DRUG TREATMENT OF CHRONIC VENOUS INSUFFICIENCY, VARICOSE VEINS OF THE LOWER EXTREMITIES

      Varicose veins of the lower extremities - is a very common and fairly well-known general public pathology. Whether it can be cured or prevented in any way? And what is the role and effectiveness of this general problem of drugs? How imminent operation and whether it solves all the problems with varicose veins?

To understand the problem, in order to obtain comprehensive answers, we must first clarify the terminology. The fact that the term "varicose veins of the lower extremities" over time became excessively broad use. And, in some cases, it raises all sorts of errors and mistakes. Not even the rather serious medical publications.

Not too going into the details, it is convenient to present the "varicose veins of the lower extremities" as an organic and more apparent cause disease (I83 index of the ICD-10), being in most cases only a cosmetic problem (see below), and a complex of symptoms related defined as "chronic venous insufficiency» (I87.2 ICD-10). It is the second defines the first complications (inflammation, ulcers, etc.), and the first one adds the second. Treatment and prevention of these conditions differ significantly from each other.

Epidemiology. Chronic venous insufficiency (CVI) is the most common disease of the peripheral vessels. According to statistics, in the U.S. are 10 times more patients suffering from CVI than from the arterial limb ischemia. In Russia chronic venous insufficiency affects 35-38 million people and in the world various forms of the disease can be detected in more than half the population of developed countries, and its incidence in women is prevalent. Annual growth rate of occurrence of CVI, which is 2.6% for women and 2% for men. The researchers of this fact, just as the spread of this disease, due to the increasing length and sedentary lifestyle of the population [1-4].

Pathogenesis. The main "supplier" of patients with chronic venous insufficiency is varicose veins of the lower extremities, which in itself is seen in 18-38% of the adult population. And it was his well-known correlation with age and gender, to some extent determined by the larger frequency of CVI is the female population. And, speaking as the most common reasons for the confusion of terms (see above). In those 72% of U.S. women and 42% men to 60 years of age have clinically significant varicose veins. The second leading cause of CVI are the traumas and thrombophlebitis (against injuries, skin diseases, etc.) and related syndromes, and congenital vascular anomalies (arteriovenous and lymphovenous fistulae, hypoplasia of the communicating valves, etc.). More rarely the disease develops in the presence of systemic diseases of connective tissue (collagenosis, dermatomyositis, rheumatoid arthritis, etc.), obesity, dishormonal states, pelvic tumors, diabetes, taking certain medications (oral contraceptives), etc. [3, 5, 6].

Clinical manifestations. Overall CVI is a syndrome, which is based on a cascade of pathological changes in the tissues of the lower limbs at the molecular, cellular and tissue levels, initiated by venous stasis. The main symptoms are pain in the legs, swelling, fatigue, heaviness, bloating, muscle twitching (usually at night). Often, this is added to other neurological symptoms - paresthesias, tingling, local hot flashes, numbness, etc. A characteristic feature of these signs is their appearance with static loads (e.g., surgeons, vendors, hairdressers). And, as a rule, they are completely disappear or reduced intensity of walking and after a night's rest. At the same time, in the early stages of pathology proceeds rather hidden and characteristic swelling almost imperceptible (0-3 stage classification CEAP). Although it may appear in the hot season. It is at these stages of CVI drug treatment is particularly effective, as it has not only therapeutic, but also with regard to prevention of possible complications and further progression of disease activity [6-8].

International Classification of chronic venous disease of the lower extremities (СЕАР)

Class 0. No symptoms of venous disease at medical checkup and palpation.

Class 1. Telangiectasia or reticular veins.

Class 2. Varicose veins.

Class 3. Swelling.

Class 4. Skin changes caused by venous disease (pigmentation, venous eczema, lipodermatosclerosis).

Class 5. Skin changes listed above and healed ulcer.

Class 6. Skin changes mentioned above, and an active ulcer.

