Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions.

AIM: The aim of this article was first to review the complex pathophysiological mechanisms responsible for symptoms and signs of primary chronic venous disease (CVD) that allow the identification of targets for pharmacological treatment. The results of CVD treatment with venoactive drugs (VADs) were emphasised and presented in the form of recommendations. The last section raises key questions to be answered to improve protocols for good clinical trials and to draw up future guidelines on these agents. METHODS: The literature has been reviewed here using PubMed and Embase. RESULTS: Venous hypertension appears to underlie all clinical manifestations of primary CVD. Inflammation is key in wall remodelling, valve failure and subsequent venous hypertension. Changes in the haemodynamics of veins are transmitted to the microcirculation, resulting in capillary alteration leading to oedema, skin changes and eventually venous ulceration. Venous symptoms may be the result of interplays between pro-inflammatory mediators and nerve fibres located in the venous wall. Therefore, venous inflammation constitutes a promising therapeutic target for pharmacological intervention, and some available VADs could attenuate various elements of venous inflammation. Based on recent studies, reviews and guidelines, tentative recommendations for the use of VADs were proposed and strong recommendations were given to two of them (micronised purified flavonoid fraction and oxerutins). CONCLUSION: VADs should be accorded a better role in the management of CVD. However, larger and more definitive clinical trials are needed to improve the existing recommendations.

Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD's effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

[What are the epidemiological data on the consequences of smoking-related increased risk in pregnant women? Dermatological consequences]. / Quelles sont les données épidémiologiques concernant les conséquences de l'excès de risque lié au tabagisme chez les femmes enceintes? Conséquences dermatologiques.

Smoking has numerous effects on skin. Some of them are well established, others are more debatable. Smoking is a cofactor of skin aging after chronic sun exposure, as demonstrated by recent histological, biochemical and cutaneous relief studies. Smoking is a well established risk factor of cutaneous, mucous membrane cancers, and some gynecologic cancers as well, in some cases increased by pregnancy. However, published studies have included small numbers of subjects. Some skin affections are worsened by smoking, and others might be improved. However scientific data on smoking and skin or pregnancy are both scarce.

Post-stripping sclerodermiform dermatitis.

BACKGROUND: Cutaneous sclerosis, a process that results in hardening of the skin, is the hallmark of scleroderma and sclerodermoid disorders. Cutaneous sclerosis is usually classified as secondary or primary, depending on the presence or absence of underlying diseases. Primary cutaneous sclerosis is a feature of idiopathic inflammatory processes that are often associated with autoimmune disorders, whereas secondary cutaneous sclerosis arises in the context of many pathological processes of varying causes, including chronic graft-vs-host disease, defined metabolic or genetic disorders, and exposure to certain infectious organisms, drugs, or chemicals. OBSERVATIONS: Three patients had localized cutaneous sclerosis overlying the site of a surgically removed (stripped) great saphenous vein. In all 3 patients, lesions were clinically characterized by multiple hypopigmented and indurated plaques distributed linearly along the path of the preexisting vein. Extensive history, physical examination, and diagnostic tests did not reveal known predisposing factors for cutaneous sclerosis. CONCLUSIONS: Although the observed association of sclerodermiform dermatitis and venous stripping in these 3 patients does not imply a causal relationship, the absence of other identifiable predisposing factors and the striking linear distribution of the cutaneous lesions along the path of the preexisting vein are suggestive. This poststripping sclerodermiform dermatitis may be a rare late complication of saphenous vein stripping.

Phlebectomy. Technique, indications and complications.

Phlebectomy, first described by Aulus Cornelius Celsus (25 BC - 45 AD), was re-invented 40 years ago by Dr. Robert Müller, in Neuchâtel, Switzerland. This safe, esthetic, effective and economical operative technique has now been fully developed and adopted all over the world. Phlebectomy hooks enable venous extraction through minimal skin incisions (1-3 mm) or even needle punctures, assuring complete and definite eradication of the veins. The small size of the skin incisions usually results in little or no scarring, contrary to that found in classical venous surgery, and avoids the possible complications of sclerotherapy, such as skin necrosis or residual hyperpigmentation. Sites particularly appropriate for ambulatory phlebectomy include incompetent saphenous veins (except the sapheno-femoral and in most cases the sapheno-popliteal junctions), their major tributaries, perforating, groin pudendal veins, reticular veins (popliteal fold, lateral thigh and leg) and veins of the ankles and the dorsal venous network of the foot. Curettage of telangiectasias is a less well known indication, but it is also quite effective in removing networks of thick blue spider veins. Ambulatory phlebectomy of body areas, other than the legs, include dilated periorbital, temporal or frontal venous networks and venous dilatation of the abdomen, arms or dorsum of the hands. Long term results, if the indications and technique were correct, are excellent. Complications, in skillful hands, seldom occur. They may be classified as cutaneous, vascular, neurological or general and are usually benign.

Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) affects a large number of people in Western countries, and is responsible for considerable inconvenience, discomfort, suffering, and costs. Micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin-Daflon 500 mg) is a potent venotropic drug used in the treatment of venous insufficiency. Pharmacological and clinical studies demonstrated the comprehensive mode of action of Daflon 500 mg: it increases venous tone, it improves lymph drainage, and it protects the microcirculation. Clinical international, prospective, multicenter, randomized, controlled studies versus placebo studies documenting the effects of Daflon 500 mg in CVI at advanced stages with edema, skin changes, and venous leg ulcer are reviewed. In edema, one of the most frequent complaints of patients, Daflon 500 mg brings about a significant reduction in leg circumference, thanks to its capacity to inhibit inflammatory reactions and to decrease capillary hyperpermeability. The rationale for the use of Daflon 500 mg for treatment of skin disorders and venous leg ulcer is its action on the microcirculation-damaging processes. Regarding skin changes, Daflon 500 mg has been shown to improve venous trophic disorders, like gravitational (stasis) dermatitis, and dermatofibrosclerosis. In venous leg ulcer, Daflon 500 mg's clinical efficacy has been demonstrated in addition to standard treatment or versus standard treatment alone. Daflon 500 mg, thanks to its comprehensive mode of action on the veins, lymphatics, and microcirculation, is the method of choice not only in the early stages of CVI treatment, but also in the severe stages of this condition, in combination with compression treatment, sclerotherapy, and surgery if appropriate.

Pharmacologic aspects of a phlebotropic drug in CVI-associated edema.

Several phlebotropic drugs, or edema-protecting drugs, are available, the most important of which are found in the gamma-benzopyrone family (flavonoids). gamma-Benzopyrones can be plant extracts, semisynthetic preparations, or synthetic preparations. This family is divided into two different groups: flavones and flavonols, and flavanes (flavanones). The flavone group contains various types of molecule and includes diosmin. Here we discuss the pharmacologic aspects in edema associated with chronic venous insufficiency (CVI) of one of the reference phlebotropic drugs, micronized purified flavonoid fraction (MPFF), a semisynthetic preparation from the diosmin group, which represents the latest improvement in flavonoid formulation. Before we detail the pharmacologic aspects, a brief summary of the pathophysiology of edema in CVI is necessary. Several factors are implicated: the veins, which create the conditions favorable to edema; the microcirculation, which is the site of fluid transfer into the interstitial tissue; and the lymphatics, which have a limited possibility to reduce edema. Major discoveries are currently being made in CVI and the microcirculation. Results of studies show that MPFF decreases capillary permeability and increases capillary resistance, which could partly be explained by inhibition of leukocyte activation, migration, and adhesion. This inhibition is linked to a significant decrease in plasma levels of endothelial adhesion molecules (VCAM-1 and ICAM-1) after MPFF treatment. Thus, the CVI-induced damage to the microcirculation is counteracted by MPFF. The lymphatic system is also improved by MPFF treatment. The lymphagogue activity of MPFF has been demonstrated in experimental animal models and confirmed by microlymphographic measurement in patients suffering from severe CVI. The pharmacologic activity of MPFF in lymphedema was observed in a study using an animal model of acute lymphedema and in a study in patients with upper limb lymphedema secondary to breast cancer treatment. All these findings point to the importance of acting on each factor involved in the formation and maintenance of edema. This pharmacologic activity is indeed reflected by the clinical efficacy on edema observed during treatment with MPFF.

The efficacy and safety of a coumarin-/troxerutin-combination (SB-LOT) in patients with chronic venous insufficiency: a double blind placebo-controlled randomised study.

BACKGROUND: The objective was to evaluate the oedema-protective effect of a vasoactive drug (coumarin/troxerutin [SB-LOT]) plus compression stockings in patients suffering from chronic venous insufficiency after decongestion of the legs as recommended by the new guidelines. PATIENTS AND METHODS: 231 patients were randomly assigned medical compression stockings plus SB-LOT (90 mg coumarin and 540 mg troxerutin per day) or medical compression stockings plus placebo for the first 4 weeks and SB-LOT or placebo for the second 12 weeks of the study. The primary efficacy endpoint was the lower leg volume measured by well-established water plethysmometry. RESULTS: 226 patients were evaluated. After ceasing compression stockings, an edema protective effect was detected in the SB-LOT-group but not in the controls. Recurrence of leg volume increase was by 6.5 +/- 12.1 ml and by 36.7 +/- 12.1 ml in the SB-LOT and placebo group, respectively (p = 0.0402). The local complaint score and general aspects of quality of life were also superior for the SB-LOT-group (p = 0.0041). Significant differences were also observed with regard to clinical global impression and therapeutic effect. No serious adverse drug reaction or clinically relevant impairment of laboratory parameters occur. CONCLUSION: This study confirms the oedema-protective effect of SB-LOT in chronic venous insufficiency and provides a treatment option for patients who discontinue compression after a short time.

[Ambulatory phlebectomy by the Muller method: technique, advantages, and disadvantages]. / La phlébectomie ambulatoire selon Muller: technique, avantages, désavantages.

Phlebectomy according to Muller is a simple and efficient method. A very narrow incision (1 to 2 mm) makes it possible to grasp the varicose vein with a small hook and to extract it. Indications are numerous: varices of the trunk (without insufficiency of the great saphenous vein junction), perforating varices, reticular varices, nutrient veins of telangiectasias or of leg ulcers, unsightly veins (in the eyelids, arms, etc.). There are numerous advantages of phlebectomy according to Muller. In terms of ambulatory patients, it is a simple technique free of risks (especially thromboembolic ones) for surgical treatment of all types of varices. This technique is particularly economical (simple infrastructure, little loss of patient work time). Elective extirpation of varicose veins allows the healthy venous trunks to be conserved (reconstructive surgery) and scars are practically invisible. In terms of hospital practice, this technique has been adopted by numerous surgeons as a complement to resection of the sapheno-femoral junction and stripping, thus permitting reduction of scar size and extirpation of the narrowest varices. The drawbacks are minimal: the usual complications of any surgical technique and too easy accessibility to the poorly trained practitioner.

[Rosacea: histopathologic study of 75 cases]. / Rosacée: étude histopathologique de 75 cas.

Few histological studies have been devoted to rosacea, a common but ill-defined disease. We have examined histological sections obtained from 75 patients (41 men aged from 23 to 72 years and 34 women aged from 32 to 68 years), thereby confirming the diagnosis of rosacea. On average, 4 sections from each patient were examined. Blocks from cases with granuloma were serially sectioned in search of remains of hair follicles, degenerated collagen fibres and Demodex folliculorum. Elastotic degeneration, vasodilatation and the number of hair follicles were evaluated; the nature and disposition of inflammatory infiltrates were determined, and the presence of D. folliculorum was looked for. Elastotic degeneration, varying degrees of vasodilatation and inflammatory infiltrates were found in all patients. The infiltrates were predominantly lympho-histiocytic in 62 cases, neutrophilic around skin appendages in 6 cases, tuberculoid unrelated to appendages in 4 cases and tuberculoid surrounding follicle-related necrosis in 3 cases. The number and appearance of hair follicles seemed to be those normally observed in the regions where our specimens were taken. On the basis of histological, immunological and therapeutic arguments, it has been postulated that D. folliculorum was involved in the pathogenesis of rosacea, notably in its granulomatous form. In particular, several cases of granuloma containing the acarid in its core have been reported. However, the significance of such findings remains uncertain. D. folliculorum might induce the formation of a granuloma, but it is also possible that granulomas are consecutive to the destruction and resorption of hair follicles, the mite being "digested" more slowly than the epithelial structures.(ABSTRACT TRUNCATED AT 250 WORDS)

[Association of filiform hematomas of the nails and Raynaud's syndrome]. / Association d'hématomes filiformes des ongles et d'un syndrome de Raynaud.

Two men (non smokers) suffer from unilateral Raynaud's phenomenon, as well as homolateral splinter hemorrhages of the nails. One of the patients has digital artery obstruction, confirmed angiographically. The other patient, in whom a thoracic outlet syndrome was diagnosed, suffers of cold-induced vascular spasm. The incidence, significance and etiology of splinter hemorrhages are discussed.

[Non-drug toxicoderma by a respiratory or probable percutaneous route (fluorocarbons, butane, phenyl-azo-beta-naphthol)]. / Toxidermies non médicamenteuses par voie respiratoire ou percutanée probable (fluorocarbures, butane, phényl-azo-bêta-naphtol).

Four cases of cutaneous rash, clinically more or less similar to erythema multiforme have been observed in patient who either stayed in a room with an accidentally high content of fluorocarbons, or had a skin contact with butane or phenyl-azo-beta-naphthol. The cutaneous lesions appear to be secondary to absorption of the toxic product, and probably induced by inhalation rather than by percutaneous penetration. Arguments for the responsibility of the substances rely on anamnestic data.

[Photosensitivity and disturbances of tryptophan metabolism (kynurenin pathway) (author's transl)]. / Photosensibilisation et perturbations du métabolisme du tryptophanne (voie de la cynurénine).

We studied a bullous photodermatosis recurring for two years in a old woman. The eruption was diagnosed as a pellagra-like syndrome on tryptophan loading test disorders without any other cause of sun sensitivity. The static and dynamic metabolic investigation was centered on tryptophan and vitaminic coenzymes which mediate catabolic reactions. The defect are located on the kinurenin pathway. The discussion analyses the possible relations between the dermatosis and the biological disturbances observed.

[The treatment of varicose ulcers]. / Le traitement de l'ulcère variqueux.

The cause of venous ulcer (deep veins and perforans veins valvular damages, muscular and articular pump deficiency) can merely be corrected by compression therapy and, in some cases, surgery. Accompanying diseases have to be treated. Although the efficiency of general and local treatment is limited, it is essential to control it correctly and avoid its side-effects.

[The skin of the aged]. / La peau du vieillard.

This is a review of physiological changes and photo-aging of the senescent skin and of their clinical aspects. It also contains a discussion of the origins pruritus in elderly people.

European guidelines for sclerotherapy in chronic venous disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guideline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidocanol and sodium tetradecyl sulphate. Other sclerosants are not discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations.