Proteases - drug of the choice in the pharmacotherapy of lymphedema
Machanova1 M., Wald2 M., Prausova3 J.,
Bechyne4 M., Adamek2 J. Proteases - drug of
the choice in the pharmacotherapy of lymphedema. 1 Oncology
Department, Liberec Hospital, 2 Department of Surgery, 2nd Medical
Faculty UK, Prague, 3 Oncology Department, Faculty Hospital Motol,
Prague, 4 Dermatology Clinic, Faculty Hospital Bulovka, Prague. 2000
In the oncological literature of the past decades mainly the
survival time was emphasized. Currently the quality of patients'
life during and after the treatment also becomes more and more
important. Each physician dealing with the treatment of malignant
tumors could confirm that some percentage of complications during
radical treatment is unavoidable. However, it is important that
treatment benefits prevail the risk of serious and unpleasant
complications. Or, if such complications occur, they could be
positively influenced by treatment. Lymphedema is one of the
complications which affect mostly patients treated by combined
treatment of surgery and radiotherapy.
Lymphedema, both primary and secondary (regardless of its cause), is
a sign of serious lymph circulation disorders in particular area. If
it is not treated adequately and in time, it leads to the
irreversible damage of lymphatic system followed by complications,
such as relapsing skin inflammations, fibrotization, tissue
induration etc. Similar condition, more difficult to diagnose,
appears during visceral disorders of lymphatic system.
Lymphedema can form shortly after the surgery or during radiation
treatment.
However, it can also develop after few years. Mechanism of this
disease is based on gradual decrease of the transport capacity of
lymphatic system in particular area.
Lymphostasis causes a damage of valvulae and endothelium of
lymphatic vessels. Their permeability increases, lymph flow is
slowed down and lymphatic plugs are formed. Edema is formed as a
result of extravazation of proteins and fibrin. Consequently, number
of fibroblasts increases, neovascularization appears, and more cells
typical for chronic inflammations occur. Number of collagen fibres
also increases and sclerotization of tissue starts. All these
mechanisms acting together multiply their effect and form a vicious
circle of the disease. Thus, elephantiasis can insconspicuously
develop.
Older conceptions of pharmacotherapy of lymphedema consisted of
symptomatic treatments (diuretics, venopharmacs). In many cases they
just aimed at prophylaxis or therapy of complications (antibiotics,
antimycotics). Later on an immunomodulating therapy was also tried.
Treatment by diuretics, which is unfortunately used up to these
days, is currently considered by number of authors to be harmful and
from the pathophysiology of lymphedema and macroorganism point of
view medicaly wrong.
Use of proteases (hydrolases), administered orally but acting
systemically (that means within the whole organism), introduced a
fundamental change in the attitude towards the pharmacology of
lymphedema. Combinations of plant and animal proteases are usually
used: papain, bromelain, trypsin, chymotrypsin and event. pancreatin,
amylase, lipase and rutoside (in our country registered
preparations: Wobenzym® coated tablets, Phlogenzym® tbl.).
These combined enzyme preparations show effect on almost all
pathophysiological mechanisms causing lymphedema. These drugs are,
therefore, able to break the circulus vitiosus and normalize
lymphatic circulation in the affected area. In the case of fully
developed lymphedema at the stage III and IV they are able to
improve significantly nutrient supply to already induced and
sclerotized tissue.
What is a concrete relationship between pharmacological effects of
proteases and pathophysiology of lymphedema?
Proteolytic and mainly fibrinolytic effect of proteases leads to a
lysis of lymphatic plugs and restoring of lymphatic passages which
can then more easily remove products of proteolysis of extravazally
deposited fibrin and other proteins.
Significant antiedematous and edemaprotective effect of proteases,
strenghtened by rutoside, improves rheological properties of lymph
(and blood) and ensures improvement in the transporting capacity of
lymphatic system and microcirculation. Activation of macrophages
ensures a fast removal of proteolysis products. Activation of NK
cells and other components of cellular and humoral immunity
significantly positively influences chronic inflammatory processes
in the indured tissue.
Analgetic effect is evoked by proteases both directly - by
peptidolytic cleavage of pain mediators and indirectly - by lowering
of oncotic pressure and restriction of inflammatory reaction.
Rheological effects (lowering of serum and plasma viscosity,
lowering of thrombocyte aggregation and increase in flexibility of
erythrocytes) ensure a better arterial blood supply and easier
venous drainage.
Very important is also the vehiculum effect: proteases increase
concentrations of antibiotics in blood and tissues and, therefore,
facilitate a faster cure of acute and chronic infections.
Marta I. Korpan and Veronika Fialka from UNI Klinik fuer
Physikalische Medizin und Rehabilitation, Wien conducted in 1993-95
a controlled randomized clinical study Wobenzym versus diuretics on
female patients suffering from lymphedema after the breast ablation
for carcinoma. Duration of the trial was 7 weeks and volumometric
parameters were evaluated. Results of the treatment in the Wobenzym
group were significantly better than in the group treated by
diuretics.
Additionally, significantly more pain-free patients were found in
the Wobenzym group.
The most frequent localization of lymphedema connected with
malignant tumor and its treatment is the edema of homolateral arm
during breast carcinoma. According to various authors a frequency of
this complication is 7-30%. Thanks to better and moderate surgical
techniques and more accurate radiation treatment the current
statistics reveal better results than the older studies. A frequency
of occurrence of breast carcinoma increases. Thus, the risk of
formation and development of lymphedema refers to a big number of
patients and represents a serious health and psychosocial problem.
Every year there is approx. 4000 newly registered cases of breast
carcinoma in the Czech Republic. Therefore, 270-1150 patients is
under the risk of developing lymphedema.
Particular groups of patients:
l. M. Machanova
2. M. Bechyne, J. Tomanova, R. Bechynova
3. J. Adamek, J. Prausova, M. Wald
4. M.I. Korpan, V. Fialka