The Myth and The fact on Naringin –A Review

 

Dr S. R Suseem¹, Dhanish Joseph²*

¹Assistant Professor, School of Advanced Sciences, VIT, Vellore

²PhD Scholar, School of Advanced Sciences, VIT, Vellore

 

ABSTRACT:

Naringin and naringenin are the two common flavonoids present in the citrus fruits especially in grapefruit. Both this does wonderful functions in human body. It is being contraindicated with many of the drug products due to extensive variation in the kinetics of drugs when both dug and this flavonoid administered together. Thus all the doctors counsel the patients not to have grape fruit with many of the drugs. The common people or the patients are much worried in taking the citrus fruit even after completion of the treatment because of certain myth behind this. The current study aims to reveal the reality behind this caption. The review conducted confirms various proven therapeutic activities of naringin and naringenin as a supplement and certain synergistic effects. It is proven that the consumption of either grape fruit or as naringin or naringenin itself keeps the body healthy away from various illnesses. And it is highly active against various major life style disorders and even as an anti-neoplastic agent.

 

 

 

INTRODUCTION:

Flavonoids are natural phenolic compounds with the wide range of bioactivities. 4000 flavonoids have been discovered, from fruits, vegetables, and herbs¹. The flavonoid structure consists of 15 carbon atoms and 3 rings of which 2 are benzene rings connected with 3-carbon chain² structure. Variety of flavonoids are found in plants, such as flavanones, flavones, isoflavones, flavonols, anthocyanidins, and flavanols^3. These flavonoids are good scavengers of free radicals and prevent oxidative stress in vivo^2,3 They were discovered by Nobel Prize-winning biochemist Albert Szent-Gyorgi, who labelled them “Vitamin P”. Bioflavonoids are phytochemicals called as polyphenols. Major polyphenols include phenolic acids, flavonoids, stilbenes, and lignans. Flavonoids are the most abundant polyphenols in our diets^4,5. Citrus fruits offer potential health benefit in diabetes and obesity.

 

 

The metabolic function of the liver was improved by Mandarin fruit extracts and also restored the antioxidant enzymes in streptozotocin-induced diabetic rats⁶.

 

Naringin has the molecular formula C₂₇H₃₂O₁₄ and poses a molecular weight of 580.4 g/mol. This flavanone glycoside found in citrus fruits and grapes with a distinctly bitter taste of grapefruit juice. Both Naringin and naringenin are strong antioxidants^7,8; whereas, naringenin is more potent than naringin, because the sugar moiety in the later causes. Naringin is water soluble. In intestine the gut microflora breaks down naringin to its aglycon naringenin; it is then absorbed⁹. Naringin becomes most popular for its synergistic activity with various supplements and potential drugs. It improves the potency of supplemented nutrients. No deficiency conditions of this flavonoids are known to exist.¹⁰

 

Furan Ring in the furanocoumarin enhances the inhibitory effect on CYP3A4. Flavonoids with more phenolic hydroxyl (-OH) groups produced better inhibition than those with fewer hydroxyl groups¹¹. Over the flavonoids we consume only 2-15% are absorbed in the GI tract¹². absolute bioavailability of naringenin is only 4%, after considering the conjugated naringenin, it increased to 8%¹³. The intracellular concentration of naringenin is only 5% and it is physiologically achievable in our tissues¹⁴. The various pharmacokinetic studies of naringin and naringenin on rat model reports Naringenin is rapidly metabolized in the liver and conjugate with glucuronide and sulphates.^15,16,17 The maximum daily dose of naringin is 1g; But, it’s good to use 50 to 100 mg per serving when combined in a formula with other supplements. Naringin support maximum benefits of bioflavonoid thus it should be consumed with meals or supplement. No known toxicity is reported.

 

Bio Applications of flavonoids:

Flavonoids act as powerful antioxidants, strengthen capillary walls, prevent bruising and bleeding, protects from free radicals, and assisting circulation. Some flavonoids are strong anti-inflammatory agents, helps to control the damage tissues¹⁸. Citrus fruit extract showed potent antioxidant activity in human umbilical vein endothelial cells,¹⁹

 

Naringin in Grapefruit seed:

Grapefruit seed extract is active against bacterial, viral, and fungal infections even yeast infections also. It is used as first-aid, as a facial cleanser, vaginal douche, a remedy for mild skin irritations, as a gargle for sore throats for ear or nasal rinse for treating infections, as a dental rinse, and as breath freshener. Its vapour inhaled for treating lung infections. In agriculture, it is used to kill fungus and bacteria, it also kills parasites in animal feeds, fight mould growth, disinfect water and preserve food²⁰.

