International Journal of

Toxicological and Pharmacological Research

e-ISSN: 0975 5160

p-ISSN: 2820-2651

Peer Review Journal

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1. Hepato- and Nephroprotective Effects of the Polyphenol Concentrate From Cabernet Sauvignon Grape Varieties Cultivated in Kazakhstan in the Experimental Model Of CCL4-Induced Toxicity
Nurgozhin T, Sergazy SH, Adilgozhina G, Gulyayev A, Shulgau Z, Abuova G, Tritek V, Saparov A
Objective: This study investigates the hepatoprotective effect and the antioxidant role of polyphenol concentrate in the experimental model of carbon tetrachloride (CCl4) induced toxicity. Methods: Antioxidant activity of Cabernet Sauvignon grape polyphenol were evaluated by radical scavenging of 1,1-diphenyl-2-picryl hydrazyl radical (DPPH), 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS.+). In addition, the effects of polyphenol concentrate on the survival of Wistar rats in the toxicity model, was also investigated. The polyphenol concentrate was administered for 5 five days prior to injection of carbon tetrachloride in a sub-lethal dose of 300 mg/kg of animal body weight in order to perform histological examinations of the liver and kidney, and detect the levels of AST, ALT and bilirubin. Results: Administration of polyphenol concentrate increased animal survival in the experimental model. Moreover, the intragastric administration of polyphenol concentrate prior to the initiation of the experimental model of toxicity, which was caused by a sub-lethal CCl4 dose, reduced morphological injuries in the liver and kidney, decreased the AST and ALT levels of the blood serum. Discussion and conclusion: Our data demonstrate that polyphenol concentrate possesses an antioxidant potential both in vitro and in vivo by reducing antioxidant stress that was caused by CCl4 administration into rats.

2. Does the Choice of Suture Material Affect the Incidence of Urethrocutaneous Fistulae After Hypospadias Repair? – A Comparison of Polyglactin 910 with Polydioxanone
Adnan Khalid, Syed Hashim Zaidi, Marvi Baloch Fahad Saleem
Background: We aimed to assess the incidence of developing postoperative urethrocutaneous fistulae (UCF) while using either polyglactin 910 or polydioxanone for the repair of subcoronal hypospadias in paediatric patients. Methods: A multicenter, two-group posttest-only randomized experimental design was adopted for the study. The study was conducted at PNS Shifa Hospital Karachi, Combined Military Hospital Malir, Military Hospital Rawalpindi and Combined Military Hospital Multan from 2009 to 2016.  Boys between the ages of 1 – 10 years with confirmed diagnosis of subcoronal hypospadias suitable for single stage repair with the Snodgrass technique and also completing a minimum follow up of 6 months were targeted for the study. The subjects were later randomized into PG group (those undergoing urethral repair with polyglactin 901) and PD group (those in whom polydioxanone was used). Both descriptive and inferential statistics were used for data analysis. SPSS v. 21.0 was used for data analysis with p < 0.05 taken as significant value.  Results: Two hundred patients with confirmed diagnosis of subcoronal hypospadias were recruited for the study in the proposed study period. Twenty-nine patients (29%) in the PG and 26 (26%) in the PD group developed UCF. There were seven (7%) cases of wound infection in the PG group compared to four cases (4%) in the PD Group; all eleven of the said were among those who developed UCF. Meatal stenosis was observed in six patients (6%) in the PG group and in nine patients (9%) of the PD group. No significant difference in the incidence of postoperative urethral fistula formation with the use of polyglactin 910 versus polydioxanone was however reported by the study findings. Conclusion: As there was no significant difference in the incidence UCF between Polyglactin 910 and Polydioxanone, the choice of suture material should be based on economical variations and availability of the two products.

3. Estimation of Median Lethal Dose of Cypermethrin and Beta-cyfluthrin
Brijender Bhushan, Prabhu Narain Saxena
Present study was aimed to evaluate the median lethal dose (LD50) of two broadly used, type II pyrethroid pesticides Cypermethrin and Beta-cyfluthrin against Wistar albino rats. The albino rats corresponding to experimental sets were orally administrated different doses of selected pyrethroids for estimation of median lethal dose. LD50 has been calculated by Log-dose/probit regression line method, and came out to be 416.98 and 354.8 mg/Kg b.wt. for Cypermethrin and Beta-cyfluthrin respectively. Difference in the median lethal of these compounds may be a consequence of structural differences.

