Current Vascular Pharmacology, 2005, 3, 1-9 1

Micronized Purified Flavonoid Fraction (MPFF)*: A Review of its

Pharmacological Effects, Therapeutic Efficacy and Benefits in the
Management of Chronic Venous Insufficiency

Konstantinos Katsenis

Vascular Surgery Dept. of 2nd Surgical Clinic of Athens University, Areteion Hospital, 76 Vas. Sofias Str., 11521
Athens, Greece

Abstract: Initially, the progression of chronic venous insufficiency is related to venous hypertension. The earliest
complaints or symptoms, as well as vessel wall deterioration, valve restructuring, and, eventually, varicose veins, result
not only from elevation of pressure, but also from a cascade of biochemical events related to both the macro- and the
microcirculation. Thickening and remodelling of the venous wall are influenced by two parameters: abnormal shear stress
and hypoxia that activate the endothelium first at the level of valve cusps and then in large veins. Hypoxia leads to
activation of the endothelium and leukocyte accumulation.
By inhibiting endothelial activation, micronized purified flavonoid fraction (MPFF) (Daflon 500 mg), an edema-
protective agent, can prevent the inflammatory cascade resulting from the leukocyte-endothelium interaction. This
subsequently delays the appearance of reflux and inhibits the initiation of the vicious circle ending in enhanced venous
pressure. This is how Daflon 500 mg relieves patients from symptoms and edema and possibly also prevents the
appearance of varicose veins.
Rheological disturbances also play a major role in the appearance of these disorders. Furthermore, venous hypertension
provokes leakage from the vessels and capillaries exhibiting increased permeability, leading to increases in hydrostatic
load, and overloading of the lymphatic network, which subsequently results fluid exudation causing edema.
Microcirculatory dysfunction leads to capillary damage, skin changes and venous leg ulcers.
The clinical efficacy of Daflon 500 mg in venous leg ulcers has been demonstrated by several randomised controlled
studies, in which the rate of ulcer healing was significantly shortened. An explanation for the ability to speed ulcer healing
comes from the protection Daflon 500 mg exerts on the microcirculation.
Keywords: Chronic venous disease, varicose ulcer, symptoms, endothelium, micronized purified flavonoid fraction.

1. INTRODUCTION by venous valvular incompetence with or without associated

Chronic venous insufficiency is a burden for society.
Taking into account its high prevalence, cost of investigation
and treatment, and associated loss of working days, the cost
of CVI has been estimated to be 1% to 3% of the total annual
health care budgets in European countries [1]. We will
review the epidemiology and pathophysiology of the disease,
and how micronized purified flavonoid fraction (MPFF)*, an
oral phlebotropic drug consisting of 90% diosmin and 10%
flavonoids expressed as hesperidine, can act on mechanisms
leading to CVI. To this end, the pharmacodynamic and
pharmacokinetic properties of MPFF, and its therapeutic
efficacy at each stage of CVI will be reviewed.
* Registered as Ardium, Alvenor, Arvenum 500,
Capiven, Daflon 500 mg, Detralex, Elatec,
Flebotropin, Variton, Venitol
2. DEFINITION OF CHRONIC VENOUS INSUFFI-
CIENCY
Chronic venous insufficiency (CVI) is defined in this
article as an abnormally functioning venous system caused
venous outflow obstruction, which may affect the superficial
venous system, the deep venous system, or both. Venous
dysfunction may result from either a congenital or an
acquired disorder [2]. Chronic venous insufficiency is
characterised by symptoms and signs that are the
consequence of venous hypertension.
Symptoms
The most frequently encountered symptoms are leg ache,
a sensation of heaviness or tension, nocturnal cramps,
sensation of swelling, restless legs, and itching. It seems that
the prevalence of symptoms increases with age in both sexes
[3]. Venous disease is symptomatic from the beginning of
the process, associated with changes in the venous wall. The
anatomic process from normal to varicose veins induces
blood stasis that leads to hypoxia. Recent work [4] suggests
that both hypoxia and venous wall distension can produce
pain and leg heaviness and tension. This may explain the fact
that pain intensity is higher at the early stages of CVI before
venous wall fibrosis and valve failure occur. For the same
reasons, symptoms may not systematically be associated

with trunk varicose veins |3] or venous reflux on duplex

Address correspondence to this author at the Vascular Surgery Dept. of 2nd
Surgical Clinic of Athens University, Areteion Hospital, 76 Vas. Sofias
Str., 11521 Athens, Greece; Tel: +30 210 7286726 7286273; Fax: +30
(210) 7211007; Email: katsenis@aretaieion.uoa.gr
ultrasonography [5]. In more advanced cases, edema
formation may play a role in pain intensity by the pressure it
exerts on nerve endings.

