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Ayoub R. Aldalou. et al. / Journal of Science / Vol 4 / Issue 3 / 2014 / 162-169.
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IMPACT OF GIVING SILDENAFIL (VIAGRA) / TRAMADOL
(TRAMAL) COMBINATION ON THE BLOOD OF DOMESTIC
RABBITS
Ayoub R. Aldalou*1, Ismail Abdel-Aziz2, Osama Shahwan3
1*
Department of Chemistry, Faculty of Applied Sciences, Al-Aqsa University, Gaza –Palestine.
2
Department of Biology, Faculty of Science, Islamic University of Gaza – Palestine.
3
Al Manar Lab – Khanyounis, Gaza Strip – Palestine.
ABSTRACT
Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction, while Tramadol HCl (Tramal) is
given in premature ejaculation performance in men. In Gaza Strip it is widely used to take these two drugs "in combination"
for the previous purposes. The present work was conducted to assess the hematological and biochemical toxicity profiles of
sildenafil & tramadol on domestic rabbits. Sixteen rabbits were randomly divided into two groups, the first one (10 rabbits)
was given 1ml saline intramuscularly and kept as a control. The second group (6 rabbits) received 25 doses of sildenafil at a
dose of 1.40 mg / kg b.wt. orally once/day and tramadol at a dose of 4 mg / kg b.wt. i. m. once/day for 25 days. It was found
that administration of sildenafil and tramadol at these doses increased serum cholesterol, triglycerides, creatinine, urea and
uric acid values. Activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline
phosphatase (ALP) were also increased following sildenafil & tramadol treatment to rabbits for 25 days. Moreover there was
a significant decrease in serum total protein, albumin and globulin levels. Concerning hematological parameters, the more
obvious changes were observed in the increment of white blood cells (WBCs), MCV and MCH and MCHC values. The
decrease in hematocrit, hemoglobin (Hb), red blood cells (RBCs) and platelets (PLT) counts in response to the administration
of the two drugs.
Keywords: Tramadol, Sildenafil, Rabbits, Blood indices.
INTRODUCTION
Sildenafil citrate (Viagra) is the first oral
pharmacological agent used to treat erectile dysfunction
in men [1].It is a selective inhibitor of phosphodiesterase5 (PDE-5), an enzyme that catalyzes the breakdown of a
potent smooth muscle relaxing agent cGMP. Sildenfil has
been shown to enhance nitric oxide (NO)-driven cGMP
accumulation in the corpus cavernosum of rabbits without
affecting cAMP formation. In the absence of NO drive,
sildenafil had no functional effect on the human and
rabbit isolated corpus cavernosum but potentiated the
relaxant effects of NO on these tissues [2]. Also, it has
been shown that sildenafil causes mild to moderate
decreases in systolic and diastolic pressure because of the
inhibition of PDE-5 in smooth muscles in the vascular
bed [3]. Because this drug has a vasodilatory effect, it was
hypothesized that such an action may induce a
preconditioning-like cardioprotective effect via opening
of mitochondrial ATP-sensitive K (KATP) channels.
Similar acute and delayed cardioprotective effects were
observed when sildenafil was administered orally in
rabbits. Systemic hemodynamics also decreased after oral
administration of the drug. However, these changes were
mild and occurred slowly [4]. Sildenafil had no effect per
se onplatelet aggregationinduced by a range of
aggregatory agents, but consistent with inhibition of
PDE5, sildenafil potentiated the antiaggregatory and
Corresponding Author:-Ayoub R. Aldalou Email:[email protected]
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disaggregatory actions of SNP both in vitro and ex vivo.
The consequences of this antiplatelet action have been
investigated. There was a trend to increased bleeding time
in rat (60% increase not statistically significant, after 0.3
mg/kg i.v.) and bleeding time prolongation was seen in
rabbits (129% increase for a dose of 1 mg/kg i.v.) [5].
