HESPERIDIN and DIOSMIN - a NOVEL DRUGS JAYDEEP ROY1, MOHAMMAD AZAMTHULLA1*, DHRUBOJYOTHI MUKKERJEE2 1Department of Pharmacology, Faculty of Pharmacy, M
Research Article HESPERIDIN AND DIOSMIN - A NOVEL DRUGS JAYDEEP ROY1, MOHAMMAD AZAMTHULLA1*, DHRUBOJYOTHI MUKKERJEE2 1Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, MSR Nagar, Bangalore, India -560054 2Department of Pharmaceutics, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, MSR Nagar, Bangalore, India -560054 *Author for Correspondence Dr. Mohammad Azamthulla Department of Pharmacology, Faculty of Pharmacy, M.S. Ramaiah University of Applied Science, MSR Nagar, MSRIT Post, Bangalore-560054, INDIA Phone: +91-080-23608942 E-mail: [email protected] Received: 01.09.19, Revised: 08.10.19, Accepted: 14.11.19
ABSTRACT: Hesperidin, famously known as Vitamin P and Diosmin are the popular, abundant and inexpensive products obtained from citrus agronomy. With no signs of toxicity, these flavonoids are largely consumed as a dietary supplement and have a long history of medication. In various studies, conducted on Hesperidin & Diosmin have reported a number of protective potentials such as neuroprotective, cardio protective, hepato protective, anti- inflammatory, antioxidant, lipid lowering, and insulin-sensitizing properties. Despite their enormous remedial potential, the poor aqueous solubility and minimal bioavailability are some major curbs that restrict the utilization of Hesperidin and Diosmin in medical perception. Though, future of medicine belongs to synthesis and usage of nano-dimensioned materials by means of nanotechnology which has been revolutionising the delivery of different constituents with much more precision oriented delivery to the target. This review highlights the in vivo and clinical studies to elucidate the therapeutic and pharmacological properties of Hesperidin & Diosmin that have been reported since 2015, also displays the gaps in our knowledge about both the compounds and the growing influence of nanotechnology to overcome the characteristic limitations which deserves more exploration.
KEYWORDS: Flavonoids, Diosmin, Hesperidin, Nano formulation
INTRODUCTION Since ancient times, mankind have been nanoparticle formulations may act as a exploiting the natural resources for numerous “panacea” which logically incorporated an medicinal purposes. With the track of time, the exemplary model for treating a varied range of inquisitiveness nature of men to explore the chronic disorders with the application of Nano- medicinal benefits of natural resources is being hesperidin/Diosmin through effective drug increased and now becoming a prime focus of delivery process. Numerous in vivo studies have scientific research (1). Flavonoids are amongst addressed about the development of specific- the class of naturally occurring phyto site delivery of Hesperidin & Diosmin with constituents which are found in most of the better permeability, and increased bio- citrus plants, berries, green tea, black tea, red distribution with significant efficient responses. wine, cocoa, etc. Diosmin and Hesperidin are Information’s were collected via electronic the two citric fruit derived flavonoids marketed search by using Science Direct, PubMed, as dietary supplements also as a combination Nature and other internet sources. famously known as micronized purified flavonoid fraction (Daflon) which act on venous Hesperidin and Diosmin tone, lymphatic vessels, micro-circulation and Diosmin and Hesperidin are flavanone treats hemorrhoids. Numerous studies on glycosides majorly found in citrus fruits (Family Diosmin and Hesperidin have reported various Rutaceae). Hesperidin (Hesperitin 7- pharmacological activities. New findings have rhamnoglucoside, Hesperitin-7-rutinoside), revealed that Dios has anti-parkinsonism C28H34O15 is a yellow to brown powder with a property and hesperidin has shown anti- molecular weight of 610.56. It is insoluble in atherogenic and anti-inflammatory activity. water, shows solubility in pyridine, DMC, Despite of continuous research transformations NaOH. Have a melting point from 250-255°C and efforts aiming to vanquish the challenges show a characteristic absorption spectrum at of Hesperidin and Diosmin, the application of 285nm (Fig.1). Diosmin is a bioflavonoid,