1570-1611/05 $50.00+.00 2005 Bentham Science Publishers Ltd.

2 Current Vascular Pharmacology, 2005, Vol. 3, No. 1
Restless legs and cramps, usually occurring at night,
would be due to prolonged immobility. Blood rheologic
disturbances, and to a lesser extent hypoxia, are mostly
involved [4].
Signs
Signs of CVI extend from telangiectasis and reticular
venules up to the most severe stage of the disease: venous
ulceration.
Signs of CVI are described by the universally adopted
Clinical, Etiological, Anatomical, and Pathophysiological
(CEAP) classification system [2]. The clinical signs of
CEAP are divided into seven classes (Table 1).
Table 1. Clinical definitions of the CEAP Classification
[Adapted from Ref 2]
C0: no visible or palpable signs of venous disease.
C1: telangiectases, reticular veins and malleolar flare.
C2: varicose veins.
C3: edema without skin changes.
C4: skin changes ascribed to venous disease (e.g. pigmentation,
venous eczema and lipodermatosclerosis).
C5: as C4 with healed ulceration
C6: as C4 with active ulceration
At an early stage of the disease CVI is signified by the
presence of submalleollar flare, then by signs of venous
dilation of different degrees. Refined definitions of these
clinical signs of venous dilation were recently suggested [6]
(Table 2a).
Table 2a. Refinement in Clinical Definitions of Venous
Dilation [Adapted from Ref 6]
Telangiectasia: a confluence of permanently dilated intradermal
venules of less than 1 mm in caliber. (Normally visible from a
distance of 2 m with good lighting conditions)
Reticular veins: Permanently dilated bluish intradermal veins
usually >1 mm in diameter and <3 mm in diameter. (Usually
tortuous, but this excludes normal visible veins in people with
transparent skin)
Varicose veins: Subcutaneous permanently dilated veins equal to or
more than 3 mm in diameter, in the upright position.(Refluxing
tubular veins may be classified as varicose veins)
Corona phlebectatica: Fan shaped intradermal telangiectasias on the
medial and or lateral aspects of the foot. May be the first sign of
advanced venous disease. (The place of corona in C is
controversial and requires some thought).
The appearance of edema indicates more functionally
advanced venous disease than the presence of venous
dilation alone.
At severe chronic stages of the disease, skin changes are
frequently encountered signs and are characterised by
pigmentation, eczema, lipodermatosclerosis, hypodermitis,
atrophie blanche (or white atrophy), and venous ulcer
(definitions recently suggested are shown in Table 2b).
Konstantinos Katsenis
Table 2b. Refinement in Clinical Definitions of Microangio-
pathies [Adapted from Ref 6]
Edema: a perceptible increase in volume of fluid in subcutaneous
tissue characterized by indentation under pressure (only for edema
attributable to venous disease, occurring usually in the ankle
region)
Pigmentation: brownish pigmentary darkening of the skin usually
occurs in the ankle region, but may extend to leg and foot
(equivalent to an early skin change)
Eczema: erythematous, blistering, weeping or scaling eruption of
the skin of the leg (located anywhere on the leg)
Lipodermatosclerosis: localized chronic induration of the skin
sometimes associated with scarring or contracture (this is a sign of
severe venous disease, characterized by fibrosis and chronic
inflammation)
Hypodermitis: an acute form of lipodermatosclerosis characterized
by diffuse reddening of the skin due to acute inflammation and by
tenderness (the absence of lymphadenitis and fever differentiates
this condition from erysipelas or cellulitis)
Atrophie blanche or white atrophy: circumscribed, often circular
whitish and atrophic skin areas surrounded by dilated capillary spots
and sometimes hyperpigmentation (scars of healed ulceration are
excluded in this definition)
Venous ulcer: chronic defect of skin which fails to heal
spontaneously caused by chronic venous disease
3. EPIDEMIOLOGY AND RISK FACTORS OF
CHRONIC VENOUS INSUFFICIENCY
The prevalence of the disease in Western countries is
very high. According to the most representative
epidemiological studies of the last 10 years [7], varicose
veins affect 30% of women and 15% of men in the adult
population. In the adult population in Europe, venous
disorders may affect 25% to 50% for all types and degrees of
varicose veins, 10% to 15% for marked varicose veins, and
5% to 15% for more severe stages of CVI (from skin
changes to active ulceration).
Varicose veins are not restricted to adults, and 27% of the
