Short-Term Effects of Supplemental L-Arginine, Diosmin, Troxerutin, and Hesperidin in Diabetic Patients: A Pilot Study.

BACKGROUND AND AIMS: Inflammatory, oxidative stress, and endothelial dysfunction play a key role in the pathogenesis of long-term cardiovascular complications in patients with diabetes. The present observational prospective study is aimed at evaluating the effects of micronutrients and phytochemicals contained in the dietary supplement Flebotrofine® (AMNOL Chimica Biologica) on biochemical markers of inflammation, endothelial dysfunction, and glycemic control in patients with diabetes. METHODS: 105 type 1 or type 2 diabetes patients regularly took a daily dose of the dietary supplement Flebotrofine® for three consecutive months, and haematological and biochemical parameters were checked at baseline, after three months of treatment, and one month after its suspension. Statistical comparison of the laboratory parameters was performed using the two-tailed ANOVA test for repeated samples with a statistical significance level set at p < 0.05. RESULTS: The daily use of Flebotrofine® did not change the glycemic metabolic compensation of enrolled patients. After three months of regular Flebotrofine® intake, the plasma levels of the antioxidant ß-carotene and of arginine were significantly higher compared with the baseline values, with a decrease in the ADMA/arginine ratio. In contrast, apolipoprotein B, ApoB/ApoA1 ratio, and platelet and leukocyte counts significantly dropped. CONCLUSION: The daily use of Flebotrofine® might be a valid supplement of arginine, the precursor of NO, and essential in the prevention of endothelial dysfunction. The regular intake of arginine and phytochemicals also improved the antioxidant and antithrombotic profile of enrolled patients. Therefore, Flebotrofine® could be a useful dietary supplement to prevent long-term complications in patients with diabetes.

Anticancer and Anti-inflammatory Effect of Diosmin against Dalton Ascitic Lymphoma Induced Leukemia.

Cancer is the world's biggest health problem and cancer-induced mortality happened all over the planet after the heart disease. The present study was to scrutinize the anti-leukemia effect of diosmin against Dalton Ascitic Lymphoma (DAL) induced leukemia in mice. DAL cell was used for induction the solid tumor. Body weight, life spans, tumor volume and mean survival time was estimated. Antioxidant, biochemical and pro-inflammatory cytokines were estimated. Diosmin showed the cell viability effect at dose dependent manner against the both cell lines. DAL induced solid tumor mice showed the decreased body weight, mean survival days, non viable cell count and increased the tumor volume, viable cell count and diosmin significantly (p < 0.001) reverse the effect of DAL. Diosmin significantly (p < 0.001) altered the hematological, differential leukocytes, antioxidant, biochemical, pro-inflammatory cytokines at dose dependently. Collectively, we can say that diosmin might alter the DAL induced abnormality via antioxidant and anti-inflammatory effects.

Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?

SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID-19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.

Aescin and diosmin each alone or in low dose- combination ameliorate liver damage induced by carbon tetrachloride in rats.

OBJECTIVE: This study evaluated hepatoprotective effect of aescin (AES) and diosmin (DIO), individually or in low-dose combination in chemically induced liver injury in rats. Rats were divided into 6 groups; Group 1, control, Group 2, injected with a single dose of a mixture of corn oil and carbon tetrachloride (CCl4) to induce hepatic toxicity. Before CCl4 injection, Groups 3-6 were treated daily for 14 days with silymarin (SIL) (200 mg/kg), aescin (AES; 3.6 & 1.75 mg/kg), Diosmin (DIO; 100 & 50 mg/kg). Serum samples were analyzed for different liver function, oxidative stress and antioxidant markers. Moreover, inflammation and tissue damage were confirmed by histological staining of liver tissue sections. RESULTS: Results indicated that CCl4 elevated serum levels of all assessed liver function markers and decreased levels of key antioxidants. Administration of AES and/or DIO significantly reversed all those CCl4-induced effects. Histopathological study showed disruption of the hepatic architecture, necrosis and inflammatory cells and depositions of glycogen and protein in the tissues of CCl4-treated group. Pretreatment with DIO and/or AES significantly improved histopathological structure of liver tissue. In conclusion, low-dose combination of AES and DIO exhibited significant and preferential hepatoprotective activity compared to individual treatment with AES or DIO.

Role of Diosmin in protection against the oxidative stress induced damage by gamma-radiation in Wistar albino rats.

