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Hypoxia-Induced Activation of Endothelial Cells as a Possible Cause of Venous Diseases: Hypothesis

Abstract

Blood stasis in leg veins is a situation commonly linked to the development of venous diseases such as varicoses. Such a stasis will provoke an ischemia, thus decreasing oxygen availability to tissues. Owing to its localization between blood and tissue, endothelium is the first target of this insult. The authors develop here a hypothesis in which the effect of oxygen deprivation on the functional state of the endothelium is the starting point of a cascade of events leading to the disorganization of the vessel wall typical of these pathologies. When venous human endothelial cells obtained from umbilical cords (HUVEC) are exposed to hypoxic conditions they become activated without change in their viability. The synthesis of a proinflammatory molecule (PAF, platelet-activating factor) and the adhesion of human polymorphonuclear neutrophils (PMN) on HUVEC are markedly increased during hypoxia incubation. These two processes are related to a calcium-dependent activation of endothelial cells due to a decrease of aden osine triphosphate (ATP) availability during hypoxia. Adherence of neutrophils to endothelial cells is the first step of diapedesis, which leads to the infiltration of these cells in the media of the veins, where they affect the smooth muscle cells and the connective tissue, leading to tissue alterations typical of the venous pa thologies. The authors propose that this sequential process which originates from a reduction in oxygen availability and which involves different cell types as one main cause of the venous disorders, in addition to genetic, hormonal, and mechanical factors.

Int Angiol. 1996 Jun;15(2):88-92.

Vessel wall modification in venous pathology. Application to the study of phlebotonic drugs.

Niebes P.
Source
Continental Pharma, Brussels, Belgium.

Abstract

Pathophysiological investigation of varicose veins show extensive metabolic perturbation and structural parietal changes. Oxygen consumption is reduced more than three-fold while levels of activity of proteolytic enzymes from lysosomes are significantly raised. Connective tissue in the venous wall undergoes profound deterioration, with a decrease in collagen fibrils and an increase in proteoglycans. Recent studies of venous endothelial cells in hypoxia have provided an etiological explanation for these disorders. These disturbances in the venous wall are of a magnitude sufficient to produce detectable changes in serum and urine of patients with varicose veins. All the foregoing data provide a basis for a pharmacological approach allowing an improved understanding of the mechanism of action of phlebotonics and the selection of the most active agents.

Venous Valvular Stasis–Associated Hypoxia and Thrombosis: What Is the Link?

Annual Review of Physiology

Vol. 73: 527-545 (Volume publication date March 2011)

Edwin G. Bovill and Albert van der Vliet

Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405; email: edwin.bovill@uvm.edu

ABSTRACT

This review focuses on the role of the venous valves in the genesis of thrombus formation in venous thromboembolic disease (VTE). Clinical VTE and the evidence for the valvular origin of venous thrombosis are reviewed. Virchow's triad is then used as a framework for discussion to approach the question posed regarding the link between venous valvular stasis–associated hypoxia and thrombosis. Thus, the effects of blood flow stasis, hypercoagulability of blood, and the characteristics of the vessel wall within the venous valvular sinus are assessed in turn.

Venous Hypoxia: A Poorly Studied Etiological Factor of Varicose Veins
C.S. Lima, b, M.S. Gohela, A.C. Shepherda, E. Paleologb, A.H. Daviesa

aImperial Vascular Unit, Department of Surgery and Cancer, Faculty of Medicine, Charing Cross Hospital, Imperial College London, and
bCytokine Biology of Vessels Group, Kennedy Institute of Rheumatology and Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK

J Vasc Res 2011;48:185-194 (DOI: 10.1159/000320624)

Abstract

Venous hypoxia has long been postulated as a potential cause of varicosity formation. This article aimed to review the development of this hypothesis, including evidence supporting and controversies surrounding it. Vein wall oxygenation is achieved by oxygen diffusing from luminal blood and vasa vasorum. The whole media of varicosities is oxygenated by vasa vasorum as compared to only the outer two-thirds of media of normal veins. There was no evidence that differences exist between oxygen content of blood from varicose and non-varicose veins, although the former demonstrated larger fluctuations with postural changes. Studies using cell culture and ex vivo explants demonstrated that hypoxia activated leucocytes and endothelium which released mediators regulating vein wall remodelling similar to those observed in varicosities. Venoactive drugs may improve venous oxygenation, and inhibit hypoxia activation of leucocytes and endothelium. The evidence for hypoxia as a causative factor in varicosities remains inconclusive, mainly due to heterogeneity and poor design of published in vivostudies. However, molecular studies have shown that hypoxia was able to cause inflammatory changes and vein wall remodelling similar to those observed in varicosities. Further studies are needed to improve our understanding of the role of hypoxia and help identify potential therapeutic targets.