25| International Journal of Pharmacy Research & Technology | July - Dec 2020 | Vol 10 | Issue 2 Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGS semi-synthetic drug, (3,5,7-trihydroxy-4 mellitus. Reporting reduction in glucose levels methoxyflavone-7-rutinoside), C28H32O15 is and cholesterol levels with no adverse events, yellow-brown to brown powder with a therefore, reducing the cardiovascular risk molecular weight of 608.54. Insolubility in factor in diabetic patients (7). water, solubility in DMSO, NaOH like organic solvents, melting point 274°C shows maximum Dietary intake of flavonoids; HES, DIOS absorption at 268nm. Being the secondary plant metabolites, Diosmin can be found in the plants Teucrium flavonoids are not synthesized in the human gnaphalodes, citrus, vetches, hyssop (2). It is body. Therefore they are consumed through the been reported for numerous activities but is dietary sources including fruits (citrus fruits, popularly known to have neuroprotective grapes, pomegranates, berries, and apples), activity (3). Hesperidin is a flavanone glycoside, vegetables (broccoli, celery, onions, and leafy obtained in a large amount from the Rutaceae greens), soy products, legumes and beverages family, citrus plants like grapefruit, lemon, (red wine, tea) (8). The intake of the flavonoids orange, tangerine, etc. even from various other varies greatly depending on the availability of plant species such peppermint and welsh onion quality food and dietary habits of the consumer (4,5). Hesperidin has been reported for with different preferences. On global numerous activities such as antioxidant, anti- comparison the intake of flavonoids in Asians is inflammatory, anti-viral, anti-carcinogenic and more than westerns; Europeans and has been reported to protect against DNA Americans. Diosmin and Hesperidin, are not damage, lipid peroxidation. In combination been widely reported for any interactions with with other bioflavonoids like Diosmin, it is drug or food substances. Dietary supplements marketed as Daflon-500mg (Servier) tablets of both the compounds are present in the which contain micronized flavonoids- market for treatment and prevention of hesperidin (50mg) and Diosmin (450mg) to vascular system-related disorders and treat lymphedema and are majorly used to improvement of cardiovascular health. Few treat blood vessel disorders such as varicose studies have shown anti-microbial, anti- veins, venous stasis, and hemorrhoids. In a inflammatory like activities but the mechanism study using animal models, the combination of action for these activities are not been was evaluated by for safety and toxicity studies revealed. Some studies (Table 1 & 2) have also showing good GIT acceptability of the reported the compounds may have a micronized formulation with no genotoxicity, no neuroprotective & cardioprotective activity drug incompatibility or interaction (6). which can help to prevent neuro-degeneration However, Maher and Sabir has investigated the & cardiac-related problems if these flavonoids effect of the Diosmin and Hesperidin are included into daily supplementary combination on hypercholesterolemia and consumption from childhood to the old ones hyperglycemia in patients with type 2 diabetes (3).