The benchmark of this study is to evaluate the radio protective efficiency of diosmin, a natural citrus flavone of hesperidin derivative on radiation-induced damage in wistar albino rats. Rats orally administered two diosmin doses (100 and 200 mg/kg body wt.) for a month (every other day) prior to exposure to high gamma radiation single dose (8Gy) or cumulative dose (10Gy). To evaluate the radio protective efficiency of diosmin various biochemical estimations, histopathological alterations as well as comet assay and caspase-3 activity for assessment of apoptosis were performed. Results indicated that radiation-induced decline in the levels of antioxidant parameters (SOD and GSH), increased lipid peroxidation, DNA damage and apoptosis were improved by pre-administration of diosmin. Diosmin dose (200 mg/kg body wt.) restored the antioxidant status to near normal and reduced lipid peroxidation, DNA and tissue damage. These results were confirmed by histopathological examinations, which showed that pre-administration of diosmin protected the liver and kidney of albino rats against gamma-irradiation induced damage. Hence, it has been illustrated that diosmin might be an effective radio protector against radiation-induced damage in rats. Moreover, diosmin alone pretreated group did not show any biochemical alterations or DNA damage indicating the protective nature of the drug.

Combating atherosclerosis with targeted Diosmin nanoparticles-treated experimental diabetes.

Diabetes with poor glycemic control is accompanying with an increased risk of disease namely atherosclerotic cardiovascular. Diosmin (DSN), which is obtained from citrus fruit used to assist the treatment of hemorrhoids or chronic venous atherosclerosis diseases, has an antioxidant, anti-hyperglycemic and anti-inflammatory effect. DSN is characterized by poor water solubility which limits its absorption by the gastrointestinal tract. To overcome this limitation, this study was designed to increase DSN bioavailability and solubility, through its loading on polymeric matrix; hydroxypropyl starch (HPS) and Poly lactide-glycolide-chitin (PLGA/chitin) to prepare Diosmin nanoparticles (DSN-NPs). Two methods were used to prepare DSN- NPs; Emulsion-solvent evaporation and Acid-base neutralization followed by further assessment on diabetes induced atherosclerosis The study was conducted on 50 animals assigned into 5 groups with 10 animals in each group: Group I: Normal rats received only normal saline, Group II: Diabetic rats, Group III: diabetic rats received oral DSN, Group IV: diabetic rats received DSN loaded HPS, Group V: diabetic rats received DSN loaded PLGA/chitin. Levels of total cholesterol, triglycerides, HDL-cholesterol, insulin, MDA and NO. plasminogen activator inhibitor-1 PAI-1), Paraoxonase-1(PON1), transforming growth factor-ß1 (TGF-ß1), NF-Ò¡B and Ang II were estimated. Our study revealed that, there was statistically significant difference between DSN treated group compared with DSN loaded HPS treated group and DSN loaded PLGA/chitin. Furthermore, the results obtained clearly disclosed no statistically significant difference between DSN loaded PLGA/chitin and control group exhibited DSN loaded PLGA/chitin has the higher ability to counteract the atherosclerosis factors induced by diabetes in all rats.

The Benefits of Micronized Purified Flavonoid Fraction (MPFF) Throughout the Progression of Chronic Venous Disease.

At the 2019 European Venous Forum in Zurich Switzerland, a symposium entitled "State of the art: benefits of MPFF throughout CVD progression" was held to discuss the developing treatment strategies for patients at all stages of chronic venous disease (CVD). At the early stages of CVD, management should be focused on preventing disease progression through lifestyle changes and conservative treatment; treatment can also include venoactive drugs (VAD) such as micronized purified flavonoid fraction (MPFF; Daflon®), which is the most well-known and most widely prescribed VAD in Europe. As the disease progresses, patients who require interventional procedures (e.g., endovenous procedure or sclerotherapy) can also benefit from MPFF treatment in the recovery period after the procedure, as MPFF has been shown to reduce periprocedural pain and bleeding (hematoma), and to improve CVD symptoms during this period. Management of CVD in patients with venous leg ulcers (VLU) is the most challenging; in these patients, recommended adjunct therapies to be combined with standard compression therapy include VAD (MPFF) and non-VAD drugs (pentoxifylline and sulodexide) which have been shown to speed VLU healing in comparison with compression therapy alone.