 

Bio Application of Naringin and Naringenin:

Naringin is used in the treatment of Diabetes, Herpes, Heart Failure, Alcoholism and Chronic venous insufficiency. Naringin is most commonly used in the nutrition industry to increase uptake of supplements such as caffeine²¹. It enhances the metabolism of ethanol and reduces negative effects of ethanol intake, it acts as antioxidant, free radical scavenger and also Significantly inhibit LDL oxidation. Reduces cytotoxicity, protects from various toxins in chemotherapy drugs and the environment, acts as an anti-apoptotic and also exert antifungal properties. Naringin prevents the receptor-mediated asialo glycoprotein uptake and degradation also prevents the okadaic acid-induced inhibition of endogenous, autophagic-lysosomal protein degradation. Naringin exist therapeutic value as protectants against pathological hyper phosphorylations, side effects of chemotherapeutic drugs and environmental toxins²². 25 mg of naringin increases the bioavailability of nutrients and drugs.

 

Enzyme inhibition:

Naringin act as an aldose reductase inhibitor, which inhibits the enzyme that converts glucose into other sugars, and allows it to drain away safely, preventing damage¹⁰ Naringenin is a competitive inhibitor of caffeine 3-demethylation by the human liver microsomes. Naringin and naringenin decreased the clearance of caffeine by 23% and extents its half-life by 31%. Naringenin inhibit CYP1A2 activity in man²³. Naringin inhibits organic anion-transporting polypeptide 1A2 (OATP1A2)-mediated fexofenadine uptake and decrease its oral bioavailability^24,25. Naringin inhibitsbenzo (a) pyrene hydroxylase (AHH) activity in vitro. Administration of 10mg/ml naringin for 7 days decreases the AHH activity by 38%²⁶.

 

Effect of Naringin on Hyperlipidemia:

Naringin supplementation lowered obesity and plasma lipids in high-fat-diet–fed rats²⁷ and decreased plasma lipids and cholesterol in high-cholesterol-diet–fed rats. LDL receptor(LDLR) knockout mice shows the cholesterol-lowering effect of naringin²⁸. A lipid-lowering effect of naringenin observed in male Long-Evan hooded rats. Naringin-supplemented with (0.02 g/100 g) reduced the Hepatic3-hydroxy3-methyl CoA (HMG-CoA) reductase activity significantly²⁹. Naringin increase levels of HDL. Slow accumulation of artery-clogging plaque were observed while boosting the levels of HDL cholesterol and it also support long-term heart health^30,21. Naringin alters the antioxidant enzyme activities and cholesterol biosynthesis in LDL receptor knockout mice under cholesterol-fed condition. Cytotoxicity can be caused by Hydrogen peroxide through oxidative stress apoptosis. Hydrogen peroxide induces cytotoxicity is reduced by Naringin^31. The effects of dietary supplementation of naringenin on the cholesterol metabolism were studied for 42 days on male rats fed with high-cholesterol diet. A control without the naringenin supplementation also conducted. Naringenin lowered the hepatic cholesterol content and the plasma cholesterol concentration compared to those of the controls. But it did not significantly alter the concentration of plasma triglycerides. ACAT and HMG-CoA reductase activities were significantly lower in the naringenin-supplemented group than in controls³².

 

Naringin inhibited the excessive release of P-selectin, improved platelet aggregation and inhibit release of PF4 in hyper lipidemic rabbits. Naringin did not cause bleeding in the hyper lipidemic rabbits. Naringin has the ability to regulate the blood cholesterol levels and [Ca2+] in platelets and it exerts an antiplatelet effect. ³³In Vitro studies have demonstrated increased atherogenicity of oxidised low-density lipoprotein (ox-LDL) compared to native LDL. Flavonoids including naringin prevent in vitro LDL oxidation and an important product to prevent atherosclerosis³⁴. Naringin reduces the level of total cholesterol significantly, a null effect on LDL, VLDL and tri glycerols with a reduction in HDL. This confirms the utility of naringin for hyperlipidemia³⁵. Naringin did not reduce the plasma triglycerides level but it reduces the plasma cholesterol and hepatic cholesterol level. And HMG-CoA reductase activity was substantially less in naringin supplemented group³⁶.

