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Lymphland International Lymphedema Online
The Benzo-pyrone Drugs in the Treatment of Lymphoedema (and other High-Protein Oedemas)
Judith R. Casley-Smith
This section is rather technical and may only be of interest to doctors and therapists who treat
lymphoedema
(lymphedema). However some patients are interested, and it can be shown to their doctors if
they wish. It is
very important for patients to obtain the agreement of their doctor before taking any drug!
Oral benzo-pyrones alone usually act slowly in lymphoedema, but by the end of a year these
give about half
to two thirds of the best reductions when patients are treated just with Complex Physical
(Lymphedema)
Therapy (C.P.T.) alone.
However, compression garments were not used in the trials of the benzo-pyrones. These drugs
are the only
treatment available for those who cannot tolerate or wear such garments. Without compression
garments,
this very slow but steady reduction is a virtue since a rapid one would leave huge potential
cavities which
would readily refill. The slowness allows the body to gradually remodel, so that the altered
fibrous tissue
takes the place of garments. The improvements produced by these drugs in many of the
symptoms which
distress patients, and in lessening the attacks of infection, were more rapid; but no change in
these should be
expected for 1 to 2 months. Benzopyrones also increase reductions gained with C.P.T. and
other therapies
and help to maintain them better (see Section on Results ).
A review (in preparation) found that benzo-pyrones have been tested by over 37 authors in 8
countries, in
(effectively) 51 clinical trials. (The word "effectively" is used since different Grades were
counted separately
if they were evaluated separately.) These are all the trials known to the authors which could be
evaluated
objectively. The benzo-pyrones were: coumarin, coumarin plus troxerutin, oxerutins (O-(-
hydroxyethyl)-
rutosides, HR) and diosmin. There were 39 trials of oral and 12 of topical preparations (11 and
6,
respectively, were combined with other therapies). In all of them, oral or topical benzo-pyrones
significantly
reduced lymphoedema (usually to a clinically important extent). In almost all the symptoms were
similarly
reduced - including infections (Secondary Acute Inflammation, SAI). Combining all 25 trials of
oral benzo-
pyrones alone, in which the reduction of oedema could be estimated, gave a mean reduction of
oedema of
36% (S.E. 6%) per year (1,225 patients in all). (About 1 to 10% should be added to this if
comparing it
with untreated patients since these worsen by amounts varying with the duration of their
lymphoedema.)
There were no significant differences between arms and legs. Elephantiasis was reduced less
(15% per year)
than Grades 1 and 2 (57%) but this was of course much greater initially. As the dose of benzo-
pyrones
increased, so did their efficacy. Nor are these drugs merely useful by themselves. Both oral and
topical
forms, and these combined, very materially increased reductions of lymphoedema obtained by a
variety of
physical and surgical techniques. In these, they often also greatly reduced the incidence, and the
severity, of
attacks of SAI.
The year 1993 saw the publication of three trials of oral coumarin for lymphoedema: in Australia
and (for the
W.H.O.) in India and China. They appeared in: the New England J. Medicine 329 (1993),
1158-1163,
Annals. Tropical Medicine Parasitology (1993) 87, 247-258, and the British Medical J., 307
(1993) 1037-
1040, respectively. The average reduction for Grade 2 arms was 2.2 % of the initial volume per
month (or
40 % of the oedema in 6 months); that for Grade 2 legs was 1.5 % of the initial volume per
month (or 33 %
of the oedema in 6 months).
The large oedemas of elephantiasis reduced more rapidly, but were often still great at the end of
the trials
because they were so much larger initially. Reductions are slow, but the drugs convert a disease
which
otherwise slowly (or sometimes rapidly) gets worse into one which slowly improves. The drug
also
improved many symptoms of lymphoedema (pain, lack of mobility, etc). Importantly, they lessen
the number
and severity of attacks of acute inflammation (sometimes called: cellulitis, erysepilas).
An analysis has been made of the first 628 Australian limbs treated with C.P.T., with and
without the benzo-
pyrones (Lymphology, 20 (1996) 76-82, and see Section on Results ). Both oral and topical
benzo-pyrones
increase the already large reductions which Complex Physical (Lymphedema) Therapy (C.P.T.)
produces in
lymphoedema and elephantiasis. A typical one-month course of C.P.T. gave average reductions
of 13 % of
the initial volume of a Grade 2 arm and 11 % of a Grade 2 leg; these were improved by a
further 5 % if oral
benzo-pyrones were taken for 3 months before the Course started, and by yet a further 2 to 3
% if topical
Coumarin was used as well. During the next 12 months, some limbs increased in volume, others
reduced still
further. Oral benzo-pyrones improved these reductions by 10 % of the volume at the end of the
first Course
of C.P.T. The next Course of C.P.T. by itself gave a 16 % reduction relative to the limb volume
at the start
of the Course. Again coumarin ointment gave a further 11 % and powder a further 16 %
improvement.
