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www.wjpps.com Vol 9, Issue 3, 2020.
285
Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
SOME PHARMACOLOGICAL STUDIES ON ANTIBACTERIAL DRUG
PROTECTIVE EFFECTS OF GINSENG ON CEFTRIAXONE-
INDUCED HEPATIC INJURY IN RATS
1Ashraf Abd El Hakeem Elkomy,
2Samar Saber Ibrahim Mohamed and
3*Mahmmoud Elsayed Mahmmoud Elmehalawy
1Pharmacology Department, Faculty of Veterinary Medicine Benha University, Egypt.
2Forensic Medicine Deparment, Benha University, Egypt.
3Glopal Human Health Department,
Merck Sharp & Dhome, Fifth Settlement, Egypt.
ABSTRACT
Ceftriaxone is a broad-spectrum semisynthetic cephalosporin antibiotic
that causes partial damage in the liver manifested by transient elevation
in some biochemical parameters. In this study, our aim was to
investigate the use of Ginseng in prevention of the hepatotoxic effect
and biochemical changes induced by ceftriaxone in rats. Rats were
divided into Five groups (control, ceftriaxone 180 mg/kg, Ginseng +
ceftriaxone 180 mg/kg, cef- triaxone 360 mg/kg, and Ginseng +
ceftriaxone 360 mg/kg). Ceftriaxone was injected intraperitone- ally,
and Ginseng was given orally daily for four consecutive weeks. Then
liver functions (serums AST, ALT, ALP, direct bilirubin, and total
protein) were assessed. Histopathological examination was performed.
Treatment of animals with ceftriaxone caused elevated activities of serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) as well as total bilirubin level.
These elevations in liver enzymes were decreased by combination ceftriaxone with Ginseng.
In addition, cef- triaxone caused a significant increase in malondialdehyde (MDA) and nitric
oxide (NO) content but significant decrease in glutathione (GSH) content. Combination of
GINSENG and ceftriaxone resulted in a significant decrease in MDA, NO content and
significantly elevated GSH content. It could be concluded that GINSENG acts as an effective
hepatoprotective agent against liver dysfunction caused by ceftriaxone, and this effect might
be related to its antioxidant properties. Hepatic functions should be monitored, and the dose
should be adjusted during ceftriaxone therapy.
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 9, Issue 3, 285-296 Research Article ISSN 2278 – 4357
*Corresponding Author
Mahmmoud Elsayed
Mahmmoud Elmehalawy
Glopal Human Health
Department, Merck Sharp &
Dhome, Fifth Settlement,
Egypt.
Article Received on
14 Jan. 2020,
Revised on 03 Feb. 2020,
Accepted on 23 Feb. 2020
DOI: 10.20959/wjpps20203-15680
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Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
KEYWORDS: Ceftriaxone; GINSENG Hepatotoxicity; Liver, Kidney Protective Role.
1. INTRODUCTION
Liver injury caused by drugs ranges from mild biochemical abnormalities to acute and
chronic liver failure. The majority of adverse liver reactions is idiosyncratic, and occurs in
most instances 5–90 days after the causative medication was last taken.[1]
Some antibiotics are considered a common cause of drug- induced liver injury.[2]
Hepatotoxicity that occurs is usually asymptomatic, transient and associated with hepatic
impairment.3 Ceftriaxone is a broad-spectrum parenteral cephalosporin with potent activity
against gram-positive and gram-negative bacteria.[4]
It widely used, because of its pro- longed
terminal half-life that allows its prescription as a single dose per day.[5]
Hepatotoxicity caused
by ceftriaxone appears after 9–11 days.[6,7]
Previous studies have reported high aspar- tate
aminotransferase (ALT) and alanine aminotransferase (AST) activities with the
administration of ceftriaxone.[8,9]
Ceftriaxone causes partial damage in the liver as a result of transient elevation in some
biochemical parameters such as AST, ALT, total bilirubin, cholesterol, triglyceride (TG) and
Low-density lipoprotein (LDL) as well as transient decrease in albumin and High-density
lipoprotein (HDL) concentrations.[10]
Liver diseases are amongst the most serious health problems in the world today and
hepatocellular carcinoma is one of the world's deadliest cancers. The aim of the current study
was to evaluate the protective effect of sider honey and/or Korean ginseng extract (KGE)
against carbon tetrachloride (CCl4)-induced hepato-nephrotoxicity in rat. Eighty male
Sprague-Dawley (SD) rats were allocated into different groups and over a 4-week period,
they orally received honey and/or KGE or were treated either with CCl4 alone (100mg/kg
b.w) or with CCl4 after a pretreatment period with honey, KGE or a combination of both.
Clinical, clinico-pathological and histopathological evaluations were done and CCl4-treated
groups were compared with rats receiving no treatment and with rats given honey, KGE or a
combination of these substances. The results indicated that oral administration of CCl4
induced severe hepatic and kidney injury associated with oxidative stress. The combined
treatment with CCl4 plus honey and/or KGE resulted in a significant improvement in all
evaluated parameters. This improvement was prominent in the group receiving CCl4 after
combined pretreatment with honey and KGE. Animals receiving honey and/or KGE (without
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Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
CCl4-treatment) were comparable to the control untreated group. It could be concluded that
honey and KGE protect SD rats against the severe CCl4-induced hepatic and renal toxic
effects. Our results suggest that the protective activity of honey and KGE may have been
related to their antioxidant properties.
