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Pharmacologic Treatments for Chronic Venous Disease
Saturday, December 1, 2012


*****Abstract from Sandra Marinovic Kulišic, MD, PhD, University Hospital Center Zagreb , Department of Dermatology and Venereology , School of Medicine, University of Zagreb , Šalata 4, HR-10000 Zagreb, Croatia


This abstract was published in Acta Dermatovenerol Croat. 2012 OcTOBER, volume 20(3): pages 197-200.


The title of the abstract is Pharmacologic Treatments in Patients with Chronic Venous Disease.


****The Absract is shown here verbatim*****


INTRODUCTION Systemic drug therapy has been tried for many years in an attempt to reduce symptoms from varicose veins and pharmacologically reduce the chronic skin sequelae of venous hypertension. A large number of naturally occurring and synthetic agents have been shown to have venoactive properties and in many countries, the use of venoactive drugs (VADs) is generally considered as an adjunct to sclerotherapy or surgery, which are regarded as more definitive treatments. The aim of this article is to review the available clinical evidence evaluating the use of pharmacotherapy for patients with chronic venous disease. It seems that presently the best hypothesis is that the mechanisms responding to drugs are those involving leukocyte activation and their interaction with endothelial cells, followed by inflammatory processes. The pathophysiological rationale for pharmacological treatments Venoactive drugs are a group of medicinal products of plants or synthetic origin, which have effects on the edema and/or symptoms related to chronic venous disease. The main mechanisms of action are anti-edematous effect, increase in venous tone, and inhibition of different trigger factors of the last stages of chronic venous disease, such as adherence of white blood cells to venous wall and valves, release of mediators of inflammation and synthesis of prostaglandins, and improvement of fibrinolysis and blood rheology (1). In general, all VADs have two pathophysiological mechanisms of action. They alter macrocirculatory changes in venous wall and valves, and they act at the microcirculatory level. At the macrocirculatory level, VADs increase venous tone by the mechanisms related to noradrenaline pathway, but they also attenuate various elements of the inflammatory cascade responsible for valve failure (2). Inflammatory processes involving leukocyte-endothelial interactions play an important role in all aspects of chronic venous disease, and the symptoms of early pain are no exception. Venous stasis within the capillaries and small venules causes leukocyte adhesion, which triggers a cascade of biochemical events. Adhesion molecules expressed by activated endothelium promote the leukocyte adhesion cascade, which involves capture, rolling, adhesion, and transmigration of leukocytes. In this manner, leukocytes accumulate in the vessel wall in considerable numbers. In the early stages of venous disease, binding between leukocytes and endothelium cells remains reversible, with rolling leukocytes still able to return to the bloodstream. Although reversible in the beginning, leukocyte adhesion may lead to cell trapping in the superficial cutaneous veins. This process is a key point in the etiology of venous symptoms. Preventing interaction of leukocytes with the endothelium is one of the main targets for the action of pharmacological treatments. Unlike other anti-leukocyte therapies, VADs are not associated with an increased risk of infections. Our opinion is that research should therefore continue to concentrate on the inflammatory cause of the disease, focusing on developing more targeted and effective venoactive agents. Actions of VADs on microcirculation include effects on capillary resistance, lymphatic drainage, protection against inflammation, and effects on blood flow (2). Although a large number of studies have investigated the efficacy of VADs in patients with chronic venous disease, a number of general drawbacks can be identified. Signs and symptoms of venous disease including edema and pain are notoriously difficult to identify or reliably measure, making meaningful assessment of the efficacy of VADs difficult. This leads to inevitable heterogeneity among studies. Moreover, there is no reliable animal model for venous disease, meaning that the usual extensive investigation that the drugs would be subjected to has not been performed for most VADs. Evaluation of venoactive drugs for chronic venous disease Venoactive drugs can be classified as naturally occurring, synthetic drugs, and animal derived extracts (Table 1). Particular features of the most important drugs are discussed below.


1. The alpha-benzopyrone coumarin has been used either alone or in combination with other VADs for the treatment of lymphedema and a number of studies have reported favorable results (3). However, the risk of hepatotoxicity has dramatically limited the use of coumarin.


2. Diosmin and its derivative micronized purified flavonoid fraction (MPFF), consisting of 450 mg diosmin and 50 mg other flavonoid components (hesperidin, linarin, and isorhoifolin), are widely used to relieve symptoms of chronic venous insufficiency (CVI). Of particular interest is the action of MPFF on inflammatory reactions associated with venous hypertension, inhibition of leukocyte activation, adhesion and migration. Specifically, MPFF modifies leukocyte endothelial interactions, inhibiting the expression of intercellular adhesion molecules (ICAM-1) and vascular adhesion molecules (VCAM), as well as the expression of leukocyte adhesion molecules on monocytes and neutrophils (4). The mechanisms of action prevent endothelial damage and suggest use of the drug in the early and advanced stages of CVI (5). The capillary protective effect is enhanced by micronization (6). Unlike other venoactive drugs, MPFF has proven efficacy in ulcer healing. In a meta-analysis of five prospective randomized controlled trials involving 723 patients with venous ulcers in which MPFF therapy was compared with compression therapy, alone in three studies and combined with placebo in two studies (7), the possibility of healing was by 32% higher in the MPFF-treated patients after 6 months and the healing time was shorter (16 weeks versus 21 weeks).


3. Rutin and rutosides increase venous tone by blocking inactivation of noradrenaline (8). They have been shown to reduce the symptoms of venous disease, particularly swelling, and to improve hemodynamic venous function (9). Oxerutins and rutosides are commonly prescribed in many European countries, but the heterogeneity between studies and the lack of large, recent randomized trials have limited the worldwide use of these agents (10).


4. Horse chestnut seed extract (HCSE) has a similar mode of action as MPFF. It has been assessed in patients with venous ulceration, but studies have generally failed to demonstrate any clinical benefit (11).


5. Other plant extracts like Ruscus extracts (12) (reduce capillary permeability), ginkgo biloba (13) and proanthocyanidines, such as the maritime pine tree bark extract (14) have been investigated, but only limited clinical benefits were observed and sample sizes were generally small.


6. Pentoxifylline was the first drug to be extensively studied. It is a xanthine derivative with evidence for a range of microcirculatory effects including reduced platelet aggregation and white cell activation (15). A Cochrane review published in 2007 included 12 randomized trials with 864 participants (16). Pentoxifylline plus compression therapy was found to be more effective than placebo plus compression for ulcer healing (RR 1.54; 95% CI 1.14-2.13). The current use of this drug is, however, limited by the frequent occurrence of side effects (chiefly gastrointestinal) and because it is not reimbursable.


7. Prostanoids. The importance of compartmental ischemia in the genesis of ulcers has led to the assessment of the potential use of these drugs administered in the treatment of advanced stage obliterating arterial disease. The most commonly used are prostaglandin E1 and a stable analogue of prostacyclin.


8. Calcium dobesilate reduces capillary permeability, blood viscosity and improves lymphatic drainage. The efficacy of calcium dobesilate is dose-dependent: the dose used must not be below 1000 mg per day, taken in two divided doses. The anti-edema effects last for around two months following discontinuation of treatment.


9. Naftazone. A placebo controlled trial of naftazone in primary uncomplicated varicose veins claimed a statistically and clinically significant improvement in disability scores as subjectively assessed on a visual analogue scale (17), although other clinical studies are scarce.


10. Animal derived extracts: Another group of drugs for treating CVI comprises the glycosaminoglycans (GAG), including mesoglycan (composed of highly purified natural GAG) and sulfodexide (polysaccharide sulfate), which have been widely tested in coadjuvant ulcer therapy. As shown in experimental and clinical studies (18,19), they display mainly endothelial-mediated activity (inhibition of platelet and leukocyte adhesion), enhancement of endogenous fibrinolysis (stimulation of tissue plasminogen activator (t-PA)) and of antithrombotic properties of plasma (activation of antithrombin III and heparin cofactor-2) (20). In a large-scale multicenter randomized double-blind study, the number of sulfodexide-treated ulcer patients who experienced healing was over one-third higher than of those who received placebo.


CONCLUSION Advances in the understanding of the pathophysiology of venous disease have illustrated the importance of inflammation and hypoxia as the potential key processes in the skin manifestations of chronic venous hypertension. Currently available venoactive agents help prevent these processes and, as shown above, they are considered as effective and safe in treating CVD. Further basic scientific developments may also identify other pathological processes amenable to other pharmacological manipulation. There is a strong rationale for the development of effective venoactive drugs and numerous naturally occurring and synthetic agents may be beneficial.


****The Absract is shown here verbatim*****

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