Scholarly article on topic 'Hypoglycemic and hypolipidemic effect of Allopolyherbal formulations in streptozotocin induced diabetes mellitus in rats'

Hypoglycemic and hypolipidemic effect of Allopolyherbal formulations in streptozotocin induced diabetes mellitus in rats Academic research paper on "Clinical medicine"

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{"Streptozotocin (STZ)" / Hypoglycemia / Gliclazide / "Polyherbal formulation (PH)" / "Allopolyherbal formulation (APH)"}

Abstract of research paper on Clinical medicine, author of scientific article — Ratendra Kumar, Vimal Arora, Veerma Ram, Anil Bhandari, Priti Vyas

Abstract Aim of the study In the present study, we examined and compared the effect of Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations on hyperglycemia, lipid profile, renal, and hepatic function in streptozotocin (STZ) induced diabetes mellitus in rats. Materials and methods The hypoglycemic activity (along with other parameters) of Polyherbal and Allopolyherbal formulations was investigated in STZ induced diabetes in rats. Polyherbal (PH) (3.63g/kgbodywt.); Allopolyherbal-A (APH-A) [(5mgGliclazide+1.81gPH)/kgbodywt.]; Allopolyherbal-B (APH-B) [(4mgGliclazide+2.17g of PH)/kgbodywt.]; Allopolyherbal-C (APH-C) [(2mg of Gliclazide+2.904g of PH)/kgbodywt.], and Gliclazide (10mg/kgbodywt.) were administered once a day, orally by gavages for 21days. Blood glucose levels were measured on 0, 7, 14, and 21days of the study; total cholesterol, triglycerides, LDL, VLDL, HDL, serum creatinine, SGOT, and SGPT were estimated on 21st day. Results Gliclazide, Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations treated rats showed significant (P <0.01) decrease in blood glucose, total cholesterol, triglycerides, LDL, VLDL, serum creatinine, SGOT, and SGPT level, along with significant increase in HDL. Conclusions Present findings provide experimental evidence that the combination of allopathic hypoglycemic drugs with hypoglycemic Polyherbal formulations provides effective and rapid glycemic control and can also minimize the cardiovascular risk factors of type II diabetes mellitus.

Academic research paper on topic "Hypoglycemic and hypolipidemic effect of Allopolyherbal formulations in streptozotocin induced diabetes mellitus in rats"

International Journal of Diabetes Mellitus (2011) xxx, xxx-xxx

Diabetes Science International International Journal of Diabetes Mellitus

diabetes

www.elsevier.com/locate/ijdm www.sciencedirect.com

ORIGINAL ARTICLE

Hypoglycemic and hypolipidemic effect of Allopolyherbal formulations in streptozotocin induced diabetes mellitus in rats

Ratendra Kumar a,% Vimal Arora Veerma Ram a, Anil Bhandaric, Priti Vyas a

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Jodhpur National University, Narnadi, Jodhpur, Rajasthan, India

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Jodhpur National University, Narnadi, Jodhpur, Rajasthan, India

c Faculty of Pharmaceutical Sciences, Jodhpur National University, Narnadi, Jodhpur, Rajasthan, India

Received 19 October 2010; accepted 11 January 2011

KEYWORDS

Streptozotocin (STZ);

Hypoglycemia;

Gliclazide;

Polyherbal formulation (PH);

Allopolyherbal formulation (APH)

Abstract Aim of the study: In the present study, we examined and compared the effect of Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations on hyperglycemia, lipid profile, renal, and hepatic function in streptozotocin (STZ) induced diabetes mellitus in rats.

Materials and methods: The hypoglycemic activity (along with other parameters) of Polyherbal and Allopolyherbal formulations was investigated in STZ induced diabetes in rats. Polyherbal (PH) (3.63 g/kg body wt.); Allopolyherbal-A (APH-A) [(5 mg Gliclazide + 1.81 g PH)/kg body wt.]; Allopolyherbal-B (APH-B) [(4 mg Gliclazide + 2.17 g of PH)/kg body wt.]; Allopolyherbal-C (APH-C) [(2 mg of Gliclazide + 2.904 g of PH)/kg body wt.], and Gliclazide (10 mg/kg body wt.) were administered once a day, orally by gavages for 21 days.