Patients at risk, after operations which cause lymphoedema, are less likely to get it if they take
benzo-
pyrones prophylactively. It also considerably reduces the oedema of accidental trauma to the
limb (cuts,
bruises, fractures, burns, stings, etc.). These are also often greatly helped by topical coumarin
(cream or
powder).
Similar reductions to those obtained with coumarin have also been observed with the (bio)
flavonoid Paroven
- also called: Venoruton, Relvène (British J. Plastic Surgery, 41 (1988), 20-27). However note
that the
doses of this need to be much larger (3,000 mg/day rather than 400, as with coumarin). Another
benzo-
pyrone - diosmin (Daflon 500®)- has also been shown to be effective in lymphoedema (Int.
Angiol. (Suppl)
14 (1995) 39-43). Again the doses of this need to be much larger (2,000 mg/day rather than
400, as with
coumarin).
Some similar drugs, which are not strictly-speaking benzo-pyrones, are also effective. These
include
Unguentum lymphaticum® (however this can only be applied to the skin) and Doxium®. A
double-blind trial
of an extract of Ruscus aculeatus (mainly ruscogenin and neoruscogenin plus hesperidin methyl
chalcone)
over 3 months, reduced oedema by 13%, compared with a 9% increase in the controls,
symptoms were
improved significantly (Lymphology, 29 (1996) 29-35).
There has been some interest in Pycnogenol® and similar products, with anecdotal reports of
their
effectiveness. However in spite of the claims by those who promote these products, clinical trial
data is
regrettably lacking. We can only find one: a double-blind trial, matched-group, placebo-
controlled, trial was
performed on post-mastectomy lymphoedema using procyanidolic oligomeres Endotélon™(33
active, 30
placebo) for 6 months (Cluzan RV, Pecking AP, Lokiec FM [eds.] Progress in Lymphology -
XIII.
Amsterdam, Elsevier, Int Cong Ser 994 (1992) 655-658). Symptoms were considerably
improved, but
there was no significant difference in the oedema (which only decreased by 1%). However the
dose was
only 300 mg/day. From their molecular weight, at least 800 mg/day would be needed to equal
400 mg/day
of coumarin. So this substance may help, but lack of good clinical trials with adequate doses
makes it
impossible to be sure of this. By contrast, many of the other benzo-pyrones (including the
flavonoids) have
had such successful trials.
How the Benzo-Pyrones Act
All oedemas cause swelling, pain (if they increase rapidly), loss of function (at both gross and
cellular levels),
poor oxygenation and poor wound healing. Chronic, high-protein oedemas cause chronic
inflammation with
excess fibrosis. Benzo-pyrones have been shown to improve all of these. {For a general review
for this
section, see: Casley-Smith JR & Casley-Smith, Judith R.. High-Protein Oedemas and the
Benzo-Pyrones.
Lippincott, Syd. & Balt., 1986 - obtainable from the L.A.A }
The benzo-pyrones reduce all forms of high-protein oedema. Almost any oedema is a high-
protein oedema,
except those from uncomplicated varicose veins, late congestive cardiac failure and some kinds
of renal
disease. The dividing line is a protein concentration in tissue fluid of 1 g/dl. Above this, the
colloidal osmotic
pressure of the protein contributes greatly to the accumulation of fluid, and the benzo-pyrones
can reduce
the oedema by removing the cause of this.
Benzo-pyrones reduce all high-protein oedemas by causing macrophages (scavanger cells in the
tissues) to
increase both their numbers and their normal lysis of the excess protein. Thus the increased
colloidal osmotic
pressure is reduced via this alternative pathway for the removal of protein. This can be detected
about 4
hours after administration and is maximal by 24 hours.
However some of the actions in lymphoedema are much slower than this since it takes many
months to
remove the accumulated excess fibrous tissues. The removal of protein and the excess fluid this
causes (and
its other deleterious effects) starts within days, but he effects of this are usually not obvious for
some six
months because of all the fibrous tissue.
Many benzo-pyrones also improve pumping by the collecting lymphatics, again aiding in the
removal of the
oedema. Some consider that this is how they act, but at least in animal studies it is evident that
proteolysis is
much more important (although increased pumping by any remaining lymphatics must also help).
Benzo-pyrones seldom affect the underlying condition but, by reducing the excess protein,
reduces the
oedema and its sequelae. They enhance another pathway for the removal of protein and water
from the
tissues when the lymphatics can no longer handle these.
If the oedema is within 1 - 2 cm of the surface of the skin, topical applications (the powder or
the ointment)
are suitable; if deeper, the oral form is also necessary.
Coumarin has a secondary action on injured blood vessels if applied topically to burns and acute
injuries. It
impairs the degradation of adrenalin, hence arterioles are more contracted. Immediate topical
application
reduces oedema (and hence the pain) via the reduction of leaking from the injured blood
capillaries.
It also improves oxygenation of ischaemic regions by a separate mechanism: opening arterio-
venous
communications. This reduces most exchanges with the tissues but, since gases are mainly
exchanged via
arterioles, it increases these. This is also useful with ischaemic skin grafts and flaps.
Finally, there is increasing evidence that coumarin's action on macrophages can be of value in
some cases of
immune-sensitive carcinomas (especially melanoma and some others, even carcinomas of the
breast). (In the
reports of these trials it is usually termed: 1,2 benzopyrone.). However it must be emphasised
that only a
relatively few such tumours are improved and such trials are only in the initial stages!
Please note that while the correct chemical name for 5,6 benzo-alpha-pyrone, or 1,2-
benzopyrone is
coumarin, it is NOT an anticoagulant. Coumarin anticoagulants are its complex derivatives.
Unfortunately, all
this causes some confusion!. Another benzo-pyrone derivative 'Coumadin' is NOT 'coumarin'
and their
effects are quite different. Note that benzo-pyrones have no relationship whatever to benzo-
pyrenes.
Oral Benzo-Pyrones (taken by mouth)
All trials show that oral benzo-pyrones alone usually work slowly in lymphoedema (including
coumarin - and
Paroven/Venoruton). A few patients do get a rapid benefit, especially those who have primary
lymphoedema in many parts of the body (lymphoedema-all-over). These drugs have been
effective in both
primary and secondary lymphoedemas - including elephantiasis (see above). Often a patient
does not feel
much improvement (except in mobility, the loss of pain and in the reduction of 'hardness' and of
secondary
infections) for about 2-3 months. One must caution patients about this to avoid discouragement.
Topical Benzo-Pyrones (used on the skin)
At present the only topical benzo-pyrone preparations are of coumarin (powder or ointment).
Topical
coumarin works much more rapidly than the oral form, but only to the depth of 1 - 2 cm. It
should be
applied once or twice a day.
Coumarin ointment permits a greater dose to be delivered (because it is difficult to get enough
powder to
stay on the skin) and is recommended for treating fibrotic regions or regions of closed
inflammation.
However the ointment is quite sticky and may affect the life of compression garments; so it is
best used
under bandages. In addition, it stings if applied to open wounds or mucous membranes
(although this can be
overcome by first applying a local anaesthetic - see below).
The powder is an excellent lubricant during the massage parts of
C.P.T. (C.L.T.) or M.L.D., and during the application of compression garments. Used in this
way more is
adsorbed than when it is simply dusted on. It is also improves lympho-cutaneous fistulae -
where lymph
weeps onto the skin. (A powder is an unusual way of giving a drug but coumarin is lipid-soluble
and so
penetrates the skin even as a dry form.)
The powder is excellent for ulcers. If it stings too much, a local anaesthetic is applied 1-2
minutes earlier (e.
g. 10% Xylocaine® spray - no prescription in Australia, or the 4% solution - prescription
needed). If
stinging recurs (e.g. after 30 minutes), a second application of local anaesthetic is applied.
When using the powder as a lubricant, therapists receive a small dose, but only via the hands, the
overworked nature of which it may well help! Some benzo-pyrones are essential (as P-
vitamins). Many take
200 mg a day prophylactically. A therapist gets much less than this; no ill-effects are reported.
The Doses of Benzo-Pyrones
We consider the minimal useful doses of benzo-pyrones in lymphoedema are: Coumarin (5,6
benzo-alpha-
pyrone ) 400 mg per day, Paroven/Venoruton 3,000 mg (six 500 mg capsules) per day, Daflon
2,000 mg
per day. For Venalot this minimal effective dose is 16 tablets per day. If there is no noticeable
improvement
after 2-3 months, many patients start to improve if these doses are doubled.
Coumarin powder or ointment is usually applied once a day, but two or three applications per
day work
better if these are feasible. The ointment allows more to be applied and so is preferred, if
possible, for
fibrous (scar) tissue. Powder is preferred under compression garments, as a lubricant for the
hands during
massage, and for application to ulcers and lymphatic fistulae.
These may be used in place of coumarin tablets if one uses 5 ml per day of the ointment or 10
ml per day of
the powder. (These should be measured in a spoon available from pharmacists.) These amounts
are rather
large, so we suggest applying half, twice a day.
Benzo-Pyrones for Children
There has been very little work done on the doses for children. We get asked about it from time
to time and
know of about 40 children who have taken them for some years without ill effects, and with
considerable
help to their lymphoedema.