The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a nonischemic myocardial disorder characterized by metabolic disturbances and oxidative stress in diabetic patients. The present paper aims to determine the protective effect of the phlebotrophic drug, diosmin, on DCM in a model of high-fat diet-fed and streptozotocin-induced type 2 diabetes in the rat. MATERIALS AND METHODS: The animals were divided into 4 groups (8 rats/group) as follows: vehicle-treated nondiabetic control group, vehicle-treated diabetic group, diosmin (50 mg/kg)-treated diabetic group and diosmin (100 mg/kg)-treated diabetic group. Treatment was given once daily orally by gavage for 6 weeks. Oxidant and antioxidant stress markers, inflammatory markers and proapoptotic and antiapoptotic gene expression using quantified real-time polymerase chain reaction were investigated. RESULTS: Diosmin treatment in diabetic rats lowered elevated blood glucose levels, homeostatic model assessment for insulin resistance, cardiac creatine kinase and lactate dehydrogenase enzymes, cardiac malondialdehyde and nitric oxide. Moreover, diosmin increased plasma insulin and c-peptide levels, cardiac glutathione content, superoxide dismutase, catalase and glutathione S-transferase activities. Also, diosmin treatment significantly (P < 0.05) lowered the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), down-regulated cardiac Bcl-2-associated X protein and caspase 3 and 9 and up-regulated B-cell lymphoma 2 mRNA expression levels. CONCLUSIONS: Diosmin may have a sizeable therapeutic potential in the treatment of DCM due to antidiabetic, antioxidative stress, anti-inflammatory and antiapoptotic effects. Detailed studies are needed to disclose the precise mechanisms motivating the protective effect of diosmin .

Diosmin for the prevention of ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate the effect of oral diosmin on the incidence and severity of ovarian hyperstimulation syndrome (OHSS) and explore the value of diosmin in preventing and treating OHSS. METHOD: A retrospective study of women attending a reproductive center in Guangzhou, China, between September and December 2016. The inclusion criterion was previous cancellation of embryo transfer after oocyte retrieval during IVF owing to a high risk of OHSS. The women were divided into two groups depending on whether they received oral diosmin (1000 mg twice daily for 10 days) after oocyte retrieval (diosmin group) or not (control group). Apart from diosmin, both groups underwent the same treatment. Baseline information and data related to OHSS were compared. RESULTS: Overall, 146 women were included: 74 in the diosmin group and 72 in the control group. The incidence of moderate-to-severe OHSS in the diosmin and control groups was 5/74 (6.2%) and 14/72 (13.4%), respectively (P=0.027). The control group included four cases of paracentesis due to ascites; there were no cases of paracentesis or severe OHSS in the diosmin group. CONCLUSION: Oral administration of diosmin effectively reduced both the incidence of moderate-to-severe OHSS and the severity of OHSS among high-risk women.

Protective role of diosmin against testosterone propionate-induced prostatic hyperplasia in Wistar rats: Plausible role of oxidative stress and inflammation.

Benign prostatic hyperplasia (BPH) is an important key health concern for aging men. Polyphenolic compounds have been found to possess important roles in the inhibition of numerous ailments that involve reactive oxygen species and inflammation. Diosmin is a citrus flavone that possesses antioxidant, anti-inflammatory, antiproliferative, and anticancer activities, so based on these properties of diosmin, we decided to evaluate its effect on testosterone propionate (TP)-induced BPH. A total of 30 Wistar rats were randomly assigned to five groups having six animals in each. This study was of 28 days in which TP (5 mg kg-1) was administered to induce BPH in the last 10 days of the study. It was found that diosmin at the doses of 20 and 40 mg kg-1 significantly reduced malondialdehyde and xanthine oxidase formation in a dose-dependent manner; however, it replenished catalase, glutathione (GSH), and GSH-dependent enzymes, that is, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase significantly against TP-induced BPH. Further, immunohistochemical study showed that diosmin alleviated inflammatory markers (nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2, and interleukin-6). It was also found that diosmin downregulated the expression of androgen receptor and decreased the prostate-specific antigen concentration dose-dependently, significantly against TP-induced BPH. Diosmin also restored histoarchitecture of the prostate in a dose-dependent manner. Findings from the present study revealed the protective role of diosmin against TP-induced BPH in Wistar rats.

A nutraceutical composition containing diosmin and hesperidin has osteogenic and anti-resorptive effects and expands the anabolic window of teriparatide.