Blood glucose levels were measured on 0, 7, 14, and 21 days of the study; total cholesterol, triglycerides, LDL, VLDL, HDL, serum creatinine, SGOT, and SGPT were estimated on 21st day.

* Corresponding authors. Tel.: +91 9784580219 (R. Kumar), +91 9414438900 (V. Arora).

E-mail addresses: ratendra1@gmail.com (R. Kumar), draroravimal@ gmail.com (V. Arora).

1877-5934 © 2011 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijdm.2011.01.005

Results: Gliclazide, Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations treated rats showed significant (P < 0.01) decrease in blood glucose, total cholesterol, triglycerides, LDL, VLDL, serum creatinine, SGOT, and SGPT level, along with significant increase in HDL.

Conclusions: Present findings provide experimental evidence that the combination of allopathic hypoglycemic drugs with hypoglycemic Polyherbal formulations provides effective and rapid glyce-mic control and can also minimize the cardiovascular risk factors of type II diabetes mellitus.

© 2011 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved.

1. Introduction

Diabetes mellitus is characterized by hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, resulting from defects in insulin secretion or reduced sensitivity of the tissue to insulin (insulin resistance) and/or combination of both [1]. The worldwide survey reported that the diabetes is affecting nearly 10% of the population [2]. It is the third leading cause of death (after heart disease and cancer) in many developed countries.

It is a serious endocrine syndrome with poor metabolic control and responsible for increased risk of cardiovascular diseases including atherosclerosis, renal failure, blindness or diabetic cataract worldwide [3,4]. Therapeutic options for diabetes are diet, exercise, oral hypoglycemic drugs, and insulin therapy.

Treatment with oral hypoglycemic agents is associated with side effects related to pharmacokinetic properties, secondary failure rates, hypoglycemia, gastrointestinal disturbances, skin reactions, hematological disorders, and rise in hepatic enzyme level.

Management of diabetes without dyslipidemia and side effects is still a challenge to the medical community. For thousands of years plants and their derivatives are being used for treatment of diabetes mellitus. Although, herbal medicines have long been used effectively in treating diseases throughout the world and frequently considered to be less toxic and free from side effects as compared to synthetic ones [1,3]. The combination of allopathic and herbal drugs can help to overcome the resistance to insulin and oral hypoglycemic therapy in case of uncontrolled diabetes mellitus. The side effects, dyslipide-mias and dose of allopathic drugs can be reduced by their use in combination with herbal drugs. One of the examples of such Allopolyherbal formulation is therapeutic approach by combination of 4-hydroxyisoleucine and pioglitazone and combined therapy of 4-hydroxyisoleucine and glyburide [5].

Streptozotocin (STZ) is a naturally occurring nitrosourea product of Streptomyces achromogenes. Usually, the intraperitoneal injection of a single dose (60 mg/kg body weight) of it exerts direct toxicity on b cells resulting in necrosis within 48-72 h and causes hyperglycemia.

In the present study, leaves and fruit pulp of Aegle marmelos, leaf pulp of Aloe barbadensis, leaves of Azadirachta indica, and seeds of Trigonella foenum graecum in Polyherbal (PH) and in combination with Gliclazide as Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations were used to investigate their effect on blood glucose, lipid profile, serum creatinine, SGOT, and SGPT in rat model of STZ induced diabetes mellitus.

A comparison was made with the Gliclazide, a standard drug used in treatment of diabetes mellitus [6]. Gliclazide is a sulphonylurea drug which stimulates insulin secretion through

the beta cell sulphonylurea receptor, and possibly through a direct effect on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type II diabetes, and also has an effect on the second phase. It is extensively metabolised, and renal clearance accounts for only 4% of total drug clearance. This pattern of insulin release is thought to explain the lower incidence of hypoglycemic episodes and weight gain compared with some other sulphonylu-reas. There is also a reduction in hepatic glucose production and improvement in glucose clearance, without changes in insulin receptors. This suggests a possible post-receptor effect on insulin action, perhaps by stimulation of hepatic fructose-2,6-bisphosphatase and muscle glycogen synthase. Gliclazide reduces platelet adhesion, aggregation, and hyperactivity and increases fibrinolysis. These actions, thought to be independent of its hypoglycemic activity, may make Gliclazide useful in halting the progression of diabetic microangiopathy [7].