Using an adult dose of 400 mg of coumarin/day (with more difficult cases, 800 mg/day) we just
scale the
child dose down using 70 kg as the mean adult weight. Thus for a 10 kg child use 40 mg/day,
with up to 80
mg/day if there is no noticeable improvement after two to three months. We have too little data
at present to
do any better. Other benzo-pyrones should be scaled down similarly. Toxicological studies
show no
particular differences between young and adult animals.
Other uses for the Benzo-Pyrones
Benzo-pyrones are so useful in lymphoedema, for which there is no other effective drug, that it is
often
ignored that they are also reduce many high-protein oedemas (i.e. protein concentrations of 1
g/dl or more).
These include almost all oedemas except those from renal or cardiac failure.
These drugs never, of course, attack the underlying cause of the oedema. However they
stimulate the
macrophages to lyse more of the excess proteins in the tissues than they usually do and greatly
increase their
numbers at this site. This reduces the oedema (since the no-longer-retained water returns to the
blood),
improves the oxygenation of the tissues, and their cellular functioning and wound healing.
Increased proteolysis provides a local alternative pathway to the lymphatic system for the
removal of excess
protein and its associated oedema. Many clinical trials and animal experiments have been
performed on a
wide range of such oedemas, showing their worth; reviewed in:
Casley-Smith JR, Casley-Smith Judith R. High-Protein Oedemas and the Benzo-Pyrones, Syd.
& Balt.:
Lippincott, 1986, pp. 536. (see publications from the L.A.A.).
Benzo-pyrones may be used to treat the symptoms, not the causes, of high-protein oedema
wherever they
arise, e.g.:
Oedema due to accidental trauma of all kinds, e.g., burns, insect bites, crushing and cutting
injuries including
infected wounds (unlike the corticoids), bruises and deeper haematomas, contusions & fractures.
Oedema due to surgical trauma (particularly important where surgery may involve damage or
removal of
part of the lymphatic system, e.g. skin grafts). They may also assist where surgery produces no
damage to
the lymphatics. It may be given three days prior to elective surgery, including dental extractions,
etc.
Oedema due to accidental and sports injuries and industrial injuries and strains.
Oedema due to infection where benzo-pyrones can reduce swelling while an antibiotic treats the
infection
(unlike the cortico-steroids, it does not interfere with the inflammatory process).
Chronic venous insufficiency (including ulcers and haemorrhoids).
Swollen ankles of the aged, when the skin is stretched and fragile.
Finally, but with only incomplete evidence, is the possibility that benzo-pyrones also stimulate
the immune
functions of macrophages against certain forms of carcinomas. If correct, this could be of
considerable value.
Animal lovers may like to know that there is also a veterinary form (tablets, powder and
ointment) called
'Pyrona®' (in Australia).
Side-Effects of the Benzo-Pyrones
Coumarin
Coumarin has been used in clinical trials for over 30 years, in many countries, and in over
100,000 patients.
It may cause initial mild nausea or diarrhoea. So, we advise taking it with food, even a part of
the dose at
each meal (if these persist as a problem). Coated tablets or delayed-release capsules help this
greatly (so
that only 1 % of patients have it). A few complained of mild dizziness or drowsiness. All these
side-effects
went after the first month. No patient ever withdrew from a trial because of them.
No interactions with any other drug have been demonstrated, including any chemotherapy.
A few patients (about 3 per 1,000) may get an idiosyncratic hepatitis (between 3 and 9
months). This
returns to normal if the drug is stopped. {Details of this have been published: Human Toxicology
8 (1989)
501-506 and Medical J. Australia 162 (1995) 391.}. Independent evaluators have reported no
'definite'
case, 20 'probables' or 'possibles' and 43 'unlikelies' or 'no-relationships' from the only 75 cases
from all
over the world reported to Sep 95 (only 63 of which gave sufficient data to be evaluated).
The incidence does not vary with the dose - neither daily nor cumulative, but may vary with the
preparation.
There have been four deaths among the patients all over the world who have been taking
coumarin. One of
these was "probably" associated with coumarin, three "possibly" were. This death rate has been
estimated as
3 per 10,000.
Most who prescribe coumarin do not use routine liver-function tests, but some now do so. If
they are to be
used, it is best to perform a test before starting the drug and then at monthly intervals for one
year (no case
has been reported after 9 months).
Patients are also advised to stop the drug and see their doctors if they have the symptoms of
hepatitis (Dr.R.
D. Thornes of Dublin - who has probably given more coumarin to patients than anyone else in
the world -
simply advises them to come back if they feel really unwell.). If the liver-function tests are then
less than
three times normal, coumarin may then be continued - with care.
No side-effects have been reported for the two topical forms of coumarin, powder or ointment
(except for a
single patient who had a rash from the ointment but not from the powder - and this over a
radiation burn, not
the rest of the arm).