4. Analysis of Bioactive Chemical Compounds of Trogoderma granarium (Insecta: Coleoptera: Dermestidae) Using Gas Chromatography – Mass Spectrometry
Jenan Mohammed Ubaid, Abeer Fauzi Al-Rubaye, Imad Hadi Hameed
Methanolic extract of bioactive compounds of Trogoderma granarium was assayed. GC-MS analysis of Trogoderma granarium revealed the existence of the Pentanoic acid , 1,1-dimethylpropyl ester , (1H)-Pyrimidinone , 5-chloro-4,6-diphenyl, Cyclobutanemethanol , α-methyl- , Nitro-2-methyl-1,3-propanediol , Hydroxylamine ,O-(2-methylpropyl)- , Uridine , 2′,3′-O-(phenylmethylene)- ,Acetic acid ,2-benzoylthio-,2-oxo-2-phenylethyl ester , methylpropyl)- , Uridine , 2′,3′-O-(phenylmethylene)- , 5′-(4-methylbenzenesulfo , Indolinol , 1-benzoyl-, Benzeneethanol , β-methyl-,(s)- , Acetic acid ,2-benzoylthio-,2-oxo-2-phenylethyl ester , Phenacyl thiocyanate , Deoxy-L-ribose-2,5-dibenzoate , Methenamine , Alanine , N-methyl-n-propargyloxycarbonyl-, decyl ester , Benzoyl chloride , Thiophene-2-ol , benzoate , Ethanone , -(5-nitrotetrazol-2-yl)-1-phenyl- , 2,5-Dimethylhexane-2,5-dihydroperoxide , Benzamide , N-(3-benzylthio-1,2,4-thiadiazol-5-yl)- , Methyl p-(2-phenyl-1-benzimidazolyl)benzoate , Methyl-2-phenoxyethylamine , Pentaborane(11) , cis-Methoxy-5-trans-methyl-1R-cyclohexanol , Nitro-1-phenyl-3-(tetrahydropyran-2-yloxy)propan-1-one , cis-Methoxy-5-trans-methyl-1R-cyclohexanol. Trogoderma granarium produce many important secondary metabolites with high biological activities.

5. Development of Hepatotoxicity Model in Rats and its Application in Evaluation of Hepatoprotective Activity of Cell Wall Contents of Probiotics
Shah G H, Patel B G, Shah G B
The objective of present work is Development of Hepatotoxicity model in rats and to evaluate hepatoprotective activity of cell wall contents of probiotics. Animals were divided in four groups. The groups were normal saline group, diseased control group, standard drug treated group and 4th group was CCl4 +Cell wall contents of probiotics. In diseased control group chronic liver injury was induced by administration of Carbontetrachloride (CCl4) via intraperitoneal route (1 ml/kg) for seventy days. For standard drug treated group 1 ml Silymarin suspension (Orally) & CCl4 was given for seventy days. In fourth group cell wall contents (1 x 10 12 CFU/ml/animal) and CCl4 was given for seventy days. During disease induction & treatment period blood samples were collected and serum was separated which was used to analyse various parameters like Alanine aminotransferase (ALT), Aspartate aminotransferase, (AST), Alkaline phosphate (ALP), direct bilirubin, total protein and albumin levels to asses liver function. Along with these cholesterol, Glucose and Malondialdehyde were also measured. Liver fibrosis & cirrhosis was quantified by histopathological studies of small portion of the excised liver. Serum AST, ALT, ALP, and direct bilirubin were found to be significantly higher in CCl4 intoxicated rats. Total protein and albumin was decreased. Manondialdehyde was found to be significantly higher in CCl4 intoxicated rats which was main end product of Lipid Peroxidation. Whereas in cell wall contents probiotics and silymarin treated group improve the liver functions in CCl4 toxicated rats. We conclude that protein oxidation may play a role in the pathogenesis of CCl4 induced liver injury and that the accumulation of oxidised proteins may be an early indication of CCl4 induced liver damage. Silymarin and cell wall contents of probiotics were effective in liver injury by inhibiting protein oxidation.