The medicinal uses of plants used in study can be summarized as follows [8]:

Plant name Family Uses

A. marmelos Rutaceae Stomachic, antimicrobial,

antidiarrhoeal, digestive, astringent, spasmolytic, hypoglycemic A. barbadensis Liliaceae Purgative, topically emollient,

anti-inflammatory, antimicrobial, hypoglycemic

A. indica Meliaceae Antimicrobial, antifungal,

anthelmintic, antiviral, antipyretic, antimalarial, spermicidal, antiinflammatory, hypoglycemic T. foenum Papilionaceae Appetizer, demulcent, hypoglycemic graecum

2. Materials and methods

Streptozotocin was purchased from Sisco Research Laboratories Pvt. Ltd., Mumbai, India; Gliclazide was purchased from Nu-Life Laboratories, India. All other chemicals and reagents used were of analytical grade and purchased from ASSES Chemicals, Jodhpur, Rajasthan. Glucose, cholesterol, triglyceride, total cholesterol, cholesterol-HDL, serum creatinine, SGPT, and SGOT kits were purchased from Logotech Delhi (India) Pvt. Ltd.

2.1. Plant material

The medicinal plants were identified and collected from local places of Jodhpur in month of August and September, authenticated by Botanical Survey of India, Jodhpur. A.

marmelos No.: JNU/PH2009 AV A-7; Aloe vera: JNU/PH2009 AV A-4; A. indica No.: JNU/PH2009 AV A-6; T. foenum graecum: JNU/PH2009 AV A-5.

2.2. Preparation of Polyherbal and Allopolyherbal formulations

The medicinal plant parts like fruits and leaves of A. marmelos, and leaves of A. indica were collected from local areas of Jodhpur, Rajasthan. Leaves of A. vera and seeds of T. foenum graecum were purchased from market. After drying the respective part of the plants under shade they were grinded by using mixer grinder and then sieved by using sieve shaker and manually by passing through 100 no. sieve. The sieved powder was collected in polyethylene bags. The Polyherbal formulation was prepared by taking 1/5th of the individual doses of respective plant part, calculated on the basis of percentage yield and dose of extract reported earlier (Table 1). The Allopolyherbal formulations (APH-A, APH-B, APH-C) were prepared by mixing Polyherbal formulation and Gliclazide in different experimental ratios (Table 2).

2.3. Animals

Adult Albino rats of Wistar strain (150-200 g) of either sex were procured from the animal house of Faculty of Pharmaceutical Sciences, Jodhpur National University, Jodhpur, Rajasthan. Animals were provided with standard pellets and drinking water ad libitum and were maintained at 12 h light and dark cycle. The protocol of the experiment (IPS/PCOL/ MPH06/002) was approved by Institutional Animal Ethics Committee (IAEC) of Jodhpur National University and were conducted in accordance with guidelines as per ''Guide for the care and use of laboratory animal'' and with permission from Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA).

2.4. Induction of diabetes and experimental design

Streptozotocin was dissolved in 100 mM citrate buffer (pH 4.5) and calculated amount of the dose (60 mg/kg) of the fresh solution was injected intraperitoneally to overnight fasted rats.

Blood glucose was checked 48 h later and animals showing blood glucose value more than 250 mg/dl were included in the experiments and termed as diabetic. Total seven groups (one non-diabetic and six diabetic) consisting of six animals in each group were taken and treatments were given orally, once a day, in the following manner:

Group I: served as control (non-diabetic) and given 1% gum acacia (1 ml/kg).

Group II: served as positive control and given 1% gum acacia (1 ml/kg).

Group III: administered Gliclazide (10 mg/ml/kg). Group IV: administered Polyherbal formulation (PH) (3.63 g/2 ml/kg).

