Increased bioavailability of diosmetin-7-glucoside-γ-cyclodextrin inclusion complex compared with diosmin in Sprague-Dawley rats.

Diosmin (DSN) is found mainly in citrus fruits, and has potent antioxidant effects. This study aimed to evaluate pharmacokinetics of diosmetin-7-glucoside-γ-cyclodextrin (DIOSG-CD) inclusion complex. The area under the curve values from AUC0-24 of DIOSG-CD, prepared by reacting DSN and naringinase with γ-CD, were approximately 800-fold higher than those of DSN following their administration in Sprague-Dawley rats.

Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review.

Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.

Preparation, evaluation and pharmacokinetics of diosmin herbosome in beagle dogs.

Diosmin is one of the most widely used phlebotonic drugs, but its poor bioavailability has restricted its usage. The aim of this study was to formulate a complex Diosmin with phospholipids (75% in PC, in 1:2 molar ratios) and to evaluate for solubility, drug content, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and in vitro dissolution study. Further to test the bioavailability of both the complex and Alvenor⌖ in beagle dogs and compare pharmacokinetic parameters. Diosmin herbosome was found to be more soluble than both pure diosmin and Alvenor⌖. The complex contained 71.94% drug content. DSC thermograms and XRD also proved the claim of the complexation. The dissolution profile of diosmin herbosome and Alvenor⌖ in water-ethanol medium showed an increase of the dissolution for diosmin herbosome. Comparison of plasma concentration and main pharmacokinetic parameters of diosmin herbosome treated and Alvenor⌖ treated dogs showed a higher Cmax for the complex with longer elimination half-life. The complexation of diosmin with phospholipids can be potentially used in enhancing the absorption and solubility, consequently increasing the bioavailability of the drug.

In-silico Designing, ADMET Analysis, Synthesis and Biological Evaluation of Novel Derivatives of Diosmin Against Urease Protein and Helicobacter pylori Bacterium.

BACKGROUND: Designing drug candidates against the urease enzyme, which has been found responsible for many pathological disorders in human beings as well as in animals, was done by insilico means. METHODS: Studies were carried out on a designed library of diosmin derivatives with the help of Schrodinger's maestro package of molecular docking software against a crystallographic complex of plant enzyme Jack bean urease (PDB ID: 3LA4). Best twelve derivatives of diosmin were selected for synthesis by considering their interaction energy along with docking score and were further investigated for antioxidant, urease inhibitory and Anti-H. pylori activity by in- vitro method along with ADMET analysis. RESULTS: In-vitro results of series concluded compounds D2a, D2d and D7 (IC50 12.6 ± 0.002, 14.14 ± 0.001 and 15.64 ± 0.012 µM respectively in urease inhibition and 5.195 ± 0.036, 5.39 ± 0.020 and 5.64± 0.005 µM in antioxidant behavior against DPPH) were found to be significantly potent with excellent docking score -11.721, -10.795, -10.188 and binding energy -62.674, -63.352, -56.267 kJ/ mol as compared to standard drugs thiourea and acetohydroxamic acid (-3.459, -3.049 and -21.156 kJ/mol and - 17.454 kJ/mol) whereas compounds D2b, D5b, D5d and D6 were found moderate in urease inhibitory activity. CONCLUSION: Selected candidates from the outcome of in-vitro urease inhibitory were further examined for anti- H. pylori activity by a well diffusion method against H. pylori bacterium (DSM 4867). Compound D2a showed good anti-H. Pylori activity with a zone of inhibition 10.00 ± 0.00 mm and MIC value 500µg/mL as compared to standard drug acetohydroxamic acid having a zone of inhibition 9.00 ± 0.50mm and MIC 1000µg/mL. In- silico studies played an important role in designing the potent ligands against urease protein as well as in explaining the binding pattern of designed and synthesized ligand within the active pocket of jack bean urease protein. ADMET studies were also carried out to check the drug similarity of designed compounds by the means of quikprop module of molecular docking software. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. pylori and urease associated diseases.

[Diosmin in the treatment of venous disease: pharmacokinetics and pharmacodynamics (in Russian only)]. / Diosmin v lechenii venoznoi patologii: osnovy farmakokinetiki i farmakodinamiki.

The issues of absorption, bacterial intestinal metabolism and hepatic metabolism of diosmin are described. The main metabolites of the drug and the ways of their elimination are indicated. The article describes the main therapeutic targets and mechanisms of influence on the course of disease including effect on the venous wall tone and permeability, lymphatic drainage, inflammation and oxidative stress.

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.

Pharmacokinetic Profile of µSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats.

