Superficial Venous Disease-An Updated Review.

BACKGROUND: This review article provides an updated review of a relatively common pathology with various manifestations. Superficial venous diseases (SVDs) are a broad spectrum of venous vascular disease that predominantly affects the body's lower extremities. The most serious manifestation of this disease includes varicose veins, chronic venous insufficiency, stasis dermatitis, venous ulcers, superficial venous thrombosis, reticular veins, and spider telangiectasias. METHODS: The anatomy, pathophysiology, and risk factors of SVD were discussed during this review. The risk factors for developing SVD were related to race, age, sex, lifestyle, and certain genetic conditions as well as comorbid deep vein thrombosis. Various classification systems were listed, focusing on the most common one-the revised Clinical-Etiology-Anatomy-Pathophysiology classification. The clinical features including history and physical examination findings elicited in SVD were outlined. RESULTS: Imaging modalities utilized in SVD were highlighted. Duplex ultrasound is the first line in evaluating SVD but magnetic resonance imaging and computed tomography venography, plethysmography, and conventional venography are feasible options in the event of an ambiguous venous duplex ultrasound study. Treatment options highlighted in this review ranged from conservative treatment with compression stockings, which could be primary or adjunctive to pharmacologic topical and systemic agents such as azelaic acid, diuretics, plant extracts, medical foods, nonsteroidal anti-inflammatory drugs, anticoagulants and skin substitutes for different stages of SVD. Interventional treatment modalities include thermal ablative techniques like radiofrequency ablationss, endovenous laser ablation, endovenous steam ablation, and endovenous microwave ablation as well as nonthermal strategies such as the Varithena (polidocanol microfoam) sclerotherapy, VenaSeal (cyanoacrylate) ablation, and Endovenous mechanochemical ablation. Surgical treatments are also available and include debridement, vein ligation, stripping, and skin grafting. CONCLUSIONS: SVDs are prevalent and have varied manifestations predominantly in the lower extremities. Several studies highlight the growing clinical and financial burden of these diseases. This review provides an update on the pathophysiology, classification, clinical features, and imaging findings as well as the conservative, pharmacological, and interventional treatment options indicated for different SVD pathologies. It aims to expedite the timely deployment of therapies geared toward reducing the significant morbidity associated with SVD especially varicose veins, venous ulcers, and venous insufficiency, to improve the quality of life of these patients and prevent complications.

Vascular uses of LP1064 applicator on the harmony XL pro device.

INTRODUCTION: Vascular lesions of the lower extremities and face, such as varicose veins and telangiectasias, are a common dilemma for the dermatologist. In recent years, laser therapy has emerged as a viable treatment option for these vascular anomalies. MATERIALS AND METHODS: Although there are several types of lasers, the 1064-nm Nd:YAG in particular is popularly selected for its safety profile and versatility. The longer 1064 nm wavelength penetrates deeper into the skin while also being less absorbed by hemoglobin and melanin, thus resulting in minimized damage to surrounding structures and less pigmentation changes. The new LP1064 applicator on the Harmony XL Pro Device is one such laser. RESULTS: Numerous publications have corroborated the efficacy of 1064 nm Nd:YAG lasers. These studies cite at least over 75% of patients experiencing significant improvement in common vascular lesions. Efficacy of this laser is also seen for other vascular lesions such as port wine stains, hemangiomas, venous lakes, poikiloderma of Civatte, and angiokeratomas. Overall, the reported studies also show a low incidence of adverse events. CONCLUSION: The 1064 nm Nd:YAG laser, such as the Harmony LP1064 applicator, is a safe and effective tool to treat vein anomalies of the face and leg. Although commonly used for vein ablation, it has demonstrated a robust response in other indications as well.

Linear endovenous energy density (LEED) should always be quoted with the power used in endovenous thermal ablation - results from an in-vitro porcine liver model study.