school children between 10 and 16 in the Bochum study
(belonging to 11 German secondary schools) [7] presented
with varicose disease. From a 1999 French survey [8] of
representative samples of the adult population aged 15 and
over, it appeared that almost half this population suffered
from lower-limb venous complaints and that 43% of them
were untreated. However, several studies conducted in
various parts of the world revealed the extent of the problem
and the inadequacies of the treatment approach to a condition
too often considered as minor. In the large (n =5052)
multicontinent (Africa, Asia, Europe, Latin America) 6-
month Reflux assessmEnt and quaLity of lIfe improvEment
with micronized Flavonoids study (RELIEF), 78% of
patients suffering from symptoms and/or signs of CVI were
untreated [9]. In Poland, Jawien et al estimated the non-
treated CVI patients at 66% [10].
Numerous risk factors for varicose veins have been
suggested, including lifestyle factors (e.g., occupations that
involve prolonged standing or sitting or a family history of
varicose veins [11]. The development of varicose veins in
Micronized Purified Flavonoid Fraction (MPFF)*
patients already susceptible to the condition may be
accentuated by obesity or pregnancy [12]. Sex hormones like
progesterone would inhibit venoconstriction [13,14] and thus
play a role in raising hydrostatic pressure in the superficial
venous system. The risk of venous ulcer is directly related to
the degree and pattern of venous insufficiency [15,16] and
may also be associated with a history of venous thrombosis
[17].
4. PATHOLOGY AND CELLULAR PHYSIOLOGY OF
CHRONIC VENOUS INSUFFICIENCY (CVI)
4.1 At the Level of the Macrocirculation
Chronic elevation of the ambulatory venous pressure and
consequently the mean venous pressure throughout the day
cause gross venous dilatation and vessel elongation.
Prolonged distension of the veins and microvessels may
affect local blood flow and alter fluid shear stress. Recent
evidence shows that hemodynamic forces such as blood
pressure changes in the wall or drop in shear stress induce
activation of both leukocytes and endothelial cells [18]. Fluid
shear stress is known to be a key regulatory component of
microvascular cells. This is one of several trigger
mechanisms of the inflammatory reaction that becomes
effective at the early stages of the disease. A second possible
trigger mechanism is likely to be hypoxia of the vein wall
(media and endothelium) [19].
The combination of the three trigger mechanisms
abnormal shear stress, hypoxia of the media, and hypoxia of
the endotheliuminduces activation of both leukocytes and
endothelial cells. The expression of a family of membrane
proteins called -integrins appears to act as an intermediary
in the adhesion of white blood cells to the endothelial surface
and in stimulating projection of pseudopodia, which allow
the complete transmigration of leukocytes into the venous
wall [20]. Expression of intercellular adhesion molecule1
(ICAM-1), vascular cell adhesion molecule1 (VCAM-1),
lymphocyte function-associated antigen-1 (LFA-1), very late
antigen-4 (VLA-4), and other adhesion molecules on the
surface of both endothelial cells and leukocytes from limbs
with chronic venous insufficiency has been reported [21].
The interaction between endothelial cells and leukocytes
leads to the release of proteolytic enzymes and free radicals
[22]. This results in toxicity of the endothelial cells which
leukocytes adhere to, and injury to the vein matrix. On the
other hand, in vitro studies evidenced that the endothelial
activation leads to release of prostaglandins (in particular
PGF 2) and b-fibroblast growth factor (b-FGF) [23]. Both
factors are known to be directly involved in vein wall
remodelling and consequently in varicose vein occurrence.
Important observations have been reported by Bergan et
al regarding mechanisms for valve failure. They found that
venous valve failure is simply due to vein distension which
prevents leaflets closing properly [18]. They also found that
venous valve damage in refluxing saphenous veins was
associated with monocyte infiltration into vein wall and in
the base of the vein leaflet [24]. These events occur long
before the development of other venous complications.
Current Vascular Pharmacology, 2005, Vol. 3, No. 1 3
This chronology of events has been confirmed in a recent
epidemiological study by Schultz-Ehrenburgh in which
schoolchildren were followed up over 20 years, from the age