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (µSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t½), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with µSMIN Plus™ compared with animals treated with micronized diosmin. In particular, µSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for µSMIN Plus™, which may represent a new tool for CVI management.

Electrospinning of diosmin from aqueous solutions for improved dissolution and oral absorption.

A nanofibrous membrane carrier for nearly water insoluble drug diosmin was formulated. The aim of this study was to evaluate the drug release and dissolution properties in an aqueous buffer of pH 7.8, and to compare the suitability of the drug carrier with the available drug forms and screen diosmin absorption extent. The membranes were produced from HPC/PVA/PEO-drug water solutions and then evaluated by SEM and DSC measurements. The results showed that diosmin was incorporated within the nanofibers in an amorphous state, and/or as a solid dispersion. The results of in vitro release experiments excerpt a very fast release of the drug, followed by the formation of an over saturated solution and partial precipitation of the drug (a "spring" effect). The enormous increases in dissolution of the drug from a nanofibrous carrier, compared to a micronized and crystalline form, was achieved. The in vivo bioavailability study carried out on rats showed higher initial drug plasma levels and higher AUC values after administration of the nanofibrous drug formulation, compared to the micronized form. The results of the study demonstrated that the improvement of the diosmin in vitro dissolution also brought the enhanced in vivo absorption extent of the drug.

[Ultrasound elastography in assessing efficacy of treatment for lower limb varicose veins with a phlebotrophic drug containing a micronized purified flavonoid fraction].

UNLABELLED: Venous hypertension combined with other pathogenetic links of the development of chronic venous insufficiency creates conditions for activation of an inflammatory process. Chronization of inflammation leads to alterations in the histological structure of the vascular wall and perivasal tissues, which is reflected by changes in their physical properties (elasticity or compressibility), which may be studied by means of ultrasound elastography (USEG). OBJECTIVE: The study was aimed at exploring the possibility of using ultrasound elastography for monitoring efficacy of conservative treatment of varicose disease of lower extremities with an agent containing a micronized purified flavonoid fraction (MPFF). MATERIAL AND METHODS: we examined a total of 19 patients (38 limbs) presenting with varicose disease of clinical class C2 according to the CEAP classification. The standard ultrasound examination and USEG were carried out using the unit of expert-class "Toshiba" (Japan) with a multi-frequency linear transducer 5-12 Hz. We examined the great saphenous vein in the area of the femur and crus, its tributaries, and the small saphenous vein. All examinations were performed with the patient in the supine, prone and standing positions from the standard approaches in the second half of the day prior to treatment with a phlebotrophic agent containing MPFF (Detralex) and three months after taking the drug at a dose of 1,000 mg/day. RESULTS: at baseline, according to the findings of USEG the intact veins of the lower limbs had a homogeneous pattern of the elastogram in the perivasal area. The presence of varicose transformation was associated with an inhomogeneous elastographic picture. On the background of treatment with MPFF, all patients showed a positive clinical effect in the form of decreased intensity of manifestations of complaints or complete disappearance thereof. According to the findings of ultrasound examination, there was a tendency towards a decrease in the wall thickness and diameter of the examined veins. USEG demonstrated an increase in the perivasal zones of elastographic homogeneity of tissues. The USEG-revealed alterations were more pronounced in large-diameter vessels. On the background of treatment with Detralex there was a trend towards normalization of the elastographic pattern of the vessel as a whole. CONCLUSION: the obtained findings confirm feasibility of using the technique of ultrasound elastography for identification of objective markers of treatment response to MPFF in varicose disease.

Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation.

Diosmin (DSN) is an outstanding phlebotonic flavonoid with a tolerable potential for the treatment of colon and hepatocellular carcinoma. Being highly insoluble, DSN bioavailability suffers from high inter-subject variation due to variable degrees of permeation. This work endeavored to develop novel DSN loaded phytosomes in order to improve drug dissolution and intestinal permeability. Three preparation methods (solvent evaporation, salting out, and lyophilization) were compared. Nanocarrier optimization encompassed different soybean phospholipid (SPC) types, different solvents, and different DSN:SPC molar ratios (1:1, 1:2, and 1:4). In vitro appraisal encompassed differential scanning calorimetry, infrared spectroscopy, particle size, zeta potential, polydispersity index, transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed under sink versus non-sink conditions. Ex vivo intestinal permeation studies were performed on rats utilizing noneverted sac technique and high-performance liquid chromatography analysis. The results revealed lyophilization as the optimum preparation technique using SPC and solvent mixture (Dimethyl sulphoxide:t-butylalchol) in a 1:2 ratio. Complex formation was contended by differential scanning calorimetry and infrared data. Optimal lyophilized phytosomal nanocarriers (LPNs) exhibited the lowest particle size (316 nm), adequate zeta-potential (-27 mV), and good in vitro stability. Well formed, discrete vesicles were revealed by transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed. LPNs demonstrated significant enhancement in DSN dissolution compared to crude drug, physical mixture, and generic and brand DSN products. Permeation studies revealed 80% DSN permeated from LPNs via oxygenated rat intestine compared to non-detectable amounts from suspension. In this study, LPNs (99% drug loading) could be successfully tailored for DSN with improved dissolution and permeation characteristics, which is promising for lowering the influence of exogenous factors and increasing drug delivery.