 

Effect of Naringin on Hypertension:

Naringin supplements are very active in reducing hypertension in high-carbohydrate, fat, fed obese rats³⁷ and stroke-prone hypertensive rats³⁸. Nitric oxide metabolites in urine were observed with naringin supplemented animals³⁸. It also act a vasodilator in high-carbohydrate fat fed obese rats³⁷ and streptozotocin-induced diabetic rats³⁹.

 

Anti-oxidant:

The comparative effect of naringin on plasma antioxidant activity and plasma lipid levels in rats, fed with cholesterol and cholesterol free diets were studied for 30 days. Naringin increased the plasma antioxidant activity and reduced the plasma lipid levels. In conclusion, naringin is highly effective in lipid lowering and exert plasma antioxidant activity⁴⁰

 

Naringin is a highly potent lipid lowering substance and also exert antioxidant activity in high cholesterol diet fed animals^41,42 Both naringin and naringenin protect hemoglobin from nitrite-induced oxidation, Its ability to scavenge oxygen free radicals can be responsible for the action because hydroxyl, superoxide and other free radicals are implicated in promoting the autocatalytic stage of oxidation of hemoglobin by nitrite. Because of the extra phenolic group in the aglycone naringenin is more effective than naringin⁴³. Naringin exhibited a comparable antioxidant capacity based on increasing the gene expressions in the antioxidant enzymes Naringin supplementation improves the hepatic superoxide dismutase (SOD) and catalyse (CAT) activities, and decreases the hepatic mitochondrial hydrogen peroxide (H(2)O(2)) compared to the HC-control. Naringin increased the plasma vitamin E concentration. And the expression of three antioxidant enzyme mRNAs^44.

 

A Comparative study on the antioxidant effect of lipid lowering drug lovastatin and cholesterol lowering bioflavonoid naringin was conducted in rabbits fed with high cholesterol diet supplemented with either lovastatinor naringin. The results indicates the effect of naringin in regulating anti oxidative capacity by increasing the enzyme superoxide dismutase (SOD) and catalase activities by regulating the gene expressions of SOD and GSH –Px and increasing plasma vitamin E⁴⁵.A study designed to evaluate and compare antioxidant activity and radical scavenging capacity of naringin and naringenin. The results showed that naringenin is far better than naringin. It exhibits higher antioxidant capacity and superoxide radical scavenger efficiency⁴⁶.

 

Naringin as an antineoplastic agent:

The hesperetin and naringenin were tested for their effects on growth and proliferation of human breast carcinoma cell line, MDA-MB-435. The inhibitory effect of naringenin on mammary tumours of female Sprague Dawley rats were tested by inducing 7,12 dimethylbenz[a]anthracene (DMBA) . Naringin is an effective inhibitor of human breast cancer cell proliferation in vitro, especially when paired with quercetin⁴⁵. The diet abundant in vegetables and fruits may protect against colon cancer. This was tested on Male Sprague-Dawley rats by inducing azoxymethane (15 mg/kg) in presence of various supplemented flavonoids such as limonin, apigenin, naringenin, nobiletin and hesperidin. Excised colons were evaluated, when compared with the control, apigenin lowered the number of high multiplicity ACF (HMACF >4 aberrant crypts/focus) by 57%, while naringenin lowered both the number of HMACF by 51% and the proliferative index by 32%. Both apigenin and naringenin increased apoptosis of luminal surface colonocytes (78% and 97%), respectively when compared with the control diet. The ability of dietary naringenin to reduce HMACF, increase apoptosis and lower proliferation and may contribute toward colon cancer prevention⁴⁷.

 

Metastasis can be the main cause of death in cancer patients. Naringin is now suggested as a new adjuvant for patients undergoing surgery for inhibiting metastasis. Orally administered during reduces the number of metastatic tumour cells ⁴⁸. Naringenin has shown inhibitory effects on tumour growth as well ascytotoxicity in various human cancer cell lines. It also accesses the brain and exhibits an interesting increase in its therapeutic applications. The study investigated confirms the in vivo effect of Naringenin in fostering apoptosis in cerebrally implanted C6 glioma cells rat model⁴⁹. The potential antineoplastic efficacy of various flavonoids were assayed in three human cancer cell lines: colon carcinomas, gastric and pancreatic as well as derived multidrug-resistant sublines. Naringenin was the most active compound which was 15-fold more effective against the atypical MDR subline of gastric carcinoma than in parental drug-sensitive cells⁵⁰.