6. Relationship of HLA-DRB1 Alleles and Rheumatoid Arthritis in West South of Iran
Karim Mowla, Elham Rajaee M D, Mehrdad Dargahi-MalAmir M D, Neda yousefinezhad, Maryam Jamali Hondori
Background: Rheumatoid arthritis is a systemic multifactor disease that presented with symmetrical polyarthritis more preferably in small wrist joint and ankle. Synovial pannus cause destruction and deformities in joints. The main reason of this disease in unknown, but past researches showed that genetically factor play important role beside environmental factors in susceptibility to this entity. Method:100 patients with rheumatoid arthritis diagnosed upon ACR 2010 criteria enrolled study.  92 healthy patents also enrolled DNA studying. of both group was extracted through DNA extraction kits by blood sampling. HLA-DRB1 typing was done by PCR-SSP method. Results: There were no significant differences in HLADRB1 *04, HLADRB1*08 and HLADRB1*11 alleles presentation between patients and healthy controls. Only there were statically significant correlation between HLA-DRB1*08 and Rheumatoid factor positive patents. (P = 0.025).

7. The Protective Efficacy of Ethanolic Leaves Extract of Citronella Gras (Cymbopogon nardus) on Glucose Metabolism Alteration Induced By Mercury in Rats
Fransisca Diana Alexandra, Dian Mutiasari, Trilianty Lestarisa, Eko Suhartono
The present study was undertaken to investigate the protective effect of ethanolic citronella grass (C. nardus) leaves extract against mercury (Hg) induced glucose metabolism alteration in rats. Four groups of rats were selected, with 6 rats for each group. Animals of group I  was received a 1 ppm of Hg only. Animals of groups II, III, and IV received a combination of 1 ppm Hg and plant extract in different dose (1650, 2520, and 3360 mg/ml). The experiment lasted for 4 weeks. The various parameters studied included liver weight, liver glucose, glycogen, and malondialdehyde (MDA) level in all groups after treatment. The results of this present studies showed that the Hg-induced glucose metabolism alteration in rats which can be seen from the increase of liver glucose and the decreasing of liver glycogen levels. The results also showed that the Hg-induced glucose metabolism alteration through its activities in the trigger the liver cells damage which can be seen from the decreasing of liver weight and the increase of liver MDA level. The ethanolic of C. nardus leaves extract shows a protective effect to maintain all parameters into a better a condition which can be seen from the significant increase in liver weight and liver glycogen level, and the significant decrease in liver glucose and MDA levels. The present study indicated that the ethanolic C. nardus leaves extract showed a potential protective effect on glucose metabolism alteration induced by Hg.

8. Effect of  Exposure to Mixture of Heavy Metals Arsenic, Cadmium and Lead on Reproductive Function and Oxidative Stress in Female Rats
Choudhuri D , Bhattacharjee T
Background : Toxicological consequences arising from exposure to mixtures of heavy metals  especially at low, chronic and environmentally relevant doses are poorly recognised. In the present study, we evaluated effects of chronic exposure to combinations of three metals arsenic (As), cadmium (Cd) and lead (Pb) present frequently in drinking water on reproductive function and oxidative damage caused to reproductive organs of female rats. Method : Female rats were exposed to mixture of metals (As, Cd& Pb) for 90 consecutive days. The gain in body weight and weight of reproductive organs were recorded following autopsy on 91 stday. The oestrus cycle were monitored during entire treatment period. Numbers of corpora lutea, implantation sites, live fetus and survival of the fetus were evaluated in rats mated successfully with untreated male  after completion of their respective treatment. Ovarian cholesterol, protein, ascorbic acid and enzyme Δ5-3β HSD levels were estimated. Serum levels of steroid hormones oestrogen and progesterone were estimated. Histopathological picture of both ovary and uterus were assessed. Levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidise (GPX) activity, amount of reduced glutathione (GSH) and malondyaldehyde (MDA) in blood, ovary and uterus were measured as biomarkers of oxidative stress.  Results : The treated rats showed reduced  body weight gain and reduction in the weight of ovary and uterus. Oestrus cycle was disrupted with continuous diestrous in treated animals. Number of corpora lutea, implantation sites and live fetus and the survival of fetus evaluate were reduced significantly in treated groups.  The levels of ovarian cholesterol and ascorbic acid increased in treated rats with decrease Δ5-3β HSD  level. There was reduction in serum level of both the ovarian steroid hormones oestrogen and progesterone. The protein levels did not differ between the groups. There was a significant increase in levels of MDA and decrease in levels of  all the antioxidant enzymes in treated group. Conclusion : The results revealed there was disruption to reproductive functions with decrease in stereoidogenic activity and associated oxidative stress in female rats treated with combination of mixture of metals (Cd, As and Pb) at low dose for 90 consecutive days.