In MS, our valves are not degraded in the same way as in varicose veins but instead our valves are stiffened which hinders outflow. It seems it would be easy to test the valves for leukocyte infiltration.

Rutoside (Rutosid, Rutin)

Rutoside, which is more commonly known as Rutin but also called quercetin-3-rutinoside and sophorin, is a bioflavonoid obtained from buckwheat, flower buds of the pagoda tree and the leaves of several species of the Eucalyptus. Rutin is actually a form of Quercetin. Quercetin, one of the most common and abundant flavonoids, occurs bound to sugars in the form known as Rutin or Rutoside. Rutin is generally found in apples, onions, and tea among others. This ingredient is said to strengthen capillaries, as well as lower "bad" cholesterol and reduce the incidence of heart disease in humans.

Calcium dobesilate belongs to category of vasoprotectant drugs. Calcium dobesilate is a type of vasoprotectant. It acts on the capillary wall by regulating the impaired physiological functions increased permeability and decreased resis tance. It opposes the breakdown of collagen and reduces plasma and blood hyper viscosity improving blood flow and tissue irrigation. It indirectly increases lymphatic drainage which reduces oedema. Calcium dobesilate (2,5-dihydroxybenzene sulfonate) is a drug commonly used in the treatment of diabetic retinopathy and chronic venous insufficiency. This drug is commonly sold as Brand Name Dobest.

Few studies have investigated potential pharmacologic agents that may protect the vein wall from hypoxia. The most commonly studied group of pharmacological agents in this context has been the venoactive drugs such as flavonoids [19,41,55,57,62]. Venoactive drugs are often derived from plant extracts, and their therapeutic actions include increased venous tone, reduced vein wall inflammation and decreased capillary permeability [6,63].

In vitro models have been used to investigate the effects of venoactive drugs on hypoxia-induced endothelial and PMN activation [41,57]. In a HUVEC model, aescine was shown to inhibit hypoxia-induced activation of endothelial cells, leucocytes, and the interactions of these cells in a dose-dependent manner [41,57]. Venoactive drugs were also shown to target complexes I and III of the mitochondrial respiratory chain or adenine nucleotide translocase, reduce oxidative stress, and increase ATP synthesis during hypoxia [8,41,64]. A further study used an ex vivo vein explant model and found that flavonoids significantly reduced the oxygen consumption of varicose veins [55].

One clinical study reported that patients who took hydroxyethylrutosides (Paroven™) 250 mg, a flavonoid, 4 times a day for 4 weeks showed significant improvements in the PO2 and saturation of blood sampled from varicose veins compared to initial levels [19]. These improvements in varicose vein oxygenation were also associated with symptomatic relief in this patient group [19]. However, the findings of this study should be interpreted with caution as patients were not randomized, neither patients nor clinicians were blinded, and the timing of venepuncture was not matched between the study groups. It was also unclear whether the patients in the study received any other treatment such as compression which might have positive effects on the oxygenation of the luminal blood. Some randomized controlled trials have also reported that venoactive drugs such as flavonoids and horse-chestnut extracts improved symptoms of CVI [63,65,66,67]. These drugs are likely to increase venous tone and decrease vein wall inflammation and capillary permeability [6,63]. Flavonoids such as micronized purified flavonoid fraction, containing 90% diosmin and 10% hesperidin, may also protect the vein wall from hypoxia and inhibit the expression of adhesion molecules on endothelium and leucocyte [6,17,67,68].

Flavonoids such as micronized purified flavonoid fraction, containing 90% diosmin and 10% hesperidin, may also protect the vein wall from hypoxia and inhibit the expression of adhesion molecules on endothelium and leucocyte [6,17,67,68].

DAFLON 500 mg is an oral phlebotropic drug indicated in the treatment of venous disease, i.e, chronic venous insufficiency (CVI) and haemorrhoidal disease (HD).

Origin and composition of DAFLON 500 mg

DAFLON 500 mg, micronized, purified flavonoid fraction (MPFF), is a semisynthetic phlebotropic drug whose active ingredients are micronized diosmin (90%) and hesperidin (10%). Hesperidin is extracted from a species of Rutaceae aurantieae of the citrus genus, a type of immature small orange harvested and dried in Spain, North Africa, and China. Diosmin, a member of the flavonoid family, is synthesized starting from this raw material.(1,2)

Why is the micronized form of DAFLON 500 mg important?