[Bioflavonoids and their significance in angiology: focus on diosmin].

The article deals with historical information dedicated to the discovery of bioflavonoids and their effect on the human cardiovascular system, also considering the modern classification of phlebotrophic agents, followed by generalization and analysis of their mechanisms of action, as well as detailed discussion of different forms of diosmin. Summing up contains generalization of the Russian, European, and American guidelines on using phlebotrophic drugs for various forms and stages of chronic venous diseases.

[On advisability of perioperative phleboprotection in endovascular treatment of lower in varicose disease: first initial results of the decision study].

Presented in the article are the results of the DECISION multicenter study dedicated io assessment of efficacy and feasibility of using the phlebotropbic drug detralex in the perioperative period in patients undergoing endovascular treatment of lower limb varicose discase. The study comprised a total of 230 patients presenting with chronic venous disease. (CVD) C2-4s according the CEAP classification, each of these had not less than three CVD- related symptoms. All patients were randomly assigned to the Study Group (126 people) and the Control Group (104 subjects). The Study Group patients 2 weeks prior to endovascular treatment and during 4 weeks thereafter took the phlebotrophic drug detralex at a standard daily dose of 1,000 mg. The Control Group patients received conventional compression thernpy using compression bandages or medicinal knitted fabric. The findings of the statistically processed results in the both groups demonstrated a significant decrease in the CVD severity score according to the VCSS scale and an increase in the quality of life parameters according to the disease-specilic questionnaire CIVIQ-14. While so doing, more pronounced dynamics was observed in patients taking detralex during the perioperative period. Besides, there was synergism between the results of the endovascular intervention and therapeutic effects from detralex. Based on the findings obtained in the present study, the authors made a conclusion on feasibility of using the drug detralex as an agent for nonspecific pharmacological protection in endovascular treatment of varicose disease.

[Micronized purified flavonoid fraction in treatment of pelvic varicose veins].

Presented herein are the results of studying efficacy of micronized purified flavonoid fraction (MPFF) in treatment of pelvic varicose veins (PVV) using reference ray-tracing methods of study. We examined a total of 85 patients with PVV. Of these, 65 subjects were found to have isolated dilatation of pelvic venous plexuses (study group), and 20 were diagnosed as having combined dilation of gonadal veins and venous plexuses of the pelvis (control group). Besides clinical examination, the patients were subjected to ultrasonographic angioscanning (USAS) and emission computed tomography (ECT) of pelvic veins before treatment and 2, 6, 12, 24, 36 and 60 months after the beginning of phlebotrophic therapy. Based on the findings of the clinical and instrumental studies, it was determined that MPFF was most efficient in patients with isolated dilatation of uterine and parametrial veins. In this group of patients, pelvic pain and other symptoms of the disease disappeared completely and the clinical effect persisted for a long time (up to 6-9 months). In the control group, venotonic therapy had a positive effect which was less pronounced as compared to the control group, and pelvic pain reappeared in the nearest time (up to 3 weeks) after withdrawal of MPFF.

Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: Application to a clinical pharmacokinetic study.

Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone) is the aglycone of the flavonoid glycoside diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-ramnoglucoside). Diosmin is hydrolyzed by enzymes of intestinal micro flora before absorption of its aglycone diosmetin. A specific, sensitive, precise, accurate and robust HPLC assay for the simultaneous determination of diosmin and diosmetin in human plasma was developed and validated. Plasma samples were incubated with beta-glucuronidase/sulphatase. The analytes were isolated by liquid-liquid extraction with tert-butyl methyl ether at pH 2, and separated on a C(18) reversed-phase column using a mixture of methanol/1% formic acid (58:42, v/v) at a flow rate of 0.5ml/min. APCI in the positive ion mode and multiple reaction monitoring (MRM) method was employed. The selected transitions for diosmin, diosmetin and the internal standard (7-ethoxycoumarin) at m/z were: 609.0-->463.0, 301.2-->286.1 and 191, respectively. A good linearity was found in the range of 0.25-500ng/ml (R(2)>0.992) for both compounds. The intra-batch assay precision (CV) for diosmin and diosmetin ranged from 1.5% to 11.2% and from 2.8% to 12.5%, respectively, and the inter-batch precision were from 5.2% to 11.5% and 8.5% to 9.8%, respectively. The accuracy was well within the acceptable range the accuracies (from -2.7% to 4.2% and -1.6% to 3.5% for diosmin and diosmetin, respectively). The mean recoveries of diosmin, diosmetin and the internal standard were 87.5%, 89.2% and 67.2%. Stability studies showed that diosmin and diosmetin were stable in different conditions. Finally, the method was successfully applied to the pharmacokinetic study of diosmin in healthy volunteers following a single oral administration (Daflon).