Flavonoids
No serious side-effects have been reported for the flavonoids mentioned here, in spite of being
used by very
many people, all over the world, for many years. About 1 % of people have minor gastric
problems, as with
coumarin.
http://www.lymphoedema.org.au/bp.html
Judith R. Casley-Smith
This section is rather technical and may only be of interest to doctors and therapists who treat
lymphoedema
(lymphedema). However some patients are interested, and it can be shown to their doctors if
they wish. It is
very important for patients to obtain the agreement of their doctor before taking any drug!
Oral benzo-pyrones alone usually act slowly in lymphoedema, but by the end of a year these
give about half
to two thirds of the best reductions when patients are treated just with Complex Physical
(Lymphedema)
Therapy (C.P.T.) alone.
However, compression garments were not used in the trials of the benzo-pyrones. These drugs
are the only
treatment available for those who cannot tolerate or wear such garments. Without compression
garments,
this very slow but steady reduction is a virtue since a rapid one would leave huge potential
cavities which
would readily refill. The slowness allows the body to gradually remodel, so that the altered
fibrous tissue
takes the place of garments. The improvements produced by these drugs in many of the
symptoms which
distress patients, and in lessening the attacks of infection, were more rapid; but no change in
these should be
expected for 1 to 2 months. Benzopyrones also increase reductions gained with C.P.T. and
other therapies
and help to maintain them better (see Section on Results ).
A review (in preparation) found that benzo-pyrones have been tested by over 37 authors in 8
countries, in
(effectively) 51 clinical trials. (The word "effectively" is used since different Grades were
counted separately
if they were evaluated separately.) These are all the trials known to the authors which could be
evaluated
objectively. The benzo-pyrones were: coumarin, coumarin plus troxerutin, oxerutins (O-(-
hydroxyethyl)-
rutosides, HR) and diosmin. There were 39 trials of oral and 12 of topical preparations (11 and
6,
respectively, were combined with other therapies). In all of them, oral or topical benzo-pyrones
significantly
reduced lymphoedema (usually to a clinically important extent). In almost all the symptoms were
similarly
reduced - including infections (Secondary Acute Inflammation, SAI). Combining all 25 trials of
oral benzo-
pyrones alone, in which the reduction of oedema could be estimated, gave a mean reduction of
oedema of
36% (S.E. 6%) per year (1,225 patients in all). (About 1 to 10% should be added to this if
comparing it
with untreated patients since these worsen by amounts varying with the duration of their
lymphoedema.)
There were no significant differences between arms and legs. Elephantiasis was reduced less
(15% per year)
than Grades 1 and 2 (57%) but this was of course much greater initially. As the dose of benzo-
pyrones
increased, so did their efficacy. Nor are these drugs merely useful by themselves. Both oral and
topical
forms, and these combined, very materially increased reductions of lymphoedema obtained by a
variety of
physical and surgical techniques. In these, they often also greatly reduced the incidence, and the
severity, of
attacks of SAI.
The year 1993 saw the publication of three trials of oral coumarin for lymphoedema: in Australia
and (for the
W.H.O.) in India and China. They appeared in: the New England J. Medicine 329 (1993),
1158-1163,
Annals. Tropical Medicine Parasitology (1993) 87, 247-258, and the British Medical J., 307
(1993) 1037-
1040, respectively. The average reduction for Grade 2 arms was 2.2 % of the initial volume per
month (or
40 % of the oedema in 6 months); that for Grade 2 legs was 1.5 % of the initial volume per
month (or 33 %
of the oedema in 6 months).
The large oedemas of elephantiasis reduced more rapidly, but were often still great at the end of
the trials
because they were so much larger initially. Reductions are slow, but the drugs convert a disease
which
otherwise slowly (or sometimes rapidly) gets worse into one which slowly improves. The drug
also
improved many symptoms of lymphoedema (pain, lack of mobility, etc). Importantly, they lessen
the number
and severity of attacks of acute inflammation (sometimes called: cellulitis, erysepilas).
An analysis has been made of the first 628 Australian limbs treated with C.P.T., with and
without the benzo-
pyrones (Lymphology, 20 (1996) 76-82, and see Section on Results ). Both oral and topical
benzo-pyrones
increase the already large reductions which Complex Physical (Lymphedema) Therapy (C.P.T.)
produces in
lymphoedema and elephantiasis. A typical one-month course of C.P.T. gave average reductions
of 13 % of
the initial volume of a Grade 2 arm and 11 % of a Grade 2 leg; these were improved by a
further 5 % if oral
benzo-pyrones were taken for 3 months before the Course started, and by yet a further 2 to 3
% if topical
Coumarin was used as well. During the next 12 months, some limbs increased in volume, others
reduced still
further. Oral benzo-pyrones improved these reductions by 10 % of the volume at the end of the
first Course
of C.P.T. The next Course of C.P.T. by itself gave a 16 % reduction relative to the limb volume
at the start
of the Course. Again coumarin ointment gave a further 11 % and powder a further 16 %
improvement.