BACKGROUND: Linear Endovenous Energy Density (LEED) is the energy used per cm of vein in endovenous thermal ablation (EVTA) but does not include time. This study examines the effect of time during EVTA. METHOD: EVTA was performed in a previously validated porcine liver model. LEEDs of 40, 60, 80 and 100 J/cm, using different powers were repeated 5 times each. Thermal spread, tissue carbonisation and device-tissue sticking during treatment were recorded. RESULT: LEED positively correlated to thermal spread and carbonisation of the tissue. Power was correlated with carbonisation but not thermal spread. Pullback had no correlations with thermal spread or carbonisation. Catheter sticking found occurred in powers >= 15 W or LEED >= 80 J/cm. CONCLUSION: LEED is a good measure of EVTA but does not include time. Power, which does include time, correlates with carbonisation and with device-tissue sticking. The power used must be quoted with the LEED.

A moderate dosage of coffee causes acute retinal capillary perfusion decrease in healthy young individuals.

AIM: Caffeinated beverages are very popular across populations and cultures, but quantitative evidence of the acute effects of moderate coffee doses on retinal perfusion is sparse and contradicting. Thus, the aim of this randomized, cross-over and parallel-group design study was to investigate whether moderate consumption of coffee alters macular retinal capillary perfusion in young healthy individuals. METHODS: Twenty-seven young healthy individuals were recruited for this study. Acute changes in retinal microvasculature were assessed using spectral-domain optical coherence tomography angiography (SD-OCTA) at baseline, 0.5 h, and 2 h after intake of coffee, or water. Meanwhile, cerebral blood flow (CBF) and retina-choroid blood flow were evaluated in a parallel-group design (4 participants each in coffee or water group) using magnetic resonance imaging (MRI) with pseudo-continuous arterial spin labeling sequences. RESULTS: Two hours after coffee intake, blood caffeine concentration increased from 0 to 5.05 ± 1.36 µg/mL. Coffee caused a significant decrease in retinal vessel diameter index (VDI) (19.05 ± 0.24 versus [vs] 19.13 ± 0.26; p < 0.001) and CBF in the frontal lobe (77.47 ± 15.21 mL/100 mL/min vs. 84.13 ± 15.55 mL/100 mL/min; p < 0.05) 2 h after intake. However, it significantly increased retina-choroid blood flow after 0.5 and 2 h (163.18 ± 61.07 mL/100 mL/min vs. 132.68 ± 70.47 mL/100 mL/min, p < 0.001, and 161.21 ± 47.95 vs. 132.68 ± 70.47; p < 0.001, respectively). CONCLUSION: This is the first study to demonstrate the acute effects of daily dose coffee consumption on retinal capillary perfusion using SD-OCTA combinate with blood flow MRI. The findings imply that although moderate coffee intake caused a significant increase in retina-choroid blood flow, there was a significant acute decrease both in macular retinal capillary perfusion and CBF.

Evaluation of Venous-to-Arterial Carbon Dioxide Tension Difference as a Complementary Parameter During Pediatric Septic Shock Resuscitation: A Prospective Observational Study.

OBJECTIVES: The aim of this study was to evaluate the venous-to-arterial carbon dioxide tension difference during early resuscitation in pediatric septic shock. METHODS: A prospective observational study was conducted in the pediatric intensive care unit of a tertiary care teaching. Children having septic shock aged from 3 to 60 months were studied within the first 24 hours of admission. Central venous and peripheral arterial blood samples for blood gases analysis at time of central venous catheter insertion and after 6 hours were obtained. Central venous carbon dioxide pressure, arterial carbon dioxide pressure, and their difference (delta Pco2) were recorded. Patients were categorized, accordingly to delta Pco2 after 6 hours of resuscitation, into high delta Pco2 group (≥6 mm Hg) and low delta Pco2 group (<6 mm Hg). RESULTS: Oxygen extraction ratio at 6 hours of resuscitation was significantly lower among the low delta Pco2 group. Arterial lactate showed marked improvement in the low delta Pco2 group to be less than 2 mmol/L at 12 hours of resuscitation. Low delta Pco2 group showed significant higher shock reversal with shorter shock reversal time. Mortality was significantly lower among low delta Pco2 group with shorter pediatric intensive care unit stay. CONCLUSIONS: Delta Pco2 after 6 hours of resuscitation of <6 mm Hg indicates normalization of tissue perfusion during pediatric septic shock management. It could be used as a complementary tool to guide the resuscitation in the early phase of pediatric septic shock.