Table 1: Products of Diosmin and Hesperidin, available respectively alone in the market S Labeller Brand Name Dosage Activity/ Purpose No 1 Dulac Farmaceutici Diosmin Expert-Omniven Gel cream Heavy legs; varicose legs veins 2 Dulac Farmaceutici Diosmin Exper- procto Gel cream Treatment of piles complex 3 Dr Max Diosmina Capsules Vascular system 4 Swanson Hesperidin dietary Capsules Cardiovascular health supplement 5 Thorne Research HMC hesperidin 250mg Capsules Vascular system 6 Piping Rock Hesperidin 500mg Capsules Vascular system Table 2: Products of Diosmin and Hesperidin combination available in the market S No Labeller Brand Name Dosage Activity/Purpose 1 Servier Daflon/ Venixxa Tablets Varicose veins, Hemorrhoids 2 Dulac Farmaceutici Diosmin Expert-Omnivon Tablets Microcirculation of 500 hemorrhoid plexus 3 Swanson Diosvein Capsules Cardiovascular health
4 Purity products Hesperidin and Diosmin Capsules Vascular system complex
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LITERATURE STUDY Flavonoids have gained popularity due to their with nanoparticles. A list of tables below had broad range of benefits, now different works been put to summarize the important works had been done on these two compounds done (Table 3 and 4). specifically to evaluate their activity alone and
Table 3: Various biological activities reported for Diosmin S. No. Reporte Research focus Results concluded by the authors Activities concluded d by 1. Ahmed Evaluation of Oral administration of diosmin Anti-oxidant, anti- et al., diosmin in causing shows normalization of the level inflammatory, anti- 2016 downregulation of of NF- kB, showing role in diabetic activity (9). oxidative markers maintaining renal function, and in alloxan-induced elevation of malondialdehyde with diabetic a declination of glutathione, nitric nephropathy along oxide and, catalase and with controlling the superoxide dismutase. Concluding NF- kB signal anti-hyperglycemia-mediated transduction oxidative stress pathway 2. Ali et Hepatoprotective The study evaluated the Hepatoprotective activity al., activity diosmin hepatoprotective activity of (10). 2018 and sildenafil diosmin alone and with sildenafil against cholestatic and found combination therapy is liver cirrhosis and more effective. Combination role of Keap- alleviates liver cirrhosis with
1/Nrf-2 and P38- upregulation of Nrf-2, GSH, MAPK/NF- SOD, eNOS, and cytoglobin and κB/iNOS signaling downregulation of Keap-1, NF- pathway κB, P38-MAPK, MDA, and iNOS. 3. Ali, neuroprotective Pretreatment with Diosmin has Neuroprotective activity Fanaei and cognitive revealed protective effects against (11). and improving action memory impairment due to (TBI). Keikha in traumatic brain The protective action may be due ei, injury (TBI) rat to a decrease in the TNF-α 2017 model concentration in the hippocampus region 4. Arab et Anti-ulcer activity Suppression of gastric Anti-Ulcer activity (12). al., against ethanol- inflammation by decreasing 2015 induced gastric myeloperoxidase, NF-κB, and injury TNF-α levels. Along with augmentation of IL-10 levels. Including suppression of oxidative stress and apoptosis by anti- oxidant and cytoprotective action 5. Carball Hyperalgesic effect The study provided evidence that Anti-hyperalgesic (13). o- centrally and diosmin produce anti-hyperalgesic Villalob peripherally in effects by acting centrally on os et neuropathic pain opioid and D2 dopaminergic al., receptors, and reduction in 2018 cytokines levels shows peripheral action 6. Queent Cardioprotection Anti-oxidant property of diosmin Cardioprotective activity hy, against inhibiting cardiac mitochondrial (14). Mainze isoprenaline- oxidative stress/damage in n and induced heart myocardial infarcted rats Babu, mitochondrial 2017 oxidative stress 7. Sawmill Reduction of The study showed a significant Anti-Alzheimer’s (15).