Group V: administered Allopolyherbal-A formulation (APH-A) [(5 mg of Gliclazide + 1.81 g of PH)/2 ml/kg]. Group VI: administered Allopolyherbal-B formulation (APH-B) [(4 mg of Gliclazide + 2.17 g of PH)/2 ml/kg]. Group VII: administered Allopolyherbal-C formulation (APH-C) [(2 mg of Gliclazide + 2.904 g PH)/2 ml/kg].

'Gliclazide, PH, APH-A, APH-B, and APH-C, formulated into suspension, using 1% gum acacia in distilled water, just before administration.

2.5. Blood glucose level monitoring

Blood glucose level was estimated using biochemistry analyzer (GOD POD method) on 0, 7, and 14th day of experiment, blood samples were taken from retro orbital plexus.

At the end of study (on 21st day), blood samples were collected by heart puncture from anesthetized (slight exposure to ether) rats and then after animals were sacrificed as per IAEC guidelines.

2.6. Biochemical analysis

The serum was separated by centrifugation at 3000 rpm for 10min in microcentrifuge (star 21, India), then various biochemical parameters: blood glucose level, serum triglycer-

Table 1 Polyherbal dose on the basis of percentage yields of extract and extract dose.

Plant name (powder) Extract yield (%) Extract dose (mg/kg) Extract yield /100 g of powder (g) Dose of powder/kg body wt. (g)

Trigonella foenum seed 2 [9] 50 [10] 2 2.5

Aegle marmelos fruit pulp 2.98 [11] 250 [12] 2.98 8.38

Aegle marmelos leaves 10 [13] 100 [14] 10 1

Aloe vera leaf pulp 5.64 [15] 300 [16] 5.64 5.31

Azadirachta indica leaf 50.2 [17] 500 [18] 50.2 0.996

Dose of Polyherbal 18.2/5 = 3.63

Table 2 Composition of Allopolyherbal formulations (Gliclazide: Polyherbal).

Allopolyherbal formulation % of Gliclazide's dose (10 mg/ kg body wt.) (mg) % of mean dose (3.63 g/kg body wt.) of plant parts powders (g)

APH-A APH-B APH-C 50% = 5 40% = 4 20% = 2 50% = 1.81 60% = 2.17 80% = 2.904

ides (TRIGLYCERIDES), high density lipoproteins (HDL), cholesterol (TOTAL CHOLESTEROL), LDL (low density lipoprotein), very low density lipoprotein (VLDL), SGPT, SGOT, and serum creatinine were estimated using biochemistry analyzer (model no. Rapid star 21, SEAC, India) using respective kits.

2.7. Statistical analysis

All the data were statistically analyzed for variance and significance, by one way ANOVA followed by Student's t-test and Dunett's test. All results are expressed as Mean ± SEM and observed P value is <0.05.

3. Results

3.1. Blood glucose

Streptozotocin causes selective destruction of b cells of islets of pancreas and brings an increase in blood glucose levels. It is evident from the present investigation that STZ administration at the dose of 60 mg/kg body weight causes significant diabetogenic response in albino rats (Table 3). Blood glucose levels were measured randomly on 0, 7th, 14th and 21st day of study.

Blood glucose levels in diabetic rats were raised nearly to 2.5-3.5-fold as compared to normal control group rats on starting (0) day. The increase in glucose levels in diabetic control group was found to be significant (P < 0.05) when compared to normal control group.

The raised levels of blood glucose declined sharply after oral administration of Gliclazide, PH, APH-A, APH-B, and APH-C. When comparisons were made between '0' day and 21st day of treated groups, there was highly statistically significant (P < 0.01) (Table 3) decline in blood glucose levels. If decline in blood glucose levels is to be the only indices, then treatment with PH, APH-A, APH-B, APH-C, and Gliclazide were highly effective in causing significant antihyperglycemic response in this strain of rats.

As far as the relative efficacy is concerned, though all the four formulations produced more anti hyperglycemic activity than Gliclazide, but APH-A has been proven the highest anti-hyperglycemic activity among all.