     As the disease develops its characteristic complications – trophic disorders of the skin (4-6 stages on CEAP). They usually appear in the area of  the medial malleolus, and can then take the circular nature. Originally appeared on areas of hyperpigmentation of the skin subcutaneous tissue and the skin thicken with time, acquiring a typical "painted" look (lipodermatosclerosis). In response to minimal trauma on this background, there is a whitish patch of skin (called "white atrophy"), followed by open trophic ulcer. Often with CVI are also noted the phenomenon of secondary lymphatic insufficiency, develop dermatitis, eczema, erysipelas. The frequency of such events, the pathophysiological basis of which is a bacterial cellulitis, according to the literature, covering from 11 to 22.8% of all patients with chronic venous insufficiency and is associated with a 5-6th stage for CEAP. Along with it an increased risk of more serious complications. So, against pregnancy during CVI deep vein thrombosis occurs in 6-10% of patients, the frequency in the population exceeding 50,000 times (!). A polyvalent allergic willingness among patients with chronic venous ulcers are diagnosed in 56-80%. And it is to a certain extent limits the use of medication, dictating the need for prescribing the most safe and effective drugs from the venotonics [9-12].

     Quite common in the recent past and a very simplistic view on the CVI, as a result of failure (primary or secondary) communicating valves (as a result of varicose veins), is now widely recognized as flawed. The fact is that in isolation, this pathology occurs not more than 10% of patients with CVI and in combination – approximately 46%. Stereotype of venous pathology was considered purely a matter of surgeons at the time led to the fact that a large number of patients do not receive adequate medical care. According to some authors, only women of reproductive age the proportion of patients was 62.3%. And of course, that it is much higher among elderly and have comorbidities [3, 13-15]. Also worth mentioning is that in some countries, the widespread use of surgical treatment of CVI is largely driven by a simple lack of paid treatment protocols of phlebotropic drugs (venotonics or phleboprotectors). In connection with this point of view, the various authoritative sources on the recommendations of the use of a method of therapy may seriously vary because of these not so obvious reasons for practitioners. By the way, as well as methods of the surgical treatment. 

     At present, the majority of patients with CVI is used non-surgical methods of treatment, including medication [3, 16-18].

     In general, the use of drugs that can be represented as follows:

1.     Basic drugs

·       Phleboprotectors (angioprotectors, venotonics, γ-benzopyrenes, flavonoids).

2.     Adjuvant medications

·       Non-steroidal anti-inflammatory drugs (diclofenac, ketoprofen, indometacin)

·       Anticoagulants: a) direct (heparin, low molecular weight heparin); b) indirect (coumarin derivatives and phenindione); c) heparinoids (sulodexide, pentosan polysulfate, dermatan sulfate); d) analogues of hirudin (lepirudin and danaparoid)

·       Antiplatelet drugs (low molecular weight dextran, dipyridamole, pentoxifylline)

·       Antibacterial and antifungal agents

·       Antihistamines (telfast, loratadine, aerius, astemizole)

·       Potassium-sparing diuretics (amiloride, triamterene, spirinolakton)

·       Oral enzymes (bromelain, papain, pancreatin, trypsin, amylase, lipase, chymotrypsin, etc.)

·       Preparations based on PGE1 (alprostadil, vazaprostan)

·       Derivatives deproteinized blood (actovegin, solcoseryl)

3.     Topical medicines (unguents, creams and gels)

If adjuvant medications (medications that are assigned separately) is used, according to the range of their activities, situational (e.g., NSAIDs - in the presence of local inflammation, and heparin-containing – with signs of blood clots and thrombosis of superficial veins), it is basic in terms of treatment of CVI are only recognized phleboprotectors (angioprotectors or venotonics). They are grouped in C05 by pharmacological classification ATC and are well represented in the pharmaceutical market in most countries.

The vast majority of phleboprotectors are products of plant origin – bioflavonoids. From a pharmacological point of view, most of them can be combined into a group of γ-benzopyrenes. The biochemical classification they belong to the flavones, flavonols and flavonoids, and chemical compounds belonging to the polyphenolic nature. Modern leadership venotonics value due to their maximum and complex influence on the basic disease processes of the target characteristic of CVI. At the same time, their natural origin determines the minimum general toxic effects [4, 19-21].

Indication for phleboprotectors are known symptoms of CVI. Because they all have a similar mechanism of action, the choice of drug is determined in practice by factors such as the individual tolerability, ease of reception, personal experience of the doctor and the patient's physical facilities. It should be noted that the co-administration of the two drugs in this group is meaningless.

Unfortunately, most of the currently existing phleboprotectors have low efficiency, despite the usefulness of theoretically sound. This is due to several reasons, the main one of which is the low bioavailability of drugs and a number of not fully respond to technological aspects. From a pharmacological point of view, they can be divided arbitrarily into three groups.