9. Preliminary Phytochemical Analysis of Extract of Spermadictyon suaveolens and its Effect on Oral Glucose Tolerance in Streptozotocin Induced Diabetic Rats
Anuradha Vivekanand Phatak, Kedar Sudhir Prabhavalkar
The preliminary phytochemical analysis of extract of Spermadictyon suaveolens was performed and its effect on oral glucose tolerance in streptozotocin induced diabetic rats studied. 1 week after the administration of streptozotocin, diabetic rats received herbal extract orally at dose 500 mg/kg body weight for 28 consecutive days. Oral glucose tolerance test was performed on overnight fasted rats on day 28. Blood samples were collected prior to glucose administration and at 30, 60, 90, 120 minutes after glucose loading and plasma glucose level was measured for all the samples. The preliminary phytochemical analysis of extract of roots of Spermadictyon suaveolens showed the presence of carbohydrates, flavonoids, glycosides, tannins and phenolic compounds. Extract of roots of Spermadictyon suaveolens improved oral glucose tolerance in streptozotocin induced diabetic rats.

10. Effects of γ-Aminobutyric Acid on the Erectogenic Properties of Sildenafil
Adefegha S A, Oyeleye S I Oboh G
Erectile dysfunction (ED) is a disorder of increasing socio-economic burden. Therapeutic drugs such as sildenafil have been in use for the treatment of ED, but with their associated side effects. γ-aminobutyric acid (GABA) is a neurotransmitter with possible vasodilatory properties. In this study, the effect of GABA on the erectogenic properties of sildenafil was investigated. Aqueous solution of GABA and sildenafil (1 mM) was separately prepared as well as the mixtures of both (75% GABA + 25% sildenafil; 50% GABA + 50% sildenafil; 25% GABA + 75% sildenafil). Thereafter, the in vitro effects of all the studied samples on the activities of arginase, angiotensin-I converting enzyme (ACE) and acetylcholinesterase (AChE) were investigated. The results revealed that all the samples inhibited arginase, ACE and AChE activities. Considering the various combinations, 25% GABA + 75% sildenafil had the highest arginase inhibitory effect, 50% GABA + 50% sildenafil showed the highest ACE inhibiting effect, while 25% GABA + 75% sildenafil exhibited the highest AChE inhibitory effect. Therefore, the observed enzyme inhibiting effect of sildenafil, GABA and their various combinations on rat penile arginase, ACE and AChE activities could be part of the mechanism by which they elicit their erectogenic properties. The various combinations could thus serve as therapeutic intervention for the management of ED with a possible reduction in the side effects associated with the use of sildenafil; nevertheless, the combination of 75% GABA with 25% sildenafil exhibited the highest erectogenic potential.