of 10 to 12 years until 29 to 31 years [25]. Almost 75%
presented with reticular veins, 50% with telangectasias, and
11% with varicose veins after 20 years of follow-up, but
refluxes were detected long before visible veins: more than
27% had venous reflux at the age of 30 while 10% already
had a detected reflux at the age of 10.
These observations suggest that valve damage is an
acquired phenomenon related to leukocyte-endothelium
interaction, and that varicose veins develop in a second step.
Valve failure leads to reflux, reinforcing venous pressure
elevation and initiating a vicious circle.
4.2 At the Level of the Microcirculation
Reflux is the basic pathological factor that causes
sustained and raised venous pressure downstream, creating
microcirculatory stasis. The microvessels react via
mechanisms similar to those in the vein trunk. Hypoxia
related to stasis and shift in fluid shear stress deregulates
endothelial cell activity, which releases enzyme granules
from within their cytoplasm, mainly inflammation factors,
and makes oxygen free radicals. These substances enable the
inflow of polymorphonuclears (the "white cell trapping" of
Coleridge Smith [26]), but also monocytes and mast cells,
which migrate in the subendothelium. Since microvessels
have neither media nor smooth muscle cells (SMCs), this
biochemical disorder results in either fibrosis or necrosis of
the ulcer.
Moreover, as a result of prolonged hyperpressure,
capillaries become elongated and dilated and develop
abnormal permeability. Gas exchange is disturbed and, as a
result of lack of reabsorption, plasma leakage leads to
superficial edema. On top of this, hemorheological
disturbances have been evidenced in CVI. Leakage indeed
induces volume contraction in circulating blood and
subsequent hyperviscosity as well as increased red cell
aggregation. This phenomenon is responsible for poor red
cell distribution in the microcirculation and poor tissue
oxygenation, and in turn causes an increase in fibrinogen
deposition around microvessels (the "fibrin cuff" of Browse
and Burnand [27]). This interferes with the circulation in
microvessels and increases the accumulation of leukocytes in
capillary endothelium.
In Summary, study of mechanisms of tissue injuries at
different stages of CVI shows how changes in the hydrostatic
pressure (excess weight of the blood column in lower-limb
veins) and in the venous wall shear stress, gradually cause
changes in cellular information, then cellular and
biochemical disorders. Tissue injury in which leukocytes
appear to be the key mediators have now been precisely
identified, and can explain the development of varicose
veins, symptoms, edema and ulcers. Adhesion of leukocytes
to the endothelium and their infiltration either into the
venous wall or microvessels most probably constitutes the
fundamental process leading to CVI.
4 Current Vascular Pharmacology, 2005, Vol. 3, No. 1
Factors involved in the pathophysiology of both macro-
and microcirculatory disorders leading to CVI are to be
targeted by pharmacological agents. The pharmacological
effect of MPFF, which could explain its therapeutic efficacy,
will be discussed below.
5. CHEMISTRY AND SAFETY OF MICRONIZED
PURIFIED FLANOVOID FRACTION
Micronized purified flavonoid fraction (MPFF) is comp-
rised in the large group of flavonoids which represent one of
the most intriguing classes of biologically active compounds,
due to the multiplicity of actions displayed by certain
individual members, including MPFF.
MPFF consists of 90% diosmin and 10% flavonoids
expressed as hesperidin (which differs from diosmin by the
absence of a double bond between two carbon atoms).
Diosmin is synthesized from hesperidin, which is extracted
from a type of small immature orange. The micronization of
diosmin to particles with a diameter <2 m has improved the
oral absorption of MPFF [28].
MPFF appears to be extremely safe and has no
substantial side effects.
In a study in rats, when MPFF was administered by
gastric intubation for 26 weeks, no deaths, changes in
weight, or abnormalities of standard functional tests were
observed [29].
In a study in humans, MPFF administration was found to
result in minor side effects in only 10% of the subjects
compared with 13.9% of those treated with placebo [30].
Adverse events were similar in nature and incidence between
these patient groups. The rate of discontinuation because of
adverse events (primarily of gastrointestinal origin) was