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er et cerebral Aβ levels, reduction of Alzheimer pathology al., tau and cognitive impairment in 2016 hyperphosphorylati Alzheimer induced and inhibited on, Aβ generation and microglial neuroinflammation activation along also inhibited APP , and cognitive γ-secretase and GSK-3β impairment in Alzheimer diseased mice 8. Shalka Diosmin against The study revealed the significant Anti-inflammatory, anti- mi, acetic acid- elevation in markers of apoptotic, anti-oxidant Hassan induced ulcerative inflammation (TNF-α, COX-II & (16). and colitis MPO) and oxidative stress Bakr, represents the increase in colon 2017 caspase-3 expression. After treatment with Diosmin, decreased colon damage index when compared with acetic acid caused damage index, and declination in inflammatory and oxidative stress markers were observed therefore reducing the expression of caspase-3 9. Christin Evaluation of anti- Under the UV-B irradiation model, Anti-inflammatory, anti- e et al., inflammatory and diosmin cream has shown radical (17). 2018 antiradical effects declination in cyclobutane 2% diosmin cream pyrimidine formation and on human skin hydrogen peroxide production culture as a model showing the anti-radical effect and decreased IL-8 release shows anti- inflammatory effect. 10. Shaban Neuroprotective Scopolamine-induced cognitive Neuroprotective activity i, 2018 activity in impairment and disruption of (18). scopolamine- synaptic plasticity prevention by induced cognitive diosmin. The decline in TNF-α degradation/ concentration as a impairment proinflammatory cytokine in the hippocampus
AST - Alanine aminotransferase, ALT - TNF-α - Tumor necrosis factor α, MPO - Aspartate aminotransferase, GSH - Myeloperoxidase, NF-κB - Nuclear factor- Glutathione, CAT - Catalase, GPx - kappa light chain enhancer of activated B cells, Glutathione peroxidase, SOD - Superoxide MAPK – Mitogen Activated Protein Kinases and dismutase, MDA - Malondialdehyde, TAC - iNOS - Inducible nitric oxide synthase Total antioxidant capacity, IL6- Interleukin 6,
Table 4: Various biological activities reported for Hesperidin S No. Reporte Research focus Results concluded by the authors Activities concluded d by 1. Ansar The study Hesperidin mitigated the Hepatoprotective (19). et al., evaluated anti- biomarker levels such as AST, ALT, 2018 effect by and MDA, 88GSH, GPx, CAT, hesperidin against SOD which are opposite in nano oxidative stress zinc oxide induced hepatotoxicity. induced by nano zinc oxide particles 2. Bharga Study the agonistic Compared to the enalapril- Cardioprotective activity va et action peroxisome Hesperidin combination, (20). al., proliferator- Hesperidin and enalapril alone 2019 activated receptor treatment exhibited similar effects, 28| International Journal of Pharmacy Research & Technology | July - Dec 2020 | Vol 10 | Issue 2 Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGS
gamma (PPAR- γ), attenuating pathological changes, which is suppressing oxidative stress along responsible for with increasing PPAR-γ inhibiting of expression cardiac hypertrophy signaling pathways 3. Homay Examined the Patients were observed with a Anti-hypertensive, anti- ouni et hesperidin significant difference in diastolic, inflammatory (21). al., supplement effect mean arterial blood pressure, 2018 on inflammatory along with a decrease in TAC markers and blood serum and anti-inflammatory pressure in type 2 markers suggesting anti- diabetes patients hypertensive and anti- in a double-blind inflammatory action controlled clinical trial 4. Hong Neuroprotective Hesperidin significantly reversed Neuroprotective activity and effect of hesperidin the decreased phosphorylation of (22). An, in learning and GSK-3β, Akt, lessened Nrf2 and 2018 memory deficit increased expression of HO-1, mice phosphorylation of IκBα along with caused inhibition of RAGE expression and NF κB/p65 5. Kosari- Influence of Depressive-like behaviors cause Anti-depressant activity Nasab hesperidin in increases inflammatory cytokines (23). et al., attenuating and oxidative markers and reduce 2018 depression-related BNDF levels in the hippocampus symptoms in mice region. Hesperidin reversed these with mild traumatic levels brain injury 6. Li et The wound healing Significant upregulation of mRNA Wound healing activity al., ability of expressions in wound tissues such (24). 2018 hesperidin against as VEGF-c, Ang-1, Tie-2, TGF-β streptozotocin- and Smad 2/3, also increased induced diabetic SOD, GSH levels by hesperidin, rats which are downregulated by streptozotocin 7. Li et Evaluated Improvement in skin lesions of Anti-dermatitis (25). al., hesperidin’s imiquimod-induced mice and 2019 activity against hesperidin also inhibited imiquimod- lipopolysaccharide-induced induced psoriasis human keratinocytes cell in mice model and proliferation. In addition, it also human decreased and normalized insulin keratinocytes cells and glucose levels, further found to modulate the levels of leptin, adiponectin, and resistin. Inhibiting the initiation of the IRS- 1/ERK1/2 signaling pathway 8. Liu et The study Hesperidin effectively inhibited Glucose reducing al., investigated the ROS production due to high activity; prevention 2018 capability of glucose and also showed against diabetic hesperidin to scavenging activity by normalizing retinopathy causing prevent high various biomarkers along with visual impairment (26). glucose-induced opposite effect on high glucose- retinal pigment induced cell apoptosis pathway epithelial cell via caspase-9/3 upregulation, damage cytochrome c release into cytosols.