These doses are equivalent to 18.5-25 and 61.7- 83.6
times, respectively, the effective dose on corpus
cavernosum pressure in anaesthetised dogs. Several
studies have been conducted to study the haemodynamic
activity of sildenafil in different animal species (rabbit,
dog, rat, cat). These studies have demonstrated that
sildenafil has vasodilator properties which can, at higher
doses, be associated with reductions in blood pressure and
accompanied by an indirect increase in heart rate. These
pharmacological properties are consistent with facial
flushing and headache reported as adverse events in
clinical studies[3]. However, these data did not show
consistent or dose-related systemic haemodynamic effects
of sildenafil at plasma concentrations up to 25-fold higher
than those active on the corpus cavernosum. Repeated
dose toxicity of sildenafil after oral administration was
studied in mice (up to 3 months), rat (up to 6 months) and
dog (up to 12 months). In repeated dose studies in rat and
dog, doses were limited by isolated deaths at 200 mg/kg
in rats and by gastric intolerance in dogs at 80 mg/kg.
There was no evidence of long term toxicity to the retina
[6]. The main effects in rat were adaptive liver changes
(associated with thyroid follicular hypertrophy). In dog,
heart rate was moderately increased in all studies, with no
consistent changes in blood pressure. In chronic dog
studies, 50 mg/kg was associated with Idiopathic Juvenile
Arteritis, a syndrome thought to be an expression of latent
disease precipitated by stress, rather than a direct toxic
effect of the compound. No adverse effect levels in the rat
and dog were 60 mg/kg and 15 mg/kg given respectively.
Toxicity to reproduction was studied in rats and rabbits.
Overall, sildenafil had no adverse effects on fertility and
has no teratogenic potential [4]. Yildizet al., 2011, found
that administration of low dose sildenafil led to
significantly increase in the levels of RBC GSH, plasma
paraoxonase, nitric oxide (NO) and blood lymphocyte
counts, but to decreases in the levels of MDA in plasma
and RBC, blood mean corpuscular volume
and
eosinophil counts. Treatment with high dose sildenafil
caused a significantly increase in PON1, vitamin E and βcarotene in plasma, levels of GSH in RBC and blood
lymphocyte counts. On the other hand, their results
showed that high dose sildenafil significantly decreased
plasma RBC and MDA levels.Since sildenafil was shown
to potentiate the hypotensive effects of nitrates, it was
found that its co-administration with nitric oxide donors
(such as amyl nitrite) or nitrates in any form is therefore
contra-indicated [6]. Several special patient groups
(severe hepatic impairment, hypotension (blood pressure
<90/50 mmHg), recent history of stroke or myocardial
infarction and known hereditary degenerative retinal
disorders such as retinitis pigmentosa) and those for
whom sexual activity is inadvisable (e.g. patients with
severe cardiovascular disorders such as unstable angina or
severe cardiac failure) have been contra-indicated. The
proposed starting dose of 25 mg sildenafil should be
considered for those with severe renal impairment,
hepatic impairment and those taking concomitant
CYP3A4 inhibitors including HIV protease inhibitors,
since sildenafil clearance is reduced in these populations.
Co-administration of sildenafil and ritonavir is not
advised, but if considered necessary, a maximum
sildenafil dose of 25 mg once every 48 hours should not
be exceeded. In order to minimise the potential for
developing postural hypotension, patients should be stable
on alpha-blocker therapy prior to initiating sildenafil
treatment. In addition, initiation of sildenafil at a dose of
25 mg should be considered [6-7].
Tramadol is a centrally acting analgesic agent
with activity at μ-opioid, adrenergic and 5hydroxytryptamine (5-HT) receptors. Its analgesic effect
is a result of its dual mechanism of action, that is, as a reuptake inhibitor of norepinephrine and serotonin and
agonist of the μ-opioid receptor [8]. Tramadol has been in
clinical use for the relief of mild to moderate pain in
human and veterinary medicine [9]. Tramadol is also used
perioperatively in veterinary anesthesia as it significantly
reduces the requirements of volatile anesthetics and
opioid agents [10-11]. Although tramadol has relatively
effective analgesic effects, a higher tramadol infusion rate
was needed to reduce sevoflurane requirements in dogs
[10]. Furthermore, recent results showed that tramadol
exhibits different metabolic rates between species:
tramadol is metabolized quickly to inactive metabolites in
goats, horses and dogs
[12], in contrast with cats and
camels [13]. Tramadol has a dose- dependent analgesic
efficacy that lies between that of codeine and morphine,
with a parenteral potency comparable to that of pethidine,
i.e. about 10- 20 % of the standard morphine [14].