Modified compression therapy in mixed arterial-venous leg ulcers: An integrative review.

Leg ulcers remain an increased burden to healthcare cost and morbidity in modern society. While most leg ulcers are venous in origin, recognition and prompt identification of concomitant arterial occlusive disease is critical to determine underlying aetiology and subsequent management. This integrative review presents the current evidence to establish the role of modified compression therapy (MCT) in treatment of mixed arterial venous leg ulcers (MAVLU). A literature search was conducted using the electronic databases CINAHL, MEDLINE, PUBMED, and Embase. Ten studies met the eligibility criteria and were subsequently analysed. Our review concludes that MCT, with compression pressures between 20 and 30 mmHg, can promote healing in MAVLU with moderate arterial insufficiency (0.5 ≤ ABPI ≤0.8). If ABPI is <0.5, MCT can be considered once restoration of acceptable ABPI is achieved. Intolerance, lack of response or further deterioration of disease within 3 months should prompt further arterial imaging and intervention. MCT is generally well tolerated with no adverse outcomes reported. A holistic yet individualised approach is vital in order to account for all factors influencing this patient-led decision-making process, ultimately ensuring effective treatment, which improves patient's quality of life and reduces socioeconomic burden of the disease.

Treatment of periocular and temporal reticular veins with 1064-nm Nd:YAG Laser.

BACKGROUND: The periocular and temporal regions are important aspects of beauty. The presence of reticular veins in these areas is undesirable and can also interfere with injection of neurotoxins to treat squint lines. 1064-nm Nd:YAG laser shows promise as an effective treatment modality with long-lasting effects. AIM: The aim of the study is to show that the long-pulsed, contact-cooled, variable spot-sized 1064-nm Nd:YAG laser is effective and safe, with good patient satisfaction and tolerability, and is able to achieve long-term results. METHODS: A retrospective study of 35 consecutive patients seen over a 3-year period in a private cosmetic clinic affiliated to the University of Toronto for periocular and temporal reticular veins was conducted. They were all treated with 1064-nm Nd:YAG laser. RESULTS: A total of 35 patients with an average age of 45.8 years old received treatment. 13 had lower eyelids treated, 9 had temples treated, 12 had both lower eyelids and temples treated, and 1 had both upper and lower eyelids treated. The first case of upper eyelid vein being treated with the 1064-nm Nd:YAG laser with great success after only 1 treatment is reported. 80% of the patients required only 1-2 treatment sessions. The average satisfaction score was 7.9 out of 10. The average pain score was 5.0 out of 10. 91% perceived the treatment outcome as excellent or good with the longest result lasting 33 months. There were 4 complications: 1 scabbing, 1 small burn, 1 skin darkening, and 1 teary eye. CONCLUSION: The study showed that the use of the long-pulsed, contact-cooled, variable spot-sized 1064-nm Nd:YAG laser is effective and safe, with good patient satisfaction and tolerability, and is able to achieve long-term results.

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

[Comprehensive treatment of indolent trophic ulcers of venous aetiology]. / Kompleksnoe lechenie dlitel'no nezazhivaiushchikh troficheskikh iazv venoznoi étiologii.