1. Rutoside and their derivatives. Least recently used and popular group of drugs based on troxerutin, O-(β-hydroxyethyl) rutosides (hydroxyethylrutosides or oxerutines). The active ingredients reduce the permeability and capillary fragility, strengthen the vascular wall, reducing its swelling and inflammation, has an antioxidant effect on the tissue, exhibit P-vitamin activity, contributing to relief of symptoms of CVI. Moderately block the aggregation of red blood cells and have a protective effect on the vascular endothelium. Along with the low bioavailability due to poor absorption in the gastrointestinal tract, have it marked irritant that causes a number of specific adverse symptoms (indigestion, nausea, epigastric discomfort, vomiting, diarrhea). This fundamentally limits the doses used and greatly reduces the effectiveness of treatment. Other adverse reactions are as frequent skin rashes, fatigue, flushing, and headache. Most drugs are contraindicated in peptic ulcer, chronic gastritis, pregnancy (especially in I trimester) and lactation, as well as on the background of hypercalcemia (the elderly, patients with cancer, etc.), renal failure in children. With increased caution used in hypercoagulability in acute thrombosis, and the presence of kidney stone disease, severity of disease of the cardiovascular system. Not suitable for combination with receiving cardiac glycosides, aminoglycosides and sulfonamides

Introduction of various excipients, the combination with other drugs, and other synthesis to reduce side effects and increase the effectiveness is not yet possible to achieve fundamental progress of this group of drugs. But in this respect, from a pharmacological point of view, they can be divided into three groups – a) on the basis of natural rutoside complex, b) semi-synthetic and c) combined (Table 1). Semisynthetic rutoside have less potential for allergic reactions because it does not contain dietary fibers of vegetable origin.

The duration of treatment is usually 1-3 months with mandatory re 2-3 months. Shorter courses are usually used in the complex treatment of exacerbations of CVI in combination with drugs other groups. To enhance the effect of oral administration is generally recommended to combine with the local form of the relevant product (gel, cream). Necessary for the prevention of dyspepsia treatment (unless otherwise stated) with meals. Positive data points venotonics include accessibility due to the relatively low cost.

Table 1.

The most widely used and their derivatives rutoside

2. Saponins. Another group venotonics on pharmaceutical market is a well-known group of drugs based on the extract of horse chestnut (Aesculus hippocastanum L.) – escine (Table 2). They reduce capillary permeability, increase the tone of the veins, reduce inflammation, and also have angioprotective and antiedematous action. Increasingly used in functional disorders of venous drainage (swelling, leg cramps, pain and a feeling of heaviness in the legs, etc.) and in the treatment of complications of CVI. Similar to the contraindications and types of side effects from the previous group: dyspepsia (epigastric discomfort, nausea, diarrhea), allergic reactions (hot flashes, hives, skin rash, pruritus, tachycardia). Can also enhance nephrotoxicity of aminoglycoside antibiotics, the effects of antiplatelet agents and anticoagulants, are not compatible with drugs inhibiting ovulation.

Table  2.

The most widely used drugs containing escin

3. Preparations based on diosmin and similar base hydrosmin, kaempferol, diosmetine, quercetin, hesperidin are the most promising and effective among phleboprotectors. This group of chemicals called gamma benzopirones or flavonoids (flavonic acid derivatives). Have the most effective and comprehensive venotonic and angioprotective action, reduce venous distensibility, increase their vitality, improves lymphatic drainage. Additionally, diosmin significantly reduces the interaction of leukocytes to the endothelium, adhesion of neutrophil granulocytes in the post-capillary venules, thus reducing the damaging effects of inflammatory mediators on the walls and valves of the veins. It is also important that they do not have most of the major shortcomings of other venotonics, optimizing the therapeutic dose and, as the results of evidence-based clinical research, to achieve much greater efficiency CVI therapy [8, 10, 14, 21-23].

Side effects from the digestive system (indigestion, nausea, etc.) and neurovegetative nature (dizziness, headache) are real, but they are much smaller in frequency (order of magnitude) and intensity, despite a doubling - up from rutoside - used therapeutic dose. Not require, unlike other groups venotonics, cancellation of the drug. Have improved bioavailability profile, which gives a much more stable therapeutic effect. It is also important that diosmin practically does not interact with other medications and food, almost no irritating effect on the gastrointestinal mucosa. This allows you to use it during pregnancy (in her terms) for various gastrointestinal diseases, the presence of comorbidity of other organs (including kidneys, cardiovascular system, liver, etc.). The use of this group of drugs does not require correction treatments of common diseases of advanced age, often requiring continuous use of appropriate medications. He has no contraindications for the treatment of children, including young children. Effective with CVI any origin at all stages [22-25].