comparable among patients receiving 2 tablets of MPFF 500
mg daily or placebo (1.1 vs. 3.2%). In this analysis, [30] the
incidence of adverse events was not significantly different in
patients aged 70 years or with concomitant diseases (i.e.,
hypertension, atherosclerosis, diabetes mellitus, neurological
/psychiatric disease or alcoholism) to that in the total
population group. In addition, MPFF did not appear to
interact with the drugs used to treat these concomitant
diseases. The incidence of adverse events did not increase
with long-term treatment with 2 tablets of MPFF 500 mg
daily [31]. Treatment with MPFF did not modify blood
pressure or laboratory parameters. Systolic or diastolic blood
pressure and laboratory values did not change during
treatment with 2 tablets of MPFF 500 mg daily for 1 year in
a clinical trial that monitored these parameters every 4
months [31]. Laboratory values (e.g., red blood cells,
leukocytes, haemoglobin, hepatic enzymes, blood urea,
blood glucose and lipids, creatinine) remained within normal
physiological ranges.
6. PHARMACOKINETICS
The pharmacokinetic parameters of MPFF in several
animal species (including rats, dogs, rabbits, and monkeys)
have been reported in data from the manufacturer [32]. There
are no known drug interactions with MPFF [33].
Absorption and Distribution
After oral administration, diosmin is rapidly transformed
in the intestine by intestinal flora and absorbed as its
Konstantinos Katsenis
aglycone, diosmetin [33]. An in vitro study showed that
13C- and 14C-diosmin incubated with human gut flora were
transformed to diosmetin, luteolin, and phenolic acids [33].
Approximately half of an oral 500 mg dose of radiolabelled
MPFF was absorbed within 48 h of administration in a
pharmacokinetic study in 12 healthy male volunteers [28].
This double-blind, crossover study with a 14-day washout
period compared the absorption of radiolabelled MPFF with
that of non-micronized diosmin. Because unabsorbed
diosmin is not excreted in the urine, absorption was
evaluated based on the urinary elimination of radioactivity.
Reduction in the particle size of diosmin led to a significant
increase in absorption; mean gastrointestinal absorption of
micronized 14C-diosmin was significantly greater than with
simple 14C-diosmin (57.9 vs 32.7% during 0 to 168 h
postdose; P =0.0004) [28]. Diosmetin had a rapid
distribution period followed by a slower elimination period
in a single-dose study of simple diosmin 10 mg/kg in five
volunteers [34]. The time to the peak plasma concentration
of diosmetin was 1 h, and plasma concentrations started to
decrease slowly after 2 h; diosmetin was still detectable after
48 h.
Metabolism and Elimination
Diosmetin is rapidly and extensively degraded to
phenolic acids or their glycine conjugate derivatives, which
are eliminated in the urine [32,34]. The predominant
metabolite in man is 3-hydroxyphenylpropionic acid which
is mainly eliminated in its conjugated form [32,34].
Metabolites found in smaller amounts include other phenolic
acids corresponding to 3-hydroxy-4-methoxybenzoic acid
and 3-methoxy-4-hydroxyphenylacetic acid and 3,4-
dihydroxybenzoic acid [34]. It is possible that unidentified
metabolites may be responsible for the pharmacological
activity of diosmin [32].
In humans, elimination of micronized diosmin is
relatively rapid, with .34% of the radiolabelled dose of 14C-
diosmin excreted in the urine and faeces over the first 24 h
and 86% over the first 48 h [28]. Unmetabolised diosmin and
diosmetin are not excreted in the urine [34]. The cumulative
excretion of the dose in the urine and faeces was 100% (109
23% 0 to 168 h) [28]. Approximately half of the dose was
eliminated in the faeces as unchanged diosmin and
diosmetin. Unchanged diosmin in the faeces corresponds to
unabsorbed diosmin as indicated by the very low biliary
excretion of radioactivity in studies of 14C-diosmin in rats
[32].
7. PHARMACOLOGICAL EFFECTS
Trials of MPFF on Venous Tone (Table 3)
MPFF at 2 tablets per day reduced venous distension and
venous capacitance, and improved venous tone in women
with various grades of venous insufficiency: healthy women,
women with venous insufficiency related to postphlebitic
syndrome, or pregnancy [35]. In a second trial, MPFF at 2
tablets per day improved venous tone in female volunteers
with abnormal venous elasticity and a high risk of
developing varicose veins [36].
Micronized Purified Flavonoid Fraction (MPFF)* Current Vascular Pharmacology, 2005, Vol. 3, No. 1 5