AIM: The study was undertaken to evaluate efficacy of comprehensive treatment with the use of erbium laser radiation in patients suffering from venous trophic ulcers of lower limbs. PATIENTS AND METHODS: The study included a total of seventy-six 45-to-80-year-old patients. Of these, there were 43 (56.6%) women and 33 (43.4%) men. The duration of the disease averagely amounted to 10.8±4.8 years. In 38 patients, the bottom of the ulcerative defect was with pronounced periulcerative inflammation and various degree of purulent discharge. All patients were admitted to the surgical department and underwent meticulous examination. Erbium laser irradiation was carried out with consideration for the ulcer size. Laser irradiation was performed at a wavelength of 2940 nm, pulse duration - 0.3 ms, laser beam diameter - 7 mm with radiation power of 2.19 J/cm2. RESULTS: Efficacy of treatment was assessed in dynamics by the degree of pain syndrome, ulcer size upon completion of treatment, as well as the rate of trophic ulcer epithelialisation. In 15 (19.7%) patients with varicose disease the vertical and horizontal reflux was eliminated with performing phlebectomy and echosclerotherapy. The obtained findings demonstrated that 42 (91.3%) patients of the study group had decreased terms of the beginning of purification of the fundus of the ulcer. After 6 months of rehabilitation and follow up, complete ulcer healing was achieved in 18 (64.3%) patients of the control group and in 39 (86.7%) patients of the study group. CONCLUSION: The obtained findings showed that laser radiation proved to be an effective method of treatment in patients presenting with indolent trophic ulcers. Comprehensive treatment made it possible to effectively influence the microflora and the state of regional lymph drainage, to stimulate the processes of reparative regeneration.

CEAP clinical classes C0S-C4: differences, similarities and role of Ruscus + HMC + vitamin C in patients with chronic venous disease.

Since the publication of the CEAP classification, new research has enriched our knowledge; notably on the heritability of CVD and the genetic and environmental factors involved in this condition, as well as the symptoms apparent within the spectrum of the CEAP clinical classes and the benefits of medical treatment. Using the CEAP classification as a special theme, a symposium with the same title as the present paper was held at the annual meeting of the 2019 European Venous Forum. The lectures presented much valuable information, from which some key points can be extracted. The influence of environmental factors was demonstrated, and the fact that a large amount of information can be obtained from comprehensive history taking. There is robust evidence for heritability. Many candidate genes/loci have been identified, potentially offering new targets for treatment. More research is needed, notably using genome-wide association studies and also on microbiota, which may play a role in CVD through the inflammation pathway. Ruscus + HMC + vitamin C acts by increasing venous and lymphatic tone, protecting microcirculation, and reducing inflammation. It improves quality of life in C0S to C3 CVD patients, while a review of clinical studies and a meta-analysis have confirmed its clinical efficacy across a wide spectrum of CVD clinical classes: C0S, C1S, C2, C3 and C4. It has been awarded a Grade 1A recommendation by the international guidelines.

Outcomes of Local and Regional Anesthesia for Superficialization of Brachiobasilic Arteriovenous Fistulas.

BACKGROUND: Superficialization, the second stage of a two-stage brachiobasilic arteriovenous fistula (BB-AVF), can be performed under local (LA), regional (RA), or general anesthesia (GA). Given the numerous comorbidities in patients with end-stage renal disease (ESRD), our preference is to use RA or LA when feasible. Our goal was to review the success rate of RA and LA, need for conversion to GA, and cardiac morbidity and mortality for BB-AVF superficialization. METHODS: We performed a retrospective cohort analysis of patients who underwent BB-AVF creation with second-stage superficialization over a 4-year period. The primary outcome measures included need for conversion to GA, myocardial infarction (MI), and 30-day mortality. A secondary outcome was total operative time (time from preoperative briefing to the time the patient left the operating room). We analyzed the data using Fisher Exact test for categorical data and nonparametric analysis for continuous data. RESULTS: There were 42 patients who underwent BB-AVF superficialization. The median age was 56 years, with a mean body mass index of 29. Most patients were male (55%) and predominantly Hispanic/Latino (60%). RA was utilized in 35 patients (83%), LA in 5 (12%), and GA in 2 (5%). The conversion rate from RA to GA was 0% and was 20% (n = 1) from LA to GA. There were no postoperative MI or deaths. There was no significant difference in total operative time (219.6 min for RA, 234.5 min for LA, and 278 min for GA, (P = 0.37)). CONCLUSIONS: Local and/or regional anesthesia can be successfully used in the majority of patients undergoing BB-AVF superficialization. LA and RA are associated with negligible cardiac morbidity and mortality. Conversion from RA to GA is rare. Use of RA does not result in a longer total operative time.

Hyperbaric treatment of air or gas embolism: current recommendations.