3.2. Serum: lipids, serum creatinine and hepatic enzymes

On 21st day there was a statistically significant (P < 0.05) increase in serum total cholesterol (>54%), triglycerides (>112%), VLDL (>219%), serum creatinine (>99%), SGPT (>215%), and SGOT (>172%) and decrease in HDL (fl13%) of positive control group rats, as compared to normal control group rats. Treatment with Gliclazide, PH, APH-A, APH-B, and APH-C for 21 days, significantly decreased total cholesterol, triglycerides, LDL, VLDL, serum creatinine, SGPT, and SGOT levels when compared to positive control group (Table 4). There was also highly significant (bP < 0.01) increase in serum HDL level by treatment with APH-C compared to positive control group.

As far as the relative efficacy is concerned, though all the four formulations showed more/comparable activity to Gliclazide on all the biochemical parameters, but as far as overall efficacy is concerned for all parameters, APH-A is the best among all.

3.3. Toxicity study

Since the dose of Allopolyherbal formulations were very high and did not produce any toxic effects or mortality during study period as evident from results showing normal hepatic as well as renal functions, therefore on this basis no separate toxicity studies were carried out.

4. Discussion

In the present study, there was significant decrease in the blood glucose level when STZ induced diabetic rats were treated with Polyherbal and Allopolyherbal formulations (Table 3).

The previous studies have suggested that the A. marmelos (fruit and leaves) and T. foenum graecum seed produce hypo-glycemic effect probably by enhancing the peripheral utilization of glucose, correcting the impaired hepatic glycolysis and limiting its gluconeogenic formation similar to insulin [19]. A study has also revealed that the A. vera pulp stimulates insulin secretion from the remnant b-cells [20]. In case of Neem leaves the probable cause of reduction of blood glucose level might be due to increased peripheral uptake of glucose and increased sensitivity of insulin receptors [21].

Table 3 Blood glucose level in control and experimental groups of rat.

Groups Day

Day 0 (mg/dl) Day 7 (mg/dl) Day 14 (mg/dl) Day 21 (mg/dl)

Normal control Positive control Gliclazide PH APH-A APH-B APH-C 108.89 ± 3.80 111.64 ±2.8 258.20 ± 6.73# 252.40 ± 5.0# 343.60 ± 40.8 256.81 ± 41.3 349.8 ± 43.1 209.2 ± 28.8a 390.8 ± 52.0 197.4 ± 29.4a 308.3 ± 24.8 126.9 ± 2.0b 319.1 ± 32.1 121.9 ± 2.1b 111.80 ± 3.5 259.20 ± 8.20# 193.82 ± 15.13b 134 ± 2.14b 132.8 ± 2.6b 124.2 ± 2.6b 119.2 ± 4.4b 114 ± 2.16 269 ± 11# 138 ± 3.71 (fl59.83%)b 120.6 ± 2.1 (fl65.52%)b 120.0 ± 2.6 (fl69.29%)b 116.4 ± 2.6 (fl62.24%)b 110.4 ± 4.4 (fl65.40%)b

Values are expressed in Mean ± SEM (n = 6 in each group). # P < 0.05; when positive control compared with normal control (followed by t-test). a P < 0.05; when other groups compared with respective '0' day (followed by Dunett's test). b P < 0.01; when other groups compared with respective '0' day (followed by Dunett's test).

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As suggested by the previous studies, the active constituents like 4-hydroxy isoleucine present in T. foenum graecum seed; marmelosin and aegeline present in A. marmelos fruit and leaves; phytosterols present in A. vera leaf pulp; tetra terpe-noids like nimocinol and isonimocinol present in A. indica leaves are responsi le for the improvement of glycemic and dyslipidemic conditions of dia etes mellitus in experimental animals [8,22].

The present study has shown similar results for hypoglyce-mic activity and other iochemical parameters in accordance with previous studies.

Allopolyher al-A formulation (APH-A) showed maximum effectiveness in decreasing lood glucose levels in the dia etic rats and proved to have a etter plasma glucose lowering effect than Gliclazide, Polyher al (PH), Allopolyher al-B (APH-B) and Allopolyher al-C (APH-C) formulations (Ta le 3).