Simultaneous determination of the flavonoid aglycones diosmetin and hesperetin in human plasma and urine by a validated GC/MS method: in vivo metabolic reduction of diosmetin to hesperetin.

Diosmetin and hesperetin are the aglycones of the flavonoid glycosides diosmin and hesperidin which occur naturally in citrus fruit. A GC/MS method for the simultaneous determination of diosmetin and hesperetin in human plasma and urine has been developed and validated. The method was linear in the 2-300 ng/mL concentration range for both diosmetin and hesperetin in plasma and urine (r > 0.999). The precision of the method was better than 6.01 and 7.16% for diosmetin and hesperetin, respectively, and the accuracy was 96.76-100.40% and 95.00-105.50% for diosmetin and hesperetin, respectively. The lower limit of quantitation was found to be 2 ng/mL for both analytes in plasma and urine. Recovery of diosmetin, hesperetin and internal standard naringenin was greater than 82.5%. The method has been applied for the determination of diosmetin and hesperetin in plasma and urine samples obtained from a healthy male subject following a single oral 1000 mg dose of the flavonoid glycoside diosmin. The presence of hesperetin in plasma and urine samples indicates the metabolic reduction of diosmetin to its flavanone analogue hesperetin through reduction of the 2,3 double bond of the C-ring by the enzymes of bacteria of the intestinal microflora.

Efectos del IFN a y la diosmina en el melanoma metastásico pulmonar murino / Effects of IFN a and diosmin on metastasic murine-lung melanoma

Antecedentes: El melanoma metastatiza en aproximadamente un tercio de los pacientes, causando una caída de la supervivencia hasta el 1-2% a los dos años. El único tratamiento eficaz es el interferón alfa (IFN a) a dosis altas, que resulta muy tóxico. Por ello se buscan antitumorales menos tóxicos, entre los que destacan los flavonoides. Nuestro objetivo ha sido estudiar el tratamiento del melanoma metastásico pulmonar combinando IFN a y diosmina en un modelo murino. Material y Métodos: Utilizamos 60 ratones Swiss inoculados con células (5 x 105) de la línea de melanoma murino B16F10, tratados durante 11 días antes y 21 días después de la inoculación: Grupo I: etanol + PBS; Grupo II: etanol + IFN a (600.000 UI); Grupo III: etanol + IFN a (1.200.000 UI); Grupo IV: diosmina + PBS; Grupo V: diosmina + IFN a (600.000 UI); Grupo VI: diosmina + IFN a (1.200.000 UI). Tras el tratamiento, los animales fueron sacrificados y realizamos el contaje macroscópico de los nódulos metastásicos subpleurales. Resultados: Encontramos diferencias significativas entre el grupo control y los tratados (p<0,001), produciéndose la mayor reducción del número de metástasis subpleurales respecto al control en el grupo III (79,74%; p<0,001), seguido del grupo V (77,38%; p<0,001), del VI (72,33%; p<0,001), del IV (61,4%; p<0,001) y del II (59,59%; p<0,001). Conclusiones: La combinación de diosmina con la dosis menor de IFN a mostró la potenciación de la actividad antimetastásica de ambos compuestos, resultando igual de eficaz que la dosis más elevada de IFNa de forma individualizada