Gas can enter arteries (arterial gas embolism, AGE) due to alveolar-capillary disruption (caused by pulmonary over-pressurization, e.g. breath-hold ascent by divers) or veins (venous gas embolism, VGE) as a result of tissue bubble formation due to decompression (diving, altitude exposure) or during certain surgical procedures where capillary hydrostatic pressure at the incision site is subatmospheric. Both AGE and VGE can be caused by iatrogenic gas injection. AGE usually produces stroke-like manifestations, such as impaired consciousness, confusion, seizures and focal neurological deficits. Small amounts of VGE are often tolerated due to filtration by pulmonary capillaries; however VGE can cause pulmonary edema, cardiac "vapor lock" and AGE due to transpulmonary passage or right-to-left shunt through a patient foramen ovale. Intravascular gas can cause arterial obstruction or endothelial damage and secondary vasospasm and capillary leak. Vascular gas is frequently not visible with radiographic imaging, which should not be used to exclude the diagnosis of AGE. Isolated VGE usually requires no treatment; AGE treatment is similar to decompression sickness (DCS), with first aid oxygen then hyperbaric oxygen. Although cerebral AGE (CAGE) often causes intracranial hypertension, animal studies have failed to demonstrate a benefit of induced hypocapnia. An evidence based review of adjunctive therapies is presented.

Spinal glycinergic and gamma-aminobutyric acid-ergic neurons inhibit the micturition reflex after electrical stimulation of the perineum in rats with pelvic venous congestion.

OBJECTIVES: To examine whether electrical stimulation of the perineum inhibited urinary frequency in rats with pelvic venous congestion, and whether electrical stimulation influences spinal glycinergic/gamma-aminobutyric acid-ergic neurons. METHODS: Bilateral common iliac veins and bilateral uterine veins were ligated to create pelvic venous congestion rats. At 4 weeks after ligation, cystometry was carried out before and after electrical stimulation with/without intrathecal injection of strychnine (a glycine receptor antagonist) and/or bicuculline (a gamma-aminobutyric acid type A receptor antagonist). In addition, measurement of amino acid levels in the lumbosacral cord was carried out with/without electrical stimulation, and cystometry was carried out after oral administration of glycine. RESULTS: Continuous cystometry showed that the interval between bladder contractions was shorter in pelvic venous congestion rats than in sham rats. Electrical stimulation did not change cystometric parameters in sham rats, but the interval between bladder contractions was increased by electrical stimulation in pelvic venous congestion rats. Electrical stimulation increased the levels of glutamic acid, glycine, gamma-aminobutyric acid, and taurine in the lumbosacral cord of pelvic venous congestion rats. Intrathecal strychnine abolished the effects of electrical stimulation in pelvic venous congestion rats, and intrathecal administration of both strychnine and bicuculline shortened the interval between bladder contractions more than before electrical stimulation. Oral administration of glycine (3%) to pelvic venous congestion rats increased bladder capacity. CONCLUSIONS: Electrical stimulation of the perineum inhibits urinary frequency mainly through activation of spinal glycinergic neurons, and partly through activation of gamma-aminobutyric acid-ergic neurons in a rat model of pelvic venous congestion.

The compelling arguments for the need of medical vascular physicians in Europe.

The burden of vascular diseases is growing worldwide, as the population ages, prompting a call to action not only in terms of awareness but also and most urgently in recognizing the need for vascular physicians, also called angiologists. Vascular medicine views the vascular system (arteries, veins, and lymphatics) as a whole, unique, and independent entity requiring specialized competencies. Vascular physicians offer a holistic and comprehensive approach to vascular patients including provision of interventional procedures, management of a heterogeneous group of multi-morbid and frail patients affected by multi-vessel diseases, and connecting different specialists in a multidisciplinary effort. Vascular medicine practise varies across European countries. While it is a firmly accepted medical speciality in many European countries it is not formally recognized by the European Union limiting adoption in the other countries. The lack of vascular physicians likely accounts for inequality of care of vascular patients as compared for example to patients with heart disease and might contribute to adverse outcomes and healthcare costs associated with vascular diseases. To move forward in the struggle to provide efficient care for multimorbid poly-vascular patients, it is essential to establish vascular medicine programs in Europe and worldwide. Important steps to achieve this goal include improving public awareness of vascular diseases, attain formal recognition by the EU of angiology/vascular medicine as a medical specialty, creating specialized treatment guidelines, and to harmonize vascular care in Europe.