11. Effect of Certain Oral Anti Diabetic Drugs on Coagulation Cascade in Diabetes Mellitus
Patil T R, Patil S T , Patil S, Patil A
Thrombotic events in diabetics contribute for almost 65-80% of cardiovascular events. Diabetes affects the platelet, the coagulation factors and fibrinolytic system leading to a state of hypercoagulation and hypofibrinolysis resulting in to thrombosis. Oral drugs commonly used in management of type II diabetes mellitus are antidiabetics like metformin, PPAR-γ agonist and DPP-4 inhibitor. They rarely produce hypoglycemia. Metformin has been proved to prevent release of mtDNA from arachidonic acid stimulated platelets, reduce membrane damage and mitochondrial ROS production in the platelets. Similarly processes like platelet adhesion, activation and aggregation on collagen coated surfaces which initiate thrombosis are prevented by metformin. PPAR- γ agonists like pioglitazone and rosiglitazone have anti atherogenic effect. They decrease the expression of inflammatory markers and affect the coagulation markers like factor VII: C and inhibit platelet activation. Pioglitazone also reduces the VLDL, triglycerides and increases HDL which further contributes in attenuation of atherosclerosis. DPP-4 inhibitors, which are relatively newer class of antidiabetics, having minimum potential for hypoglycemia induction, due to their novel mechanism of action. Studies have proved that long term use of DPP-4 inhibitors have reduced cardiac mortality by their lipid lowering action, increased release of NO from endothelium and inhibition of TNF- α, PAI-1 and VCAM expression. Increased levels of stromal cell derived factor – 1α helps to maintain endothelial homeostasis and vascular repair. Decreased oxidative stress, inhibition of inflammatory genes like IL-6, IL-12, TNF- α provide additional benefit. Destabilization of vasculo-atherosclerotic plaque is prevented by DPP-4 inhibitors. Thus these oral antidiabetics drugs offer many benefits beyond blood glucose control which prevent atherosclerosis, inhibits hypercoagulable state and enhances fibrinolysis which translates into decreased cardiac complications in diabetes.

12. Screening of Antidiabetic Activity of Extract and Fraction of Biophytum sensitivum in Rats Using STZ-Nicotinamide Induced Diabetes Model
Manisha, Kumar Suresh
Objective: Biophytum sensitivum DC. (Family – Oxalidaceae) has long tradition of use in the treatment of diabetes but no systematic work has been carried out to explore its potential thus it was envisaged to evaluate antidiabetic activity of methanol extract of B. sensitivum and its ethylacetate fraction in rats using STZ-Nicotinamide-induced type 2 diabetes model. Methods: The methanol extract of B. sensitivum whole plant was prepared by exhaustive extraction of defatted plant material with methanol in a Soxhlet apparatus. It was then partitioned with ethyl acetate using standardized procedure to get ethyl acetae fraction. The methanol extract was subjected to acute toxicity at a dose of 2000 mg/kg, p.o. in rats. The methanol extract (200 or 400 mg/kg, p.o.) and ethyl acetate fraction (15 or 30 mg/kg, p.o.) were screened for their antidiabetic potential using STZ-Nicotinamide-induced type 2 diabetes model. The antidiabetic effects of test drugs were statistically compared with the standard drug metformin (150 mg/kg, p.o.). Results: In acute toxicity studies, methanol extract did not show lethality in rats. The methanol extract and ethyl acetate fraction significantly reduced the blood glucose level in diabetic rats at 200 mg/kg, p.o. and 15 mg/kg, p.o. respectively with respect to control and statistically equivalent to the standard drug. The phytochemical screening reveals the presence of flavonoids as the major class of phytoconstituents. Conclusion: The traditional claims for the antidiabetic effect of B. sensitivum are validated.

13. Possible Mechanisms of Endothelioproteсtion 4-Hydroxy-3,5-Di-Tretbutyl Cinnamic Acid in the Cerebral Ischemia in Experiment
D.I. Pozdnyakov, A.V. Voronkov, D.S. Zolotych.

Conducted research devoted to the study of potential mechanisms of action implementation endotelioproteсtion 4-hydroxy-3,5-di-tretbutyl cinnamic acid in experimental conditions simulated cerebral ischemia in rats. The research found that the cerebral ischemia in rats is accompanied by the development of endothelial dysfunction, expressed in increasing the concentration of asymmetric dimethylarginine, nNOS, iNOS and PKC, as well as reducing the concentration of eNOS. Introduction of sulodexide (to a greater extent compared with thioctic acid and mexidol restores endothelial function in conditions of brain ischemia in rats. The use of 4-hydroxy-3,5-di-tretbutyl cinnamic acid helped reduce the concentration of ADMA, nNOS, iNOS and PKC on 83.9% (p <0.05), 60.6% (p <0.05), 61. 9% (p <0.05), 108.6% (p <0.05), respectively, as well as improve the content of eNOS at 114.2% (p <0.05), thereby contributing to the correction that has developed in conditions cerebral ischemia, endothelium dysfunction.

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