The level of serum lipids are usually elevated in dia etes which represents a high risk factor for coronary heart disease. Under normal circumstances, insulin activates the enzyme lipo-protein lipase, which hydrolyses triglycerides. However, in a diabetic state, lipoprotein lipase is not activated in sufficient amount due to insulin deficiency resulting in hypertriglyceride-mia [23]. The treatment with Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations, led to a significant decrease in total cholesterol, triglycerides, LDL, and VLDL levels (Table 4), which implies that these formulations can reduce the complications of lipid metabolism and associated cardiovascular risk factors during diabetes. Allopolyherbal-C (APH-C) formulation has proved to be most effective in improving lipid metabolism in the present study as compared to Gliclazide.

Generally an increase in plasma serum creatinine levels is a sign of impaired renal function; treatment with Polyherbal (PH), Allopolyherbal-A (APH-A), Allopolyherbal-B (APH-B), and Allopolyherbal-C (APH-C) formulations led to a decrease in serum creatinine levels (Table 4), which shows improved renal function.

Hepatotoxicity is another risk factor associated to oral hypoglycemics on long term use. This risk factor can be minimized by reducing the dose of oral hypoglycemics and using them in combination with herbal drugs. The Polyherbal (PH) and Allopolyherbal formulations (APH-A, APH-B, and APH-C) exhibited better results than Gliclazide, for SGOT and SGPT levels (Table 4).

Though Polyherbal and different Allopolyherbal formulations showed maximum efficacy for different biochemical parameters, but looking to the results for all the parameters, it may be concluded that Allopolyherbal-A formulation (APH-A) was most effective in comparison to Polyherbal (PH), Allo-polyherbal-B (APH-B), Allopolyherbal-C formulations, and Gliclazide. There were no toxic effects during the 21 days of study, regarding to hepatotoxicity and nephrotoxicity. So, the Allopolyherbal-A formulation (APH-A) may be an ideal alternative for the existing hypoglycemic formulations with an additional advantage of hypolipidemic effect and minimizing the cardiovascular risk factors associated with diabetes mellitus.

5. Conclusion

The data suggest that the Polyherbal formulation and Allo-

polyherbal formulations exhibit significant and consistent

hypoglycemic and Hypolipidemic along with improved hepatic and renal function, in diabetic rats. Allopolyherbal-A formulation (APH-A) has been proved to be most effective out of all these formulations in improving the diabetic complications. Therefore it may have beneficial effects in type II diabetes mel-litus and holds the hope of new generation oral hypoglycemic drugs. A number of Polyherbal formulations are available in the market for the treatment of diabetes like Diabegon, Diabet, Glyoherb, Epinsulin, Diakyur, Dihar, Diashis, Diabetica, Diacamp, Diavite, Glucocare, Glucotize, Gluconase, Sug-armax, etc.

From the preceding results it can be concluded that the Allopolyherbal-A formulation (APH-A) possesses the best hypoglycemic and hypolipidemic actions along with improved renal and hepatic functions. By using herbs with allopathic drugs, the side effects of allopathic drugs can be minimized with prolonged use. It was an effort to counteract or retard the risk factors associated with diabetes mellitus by the use of herbs along with allopathic drugs.

Since the dose of PH (3.63 g/kg body wt.) constituting the Allopolyherbal formulation was on higher side so there is a need for further extensive investigations, to decrease the dose and prepare a suitable dosage form of Allopolyherbal-A formulation (APH-A) that can be used as an effective oral hypo-glycemic with an additional advantage of decrease in complications associated to syndrome-X or it would be better to use extracts of the respective plant part for the same.

Acknowledgments

The work is supported by Jodhpur National University, Jodh-pur. The authors are grateful for the assistance of Faculty of Pharmaceutical Sciences of the University, Jodhpur for completion of research project. The authors would also like to thank the Animal House staff and animal care takers, Mr. Bhura Ram and Mohammad Faheem for their help and hard work.

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