 

Disruption of lipid and carbohydrate homoeostasis helps in the development of prevalent metabolic diseases such as obesity, diabetes, and atherosclerosis. Thus molecules that can reduce insulin dependence and regulate dyslipidemia will have a dramatic effect on public health. Naringenin normalise, lipids in hypercholesterolemia and diabetes, as well as inhibit the production of HCV. This explains the myriad effects of naringenin⁵¹.

 

The apoptosis inducing the activity of naringin and naringin in were studied on HL 60 Cells. The results suggest by MTT assay that both naringin and naringenin doesn’t exist any cytotoxic effect on HL-60 cells. It also shows rapid and transient induction of caspase-3/CPP32 activity, but not caspase-1 activity. A reduction in antiapoptotic protein, Mc-1, was detected in naringin-treated HL-60 cells. It also doesn’t induce apoptosis in mature monocytic cell line THP-1 and primary human polymorphonuclear cells. The study concludes the that naringin prevent the induction of apoptosis⁵²

 

Naringin and naringenin were again tested for its effect on tobacco-induced carcinogenesis. Tobacco-specific nitrosamine NNK is a potent environmental carcinogen to which both smokers and non-smokers are exposed. The NNK metabolism happens in hamster liver by reduction and in lungs by alpha-hydroxylation. The metabolic product may methylate pyridyloxobutylate DNA. Naringin plays the important role by inhibiting the alpha-hydroxylation in both liver and lungs thereby it provides protection against NNK-induced carcinogenesis⁵³. Naringin possesses tremendous antimutagenic activity .half the equimolar dose can reduce the mutagenic potency of carcinogen up to 50%⁵⁴.

 

Hepatitis C:

Without affecting intracellular levels of the viral RNA or protein, naringenin inhibits Hepatitis C virus (HCV) production. The upstream of viral egress and assembly of intracellular infectious viral particles are blocked by naringenin. By the activation of PPARα, his antiviral effect is mediated leadsto decrease in VLDL production without causing hepatic lipid accumulation in primary human hepatocytes and Huh7.5.1 cells. A rapid reduction in HCV is achieved in long-term treatment with naringenin, similar to 1000U of interferon. The data demonstrate that naringenin is a non-toxic inhibitor of HCV and that other PPARα agonists play a similar role in blocking viral production⁵⁵.

 

DNA repair:

The risk of prostate cancer, increases with age. Naringenin, repair damaged DNA in human prostate cancer cells. DNA repair is one of the body's primary defence mechanisms since it removes potentially cancer-causing mutations in the cells. Naringenin restores DNA health by inducing two enzymes that repair DNA during the replication stage. These enzymes, DNA polymerase beta (DNA poly beta) and 8-oxoguanine-DNA glycosylase 1 (hOGG1), are both involved in the DNA base excision repair (BER) pathway. prostate cancer remains undetectable and slow growing initially. Enjoying grapefruit regularly may be one way to prevent its progression by promoting the repair of damaged DNA in prostate cells,¹⁴ naringenin showed an effectiveness in the protection against oxidative damage to lipids. Both flavanones were equally effective in reducing DNA damage⁴⁶.

 

Anti-inflammatory activity:

During inflammation, the inflammatory cytokines and bacterial products induces the formation of large amounts of nitric oxide by inducible nitric oxide synthase (iNOS). Thus the compounds that inhibit nitric oxide production have anti-inflammatory effects. The effect of flavonoids on nitric oxide production in macrophages were evaluated. Eight active compounds inhibited the activation of nuclear factor-kappaB (NF-kappaB), which is a significant transcription factor for iNOS. The results explain the anti-inflammatory effect of flavonoids⁵⁶. Flavonoids- naringin quercetin and hesperidin, exert anti-inflammatory activity by regulating the enzyme activities responsible for the PAF and acyl-PAF biosynthesis and by modifying monocyte adhesion in the inflammatory process of atherosclerosis ⁵⁷.