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9. Meng Investigated Significantly decreased levels of Cardioprotective activity et al., hesperidin's ability TNF-α, IL-1β, CAT, SOD along (27). 2018 to modulate with suppressed expression of Bcl- inflammatory 2/Bax and elevated PPAR- γ in responses, acute mice model myocardial infarction, and anti-oxidant activity 10. Poetini Attenuating action It significantly decreased the iron Anti-parkinsonis (28) et al., against Iron- levels in the brain responsible for 2018 induced oxidative Parkinson disease, along with stress and scavenging of reactive species, dopamine improving motor function, and reduction in cholinergic activity in the flies Drosophila Melanogaster as Parkinson's disease model
AST - Alanine aminotransferase, ALT- Aspartate Glycogen synthase kinase 3 beta, Akt - also aminotransferase, GSH - Glutathione, CAT - known as Protein kinase B, Nrf2 - Nuclear Catalase, GPx - Glutathione peroxidase, SOD - factor erythroid 2, IκBα - Inhibitor of kappa B Superoxide dismutase, MDA - protein alpha Malondialdehyde, TAC - Total antioxidant Other than animal studies, clinical studies are capacity, IL6 - Interleukin 6, TNF-α - Tumor also been done to evaluate their effects. In necrosis factor α, VEGF-c - Vascular Endothelial table 5 and 6 Hesperidin and Diasmin clinical Growth Factor C, Ang-1 - Angiopoietin 1, TGF- studies are reported (Table 5 and 6). β - Transforming growth factor beta, GSK-3β -
Table 5: Status of recent and on-going clinical trials reported for Hesperidin for various diseases S No Study Sponsor Status Phase Conditions 1. Effect of hesperidin on insulin University of Withdrawn 2 Insulin Resistance sensitivity Maryland 2. Effect of hesperidin on Bone Nestlé Completed 3 Osteoporosis metabolism and Bone mineral density of postmenopausal women 3. vascular effect of hesperidin University of Completed 4 Incompetent on metabolic syndrome Rome Tor accessory Vergata saphenous veins
Table 6: Status of recent and on-going clinical trials reported for Diosmin for various diseases S. No. Study Sponsor Status Phase Conditions 1. Effect of Detralex (Daflon) University Completed 4 Chronic for anti-inflammatory Hospital Venous activity Dubrava Insufficiency 2. Effect of Diosmin for -NA- Completed 2, 3 Infertility infertilites prevention 3. Effect of Diosmin 600mg Fundação Completed 4 Incompetent and Diosmin+Hesperidin Educacional accessory for chronic venous Serra dos saphenous insufficiency Órgãos veins 4. The efficiency of Diosmin Laboratoire Completed 3 Chronic 600mg for chronic venous Innotech Venous disease disease of lower limbs International of Lower Limb
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Nano-approach for Hesperidin & Diosmin focusing on how to improve the bioavailability to enhance bioavailability for various and provide efficient targeted delivery with activities: transport stimulation. New approaches to As both the compounds endow various kinds of providing direct delivery into the cells include properties such as anti-microbial, anti-viral, nano formulation like entrapment in diamond- anti-inflammatory, anti-oxidant and anti- like nanoparticles, phospholipid complex, tumour effects as summarized in above tables. cyclodextrin complex, etc. Various biological Hesperidin and Diosmin face GIT absorption activities reported for Diosmin and Hesperidin problem due to low solubility in water, they are and application of nanoparticles and showed only soluble in few organic solvents and this in table 7. results in low bioavailability of the compounds in the body. Numerous research groups are