The venodilation effects of tapping versus massaging for venipuncture.

AIM: To compare the effectiveness of tapping and massaging venodilation techniques by evaluating venous cross-sectional area, venous depth, venous palpation score, and questionnaire responses of study participants. METHODS: This study had a quasi-experimental design. Between August 2016 and October 2016, healthy adult volunteers (n = 30, mean ± standard deviation of age: 22.3 ± 2.2 years) were enrolled in this study. Three venodilation techniques were evaluated: the application of a tourniquet (Control Group), the application of a tourniquet and tapping of the participant's forearm (Tapping Group), and the application of a tourniquet and massaging of the participant's forearm (Massage Group). RESULTS: In all three groups, venous cross-sectional areas increased significantly after the application of the venodilation technique. The change ratio of venous cross-sectional area was significantly larger in the Massage Group than in the Control Group. Additionally, 83.3% of the participants selected massaging as their preferred venodilation technique, stating the technique was comfortable and provided a feeling of relief. CONCLUSIONS: No significant differences were observed between the degrees of venodilation that were achieved using the three investigated venodilation techniques. Nonetheless, massaging was deemed the most effective technique after considering the participants' subjective comments.

Vitamin D intervention does not improve vascular regeneration in diet-induced obese male mice with peripheral ischemia.

Vitamin D appears to either promote or inhibit neovascularization in a disease context-dependent manner. The effects of vitamin D, alone or in combination with niacin, on endothelial cell (EC) angiogenic function and on revascularization in obese animals with peripheral ischemia are unknown. Here, we report that supplementation of high palmitate medium with vitamin D, niacin or both vitamins increased EC tube formation, which relies primarily on cell migration, and also maintained tube stability over time. Transcriptomic analyses revealed that both vitamins increased stress response and anti-inflammatory gene expression. However, vitamin D decreased cell cycle gene expression and inhibited proliferation, while niacin induced stable expression of miR-126-3p and -5p and maintained cell proliferation in high palmitate. To assess vascular regeneration, diet-induced obese mice received vitamin D, niacin or both vitamins following hind limb ischemic injury. Niacin, but not vitamin D or combined treatment, improved recovery of hind limb use. Histology of tibialis anterior sections revealed no improvements in revascularization, regeneration, inflammation or fibrosis with vitamin D or combined treatment. In summary, although both vitamin D and niacin increased angiogenic function of EC cultures in high fat, only niacin improved recovery of hind limb use following ischemic injury in obese mice. It is possible that inhibition of cell proliferation by vitamin D in high-fat conditions limits vascular regeneration and recovery from peripheral ischemia in obesity.

Chronic venous disease: from symptoms to microcirculation.

The recently published European Venous Forum (EVF) Guidelines 2018 update on the management of chronic venous disorders of the lower limbs has focused on several new aspects: a new place for early symptoms, new data on microcirculation alterations, and a re-evaluation of veno-active drugs (VADs), based on new criteria. The symposium "Chronic Venous Disease (CVD): From Symptoms to Microcirculation", held at the annual meeting of the EVF on 28 June 2018 in Athens, Greece, highlighted this perspective by answering three questions: What do symptoms mean and how do they influence our choice of investigations? Is there a link between symptoms and microcirculation alterations? How to choose the right VAD for the right patient based on the updated EVF guidelines? The answers given led the speakers to three conclusions: early symptoms reveal the initial stage of CVD and patients with C0S disease should be properly diagnosed, investigated, and treated; damage to the microcirculation is likely to be the first evidence of the onset of venous disease; Ruscus+HMC+VitC has proven efficacy in randomized controlled trials, and has been given a strong recommendation (Grade 1A) by the 2018 EVF guidelines for treatment of pain, heaviness, feeling of swelling, paresthesia, and edema, and should be considered as one of the preferred treatments to relieve these symptoms in CVD patients.

[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.