Table 3. Pharmacodynamic Properties of MPFF on Venous and resolved capillary stasis by increasing red blood cell
Tone [Adapted from Ref 55] velocity in capillaries [39].

Prolongs, in vitro, the vasoconstrictor effect of noradrenaline Effects on Microcirculatory Disorders

(norepinephrine) on the vessel wall and reduces blood venous stasis
Increases mechanical tension on bovine metacarpal vein rings
Increases Ca 2+ sensitivity of the contractile apparatus in rat isolated
femoral vein
Inhibits increases in red blood cells, hematocrit, and plasma protein
concentrations elicited by the upright position in dogs
This beneficial effect of MPFF on venous tone is
explained by its ability to prolong the activity of parietal
norepinephrine.
Anti-inflammatory Effects
MPFF has been demonstrated to improve multiple
histological aspects of the acute inflammatory reaction, and
its pharmacological properties are described in (Table 4).
Effects of MPFF on Hemorrheologic Disorders
MPFF improved venous PO2 measurements in 90
patients with mild to moderate CVI [37,38]. In 24 patients
with CVI, Daflon 500 mg improved venous microangiopathy
Pre-treatment with MPFF prior to the induction of
tourniquet ischaemia significantly lowered the number of
adherent leukocytes, thereby controlling edema in clinical
situations [40] MPFF acts favourably on the complications
of microcirculatory dysfunction by normalising the synthesis
of prostaglandins and free radicals. It decreases bradykinin-
induced microvascular leakage and inhibits leukocyte
activation, trapping, and migration (Table 4). Recently,
Bouskela revealed, in a study in the hamster cheek pouch
model, that due to its micronisation the protective effect of
MPFF on the microcirculation (reduction of leakage points
by 83%) is significantly greater than that of simple diosmin
at all doses [41].
Effects on Leukocyte Adhesion
MPFF has been shown to modify the interaction of
leukocytes with endothelium. A hamster dorsal skinfold
model was used to investigate the effect of MPFF on the
microcirculation following ischaemia-reperfusion. The group
of animals pre-treated with MPFF exhibited less neutrophil
adhesion in the postcapillary venules at 30 min, 2 h, and 24 h

Table 4. Effects of MPFF on Microcirculation (Adapted from Ref 55)

Capillary permeability and resistance

Inhibits the increase in volume of induced-edema in rat paw
Improved microvascular reactivity and functional capillary density after ischaemia/reperfusion in hamster cheek pouch
Significantly improved capillary hyperpermeability compared with placebo and evaluated using the Landis isotope test in patients with idiopathic cyclic
edema
Decreased the abnormal capillary filtration rate in patients with chronic venous insufficiency (CVI) and evaluated using strain gauge plethysmography
Significantly improved capillary resistance compared with placebo in patients with abnormal capillary fragility.

Lymphatics
Increases contractility of mesenteric lymphatic collecting ducts in sheep
Increases the frequency of spontaneous contractions in bovine mesenteric lymphatics
Improves lymphatic drainage in sheep and dogs
Decreases thigh weight, protein concentration in tissue, and fibroblast number in rats with acute leg lymphostasis
Improved lymphatic microangiopathy associated with CVI in patients with severe CVI (without active ulcer), decreased intralymphatic pressure, and
increased the number of functional lymphatic capillaries.

Inflammatory mediators
Normalizes synthesis of prostaglandin E2 or F2 and thromboxane B2 in inflammatory granuloma in rats
Inhibits, in vitro, oxygenated free radical production in zymosan-stimulated human neutrophils, rat leukocytes, or mouse macrophages
Protects endothelial cells from lipid peroxidation in bovine aortic endothelial cells and human skin fibroblasts
Inhibits the increase in microvascular permeability induced by bradykinin or ischaemia in rat cremaster muscle and histamine, bradykinin, leukotriene
B4 ischaemia/reperfusion or oxidant challenge in hamster cheek pouch
Inhibits platelet functions in rats.