Tramadol is also thought to have some NMDAtype antagonist effects, which has given it a potential
application in neuropathic pain states [15]. Increasing
serotonin and norepinephrine may also reduce
inflammatory cytokines which are released by the brain in
response to stress. The inflammatory cytokines would
have slowed down recovery from a workout or illness impairing one's immune system and healing, thus
tramadol may have an anti-inflammatory effect [16].
Tamadol carries all possible risks known from other
opiates [17-18]. Side effects include dizziness, headache,
somnolence, nausea, constipation, sweating, pruritus, and
central nervous system stimulation [19-20]. Tramadol
causes respiratory depression, although usually weaker
than that seen with other opiates and opioids [21].
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The proposed study is interested to investigate the
hematological and biochemical effects of sildenafil and
tramadol combination in domestic rabbits.
The hematological and biochemical toxicity profiles of
tramadol during therapeutic use were studied by Elyazji et
al., in which they found that changes of the blood indices
were very clear during long term therapy specially in
large doses.
MATERIALS AND METHODS
Experimental animals and dosing
The used adult rabbits in the present study were
weighting 1000-1500g. They were purchased from local
markets. Rabbits were left in the animals house for 1
week before experimentation to adapt to laboratory
condition. They were kept in plastic cages with wire mesh
covers and maintained under the following conditions:
temperature (20ºC– 21ºC), relative humidity (40% - 60%)
and a light /dark cycle of 14 and 10 hours. The cages were
freshly spread by wood saw to absorb urine of animals.
Rabbits were given free access to commercial balanced
diet and watered libitum all over the experimental period.
Animals were divide into two groups, as follows : the first
group was comprised 10 rabbits and given 1 ml saline
orally and kept as a control. The second group (6 rabbits)
received 25 doses of sildenafil at a dose of 1.40 mg / kg
b.wt. orally once/day and tramadol at a dose of 4 mg / kg
b.wt. i. m. once/day for 25 days. All chemicals used were
of analytical grade and were procured from Sigma
Chemical Company Germany. Sildenafil and tramadol
tablets were purchased from Gaza local pharmacies.
Blood sampling and processing
Control and treated rabbits were decapitated at
the end of 25 days respectively. Blood was collected in
dry centrifuge tubes. Sera were separated and kept at 20ºC until analysis. However, determinations of enzyme
activities were carried out on fresh serum samples, On the
other hand, about 2 mL of blood samples were collected
in a tube containing dipotasium ethylene diamine tetra
acetate (EDTA) for the hematological tests.
Measurement of biochemical blood indices
Serum glucose, triglycerides and total cholesterol
were determined using the method described by Trinder
(1969). Serum urea measurement was based on the
cleavage of urea with urease ( Berthelot's reaction)
according to Faweett and Scott (1960), serum uric acid
was determined following the method described by
Fossati et al., 1982. Serum creatinine was measured
without protein precipitation according to Bartels et al.,
1972 , serum total protein was determined according to
Biuret reaction ass designed by Armstrong and Carr,
1964. The kits were purchased from Biotech laboratories,
UK. Serum albumin was determined using RANDOX
reagent kits, following their instruction manual according
to the method of Doumas et al., 1971. The concentrations
of globulins (g/dL) were equal to total protein – albumin.
The activities of serum AST and ALT were determined
according to the method of Gloiser and Mager, 1972. The
measurement of serum ALP and bilirubin activity was
based on the method of Bessey et al., 1946 and Perry and
his colleagues 1983.
Hematological parameters
Determination of hematological parameters was
carried out using an 18 automated parameter hematology
analyzer. ABX Micros 60 from Horiba ABX. France.