Patients at risk, after operations which cause lymphoedema, are less likely to get it if they take
benzo-
pyrones prophylactively. It also considerably reduces the oedema of accidental trauma to the
limb (cuts,
bruises, fractures, burns, stings, etc.). These are also often greatly helped by topical coumarin
(cream or
powder).
Similar reductions to those obtained with coumarin have also been observed with the (bio)
flavonoid Paroven
- also called: Venoruton, Relvène (British J. Plastic Surgery, 41 (1988), 20-27). However note
that the
doses of this need to be much larger (3,000 mg/day rather than 400, as with coumarin). Another
benzo-
pyrone - diosmin (Daflon 500®)- has also been shown to be effective in lymphoedema (Int.
Angiol. (Suppl)
14 (1995) 39-43). Again the doses of this need to be much larger (2,000 mg/day rather than
400, as with
coumarin).
Some similar drugs, which are not strictly-speaking benzo-pyrones, are also effective. These
include
Unguentum lymphaticum® (however this can only be applied to the skin) and Doxium®. A
double-blind trial
of an extract of Ruscus aculeatus (mainly ruscogenin and neoruscogenin plus hesperidin methyl
chalcone)
over 3 months, reduced oedema by 13%, compared with a 9% increase in the controls,
symptoms were
improved significantly (Lymphology, 29 (1996) 29-35).
There has been some interest in Pycnogenol® and similar products, with anecdotal reports of
their
effectiveness. However in spite of the claims by those who promote these products, clinical trial
data is
regrettably lacking. We can only find one: a double-blind trial, matched-group, placebo-
controlled, trial was
performed on post-mastectomy lymphoedema using procyanidolic oligomeres Endotélon™(33
active, 30
placebo) for 6 months (Cluzan RV, Pecking AP, Lokiec FM [eds.] Progress in Lymphology -
XIII.
Amsterdam, Elsevier, Int Cong Ser 994 (1992) 655-658). Symptoms were considerably
improved, but
there was no significant difference in the oedema (which only decreased by 1%). However the
dose was
only 300 mg/day. From their molecular weight, at least 800 mg/day would be needed to equal
400 mg/day
of coumarin. So this substance may help, but lack of good clinical trials with adequate doses
makes it
impossible to be sure of this. By contrast, many of the other benzo-pyrones (including the
flavonoids) have
had such successful trials.
How the Benzo-Pyrones Act
All oedemas cause swelling, pain (if they increase rapidly), loss of function (at both gross and
cellular levels),
poor oxygenation and poor wound healing. Chronic, high-protein oedemas cause chronic
inflammation with
excess fibrosis. Benzo-pyrones have been shown to improve all of these. {For a general review
for this
section, see: Casley-Smith JR & Casley-Smith, Judith R.. High-Protein Oedemas and the
Benzo-Pyrones.
Lippincott, Syd. & Balt., 1986 - obtainable from the L.A.A }
The benzo-pyrones reduce all forms of high-protein oedema. Almost any oedema is a high-
protein oedema,
except those from uncomplicated varicose veins, late congestive cardiac failure and some kinds
of renal
disease. The dividing line is a protein concentration in tissue fluid of 1 g/dl. Above this, the
colloidal osmotic
pressure of the protein contributes greatly to the accumulation of fluid, and the benzo-pyrones
can reduce
the oedema by removing the cause of this.
Benzo-pyrones reduce all high-protein oedemas by causing macrophages (scavanger cells in the
tissues) to
increase both their numbers and their normal lysis of the excess protein. Thus the increased
colloidal osmotic
pressure is reduced via this alternative pathway for the removal of protein. This can be detected
about 4
hours after administration and is maximal by 24 hours.
However some of the actions in lymphoedema are much slower than this since it takes many
months to
remove the accumulated excess fibrous tissues. The removal of protein and the excess fluid this
causes (and
its other deleterious effects) starts within days, but he effects of this are usually not obvious for
some six
months because of all the fibrous tissue.
Many benzo-pyrones also improve pumping by the collecting lymphatics, again aiding in the
removal of the
oedema. Some consider that this is how they act, but at least in animal studies it is evident that
proteolysis is
much more important (although increased pumping by any remaining lymphatics must also help).
Benzo-pyrones seldom affect the underlying condition but, by reducing the excess protein,
reduces the
oedema and its sequelae. They enhance another pathway for the removal of protein and water
from the
tissues when the lymphatics can no longer handle these.
If the oedema is within 1 - 2 cm of the surface of the skin, topical applications (the powder or
the ointment)
are suitable; if deeper, the oral form is also necessary.
Coumarin has a secondary action on injured blood vessels if applied topically to burns and acute
injuries. It
impairs the degradation of adrenalin, hence arterioles are more contracted. Immediate topical
application
reduces oedema (and hence the pain) via the reduction of leaking from the injured blood
capillaries.