To achieve and enhance the positive effects of diosmin and optimum daily dosage, a variety of processing methods - ultrasonic micronization, making water-soluble powder form, with a combination of natural ingredients, etc. In this respect, we can divide the drugs used in practice in the two groups (Table 3).

Table  3.

The most widely used drugs diosmin and its analogues

At the same time, different preparations of this phleboprotectors group have certain advantages and disadvantages. And the inclusion of these features allows in a given case, to recommend the use of any particular one of them. To this end, clinical pharmacology made ​​preparations to analyze the profiles of safety, efficacy and cost (affordability).

Other groups of drugs used to treat CVI include coumarins (alpha benzopirones – acenocoumarol, carbochromen, ensakulin, tioklomarol), pycnogenoles (endotelon, pycnogenol), ergot alkaloids (dihydroergotamine, dihydroergocristine, dihydroergocriptine) and some others. At the same time, most of them positioned as a means of additional therapy or are far from comprehensive efficiency above groups of phleboprotectors.

Safety is defined in special controlled trials of evidence based tolerability of side effects and complications. Especially fixed ones that demanded the cancellation of the drug or use complementary therapies.

Thus, Venosmil on the basis hydrosmin (mix 5,3-mono-O-(β-hydroxyethyl)-diosmin and 5,3-di-O-(β-hydroxyethyl)-diosmin) is considered the most new development. The mechanism of action of the active substance is associated with the inhibition of the degradation of catecholamines inhibition of catecholamine-O-methyltransferase. However, the drug and the most poorly understood. And therefore it is not recommended for use during pregnancy and lactation, in children, and in taking any other medications. Such research, including drug interactions with food, until just spent.

Detralex, Dioflan and Normoven and also used only in III trimester of pregnancy and is officially not recommended during breast-feeding. They retain the above side effects from the gut and the nervous system (see above) are considered, due to the content in the structure of natural hesperidin. Contraindicated in children (under 18 years)

At the same time Phlebodia and Vazoket include only synthetically produced diosmin. This principle eliminates the issue of formation or implementation of routine for patients with CVI allergic challenge readiness and irritating to the gastrointestinal mucosa. In addition, currently used Phlebodia 600 diosmin also with improved, compared to the natural analogue by co-aggregation pharmacokinetic parameters. This provides an adequate dose of the active substance in the target organs - the walls of the veins and ischemic tissues.

In this regard, safety profile of drugs in this group can be represented in the sequence Phlebodia 600, Vazoket 600, Detralex, Dioflan, Normoven and Venosmil.

Effectiveness of the drug is determined by clinical trials in relation to a particular disease. In this regard, sufficient for the use with CVI have only two drugs of this group - Detralex and Phlebodia 600. Summary analysis of the available literature suggests roughly comparable in importance to the effectiveness of this pathology in general, and in most of its stages [22, 23-27].

However, the published data regarding the pharmacokinetics of Detralex, where the urine is eliminated only 14% and 80% of the bowel (this represents only a small proportion of biliary elimination) do not allow to assert that the claimed high permeability and significant revenues to the target tissue. For comparison, a similar study on Phlebodia give elimination in the urine 79% of the drug, and the gut – only 11%. In the first method, the dose of the active ingredient - the target - just does not reach. Naturally, that for a comparable positive effect Detralex recommended to receive at different stages of CVI for 2-3 months, and Phlebodia – 1-2 months [22, 28, 29].

Widely replicated in Russian literature thesis on the "gold standard" and "reference phleboprotector" in the treatment of CVI against micronized diosmine - Detralex [30, 31] does not hold water, because the drug, as well as the effectiveness of micronized diosmine result is not recognized FDA, the main "trendsetter" in the world of medical treatment. The reason is simple - lack of efficacy and safety of the technology [32].

Cost of treatment is taken into account pharmacoeconomic calculations necessary expenses. Without the use of specific indicators and given the current retail prices, material costs for treatment Phlebodia 600 compared Detralex to approximately 40% lower than the first one.

In conclusion, it must be emphasized that the CVI is an integrated multi-disciplinary medical problem, the successful solution of which in each case report is possible only with a rational combination of advanced diagnostic, therapeutic and preventive technologies. And the adequacy of medical therapy of fleboprotectors among them the most prominent position. At the same time, of course, that the observance of safety, effectiveness and cost accounting of the ongoing course of treatment increases the effect of treatment of this complex disease in general.

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