2. MATERIALS AND METHODS
2.1. Animals
The present study was carried out on a total number of 35 white Albino male rats weighting
185-210 gm. Rats were obtained from Center of Laboratory Animal, Faculty of Veterinary
Medicine, Benha University, Egypt. They acclimatized for one week prior to the experiment.
All rats received standard laboratory balanced commercial diet and water ad libitum.
Drugs
Ceftriaxone (Mesporin®): Injectable solution, Each vial contains Mesporin sodium
equivalent to 250 mg, 500 mg, 1 gram or 2 grams of Mesporin activity. Mesporin for
Injection, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of Mesporin
activity for EIPICO Egypt.
Gensing (Gensing®
): An oral Gelatin Capsule, hydroalcoholic extract of Ginseng root
(Panax Ginseng), containing 4% ginsenoside - 100 mg; It was purchased from Pharco group.
2.2. Experimental design
The rats were divided randomly into five experimental groups, each consisting of Seven rats,
that were treated as follows: group 1 received vehicle and served as a control, group 2
ceftriaxone (180 mg/kg), group 3 received combined oral doses of GINSENG 20 mg/kg and
ceftriaxone 180 mg/kg, group 4 received ceftri- axone (360 mg/kg) and finally group 5
received combined oral doses of GINSENG 20 mg/kg and ceftriaxone (360 mg/kg). Ceftri-
axone was i.m. injected while GINSENG was orally administered for 3 weeks.
At the end of the experiment blood samples were collected from the retro-orbital plexus and
used for serum separation. All the rats were sacrificed by decapitation and the livers of rats
were immediately dissected out. Part of the liver tissues was homogenized in ice-cold 0.9%
w/v saline using a homog- enizer to obtain 20% homogenate. Aliquots of the liver
homogenate were stored at 4 °C prior to biochemical analy- sis. The other part of the liver
was preserved in 10% formalin solution for histopathological examination.
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2.3. Determination of biochemical parameters
Hepatic enzymes in the serum such as AST and ALT were used as biochemical markers for
hepatotoxicity and assayed by the method of Reitman and Frankel.[17]
Serum alkaline
phospha- tase (ALP) was determined according to the method of Belfield and Goldberg[18]
using colorimetric kit obtained from Diamond Co., Egypt. Total serum bilirubin was
determined spectrophotometrically according to the method of Walter and Gerade.[19]
2.4. Preparation of sections for histopathological examination
Formalin (10%): from Middle East Company, Cairo, Egypt.
Hematoxylin and Eosin (H&E) stain :from Middle East Company, Cairo, Egypt.
2.5. Statistical analysis
Statistical analysis was performed using SPSS (Version 20.0; SPSS Inc., Chicago, IL, USA).
The significant differences between groups were evaluated by one way ANOVA using
Duncan test as a post hoc. Results are expressed as mean ± SEM. P<0.05 was considered
significant.
Data analysis was accomplished using the software program graphpad prism (version 5).
3. RESULTS
GROUP OF RATS KEPT AS CONTROL
LIVER
There was no histopathological alteration and the normal histological structure of the central
vein and surrounding hepatocytes in the parenchyma were recorded in (Fig.1).
KIDNEY
There was no histopathological alteration and the normal histological structure of the
glomeruli and tubules at the cortex were recorded in (Fig.2).
GROUP OF RATS ADMINISTRATED THERAPEUTIC DOSE OF THE
CEFTRIAXONE
LIVER
Dilatation and congestion were detected in the portal vein (Fig.4).
KIDNEY
The cortical area showed congestion in the blood vessels and degeneration in the lining
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Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
epithelial cells of some tubules (Fig.5).
GROUP OF RATS ADMINISTRATED THE DOUBLE THREAPEUTIC DOSE OF
THE CEFTRIAXONE
LIVER
The central and portal veins were dilated and congested (Fig.7) associated with inflammatory
cells infiltration in the portal area surrounding the bile ducts and congested portal vein
(Fig.8). There were dilatation in the hepatic sinusoids and microvacuolar degeneration in the
cytoplasm of some hepatocytes (Fig.9.)
KIDNEY
Perivascular inflammatory cells infiltration with oedema were detected surrounding the
congested cortical blood vessels (Fig.10). The corticomedullary junction showed focal
haemorrhages in between the tubules (Fig.11).
GROUP OF RATS ADMINISTRATED GINSENG AND THERAPEUTIC DOSE OF
THE CEFTRIAXONE
LIVER
Few inflammatory cells infiltration was detected in the portal area while the hepatocytes
surrounding the dilated central vein showed microvacuolar degeneration in the cytoplasm
(Fig.13).