 

Wound healing:

By maintaining capillaries, naringin prevents and heal injuries, including bleedingand bruising. It allows oxygen, nutrients, hormones, and antibodies to pass from the blood into cellsthrough the microscopic blood vessels²¹.

 

Effect of Naringin on Obesity:

Reduction of adiposity in rats with in6 weeks were observed when Naringen given as supplement at 0.003%, 0.006%, and 0.012% of the diet²⁹. Naringenin-fed animals had a significant increase in carnitinepalmitoyltransferase 1 (CPT-1), and uncoupling protein 2 (UCP-2) expression in the liver peroxisome proliferator-activated receptor (PPAR) α, which might be responsible for the reduction in adiposity²⁹. Adipocyte differentiation is a key regulatory step in fat deposition in adipose tissues. Naringenin promoted adiponectin protein secretion from 3T3-L1 adipocytes and promoted gene expression⁵⁸ Naringenin inhibited the production of nitric oxide (NO), MCP-1,TNF-αand MCP-1, in a dose-dependent manner in coculture of 3T3-L1 adipocytes, RAW264 macrophages and RAW264 macrophages stimulated by LPS⁵⁹.

 

Anti-Sindbis activity:

Naringin was tested for its effect on Sindbisneurovirulent strain (NSV) replication on hamster. The ID50 was confirmed as 14.9 micro G/ml. whereas its glycosides don't exist the activity⁶⁰.

 

Alcohol effect:

The effect of naringin supplements on the alcohol, antioxidant metabolism and lipid, in ethanol-treated rats was studied. Among the ethanol treated, the naringin supplements lowered the plasma ethanol concentration with increase in the ADH and/or ALDH activities. among the ethanol-treated, naringin supplementation decreases the and hepatic total cholesterol and hepatic triglycerides compared to that in the naringin-free group. Naringin supplementation increased the HDL-cholesterol. Lipid accumulation in liver was also significantly reduced in the naringin-supplemented groups compared to the naringin-free group among the ethanol-treated groups⁶¹.

 

Hematocrits –Normalization

The effect on hematocrits of adding grapefruit to the daily diet was determined using 36 human subjects there was a differential decrease in the haematocrit content. At the same time, no difference between ingesting 1/2 or 1 grapefruit per day but a decrease in hematocrit due to ingestion of grapefruit was statistically significant⁶².

 

Bio enhancer:

The effect of naringin on the pharmacokinetics of quinine was tested over female Wister rats of 190-200g weight. By oral and IV routes of administration. There was no change in pharmacokinetics parameters for IV dose but a tremendous increase for oral administration. The pre-treatment with naringin lead to 208% increase in Cmax, 152% increase in AUC and bioavailability from 17%- 42 %. The results confirmed the pre-treatment with naringin improve the pharmacokinetics of drugs⁶³.

 

Gastro protective:

The gastro protective effect of naringin on mucosal injury produced by absolute ethanol was tested with the involvement of endogenous prostaglandins on rats. Pre treating the animal with 400mg/kg dose of naringin before 60 min administration of absolute ethanol has shown a significant effect on gastro protection. The content of gastric mucosa and protein does not increase significantly but a significant increase in hexosamine levels. The study was also done along with administration of indomethacin 10 mg/kg Subcutaneously but there was no significant increase in hexosamine levels. The results confirm naringin has cyto protective effect against ethanol injury in rats⁶⁴. Naringin also acts as a gastro protective agent for mucosal injury produced by absolute ethanol⁶⁵.

 

 

Anti-ulcer:

The anti-ulcer property of naringin and naringenin was studied on aspirin and phenyl butazone induced ulcer on rats, pylorus-ligated, and restraint ulcers on rats. Naringenin significantly possesses anti-ulcer property in all three models. The ED 50 value against pylorus –ligated rats was significantly greater than that against restraint rats. Thus the study confirms the naringenin and naringin possess a strong anti-ulcer protective property on rats by the mechanism of inhibiting the formation and release of endogenous histamine in the gastric mucosa⁶⁶.