Data analysis
Data were computer analyzed using SPSS
version 13.0 for windows (Statistical Package for the
Social Sciences lnc. Chicago, Illinois, USA). Means were
compared by independent-samples test followed by
Duncan's multiple range test (DMRT), p<0.05 were
considered as significant. Percentage change was also
calculated.
RESULTS
Table1 was shown serum glucose and lipid
profile mean values of rabbits affected by the combination
of sildenafil (1.40 mg/kg/day) and tramadol (4 mg/kg
day). The data revealed that administration of this
combination doses for 25 days significantly increase
serum glucose level by 20.01% compared to the control
level. Cholesterol and triglycerides were increased in a
highly significant values by the treatment of these two
drugs to be 14.97% and 44.04% respectively.
Data in Table (2) showed that administration of
the combination of sildenafil (1.40 mg/kg/day) and
tramadol (4 mg/kg day) for 25 days increased urea in a
non- significant value by 8.44%. Uric acid and creatinine
concentration were highly significantly increased (p<
0.01) by 50.61% and 18.58% at 25 doses respectively.
Table (3) summarized the results after
administration of sildenafil (1.40 mg/kg/day) and
tramadol (4 mg/kg day) for 25 days. The combination was
increase the levels of ALP, ALT and AST at 5.80%,
3.08% and 1.78% respectively compared to control level.
However, it was found that giving the combination at 25
doses was highly significant decreased (p< 0.01) serum
albumin concentration by -17.06 % , while serum total
protein and globulin concentrations were decreased nonsignificantly by -9.89 % and -3.19 % at the same doses
compared to control level .
The data in (table 4) represent blood indices in
rabbits after administration of sildenafil (1.40 mg/kg/day)
and tramadol (4 mg/kg day) for 25 days. The more
obvious changes resulted from the administration of the
combination were a highly significant increase in WBC
count, MCV and MCH by 19.21% , 48.92% and 53.32%
respectively at 25 doses respectively.
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Table 1.Effect of sildenafil (1.40 mg/kg/day) and tramadol (4 mg/kg day) administration on glucose and lipid profile
of rabbits
Experimental period
Parameters
Controln=10
Treated(25 doses)n=6
108.37±0.30
Glucose (mg/dl)
90.32±0.37
20.01
% change
P <0.01
P value
230.16± 0.42
Cholesterol (mg/dl)
200.20±0.39
14.97
% change
P < 0.01
P value
152.19±0.36
Triglycerides (mg/dl)
105.66±0.60
44.04
% change
P < 0.01
P value
All values were expressed as mean ± S.E; P<0.05 significant; P<0.01 highly significant.
Table 2. Effect of sildenafil (1.40 mg/kg/day) and tramadol (4 mg/kg day) administration on urea uric acid and
creatinine of rabbits
Experimental period
Treated(25 doses)n=6
35.96 ± 0.30
Urea (mg/dl)
33.16±0.69
8.44
% change
P > 0.05
P value
6.19± 0.18
Uric acid (mg/dl)
4.11±0.19
50.61
% change
P < 0.01
P value
1.15±0.04
Creatinine (mg/dl)
0.97±0.03
18.56
% change
P < 0.01
P value
All values were expressed as mean ± S.E; P<0.05 significant; P<0.01 highly significant
parameters
Controln=10
Table 3. Effect of sildenafil (1.40 mg/kg/day) and tramadol (4 mg/kg day) administration on enzymes activities and
protein profile of rabbits
Experimental period
parameters
Control
n=10
ALP (U/L)
48.10±0.27
% change
P value
ALT (U/L)
34.10±0.24
% change
P value
AST (U/L)
28.70±0.25
% change
P value
Total Protein
7.89±0.28
% change
P value
Albumin
3.81±0.13
% change
P value
Globulin
4.08±0.10
% change
P value
All values were expressed as mean ± S.E; P<0.05 significant; P<0.01 highly significant
Treated (25 doses)
n=6
50.89± 0.13
5.80
P > 0.05
35.15± 0.20
3.08
P > 0.05
29.21±0.22
1.78
P > 0.05
7.11±0.16
-9.89
P > 0.05
3.16±0.14
-17.06
P < 0.01
3.95±0.11
-3.19
P > 0.05
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Data also reveal that there were a highly significant decreases in RBC count, hematocrit and platelets by - 44.64% , -17.55%
and -45.62% respectively. It was found that there was a significant decrease in hemoglobin by -15.13% and a non-significant
increase of MCHC value by 2.94% at 25 doses compared to control levels.