A combination of diosmin and hesperidin (9:1 ratio) is marketed as a dietary supplement/nutraceutical for cardiovascular health. We studied the skeletal effect of this combination (90% diosmin and 10% hesperidin, henceforth named as DH). We showed that a) in rats with femur osteotomy, DH stimulated callus bone regeneration, b) in growing rats, DH promoted peak bone mass achievement and c) in OVX rats rendered osteopenic, DH completely restored femur trabecular bones and strength along with the increases in surface referent bone formation and serum osteogenic marker. Furthermore, DH suppressed bone resorption in OVX rats as well as in OVX rats treated with teriparatide (human parathyroid hormone 1-34) but did not affect the osteoanabolic effect of teriparatide. These data suggested that DH could prolong the anabolic window of teriparatide. To understand the mechanism of DH action, we performed pharmacokinetic studies and observed that upon its oral administration the only circulating metabolites was diosmetin (the aglycone form of diosmin) while none of the two input flavanones were detectable. Accordingly, subsequent experiments with diosmetin revealed that it was a selective estrogen receptor-ß agonist that stimulated osteoblast differentiation and suppressed sclerostin the anti-osteoblastogenic Wnt antagonist. Taken together, our study defined a positive skeletal effect of DH.

Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment in the management of patients with post-trauma/surgery persistent hand edema: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness and safety of oral administration of Linfadren® in addition to conventional treatment in patients with post-trauma/surgery persistent hand edema. DESIGN: Parallel-group randomized controlled trial. SETTING: Outpatient rehabilitation center. SUBJECTS: A total of 60 outpatients (mean age 48.5 (standard deviation (SD) = 12.3) years) with post-trauma/surgery persistent hand edema. INTERVENTIONS: Patients were randomized to either receive six-week conventional treatment plus Linfadren® (Study Group) or conventional treatment (Control Group). MAIN MEASURES: Primary outcome was hand edema as measured by figure-of-eight method. Secondary outcomes were hand function, patient's overall perceived treatment effectiveness and rescue medication request. Tolerability of Linfadren® was also evaluated. Assessments were performed at baseline, at the end of treatment and three months after the end of treatment. RESULTS: All patients completed the six-week program and 57 patients (95%) completed the three-month follow-up. At six weeks, the Study Group had significantly greater improvement in hand edema (423.3 (SD = 23.8) mm vs 439.4 (SD = 22.6) mm; P = 0.009) and upper limb function ( Quick Disabilities of Arm, Shoulder and Hand questionnaire: 23.6 (SD = 13.6) vs 37.7 (SD = 15.9); P = 0.005) compared to the Control Group. Moreover, the percentage of patients who perceived treatment as effective was significantly higher in the Study Group than in the Control Group both after treatment (70% vs 37%, P = 0.002) and at follow-up (77% vs 30%, P < 0.0001). The rescue medication request was not different between groups. No adverse events were recorded. CONCLUSION: Linfadren® in addition to conventional treatment was safe and more effective than conventional treatment alone in patients with post-trauma/surgery persistent hand edema.

Diosmin Nanocrystal-Loaded Wafers for Treatment of Diabetic Ulcer: In Vitro and In Vivo Evaluation.

This work aimed at loading of diosmin nanocrystals into alginate-based wafers for treatment of highly exuding diabetic ulcer in rats using topical route of administration. For this purpose, different formulation variables and preparation techniques to enhance the flexibility and adhesion properties of the prepared sodium alginate (SA) wafers were carried out. The prepared wafers were characterized regarding hydration capacity, bioadhesion, scanning electron microscope, and Fourier-transform infrared spectroscopy. Efficacy of treating diabetic ulcer was studied using diabetic-induced rat model using streptozotocin. Results obtained showed that using SA:gelatin with 1.5%/1.5% w/w gave acceptable wafers with a sustained release of diosmin over 8 h. A complete re-epithelialization, well-organized dermal layers, well-formed granulation tissue, and mature collagen bundles were observed in treated rats. It was concluded that combination of gelatin with SA provided an excellent wafer as a promising medicated wound dressing holding diosmin nanocrystals while maintaining its stability.

Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema.

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.

[Endotheliotropic effects of venotonic drugs in treatment of patients with varicose veins]. / Éndoteliotropnye éffekty venotoniziruiushchikh preparatov pri lechenii bol'nykh s varikoznoi bolezn'iu.