Micronization means that the active ingredient of DAFLON 500 mg undergoes a high-tech grinding process with a jet of air at supersonic velocities, reducing the size of standard particles from more than 20 µm to less than 2 µm. Thanks to its micronized form, DAFLON 500 mg has better and faster absorption, and thus an increased bioavailability, which leads to faster and more powerful clinical efficacy in venous disease.(3-7)

How does DAFLON 500 mg act?

DAFLON 500 mg has a comprehensive and rigorously demonstrated mode of action, which enables it to fight simultaneously all the pathophysiological aspects of venous disease, affecting the veins, lymphatics, and microcirculation.

* Veins
DAFLON 500 mg prolongs the vasoconstrictor effect of noradrenaline on the vein wall,(8) even under warm and acidotic conditions, increasing venous tone, and therefore reducing venous capacitance, distensibility, and stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.

* Lymphatics
DAFLON 500 mg improves lymphatic drainage by increasing the frequency and intensity of lymphatic contractions, and by increasing the total number of functional lymphatic capillaries. Furthermore, DAFLON 500 mg decreases the diameter of lymphatic capillaries and the intralymphatic pressure (9,10)

* Microcirculation
At the microcirculation level, DAFLON 500 mg reduces capillary hyperpermeability and increases capillary resistance by protecting the microcirculation from damaging processes. DAFLON 500 mg reduces the expression of endothelial adhesion molecules (ICAM1, VCAM1),(11) and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and prostaglandins (PGE2, PGF2).(12-18)
This protective and reinforcing action on the venous and lymphatic system, associated with the vasculoprotective effect on the microcirculation, explains the restorative and protective efficacy of DAFLON 500 mg in chronic venous insufficiency and haemorrhoidal disease, both of which are associated with perivascular inflammation and edema.

Has DAFLON 500 mg demonstrated its clinical efficacy in chronic venous insufficiency?

In patients suffering from CVI, DAFLON 500 mg provides significant relief by improving disabling symptoms, (18-20) such as pain, heavy legs, cramps, and sensation of swelling. Moreover, DAFLON 500 mg also significantly improves clinical signs, such as leg edema,(20,21) skin disorders,(22) and venous leg ulcer.(23,24) This improvement of signs and symptoms contributes to a significant increase in patients' quality of life, as assessed with a validated international scale specific to CVI: the CIVIQ questionnaire.(19)

Can DAFLON 500 mg be useful in treating complications of chronic venous insufficiency?

*Venous leg ulcer
In venous leg ulcer, the combination of DAFLON 500 mg and conventional compression therapy has been proven not only to accelerate the healing rate, but also to increase the total number of completely healed leg ulcers.(23,24) A recent study confirmed the same and also showed that addition of Daflon 500 reduces healing time by 1 month (25) and improves cost – effectiveness ratio by 45%.

* Postsurgical and postradiotherapy lymphedema
Administration of DAFLON 500 mg, 2 tablets daily, for 6 months in patients who had lymphedema after breast cancer surgery leads to a 1.5% to 13.4% decrease in circumference of the affected arm, an improvement in tissue elasticity, and an improvement in lymphatic drainage functional parameters, evaluated by isotope scan.(26) Another double-blind, placebo controlled study, with an equal treatment period and dosage, demonstrated that DAFLON 500 mg induces and increases the velocity of lymphatic drainage on isotope scan, improves functional disturbances, and constantly decreases the volume of the affected arm.(27)

What about the efficacy of DAFLON 500 mg in haemorroidal disease?

In acute haemorrhoidal attacks, DAFLON 500 mg is highly effective, right from the second day of treatment, in improving all signs and symptoms, such as bleeding, pain, discharge, tenesmus, and proctitis, thereby reducing the consumption of oral analgesics.(28,29)

The efficacy of DAFLON 500 mg associated with fiber supplement has been superior to fiber supplement alone and equivalent to rubber-band ligation plus fiber supplement in stopping anal bleeding due to haemorrhoids.(31)

DAFLON 500 mg combined with haemorrhoidectomy significantly reduces the risk of postoperative bleeding.(31) In a recent study , Daflon 500 when used in combination with short- term antibiotic and anti-inflammatory treatment reduced both the duration and extent of post operative symptoms ( pain, tenesmus, pruritus ) and wound bleeding following haemorrhoidectomy.(32)

In long-term treatment for chronic haemorrhoidal disease, DAFLON 500 mg has been proven to significantly reduce recurrence, duration, number, and severity of haemorrhoidal attacks.(30,33)

What is the dosage of DAFLON 500 mg?

Chronic venous insufficiency: 2 tablets daily
Haemorrhoidal disease:
- Haemorrhoidal attacks: 6 tablets daily for 4 days followed by 4 tablets daily for 3 days
- Chronic haemorrhoids: 2 tablets daily

Manufactured by: SERDIA PHARMACEUTICALS LTD