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
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.
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