The authors analysed the effect of Venarus on the endothelial function in patients suffering from lower limb varicose veins. Our open-label prospective study included a total of 100 patients diagnosed as having CEAP class C1-C2 varicose veins and divided into two equal groups. Dynamic assessment of the clinical course of the disease in Group One patients was carried out on the background of taking Venarus and compression therapy, with Group Two patients evaluated without taking Venarus. At defined stages we determined the level of biochemical markers of endothelial function. The obtained findings demonstrated that the use of phlebotonic Venarus resulted in decreased activity of lipid peroxidation processes and reduced activity of antioxidant system enzymes. Using Venarus was followed by a statistically significant decrease in the concentration of malonic dialdehyde (from 1.220±0.190 µmol/l at baseline to 0.858±0.231 µmol/l after 2 months of treatment), whereas in Group Two patients the changes were insignificant (1.191±0.204 µmol/l before treatment and 1.138±0.175 µmol/l at 2 months thereafter). Patients taking Venarus were also found to have a higher level of nitric oxide metabolites compared with the patients treated by compression therapy alone (51.646±11.757 and 36.310±6.921 µmol/l in Groups One and Two, respectively). Hence, an evidence-based conclusion was drawn that Venarus proved efficient and may therefore be prescribed as pharmacotherapy for correction of endothelial dysfunction.

Conservative Treatment of Hemorrhoids: Results of an Observational Multicenter Study.

INTRODUCTION: This study was conducted to determine the frequency of complaints in a cohort of patients with symptomatic hemorrhoidal disease (HD) treated with micronized purified flavonoid fraction (MPFF, Detralex). MPFF was selected for conservative treatment in this population owing to its proven effects on hemorrhoidal symptoms in a large number of patients. METHODS: This multicenter, non-interventional study was part of the international CHORUS survey (Chronic venous and HemORrhoidal diseases evalUation for improvement of Scientific knowledge), conducted in nine centers in different regions of Russia with the participation of 80 coloproctologists. The study enrolled consecutive patients with complaints of hemorrhoids. All were prescribed MPFF-based conservative treatment. The effect of treatment on HD clinical signs and symptoms was assessed at two follow-up visits performed 5-7 days and 25-30 days after enrollment. Surgical and minimally invasive treatment could be performed from day 7 onwards if required. RESULTS: A total of 1952 patients were enrolled. Over the entire period of observation, MPFF-based conservative treatment was effective in 1489 (76.3%) patients in eliminating the main clinical manifestations of disease, i.e., bleeding and prolapse of internal nodes. Invasive treatment was performed in 68 (3.5%) patients with grade IV hemorrhoids and was combined with MPFF conservative treatment in 395 (20.2%) patients with grades I-III hemorrhoids. CONCLUSION: Conservative therapy with MPFF was beneficial for relieving hemorrhoidal symptoms in the majority of patients. MPFF-based treatment was most effective in patients with grade I and II hemorrhoids before irreversible degenerative changes in ligaments of the hemorrhoidal plexuses have occurred. It was also beneficial in preventing disease relapse in patients with more advanced HD and for promoting optimal conditions in the postoperative period. FUNDING: Servier.

[Common sense of diosmin administration in combined treatment of hemorrhoids]. / Zdravyi smysl primeneniia diosmina v kombinirovannom lechenii gemorroia.

Flavonoids are herbal medicines and widely used for chronic venous diseases and hemorrhoids. Flavonoid diosmin in both micronized and non-micronized form is a part of various drugs. According to literature data, flavonoids are able to reduce venous stasis, suppress local inflammation, improve venous tone and lymphatic outflow. It should be noted that biological models of in vivo trials have certain limitations while available data of different researches are contradictory. However, flavonoids were recommended for hemorrhoids in view of meta-analysis of 14 trials comparing flavonoids (diosmin, micronized purified flavonoid fraction and rutosides) with placebo in 1514 patients with hemorrhoids and Cochrane review of 24 randomized controlled trials (2,334 participants). These drugs should be administered as a part of complex therapy. At the same time, there is no conclusive evidence to prefer only one of these medicines. There are also no data confirming the benefits of daily dosage of 3000 mg per day of micronized fraction of flavonoids compared with 1800 mg of purified diosmin per day for treatment of acute hemorrhoids.

Anti-inflammatory and antiradical effects of a 2% diosmin cream in a human skin organ culture as model.