KIDNEY
The cortex showed focal inflammatory cells infiltration in between the tubules (Fig.14)
associated with perivascular inflammatory cells infiltration surrounding the congested blood
vessels (Fig.15).
GROUP OF RATS ADMINISTRATED GINSENG AND DOUBLE DOSE OF THE
CEFTRIAXONE
LIVER
There was no histopathological alteration as recorded in (Fig.17).
KIDNEY
The cortical portion showed degeneration in the lining epithelial cells of some tubules
(Fig.18).
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4. DISCUSSION
The use of herbal medicines has increased considerably, because they are becoming a popular
alternative treatment in different countries. Plants constitute an important source of active
natural products with different biological properties. Various phytochemical components,
especially polyphenols (such as flavonoids, phyenyl propanoids, phenolic acids, tannins, etc)
are known to be responsible for the free radical scavenging and antioxidant activities of
plants. The got outcomes indicated that organization of ceftriaxone incited an assortment of
symptoms. These are spoken to by decrease of testicles, epididymis and adornment sex organ
weight, changes in sperm characters (lessening of sperm check and motility) and increment of
sperm variationsIn this manner, alert is required when utilizing enormous portions of
ceftriaxone because of its lethality to conceptive organs just as its expanding impact on liver
compound.Discover the Frequency of hepatotoxicity brought about by the wide range anti-
toxin mix amoxicillin-clavulanic corrosive (Co-amoxyclav) has been progressively perceived
and the component of this harmfulness stays vague. Then again, Ursodeoxycholic corrosive
(UDCA) has been recommended as effective cancer prevention agent treatment in different
liver ailments. Thusly, the present examination was intended to clarify the conceivable job of
oxidative worry in hepatotoxicity prompted by Co-amoxyclav and the putative defensive job
of UDCA in rodents. Impacts of amoxicillin (Amox; 50 mg/kg, orally, 21 d) or clavulanic
corrosive (Clav; 10 mg/kg, orally, 21 d) and their consolidated organization on the
biochemical liver parameters, decreased glutathione (GSH), lipid peroxidation estimated as
hepatic malondialdehyde (MDA) levels. Furthermore, myeloperoxidase (MPO) action and
receptive oxygen species (ROS) creation in liver homogenate were likewise assessed. Then
again, the defensive impacts of pretreatment with UDCA (20 mg/kg, orally, 21 d) on these
parameters were likewise assessed. Our outcomes show that pretreatment with UDCA
diminished the liver parameters that were upgraded by single or joined organization of Amox
or potentially Clav, for example, serum exercises of alanine aminotransferase (ALT),
aspartate aminotransferase (AST), soluble phosphatase (Snow capped mountain) and serum
bilirubin levels. In addition, pretreatment with UDCA standardized the GSH level and
hindered the height in hepatic MDA focus. The upgraded MPO action and ROS generation in
liver homogenate of rodents treated with Clav or Co-amoxyclav were additionally
standardized by UDCA pretreatment. Taking everything into account, the present information
recommend that UDCA goes about as compelling hepatoprotective operator against liver
brokenness brought about by Co-amoxyclav and this impact is identified with its cancer
prevention agent properties. State As of now, the utilization of β-lactamase inhibitors in
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Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
explicit obstruction instrument of β-lactamase creating creatures in blend with β-lactams
filled in as exceptionally compelling and promising treatment. It recapture the
defenselessness profile of microscopic organisms to blend operator. The present examination
explores lethality profile of comparative routine, an intense and synergistic blend of third era
cephalosporins and β-lactamase inhibitor, Ceftriaxone-Tazobactam by directing rehashed
portion subchronic danger study on rodent (male and female). Three portion levels were
chosen for the investigation. Results of present examination proposed no critical changes in
physiological, biochemical just as hematological parameters. No mortality was seen in any of
the treatment gatherings. It was presumed that Ceftriaxone-Tazobactam mix applies no
danger and is protected on long haul treatmen utilization.
Figure 1: A There was no histopathological alteration and the normal histological
structure of the central vein and surrounding hepatocytes in the parenchyma were
recorded (H&E, ·100).
Figure 2 There was no histopathological alteration and the normal histological structure
of the glomeruli and tubules at the cortex were recorded (H&E, 100).
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Figure 4: Dilatation and congestion were detected in the portal vein (H&E, ·50).
Figure 5: The cortical area showed congestion in the blood vessels and degeneration in
the lining epithelial cells of some tubules.
The central and portal veins were dilated and congested (Fig.7) associated with
inflammatory cells infiltration in the portal area surrounding the bile ducts and
congested portal vein (Fig.8). There were dilatation in the hepatic sinusoids and
microvacuolar degeneration in the cytoplasm of some hepatocytes (Fig.9).
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Elmehalawy et al. World Journal of Pharmacy and Pharmaceutical Sciences
5. CONCLUSION
In conclusion; the results of the present study demonstrate that GINSENG has a
hepatoprotective effect against liver injury caused by ceftriaxone owing to its antioxidant and
immuno- modulatory properties. Further, clinical studies are required to confirm this effect.
6. Conflict of interest
The authors declare that there is no conflict of interest.
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