Background: Melanoma metastasizes in approximately one third of patients, causing a drop in survival of 1-2% at two years. The only effective treatment is Interferon alpha (IFN a) at elevated doses, which is highly toxic. Thus, less toxic antitumoral agents are being sought, among which flavonoids are to be highlighted. Our aim was to study the combined treatment of metastasic lung melanoma with IFN a and diosmin in a murine model. Material & Methods: 60 Swiss mice inoculated with cells (5 x 105) from the B16F10 murine melanoma cell line, treated over 11 days prior and 21 days following inoculation: Group I: ethanol + PBS; Group II: ethanol + IFN a (600,000 IU); Group III: ethanol + IFN a (1,200,000 IU); Group IV: diosmin + PBS; Group V: diosmin + IFN a (600,000 IU); Group VI: diosmin + IFN a (1,200,000 IU). Following treatment, animals were sacrificed and a macroscopic count of subpleural metastasic nodules was performed. Results: We found significant differences between the control and the treated groups (p<0.001), there being a greater drop in the number of subpleural metastasis in group III with respect to the control (79.74%; p<0.001), followed by group V (77.38%; p<0.001), VI (72.33%; p<0.001), IV (61.4%; p<0.001) and II (59.59%; p<0.001). Conclusions: The combination of diosmin with the lower dose of IFN a showed a strengthening of the anti-metastasic action of both compounds, being equally as effective as the highest dose of IFN a on its own

[Studies on pharmacokinetics of diosmin in rats].

OBJECTIVE: To establish a HPLC method for the determination of diosmin in Rats plasma and to study the pharmacokinetics of diosmin in Rats. METHOD: Rats were given diosmin with 3 doses as 225, 325, 425 mg x kg(-1). Blood samples were collected at different times after oral administration. The plasma concentration of diosmin was determined by HPLC, and the pharmacokinetics parameters were calculated by 3p97 program. RESULT: The typical equation of diosmin in rats plasma was Y = 3.05 x 10(-3) C + 1.55 x 10(-3), the calibration curves of diosmin was linear in the range from 0.5-100 microg x mL(-1) (R =0. 996 4). The lowest concentration of diosmin in plasma was 0. 2 g x mL(-1). Its recoveries was more than 85%, and the interday and intraday precision, which was expressed as RSD, were all less than 15%. After 3 doses oral administration of diosmin in rats, the mean plasma concentration-time curves were found to fit one compartment model, and the main pharmacokinetics parameters were obtained. CONCLUSION: It is first time to establish the HPLC method to determine the concentration of diosmin in rats plasma, and the method described in this report has high sensitivity and selectivity, and it was suitable for pharmacokinetics studies of diosmin. The internal process of diosmin in rats is fit to one compartment model.

A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice.

In this study, we have evaluated the efficacy of dosmalfate, a new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1 beta, prostaglandins (PG)E(2) and (PG)D(2) concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800 mg/kg body weight, p.o.) ameliorated severe colitis reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 beta levels. (PG)E(2) and (PG)D(2) synthesis were significantly reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude that dosmalfate is protective in acute DSS-induced colitis. The beneficial effects seem to be related to a decrease of neutrophil infiltration, absence of up-regulation of IL-1 beta and increase of PG production in colon mucosa.

Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids.

Micronised purified flavonoid fraction (MPFF) [Daflon 500 mg], an oral phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its micronisation to particles with a diameter <2 microm. Compared with placebo, MPFF 500 mg twice daily significantly decreased ankle or calf circumference, and improved many symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial. Significantly more venous leg ulcers

Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting.

Daflon 500 mg, is a micronized purified flavonoid fraction, containing 90% w/w diosmin and 10% w/w of flavonoids expressed as hesperidin, used clinically in the treatment of chronic venous insufficiency and hemorrhoidal disease. This study was designed to investigate the influence of particle size on the overall absorption of diosmin after oral administration of micronized (mean particle size = 1.79 microm, with 80% of particles having a size lower than 3.45 microm) and nonmicronized diosmin (mean particle size = 36.5 microm, with 80% of particles comprised between 19.9 and 159 microm). In a double blinded, cross-over study design, 500 mg tablets containing trace amounts (approximately 25 nCi) of (14)C-diosmin were administered to 12 healthy male volunteers as a single oral dose. Accelerator mass spectrometry and liquid scintillation counting were used for the measurement of (14)C-diosmin in urine and feces. Absorption of (14)C-diosmin from the gastrointestinal tract, measured by the urinary excretion of total radioactivity, was significantly improved with the micronized (57.9 +/- 20.2%) compared with the nonmicronized material (32.7 +/- 18.8%). Statistical comparison of the urinary excretion of the two pharmaceutical formulations showed this difference to be highly significant (p = 0.0004, analysis of variance). The overall excretion of the radiolabeled dose was 100% with mean +/- SD of 109 +/- 23% and 113 +/- 20% for the micronized and nonmicronized forms, respectively. The results of this study show: 1. the impact of a reduction of particle size on the extent of absorption of diosmin, giving a pharmacokinetic explanation to the better clinical efficacy observed with the micronized formulation, and 2. the use of accelerator mass spectrometry in conjunction with liquid scintillation counting in measurement of bioavailability in a human cross-over study comparing two drug formulations containing trace amounts of radioactivity.