[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.

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.

Micronization: a method of improving the bioavailability of poorly soluble drugs.

For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are use to micronize powders: either jar mills or fluid energy mills. Theses processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy.