Venoactive Drugs

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CHAPTER 14 Venoactive Drugs

Introduction

Venoactive drugs (VAD) are a heterogeneous group of medicinal products, of plant or synthetic origin, which have effects on edema (C3) and on symptoms related to chronic venous disease (CVD, classes C0s–C6s according to the CEAP classification).1,2 A specific ‘pain-killer’ effect has been suggested, as VAD are active on venous pain, which does not respond to anti-inflammatory drugs.15

VAD have no demonstrated effect on varicose veins or in varicose vein prevention. Flavonoids may be an adjuvant factor to leg ulcer healing.

Many names have been used to describe VAD: edema-protective agents, phlebotonics, venotonics, vasoprotectors, phlebotropics, and venotropics. These names should be discarded, as a standardization of appellations is highly desirable.

The main mechanisms of action of VAD are:

As a consequence of lack of interest in CVD, publications devoted to VAD are scattered in journals of different languages, which are not always indexed in PubMed.

Although most authors are certainly perfectly honest, it must be emphasized that one group has been accused of fraudulent behavior. As their studies have already been published, they are, unfortunately, still available in reviews and meta-analyses.

Effectiveness of VAD has been regularly discussed, mostly by pharmacologists. Some of them have a poor knowledge of phlebology and VAD; their assertions are debatable. Others are not aware of the difficulty of assessing the activity of VAD.13 Symptoms are subjective, although they can be correctly quantified. Clinical signs such as edema are not easy to measure, owing to significant daily variations in each individual. Efficacy of VAD on edema and venous symptoms may currently be considered as correctly established. However, there is a need for further randomized, controlled clinical trials with greater attention paid to methodological quality.1315

Classification of VAD

The various classes of VAD are shown in Table 14.1.13

In this chapter, we shall distinguish VDA as:

Benzopyrones

This large group of medicines contains many substances, which are often closely related and endowed with multiple pharmacologic properties. Benzopyrones (alpha-pyrones and gamma-pyrones) are obtained from many indigenous and exotic plants, often used in traditional medicine. They belong to the family of phytophenols, and are related to resveratrol, which is currently undergoing a wide range of studies to assess its possible preventative and therapeutic value in atherosclerosis.16

Gamma-benzopyrones (flavonoids)

These have been previously defined as ‘vitamin P’ or factor P (permeability), as flavonoid deficiency results in capillary fragility and increased vessel wall permeability in the animal. These appellations are obsolete.

Many plant pigments belong to this group. They are used in the form of plant extracts, in semisynthetic or synthetic preparations. The main distinction is between:

Substances mostly used therapeutically in CVD are described below.

Diosmin and Micronized Purified Flavonoid Fraction

Diosmin (3′,5,7-trihydroxy-4′-methoxyflavone-7-rhamnoglucoside) is extracted from plants (rutaceae) or obtained by synthesis (as another bioflavonoid, hidrosmin).19 The half-life of diosmin is 8 to 12 hours, with its elimination being renal (65%) and biliary (35%).

Micronization enables a decrease in particle size of the flavone fraction from 20 to 2 µM (MPFF2045), thereby increasing the intestinal absorption and bioavailability of the substance, as has been demonstrated in two clinical trials.2227

Diosmin and MPFF act:

MPFF is indicated in the treatment of edema and of symptoms related to venous insufficiency (edema, heavy legs, discomfort, pruritus, night cramps, pain, swelling), pelvic congestion syndrome,42 venous surgery (decrease in postoperative pain and more rapid recovery43,44) as well as lymphedema, including filarial.45 Its other indications are gynecological (tense painful breasts, IUD-related bleeding) and proctological.

All of these effects have been confirmed in double-blind clinical trials,2044 which also showed a significant improvement in the quality of life of patients suffering from (chronic venous insufficiency) CVI. According to five clinical trials joined in a meta-analysis, MPFF may hasten the healing of leg ulcers.41

Synthetic drugs