarea HAI.
Cuvinte cheie: antimicrobiene, secții de terapie intensivă (ICUs), infecții intraspitalicești (HAI)40

Fiziologia - Physiology • 2014.24.4(84)