Table 7: Various biological activities reported for Diosmin and Hesperidin and application of nanoparticles S. No. Reported by Research focus Results concluded by the Activities authors concluded 1. Corciova et Evaluation of agar diffusion method was Antioxidant, anti- al., 2015 antibacterial and used to culture bacterial (29). antioxidant activity of Staphylococcus Hesperidin:β- aureus ATCC cyclodextrin 25923, Escherichia complexes coliATCC 25922 and Candida albicans ATC C 10231, the complex showed antibacterial activity. Inhibition of lipoxygenase activity, DPPH radical scavenging activity showed antioxidant activity 2. Sahu et al., Synthesizing Ag using human promyelocytic Antibacterial, 2016 nanoparticles for leukemia (HL-60) cells cytotoxicity (30) flavonoids: investigated cytotoxicity and hesperidin, diosmin, bacterial effect concluding and naringin to Ag nanoparticles from evaluate antibacterial flavonoids showed good and cytotoxicity effect stability, better antibacterial, and cytotoxic activity 3. (Thomas et Mechanism of The complex formation of Anti-cancer al., 2019) interaction of Diosmin-AuNps with ctDNA, activity (31) Diosmin and gold through MTT assay, revealed nanoparticles with toxicity and anti-proliferative calf thymus DNA effect on normal human cell lines and MCF-7
(Mary et al., 2017) formulated a chitosan- Conclusion and future perspective based nanoformulation for hesperidin to Diosmin and Hesperidin are among the class overcome its water insolubility, aimed to of flavonoids gaining popularity globally passively target cancer cells (32). Chitosan- because of their potential health benefits in based hesperidin nano-formulation enhances minimizing neurodegenerative signs, blood hesperidin induced apoptosis of HCT15 cells vessels inflammation, microbial, improving exposing it be a likely candidate to treat cardiovascular health and effective antioxidant, colorectal cancer. Another β-Cyclodextrin and influencing immunomodulation activities. based nanocomplexes of hesperidin was Either alone or in combination, they are able to formulated by (Corciova et al., 2015), modulate the activities of various targets which demonstrated the enhancement in the play a pivotal role to produce a biological and solubility, anti-bacterial and antioxidant therapeutic action, where they are also activities of hesperidin (29). depended on their physiochemical and structural properties.
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Both the compounds show poor solubility, 6. Meyer, O.C., 1997. Angiology Safety and Security absorption, and distribution which are the of Daflon 500 mg in Venous Insufficiency and in major setbacks to produce any therapeutic Hemorrhoidal Disease. Angiology, 45(6), pp.579 - activity and Nanotechnology plays a vital role 584. here. The reasons for these could be their 7. Maher, S., Sabri, N.A., 2009. Evaluation of clinical molecular weight, solubility, structure, pH activity and safety of Daflon 500 mg in type 2 sensitivity etc. at present scenario the diabetic female patients. Saudi Pharm J, 17(3), micronization of their combination (Daflon pp.199–207. 500mg) have helped in improving its solubility 8. Manach, C., Scalbert, A., Morand, C., Remesy, C., and GIT absorption. Interestingly, recent studies Jimenez LRemesy, C., 2018. Polyphenols: food sources and bioavailability. Am J Clin Nutr, 79(5), have proposed the application of pp. 727–747. nanotechnology can improve the solubility, 9. Ahmed, S., Mundhe, N., Borgohain, M., bioavailability, pharmacokinetics, targeted Chowdhury, L., Kwatra, M., Bolshette, N., Lahkar, treatment, and their therapeutic action. M., 2016. Diosmin Modulates the NF-kB Signal Nanotechnology has already achieved many Transduction Pathways and Downregulation of milestones in the bio and medical field and Various Oxidative Stress Markers in Alloxan- helping to explore more new and better ways to Induced Diabetic Nephropathy. Mediat Inflamm, treat and prevent modern day diseases. 39(5), pp. 1783–1797. Nanotechnology application is modifying the 10. 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