 

Anti atherogenic effect:

The effect of naringin on atherosclerosis was studied by evaluating its effect on blood lipid levels and aortic fatty streaks. Its mechanism in hypercholesterolemia effect also studied in rabbits. The study was compared with the effect of lovastatin in the same model. The rabbits were fed with cholesterol supplements along with naringin and lovastatin. The cholesterol level in an untreated group of rabbits increased 17 times as compared with the treated group containing naringin and lovastatin, both naringin and lovastatin decrease the area of fatty streak. Hypercholesterolemia causes fatty liver and elevation of liver enzymes, that is prevented by naringin, not by lovastatin. Naringin reduces fatty streak formation and neointimal macrophages infiltration and also inhibit ICAM-1 in endothelial cells with a suggestion that inhibition of ICAM-1 reduces the anti atherogenic effect. This study also concludes naringin has hepato protective action⁶⁷.

 

The interactive effect of naringin and vitamin E for cholesterol metabolism and antioxidant activity was studied on rats by supplementation. The naringin supplementation has lowered the cholesterol and triglyceride concentration as compared with the naringin free treated group. The naringin is more active in cholesterol lowering when the dietary intake of vitamin E is normal as compared with low vitamin E intake. This concludes the interactive effect of naringin and Vitamin E in cholesterol lowering⁶⁸. Anti-atherogenic effect of naringin and naringenin were evaluated in high cholesterol rabbits by supplementation of cholesterol for the control group and also with naringin and naringenin for two other groups. Hepatic acyl-CoA: Cholesterol acyltransferase (ACAT) activity and aortic fatty streak areas were slow in both naringin and naringenin. These results suggest the anti-atherogenic effect of naringin and naringenin in rabbits⁶⁹.

 

Bone marrow protective:

Naringin was tested for its bone marrow protective property on gamma radiation. The study conducted on the mouse by pre-treating the mouse with naringin and thereafter exposed to 2Gy of 60 Co gamma radiation. The change in radiation-induced micronucleated polychromatic (MPCE) and normochromic (MNCE) erythrocytes were studies. Pre-treatment with 2mg/kg dose of naringin on mouse significantly decline the formation of MPCE, MNCE and also reduce the formation of complex chromosomes aberrations. The study concludes that the naringin protects against radiation-induced DNA damage and reduces the cell proliferation⁷⁰. Combination of flavonoid like naringin can enhance the bioavailability of drugs⁷¹.

 

Recently reported Pharmacological activity of some rare plants

Name of the plant	Pharmacological activity
Polianthestuberosa	Anti-inflammatory and Anti-fungal 72
Cassia angustifolia	Gastro protective 73
Linseed oil	Treatment of edima 74
Ginger oleoresin	Treatment of edima 74
Sida rhombifolia	Antiseptic, Wound-Healing, Diarrhoea, Cough And Ulcer, Dysenteries, Tuberculosis, Urogenital Diseases , Chicken Pox, Female Infertility, Antioxidant, Anti-Inflammatory Antimicrobial, Anthelminthic, Antifungal, And Anti-Rheumatic Properties 75
Vitex trifolia	Antipyretic, Antibacterial And Allergic Diseases. 76
Andrographis paniculata	Anti-inflammatory 77
Ougeiniaoojeinensis (Roxb.)	Anti-inflammatory 78
Sitopaladichurna	Mast cell stabilizing 79
Thespesia Lampas Dalz and Gibs	Anti-hyperlipidemic80
Sapindusemarginatus	Anti-hyperlipidemic81
Aqueous Extract of Lantana Camara Linn	Analgesic, Anti–Inflammatory and Anti–Hemorrhoidal82
Memecylonumbellatum Burm Roots	Analgesic and Anti-Inflammatory 83
Adiantumcapillus	Anti-Nociceptive 84
Moringaoleifera	Wound Healing, Anti-inflammatory and Antioxidant 85
Quercusinfectoria	Antioxidants, Antimicrobial, Anti-Inflammatory, Anthelmintic 86
Papaversomniferum	Antioxidants, Antimicrobial, Anti-Inflammatory, Anthelmintic 86

 

CONCLUSION:

The real facts and various biological application behind the naringin and naringenin were studied. The review concludes with the impression that both the flavonoid has various applications as dietary supplement and has various therapeutic activities. since it exhibit the bio enhancer property it has to be taken with little caution only on treatment with any drug if not it can be added in our daily diet which keep and make the body healthier.

 

CONFLICT OF INTEREST:

No Conflict of Interest for this article.

 

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Accepted on 24.09.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2019; 12(1): 367-374.