BACKGROUND: Diosmin, a naturally occurring flavonoid, is considered as a vascular-protective agent and is used orally to treat chronic venous insufficiency. It exhibits anti-inflammatory and free radical scavenging properties, but, like many other flavonoids, it is poorly absorbed in the small intestine. OBJECTIVE: Our aim was to investigate the skin protective effects of a diosmin-based cream, using skin organ culture as model. METHODS: Fragments of human skin explants, cultured ex vivo, were allocated to four treatment groups: no cream, no cream + stress, placebo cream + stress, and 2% diosmin cream + stress. Stress was induced by exposure to either substance P (anti-inflammatory effects' assessment) or UVB irradiation (free radical scavenging effects' assessment). Vascular dilation and the pro-inflammatory mediator IL-8 release were determined in the first model, whereas hydrogen peroxide level and the number of cyclobutane pyrimidine-positive cells were evaluated in the second model. RESULTS: In the substance P-induced inflammation model, 2% diosmin cream exhibited significant vasoconstrictive (proportion of dilated capillaries: -29%, capillary luminal area: -49% vs no cream + stress) and anti-inflammatory (IL-8 release: -36% vs no cream + stress) effects. In the UVB irradiation model, 2% diosmin cream significantly reduced hydrogen peroxide production and cyclobutane pyrimidine dimer formation (-45% and -36% vs no cream + stress, respectively). These effects were not observed with placebo cream. CONCLUSION: Diosmin administered topically may protect skin against the biological effects of various exogenous or endogenous stresses, such as those involved in chronic venous disease.

Comparative Bioavailability of Two Diosmin Formulations after Oral Administration to Healthy Volunteers.

Diosmin is a flavonoid commonly found in citrus fruits, largely used as adjuvant treatment for circulatory disorders, including chronic venous insufficiency (CVI) and hemorrhoids. Following oral administration, diosmin is not directly absorbed but must first be hydrolyzed into its aglycone, diosmetin, which is then absorbed into the systemic circulation. The aim of the current cross-over clinical study was to assess the pharmacokinetic profile of µSmin® Plus, a micronized diosmin flavonoid complex standardized in diosmin and formulated with a buffering agent (tested formulation). The study compared this to unformulated micronized diosmin (reference), in 16 healthy volunteers. Plasma samples were analyzed by HPLC-MS and plasma diosmetin concentration was measured after deconjugation with ß-glucuronidase. For the tested formulation area under the curve (AUC0-t), and maximum plasma and time concentration (Cmax; tmax) were found to be 298.4 ± 163.7, 50.3 ± 22.6 and 2.2 ± 2.9, respectively. AUC0-t and Cmax of the reference were 31.9 ± 100.4 and 2.4 ± 1.9, respectively. The tested formulation showed higher plasmatic concentrations of diosmetin in comparison to those obtained after the administration of unformulated micronized diosmin. The relative bioavailability was 9.4 greater for the tested formulation than in micronized diosmin. In conclusion, our data indicate that µSmin® Plus was rapidly and well absorbed into systemic circulation and may therefore be ideally suitable to deliver diosmin in human interventional trials.

Dual-targeted casein micelles as green nanomedicine for synergistic phytotherapy of hepatocellular carcinoma.

In recent years, green nanomedicines have made transformative difference in cancer therapy researches. Herein, we propose dual-functionalized spray-dried casein micelles (CAS-MCs) for combined delivery of two phytochemicals; berberine (BRB) and diosmin (DSN) as targeted therapy of hepatocellular carcinoma (HCC). The nanomicelles enabled parenteral delivery of the poorly soluble DSN via its encapsulation within their hydrophobic core. Moreover, sustained release of the water soluble BRB was attained by hydrophobic ion pairing with sodium deoxycholate followed by genipin crosslinking of CAS-MCs. Dual-active targeting of MCs, via conjugating both lactobionic acid (LA) and folic acid (FA), resulted in superior cytotoxicity and higher cellular uptake against HepG2 cells compared to single-targeted and non-targeted CAS-MCs. The dual-targeted DSN/BRB-loaded CAS-MCs demonstrated superior in vivo anti-tumor efficacy in HCC bearing mice as revealed by down regulation of cell necrosis markers (NF-κB and TNF-α), inflammatory marker COX2, inhibition of angiogenesis and induction of apoptosis. Histopathological analysis and immunohistochemical Ki67 staining confirmed the superiority of the dual-targeted micelles. Ex-vivo imaging showed preferential liver-specific accumulation of dual-targeted CAS-MCs. Overall, this approach combined the benefits of traditional herbal medicine with nanotechnology via LA/FA-CAS-MCs loaded with BRB and DSN as a promising nanoplatform for targeted HCC therapy.