Table 4. Effect of sildenafil (1.40 mg/kg/day) and tramadol (4 mg/kg day) administration on total blood counts of
rabbits
Experimental period
parameters
Control
n=10
7.55±0.20
WBC count (x103cell/ul)
% change
P value
5.60±0.19
RBC count (x106 cell/ul)
% change
P value
11.90±0.16
Hb (g/dl)
% change
P value
37.60±0.22
Hematocrit (%)
% change
P value
67.15±0.18
MCV (fi)
% change
P value
21.25±0.17
MCH (pg)
% change
P value
31.65±0.13
MCHC (g/dl)
% change
P value
388.0±26.69
Platelets(x103 cell/ul)
% change
P value
All values were expressed as mean±S.E; P<0.05 significant; P<0.01 highly significan
DISCUSSION
Sildenafil citrate (Viagra) is currently one of the
approved oral drug for treatment of erectile dysfunction
,while Tramadol HCl (Tramal) is given in premature
ejaculation performance in men. In Gaza Strip it is
widely used to take these two drugs "in combination" for
the previous purposes. However, little is known about the
beneficial or side effects of these two drugs when
administered together. We report here our observation
about changing in hematological and biochemical toxicity
profiles of sildenafil & tramadol on domestic rabbits. In
comparison with the respective control rabbits, there was
a general increase in serum glucose levels in rabbits in
response to administration of sildenafil (1.40 mg/kg/day)
and tramadol (4 mg/kg day) for 25 days. It wasfound
that sildenafil/tramadol may indirectly, increases the
glycogen content of the hepatocytes and impaires ATP
synthesis by the mitochondria . Sildenafil has been shown
Treated
(25 doses)
n=6
9.00±0.22
19.21
P <0.01
3.10±0.18
-44.64
P <0.01
10.10±0.19
-15.13
P <0.05
31.0±0.17
-17.55
P <0.01
100.05±0.16
48.92
P <0.01
32.58±0.15
53.32
P <0.01
32.58±0.14
2.94
P >0.05
211.0±30.31
-45.62
P <0.01
to enhance nitric oxide (NO)-driven cGMP accumulation
in the corpus cavernosum of rabbits without affecting
cAMP formation. Nitric oxide increases glucose uptake
through a mechanism that is distinct from the insulin and
contraction pathways. Cholesterol and triglycerides were
increased in a highly significant values in response to
treatment by sildenafil/tramadol administration drugs;
take place in the liver due to imbalance between the
normal rabbits of lipid synthesis, utilization and secretion.
The possible explanation of these observed increment
may be reside on the action of sildenafil/tramadol
combination on lipid metabolism or lipid peroxidation. It
is well known that the central role of liver and kidney in
drug metabolism predisposes them to toxic injury. Every
drug has been associated with hepatotoxicity almost
certainly due to the pivotal role of the liver in drug
metabolism. Hepatic metabolism is, first and foremost, a
mechanism that converts drugs and other compounds into
products that are more easily excreted and that usually
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have a lower pharmacologic activity than the portent
compound [22]. A metabolite may have higher activity
and/or greater toxicity than the original drug. Metabolites
of the drugs that are excreted from kidneys may also
cause cellular damage leading to kidney dysfunction [23].