It also improves oxygenation of ischaemic regions by a separate mechanism: opening arterio-
venous
communications. This reduces most exchanges with the tissues but, since gases are mainly
exchanged via
arterioles, it increases these. This is also useful with ischaemic skin grafts and flaps.
Finally, there is increasing evidence that coumarin's action on macrophages can be of value in
some cases of
immune-sensitive carcinomas (especially melanoma and some others, even carcinomas of the
breast). (In the
reports of these trials it is usually termed: 1,2 benzopyrone.). However it must be emphasised
that only a
relatively few such tumours are improved and such trials are only in the initial stages!
Please note that while the correct chemical name for 5,6 benzo-alpha-pyrone, or 1,2-
benzopyrone is
coumarin, it is NOT an anticoagulant. Coumarin anticoagulants are its complex derivatives.
Unfortunately, all
this causes some confusion!. Another benzo-pyrone derivative 'Coumadin' is NOT 'coumarin'
and their
effects are quite different. Note that benzo-pyrones have no relationship whatever to benzo-
pyrenes.
Oral Benzo-Pyrones (taken by mouth)
All trials show that oral benzo-pyrones alone usually work slowly in lymphoedema (including
coumarin - and
Paroven/Venoruton). A few patients do get a rapid benefit, especially those who have primary
lymphoedema in many parts of the body (lymphoedema-all-over). These drugs have been
effective in both
primary and secondary lymphoedemas - including elephantiasis (see above). Often a patient
does not feel
much improvement (except in mobility, the loss of pain and in the reduction of 'hardness' and of
secondary
infections) for about 2-3 months. One must caution patients about this to avoid discouragement.
Topical Benzo-Pyrones (used on the skin)
At present the only topical benzo-pyrone preparations are of coumarin (powder or ointment).
Topical
coumarin works much more rapidly than the oral form, but only to the depth of 1 - 2 cm. It
should be
applied once or twice a day.
Coumarin ointment permits a greater dose to be delivered (because it is difficult to get enough
powder to
stay on the skin) and is recommended for treating fibrotic regions or regions of closed
inflammation.
However the ointment is quite sticky and may affect the life of compression garments; so it is
best used
under bandages. In addition, it stings if applied to open wounds or mucous membranes
(although this can be
overcome by first applying a local anaesthetic - see below).
The powder is an excellent lubricant during the massage parts of
C.P.T. (C.L.T.) or M.L.D., and during the application of compression garments. Used in this
way more is
adsorbed than when it is simply dusted on. It is also improves lympho-cutaneous fistulae -
where lymph
weeps onto the skin. (A powder is an unusual way of giving a drug but coumarin is lipid-soluble
and so
penetrates the skin even as a dry form.)
The powder is excellent for ulcers. If it stings too much, a local anaesthetic is applied 1-2
minutes earlier (e.
g. 10% Xylocaine® spray - no prescription in Australia, or the 4% solution - prescription
needed). If
stinging recurs (e.g. after 30 minutes), a second application of local anaesthetic is applied.
When using the powder as a lubricant, therapists receive a small dose, but only via the hands, the
overworked nature of which it may well help! Some benzo-pyrones are essential (as P-
vitamins). Many take
200 mg a day prophylactically. A therapist gets much less than this; no ill-effects are reported.
The Doses of Benzo-Pyrones
We consider the minimal useful doses of benzo-pyrones in lymphoedema are: Coumarin (5,6
benzo-alpha-
pyrone ) 400 mg per day, Paroven/Venoruton 3,000 mg (six 500 mg capsules) per day, Daflon
2,000 mg
per day. For Venalot this minimal effective dose is 16 tablets per day. If there is no noticeable
improvement
after 2-3 months, many patients start to improve if these doses are doubled.
Coumarin powder or ointment is usually applied once a day, but two or three applications per
day work
better if these are feasible. The ointment allows more to be applied and so is preferred, if
possible, for
fibrous (scar) tissue. Powder is preferred under compression garments, as a lubricant for the
hands during
massage, and for application to ulcers and lymphatic fistulae.
These may be used in place of coumarin tablets if one uses 5 ml per day of the ointment or 10
ml per day of
the powder. (These should be measured in a spoon available from pharmacists.) These amounts
are rather
large, so we suggest applying half, twice a day.
Benzo-Pyrones for Children
There has been very little work done on the doses for children. We get asked about it from time
to time and
know of about 40 children who have taken them for some years without ill effects, and with
considerable
help to their lymphoedema.
Using an adult dose of 400 mg of coumarin/day (with more difficult cases, 800 mg/day) we just
scale the
child dose down using 70 kg as the mean adult weight. Thus for a 10 kg child use 40 mg/day,
with up to 80
mg/day if there is no noticeable improvement after two to three months. We have too little data
at present to
do any better. Other benzo-pyrones should be scaled down similarly. Toxicological studies
show no
particular differences between young and adult animals.