Leukocyte activation and adhesion

Inhibits leukocyte adhesion and/or migration after ischaemia/reperfusion injury in hamster skinfold or rat skeletal muscle
Inhibits oxidant challenge in hamster cheek pouch
Inhibits leukocyte rolling, adhesion, and migration and decreases the number of parenchymal dead cells after venular mesenteric occlusion in
rats
Reduced the expression of plasma markers of endothelial activation: intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
(VCAM-1) on human leukocytes from patients with CVI
Decreased plasma levels of lactoferrin or vascular endothelial growth factor (VEGF) in patients with skin changes
Reduced the surface expression of monocyte or neutrophil CD62L in patients with CVI.
6 Current Vascular Pharmacology, 2005, Vol. 3, No. 1
after reperfusion following ischaemia, compared with the
control group.[40] This observation may well be linked to
the protective effect of flavonoids in the treatment of edema.
Decreased leukocyte activation is also associated with a
decreased platelet and complement system activation,
leading to a lowered release of histamine and decreased
leukocyte-dependent endothelial damage [40,41]. Takase et
al have developed a venous hypertension model in the rat
mesentery by occluding a vein draining part of the gut. This
results in a pressure of about 30 mm Hg in the mesenteric
venules, and results in increased leukocyte adhesion to
postcapillary venules, seen through a capillary microscope
[42]. Pre-treatment with MPFF for seven days significantly
decreased the number of rolling, adherent, and migrating
leucocytes in the rat mesentery. MPFF reduced neutrophil
expression of CD62L even though CD18 was not affected
[43].
In summary, there are numerous sites along the vascular
tree where MPFF exerts a precise mechanism inhibiting or
delaying the occurrence of CVI: first, by reducing vein
distension, i.e. increasing venous tone (this results in
normalised blood flow, dispersed red cell aggregates, and
better oxygenation), secondly, by a recently discovered
effect that is distinctive to MPFF: inhibition of leukocyte
adhesion to endothelial cells and its transmigration into the
venous wall of trunk veins or subendothelium of
microvenules, and in a final step, by protecting the
microcirculation and thus decreasing edema.
The therapeutic efficacy of MPFF has been demonstrated
in a number of studies that are reviewed below.
8. THERAPEUTIC EFFICACY OF MPFF
Effects of MPFF on symptoms of CVI
Randomized Placebo-controlled Trials
Two randomised, double-blind, placebo-controlled trials
in patients with CVI have demonstrated that MPFF taken
twice daily for 2 months improved many symptoms of CVI
(functional discomfort, heat sensation, pain, leg heaviness,
sensation of swelling) [44,45]. After 2 months of treatment, a
significant reduction in ankle circumference was found in the
patients who received Daflon 500 mg [45,46]. Improvements
in venous hemodynamics consisted of increased venous tone
in the study by Chassignolle et al [44,46] and decreased
venous capacitance at 50 mm Hg, venous distensibility at 40,
50, and 60 mm Hg, total time of venous emptying, and the
emptying of the final 50% (considered the active phase of
venous outflow) (P <0.001 for all) [44].
Long-term Treatment
Two tablets of MPFF daily maintained its efficacy in the
long-term treatment of patients with symptoms of CVI in
two non-blind, multicentre trials of 6 [47] and 12 months
[31] duration, respectively. In the Reflux assEssment and
quality of lIfe improvEment, with micronized Flavonoids
(RELIEF) study (n =4527 intention-to-treat population),
patients receiving 2 tablets of MPFF daily showed
progressive improvement in the symptoms of CVI, (Fig. 3)
which were paralleled by improvement from more severe
(C3 or C4) to less severe (C0C2) CEAP clinical classes of
Konstantinos Katsenis
CVI [47]. After 6 months, patients in the per-protocol
population showed significant improvement from baseline in
the study outcome measures (ankle circumference, pain, leg
heaviness, cramps, sensation of swelling; P <0.012). In the
1-year trial of 2 tablets of MPFF daily in 170 patients, [31] a
significant reduction from baseline values in physician-
assessed clinical symptoms (functional discomfort, cramps,
and evening edema), ankle and calf circumference, and
patient overall assessment of symptom severity was
demonstrated at each 2-month evaluation (P <0.001). The
rapid reductions observed during the first 2 months of the
treatment represented approximately 50% of the total
improvement ultimately observed after 1 year of the
treatment. Continuing improvement in all parameters, albeit
less rapid, was reported at each time point from month 2 to
month 12.
Effects of MPFF on Leg Edema
Compared with placebo, MPFF twice daily for 2 months
significantly decreased ankle and calf circumferences from
baseline in two double-blind trials [48,49]. In a double-blind,
controlled, randomised trial of MPFF versus placebo, 200
patients with functional or organic venous insufficiency were
included. After 2 months of the treatment, a significant
reduction in ankle circumference was found in the patients
who received MPFF [48]. The reduction in leg edema with
MPFF, 2 tablets daily, was also demonstrated in another
study in which the reduction was assessed by volumetric
measurements after 6 weeks of the treatment [49]. In this
study, the reduction in the mean volume was 263 mL (8%) in
all patients, and was 392 mL (12%) in patients with leg
edema associated with varicose veins. In both trials, the
reduction in leg volume was highly significant (P <0.001).
In a double-blind, placebo-controlled study [50]
including patients with stage C3 to C6 of the CEAP
classification, reflux time in patients with edema (43
patients) was reduced to a significantly greater extent in the
MPFF group (20 patients) than in the placebo group (23
patients, P =0.03). This might be an effect of
venoconstriction.
Edema, measured by leg circumference, significantly
decreased compared with baseline in patients of the RELIEF
study.
Effect of MPFF on Venous Leg Ulcer Healing
In three randomised, controlled, multicenter trials, 2
tablets of MPFF 500 mg daily plus standard venous leg ulcer
management was compared with standard venous leg ulcer
management alone [51,52] (n =140 and 150, respectively) or
in addition to placebo [53] (n =107). The group receiving
MPFF presented a significantly higher ulcer healing rate than
the other group (results in Table 5). In the Glinski study, [51]
ulcers with a diameter less than 3 cm were cured in 71% of
the Daflon 500 mg group and 50% of the standard therapy
group. When the ulcers diameter was between 3 and 6 cm,
they were cured in 60% and 32% (P <0.05) in the MPFF
group and the control group, respectively. The beneficial
effect of MPFF has also been demonstrated, in terms of the
percentage reduction in ulcer area [52]. The mean reduction
in ulcer size was found to be greater in patients treated with
Micronized Purified Flavonoid Fraction (MPFF)* Current Vascular Pharmacology, 2005, Vol. 3, No. 1 7