Urea is the principal end product of protein
catabolism an accelerated amino acid deamination for
gluconeogenesis is probably an acceptable postulate to
interpret the elevated level of urea. The increment in
blood urea, might be also due to the destruction of RBCs
during the treatment. The presence of some toxic
compounds might increase blood urea and decrease
plasma protein [24]. on the other hand the elevation of
blood urea might suggest that animals experienced hemoconcentration due to mild dehydration. Moreover, the
serum uric acid levels exhibited an increment in the
treated rabbits for the experimental duration. This may be
due to high degradation of purines or an increase of uric
acid level by in ability of its excretion by urinary system
[25]. Nevertheless arise in blood damaging of function
nephrons and impaired renal function. On the other hand,
current results indicated a significant increase in
creatinine levels in rabbits received sildenafil/tramadol
after 25 days treatment.These are in accordance with Atici
et al. (2005) who reported an increase in BUN and
creatinine levels in rats receiving morphine for a month
[23]. In this study it was found that serum transaminases
(AST&ALT) and ALP exhibited a non-significant
increase in sildenafil/tramadol treated rabbits compared to
the control. The liver enzymes are normally found in
circulation in small amounts because of hepatic growth
and repair. As a liver specific enzyme ALT only
significantly elevated in hepatobiliary disease. Increase in
AST level, however can occur in connection with
damages of heart or skeletal muscle as well as of liver
parenchyma. The liver and kidney are responsible for
tramadol and sildenfil metabolism and excretion. It may
cause hepatotoxicity and nephrotoxicity during its
metabolism. Consequently, elevated ALT and AST
activities observed in the current study in response to
sildenafil/tramadol administration could be a common
sign of impaired liver function.On the other hand, alkaline
phosphatase (ALP) belongs to a group of enzymes
catalyze the hydrolysis of phosphomonoesters at alkaline
pH. ALP present in cell surface in most human tissues.
The highest concentrations are found in the intestine, liver
bone, spleen and kidney. The specific location of the
enzyme with both sinusoidal and bile canalicular
membranes accounts for the more predominant elevations
in certain disorders as observed in the present study with
tramadol administration.Impaired secretion of hepatic
ALP of liver cell origin. Acute cell necrosis liberate ALP
in the circulation and serum enzyme level is elevated.
However, the activities of these enzymes were reduced
after the recovery period.
Results of the current
investigation were in agreement with the findings given
by Senay et al., (2003) who reported that the levels of
ALT, AST, LDH and Blood urea nitrogen (BUN), and
creatinine were significantly higher in morphine grouped
compared to the control group. The non-significant
decreased on levels of total protein and globulin after
sildenafil/tramadol treated rabbits could be attributed to
an increase in amino acids deamination. This decrease in
serum total protein may be due to lowered synthesis of
albumen and globulin in the liver in response to drugs
intake. It was reported that albumin levels are decreased
in liver disease [26-28]. The decrease in these blood
proteins of the rabbit may be due to usage of different
amino acids in the production of antibodies in response to
sildenafil/tramadol administration. The present study
showed a highly significant increase of WBCs count,
MCV, MCH and MCHC. This significant increase in
WBCs count indicated the activation of defense
mechanism and immune system of rabbit. This induction
of white blood cells is a positive response for survival due
to cell mediated immune response of animals.
Leukocytosis was manifested by lymphocytosis, which
was the main features of the differential leukocytic count.
The red blood cells(RBCs) count showed also a highly
significant decrease in response to sildenafil/tramadol
administration. This finding may be explained on the
basis of inhibitory effect of tramadol on histogenesis. The
decreased in RBC count and hemoglobin (Hb) lowered
the oxygen supply to different tissues thus resulting in
low energy production. Decrease in Hb contained MCH
can be explained due to decreased size of RBC or
impaired biosynthesis of heme in bone marrow. These
result s confirm the reported decrease in RBC count and
Hb content after treatment with tramadol. Our finding is
not agreed with Yildiz et al., 2011, who found that
administration of low dose sildenafil led to significantly
increase in the levels of RBC GSH , plasma paraoxonase ,
nitric oxide (NO) and blood lymphocyte counts , but to
decreases in the levels of MDA in plasma and RBC,
blood mean corpuscular volume and eosinophil counts
[29].
In this study it was found that rabbits showed a
hyperactivity in body during treatment with
sildenafil/tramadol combination.
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