Other uses for the Benzo-Pyrones
Benzo-pyrones are so useful in lymphoedema, for which there is no other effective drug, that it is
often
ignored that they are also reduce many high-protein oedemas (i.e. protein concentrations of 1
g/dl or more).
These include almost all oedemas except those from renal or cardiac failure.
These drugs never, of course, attack the underlying cause of the oedema. However they
stimulate the
macrophages to lyse more of the excess proteins in the tissues than they usually do and greatly
increase their
numbers at this site. This reduces the oedema (since the no-longer-retained water returns to the
blood),
improves the oxygenation of the tissues, and their cellular functioning and wound healing.
Increased proteolysis provides a local alternative pathway to the lymphatic system for the
removal of excess
protein and its associated oedema. Many clinical trials and animal experiments have been
performed on a
wide range of such oedemas, showing their worth; reviewed in:
Casley-Smith JR, Casley-Smith Judith R. High-Protein Oedemas and the Benzo-Pyrones, Syd.
& Balt.:
Lippincott, 1986, pp. 536. (see publications from the L.A.A.).
Benzo-pyrones may be used to treat the symptoms, not the causes, of high-protein oedema
wherever they
arise, e.g.:
Oedema due to accidental trauma of all kinds, e.g., burns, insect bites, crushing and cutting
injuries including
infected wounds (unlike the corticoids), bruises and deeper haematomas, contusions & fractures.
Oedema due to surgical trauma (particularly important where surgery may involve damage or
removal of
part of the lymphatic system, e.g. skin grafts). They may also assist where surgery produces no
damage to
the lymphatics. It may be given three days prior to elective surgery, including dental extractions,
etc.
Oedema due to accidental and sports injuries and industrial injuries and strains.
Oedema due to infection where benzo-pyrones can reduce swelling while an antibiotic treats the
infection
(unlike the cortico-steroids, it does not interfere with the inflammatory process).
Chronic venous insufficiency (including ulcers and haemorrhoids).
Swollen ankles of the aged, when the skin is stretched and fragile.
Finally, but with only incomplete evidence, is the possibility that benzo-pyrones also stimulate
the immune
functions of macrophages against certain forms of carcinomas. If correct, this could be of
considerable value.
Animal lovers may like to know that there is also a veterinary form (tablets, powder and
ointment) called
'Pyrona®' (in Australia).
Side-Effects of the Benzo-Pyrones
Coumarin
Coumarin has been used in clinical trials for over 30 years, in many countries, and in over
100,000 patients.
It may cause initial mild nausea or diarrhoea. So, we advise taking it with food, even a part of
the dose at
each meal (if these persist as a problem). Coated tablets or delayed-release capsules help this
greatly (so
that only 1 % of patients have it). A few complained of mild dizziness or drowsiness. All these
side-effects
went after the first month. No patient ever withdrew from a trial because of them.
No interactions with any other drug have been demonstrated, including any chemotherapy.
A few patients (about 3 per 1,000) may get an idiosyncratic hepatitis (between 3 and 9
months). This
returns to normal if the drug is stopped. {Details of this have been published: Human Toxicology
8 (1989)
501-506 and Medical J. Australia 162 (1995) 391.}. Independent evaluators have reported no
'definite'
case, 20 'probables' or 'possibles' and 43 'unlikelies' or 'no-relationships' from the only 75 cases
from all
over the world reported to Sep 95 (only 63 of which gave sufficient data to be evaluated).
The incidence does not vary with the dose - neither daily nor cumulative, but may vary with the
preparation.
There have been four deaths among the patients all over the world who have been taking
coumarin. One of
these was "probably" associated with coumarin, three "possibly" were. This death rate has been
estimated as
3 per 10,000.
Most who prescribe coumarin do not use routine liver-function tests, but some now do so. If
they are to be
used, it is best to perform a test before starting the drug and then at monthly intervals for one
year (no case
has been reported after 9 months).
Patients are also advised to stop the drug and see their doctors if they have the symptoms of
hepatitis (Dr.R.
D. Thornes of Dublin - who has probably given more coumarin to patients than anyone else in
the world -
simply advises them to come back if they feel really unwell.). If the liver-function tests are then
less than
three times normal, coumarin may then be continued - with care.
No side-effects have been reported for the two topical forms of coumarin, powder or ointment
(except for a
single patient who had a rash from the ointment but not from the powder - and this over a
radiation burn, not
the rest of the arm).
Flavonoids
No serious side-effects have been reported for the flavonoids mentioned here, in spite of being
used by very
many people, all over the world, for many years. About 1 % of people have minor gastric
problems, as with
coumarin.
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