Table 5. Published Studies Demonstrating Efficacy of MPFF in Ulcer Healing (Adapted from Ref. 51, 52, 53)

Control Complete ulcer healing % Time to complete ulcer healing

Patient Trial Period
Study ulcer MPFF 500 MPFF
no design* (month) Control P Control P
Size (cm) mg 500mg

Guilhou Shorter
107 Placebo 2 10 31.8 12.8 0.028 0.037
[62] time

Glinski
140 Open 6 <3; 3-6; >6 46.5 27.5 <0.05 - - -
[60]

Roztocil
150 Open 6 2; 10 64.6 41.2 0.004 137 days 166 days 0.04
[61]

* Each study included a prospective, multicenter, randomised controlled design

MPFF 500 mg, 2 tablets daily, in association with standard therapy
control group: placebo + standard therapy
control group: standard therapy alone

MPFF than in the control patients (80% vs. 60%, P <0.05
[60]; 77% vs. 69%, P =0.012 [61]).
According to Roztocil et al [52], the time to achieve
complete healing was significantly shorter in the Daflon 500
mg group (137 days compared with the control group =166
days [P =0.042]), and a significantly larger number of
patients had complete ulcer healing during the study with
Daflon 500 mg (64.6%) in comparison with the control
group (41.2%; P =0.04).
The preliminary results of this meta-analysis of seven
comparable, prospective, randomised, controlled studies
identified from medical literature databases and from the
files of the manufacturer in which 723 patients were pooled
[54] confirm that venous ulcer healing is accelerated by
adding MPFF to conventional treatments: the rate of
complete ulcer healing at 6 months was in favour of the
MPFF group (61.3% vs. 47.7%; OR =2.02; CI =1.05-3.89; P
=0.035). This was significant from the second month (OR
=1.62; CI =1.13-2.33; P =0.0088).
9. DOSAGE AND ADMINISTRATION
MPFF is administered orally and is available as 500 mg
tablets. It is generally indicated for the treatment of edema
and symptomatic CVI of the lower limbs (heavy legs, pain,
nocturnal cramps, sensation of swelling, restless legs, and
itching) at any stage of the disease [55]. MPFF is approved
for use in over 100 countries. The recommended dosage of
MPFF 500 mg in CVI is 2 tablets daily (as a single dose in
the morning or evening). There are no documented drug
interactions with MPFF. Caution is recommended when
administering MPFF to patients who are breast-feeding
because of the absence of data concerning the diffusion of
MPFF into breast milk. No adverse effects have been
reported to date when MPFF was administered during
pregnancy.
10. ROLE OF MPFF IN THE MANAGEMENT OF CVI
In recent guidelines on the treatment of CVI [56,57], the
use of MPFF is indicated to treat edema and the symptoms of
CVI in any stage of the disease. In the more advanced stages
of CVI, MPFF may be used in conjunction with
sclerotherapy, surgery and/or compression therapy [63], or as
an alternative treatment when surgery is not indicated or is
unfeasible [56] or when patients are unwilling or unable to
use compression therapy (elastic stockings or compression
bandages) [57]. These recommendations were supported by
clinical trials of MPFF, which has been extensively
evaluated for use in patients with CVI.
CONCLUSION
In conclusion, MPFF is a well-established and well-
tolerated treatment option for patients with CVI, whatever
the grade of severity, from symptoms to venous ulcers.
MPFF is indicated as a first-line treatment of edema and the
symptoms of CVI in patients at any stage of the disease.
The healing of venous ulcers is accelerated by the
addition of MPFF to standard venous ulcer management
(compression therapy and local treatment). Therefore, in
more advanced disease stages, MPFF may be used in
conjunction with sclerotherapy, surgery and/or compression
therapy, or as an alternative treatment when surgery is not
indicated or is unfeasible.
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