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Venoactive Drugs
Introduction
Venoactive drugs (VAD) are a heterogeneous group of medicinal products, of plant or synthetic origin, which have effects on edema (C 3 ) or on symptoms related to chronic venous disease (CVD) (classes C 0s –C 6s according to the CEAP [clinical, etiology, anatomy and pathophysiology] classification). A specific ‘painkiller’ effect has been suggested, as VAD are active on venous pain, which does not respond to anti-inflammatory drugs.
In Germany approximatively 7% of the general population regularly use VAD, usually combined with compression stockings (70%). VAD appear to be taken mainly by female, preobese and obese patients in stages C 2 and C 3 .
VAD have no demonstrated clinical effect on varicose veins or in varicose vein prevention.
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 following are the main mechanisms of action of VAD :
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Increasing venous tone (this results in restoration of normal blood flow, dispersion of red cell aggregates and better oxygenation).
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Improving capillary hyperpermeability and lymph flow (thus protecting the microcirculation and decreasing the risk of edema).
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Inhibiting the leukocyte adhesion to endothelial cells and the transmigration of leukocytes into the venous wall.
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Improving fibrinolysis and blood rheology.
In the majority of published studies, major bias may be present; potential or evident conflicts of interest are not always mentioned (including in recent guidelines). It must be emphasized that at least 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.
The effectiveness of VAD has been regularly discussed, mostly by pharmacologists. Some pharmacologists 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. 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. The 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 methodologic quality.
Classification of VAD
The various classes of VAD are shown in Table 14.1 .
Table 14.1
Classification of the Main Venoactive Drugs
| Group | Substance | Origin | Dosage (mg/Day) | Pregnancy | Breastfeeding | Number of Intakes/Day |
|---|---|---|---|---|---|---|
| Benzopyrones | ||||||
| α-Benzopyrones | Coumarin | Melilot ( Melilotus officinalis L.) Woodruff ( Asperula odorata L.) |
90 and troxerutin (540) | + | − | 3 |
| γ-Benzopyrones (flavonoids) | Diosmin | Citrus spp. Sophora japonica L. |
300–600 | + | − | 1 or 2 |
| Micronized purified flavonoid fraction | 1000 | + | − | 1 or 2 | ||
| Rutin and rutosides O -(β-hydroxyethyl)-rutosides (troxerutin, HR) |
Sophora japonica L. Eucalyptus spp. Buckwheat ( Fagopyrum esculentum Moench) |
1000 | + | − | 1 or 2 | |
| Saponins | ||||||
| Escin | Horse chestnut seed ( Aesculus hippocastanum L.) |
120, then 60 | ? | − | 3 | |
| Ruscus extract | Butcher's broom ( Ruscus aculeatus L.) | 2–3 tablets | + | − | 2 to 3 | |
| Other Plant Extracts | ||||||
| Anthocyans (and flavonoids) | Bilberry ( Vaccinium myrtillus L.) | 116 | ? | − | 2 | |
| Red vine leaves ( Vitis vinifera L.) | 360–720 | − | − | 1 or 2 | ||
| Proanthocyanidines (oligomers) | Grape pips ( Vitis vinifera L.) | 100–300 | + | − | 1 to 3 | |
| Maritime pine ( Pinus maritima Lank) (Pycnogenol) |
300–360 | ? | − | 3 | ||
| Ginkgo biloba | Ginkgo biloba L. | 2 ampules or capsules (extracts of Ginkgo, heptaminol and troxerutin) | − | − | 2 | |
| Synthetic Products | ||||||
| Calcium dobesilate | Synthesis | 1000–1500 | − | − | 2 to 3 | |
| Benzarone | Synthesis | 400–600 | + | − | 2 to 3 | |
| Naftazone | Synthesis | 30 | + | − | 1 | |
| Animal-Derived Extracts | ||||||
| Mesoglycan, Suledoxide | Polysaccharides from different animal tissues | 250–500 ULS * | ? | ? | 1 or 2 | |
+, The product has been administered during pregnancy; −, the manufacturer gives no indication, making the physician responsible for his or her decision; HR, hydroxyethylrutosides.
In this chapter, we shall distinguish VAD as:
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Benzopyrones
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Saponins
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Other plant extracts
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Synthetic drugs
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Animal-derived extracts
Benzopyrones
This large group of medicines contains many substances, which are often closely related and endowed with multiple pharmacologic properties. Benzopyrones (α- and γ-pyrones) are obtained from many 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.
α-Benzopyrones
Coumarin (1,2-benzopyrone; 5,6-benzo-α-pyrone) has been used either alone (mainly for the treatment of lymphedema) or in low doses in combination with oxerutin.
Esculetin (6,7-dihydroxycoumarin) and umbelliferone (7-hydroxycoumarin) are coumarin derivatives. Dicoumarols (dimers of 4-hydroxycoumarins) are powerful oral anticoagulants (acenocoumarol, phenprocoumon, warfarin). Their therapeutic properties thus differ fundamentally from those of VAD, despite their chemical similarities.
Coumarin is quickly absorbed and has a short half-life of 1 hour. Both it and its metabolites are excreted via the kidney.
Coumarin induces proteolysis of high-molecular-weight proteins present in lymphedema. Small-size protein fragments can then be more easily drained via the lymphatics. The oncotic pressure drops and edema lessens. However, effectiveness is debatable. Although coumarin and its derivatives have an antiedematous effect, they do not modify the coagulation of blood, in contrast to dicoumarols. Alongside its therapeutic properties, the aromatic properties of coumarin are extensively used in spices for cooking, cosmetology (soap, perfumes) and the tobacco industry.
Several cases of drug-related hepatitis after taking high doses of coumarin or dicoumarols as an anticoagulant have been reported. Coumarin has been withdrawn from the market for this reason, except in brands associating low doses of coumarin and troxerutin. Poor cytochrome P450 (CYP)2A6 metabolizers may be concerned by this hepatotoxicity. Identifying such patients might avoid such side effects happening.
γ-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:
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Flavone and its derivatives, flavonols (kaempferol, diosmetin, diosmin, hidrosmin, quercetin, rutin [rutoside, oxerutin])
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Flavanes (or flavonones): hesperitin, hesperidin and its derivatives, Pycnogenol, procyanidolic oligomers, etc.
Substances mostly used therapeutically in CVD are described below. Each manufacturer has developed its own techniques to demonstrate some effects of its drug. Comparison between the various VAD is therefore quite difficult. One may, however, consider that many results may be extrapolated from one VAD to another.
Diosmin and Micronized Purified Flavonoid Fraction
Diosmin (3′,5,7-trihydroxy-4′-methoxyflavone-7-rhamnoglucoside) is extracted from plants (from the family Rutaceae) or obtained by synthesis (as another bioflavonoid, hidrosmin). The half-life of diosmin is 8–12 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, thereby increasing the intestinal absorption and bioavailability of the substance.
Diosmin and micronized purified flavonoid fraction (MPFF) act on venous tone (by inhibiting the breakdown of norepinephrine [noradrenaline] by catechol- O -methyltransferase. The degree of this effect varies in linear relation to the dose administered, lymphatic drainage (decrease in the diameter of lymphatic vessels and intralymphatic pressure, increased peristalsis) and the microcirculation (inhibition of adhesion of leukocytes, their intratissue migration, the release of inflammatory mediators).
MPFF is indicated in the treatment of edema and of symptoms related to venous insufficiency (edema, heavy legs, discomfort, pruritus, night cramps, pain, swelling). It may be indicated in pelvic congestion syndrome, venous surgery (decrease in postoperative pain and more rapid recovery) and lymphedema, including filarial. Its other indications are gynecologic (tense, painful breasts, intrauterine device–related bleeding) and proctologic.
Double-blind clinical trials also demonstrate a significant improvement in the quality of life of patients with chronic venous insufficiency. However, the number of patients registered in these trials is small. One study did not demonstrate a beneficial effect of MPFF, except on night cramps.
According to five clinical trials joined in a meta-analysis, MPFF may hasten the healing of leg ulcers. However, relative efficacy was demonstrated only in a small subgroup of venous ulcers (ulcers between 5 and 10 cm 2 in area, and those present for 6–12 months), and the results need to be interpreted very cautiously. Moreover, the most rigorously conducted study (Zucarelli F, Rieger H, 2004) was not published and yielded negative results. Therefore, this indication is not considered in the latest guidelines.
Rutosides and Oxerutin
A standard mixture of several flavonoid derivatives is obtained by hydroxyethylation of a natural substance, rutin (oxerutin, HR or hydroxyethylrutosides). Troxerutin is a fraction of oxerutine. Absorbed by the digestive tract, oxerutine has a half-life of 24 hours and is principally excreted in bile. A large number of pharmacologic and clinical studies have provided evidence of its influence on disturbances of capillary permeability, effects on erythrocyte deformation and aggregation, antiedematous actions and inhibition of prostaglandin synthesis. Its diffusion and accumulation in the venous wall have been demonstrated.
Rutosides are indicated as an antiedematous agent in venous disorders, in proctology (hemorrhoids) and in ophthalmology (retinopathy). Oxerutine is absorbed following topical application, and its action on cutaneous capillary fragility has been demonstrated.
Saponins
Escin
Escin is a mixture extracted from horse chestnut seed (HCSE). It contains many compounds, such as protoescigenin, barringtogenol, α- and β-escin, cryptoescin and benzopyrones.
HCSE compounds are poorly absorbed in the digestive tract (12.5%). Maximum activity of the preparation occurs 16 hours after ingestion. Escin and its metabolites are eliminated via the kidney and gallbladder; its percutaneous absorption has also been demonstrated.
Escin increases venous wall tone and has a well-demonstrated antiedematous effect. The HSCE extracts were evaluated in one Cochrane study, which curiously excluded other VAD.
Ruscus
Extracts of ruscus (butcher's broom) contain saponins and flavonoids. The precise composition of these extracts is poorly understood. Venotonic and antiedematous actions have been well demonstrated in open and randomized controlled trials (RCTs) and are associated with a reduction of symptoms and improvement in quality of life in patients with CVD.
Other Plant Extracts
Extracts of Ginkgo biloba contain terpenes and flavonoids. Antagonists of platelet-activating factor, they have an action on platelet aggregation, blood viscosity and edema. Extracts of Centella asiatica are believed to enhance collagen synthesis in connective tissue.
Many other plants are used successfully in the treatment of symptoms of CVD. All of them contain flavonoids, among other active substances: procyanidolic oligomers (anthocyans in bilberry extracts; proanthocyanidols in white grape seeds, red vine leaves ( Vitis vinifera ), and maritime pine [Pycnogenol]).
Phytotherapy
Plant extracts used in phytotherapy are often poorly standardized and controlled. Their active substance content may vary according to plant genetics, as well as according to climatic factors, quality of the ground in which the plants were grown, the time of harvesting and the extraction methods used. Flavonoids may be at least partially responsible for their pharmacologic effects, but other glycosides might also be active.
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