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| 1- Composition: |
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1 dragee Legalon contains 35 mg silymarin
1 dragee Legalon 70 contains 70 mg silymarin |
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| 2- Mechanism of
Action: |
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The liver has several vital functions
to perform in the human body: e.g. it plays a dominant role in metabolism
(sugar, protein and fats), in digestion (bile secretion) and in
the detoxication of waste product. Every form of liver damage causes
changes in the membranes of the liver cell and in this way impairs
the functional capacity if the liver. Silymarin, the active principle
of Legalon, is of plant origin. It acts as a cell membrane stabilizer
and capable of protecting the liver against deleterious agents and
of restoring damaged liver cells to normal. |
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1:
Stimulation and Protection of Kupffer cells.
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These sinusoidal cells participate
very actively in the detoxifying function of the liver, which
is basically performed by the hepatocytes. Silymarin, the
active substance in Legalon, has been shown in different experiments
to be capable of positively influencing the Kupffer cells
even in the presence of the noxious factor, so that the cells
are able to maintain their structure as well as their phagocytic
activity. When under the effects of the Silymarin, the Kupffer
cells also display an increased mitotic activity. |
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Legalon shortens the
duration of the illness:
It has been established that the phagocytic activity of
the Kupffer cells increases with silymarin. Hepatic cells
lesions are thereby reduced and virus elimination accelerated.
This is reflected clinically and biochemically in a more rapid
return to normal liver function.
In a double blind study with patients suffering from acute
viral hepatitis there was a reduction in the duration of the
disease by 20 - 30%. This is of particular importance when
one considers that precisely those patients who undergo a
prolonged acute phase show a greater tendency chronicity.
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2:
Antiperoxidative effect
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Many substances are not toxic
per se but become toxic by their forming free radicals in
the hepatocytes. The formation of radicals in the liver results
in peroxidation or membrane lipids in just the same way that
they are induced, for example, by chronic alcohol intake.
Biological membranes are thereby destroyed. Cell damage occurs.
Silymarin prevents lipid peroxidation, and consequently reduces
pathologically increased lipid metabolism and keeps the membranes
and the membrane-bound enzymes functioning normally. |
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Legalon prevents
toxic metabolic liver damage
When taken over long periods, alcohol and certain drugs may
cause liver damage which is prevented to a large extent by
treatment with Legalon. In a controlled study of alcohol-induced
fatty liver and fatty hepatits. Fintelmann demonstrated a
significant improvement in the bromsulphthalein test (p=0.02)
and SGOT (p = 0.04) in the cases treated with Legalon in comparison
with the placebo group. In a long-term study with controls,
Saba demonstrated that, in 19 patients (control group = 18)
with liver damage induced by psychoactive drugs, Legalon improved
the most significant liver function parameters, even when
administration of the hepatotoxic substances continued.
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3:
Stimulation of Protein Synthesis
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The cell nucleus
is the centre of all metabolic processes
As could be shown with isolated hepatocytes, Legalon acts
directly on the metabolism of the cell nucleus. Legalon lead
a normalization of the pathologically altered protein synthe~
by increasing RNA synthesis (1).
This improvement or normalization of the plasma protein picture,
having been proven in several clinical studies, can I further
explained by these experimental results (2, 3,4).
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Legalon is effective
in inflammatory degenerative diseases
In two double blind studies involving patients with chronic
hepatitis Legalon showed a significant superiority in influencing
the mesenchymal inflammatory reaction within the liver parenchyma
(p < 0.05). Furthermore, there are indications of such
a superiority in influencing the inflammatory reaction in
the connective tissue of the liver, the production of piecemeal
necrosis, and changes in the parenchyma.
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| 3- Indications: |
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For acute and chronic hepatitis.
Cirrhosis.
Fatty degeneration.
For functional impairment of the liver caused by toxic states.
To protect the liver cells during administration of drugs hazardous
to the liver.
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| 4- Contraindications: |
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| NONE |
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| 5- Dosage: |
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Unless otherwise directed,
in severe cases 2 degrees. Legalon 70 should be taken 3 times daily.
As a maintenance dose and as initial dosage in moderate cases 1
dragee Legalon 70 three times daily.
In mild cases 1 dragee Legalon (35 mg) 3 time daily.
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| 6- Presentation: |
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Packs of 40 and 80 dragees Legalon.
Packs of 80 dragees Legalon 70. |
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| 7- Clinical Studies: |
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Apart from the pharmacological
investigations referred to above more than 120 clinical studies
have been published up to the end of 1985. In all, they comprise
reports on the treatment of approximately 3000 patients with acute
or chronic hepatitis, hepatic cirrhosis or liver damage of toxic
or metabolic origin.
Among the points of special importance in the clinical bibliography
of Legalon are not only the numbers of published studies but also
the experimental methods employed. Clinical research on Legalon
has utilized the most up to date experimental techniques. The main
items are certain controlled double-blind trials with statistical
analysis by variation tech- niques. This fact deserves special emphasis
in view of the difficulties which attend the selection of patients
with liver disease owing to the multiplicity of symptoms and signs
and the lack of uniformity in the aetiology of the conditions. Nevertheless,
the following studies have been completed and published:
-12 double-blind clinical-trials
-10 controlled trials. These were clinical trials in which despite
the inclusion of a control group it was not feasible to employ the
methods of a double- blind trial.
-more than 100 progress trials. These trials comprised those forms
of liver disease in which -owing to their evolution and duration
of treatment -it was extremely difficult, and in many cases impossible,
to assemble a control group.
These publications comprise the following numbers of patients: Acute
hepatitis 284 patients
Chronic hepatitis 657 patients Hepatic cirrhosis 476 patients Liver
damage of toxic or metabolic origin 955 patients Miscellaneous liver
diseases 411 patients
Total 2,783 patients
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| Legalon in acute hepatitis |
Any attempt to evaluate the effects of
Legalon in acute hepatitis is subject to great difficulty owing to
the tendency to spontaneous recovery. Nevertheless, the accumulated
observations in 284 patients provide evidence that Legalon has a beneficial
influence on those forms which present therapeutic difficulties, e.
g., serum hepatitis (Hepatitis B) and hepatitis with superimposed
cholestasis, and can slow down or prevent transition to the chronic
stage.
In four controlled clinical trials the duration of illness was used
as the criterion for the efficacy of Legalon: two of these trials
were carried out under double-blind conditions:
1) MAGLIULO, E., GAGLIARDI, B., FIORI, G. P. Medizinische Klinik 73,
1060 (1978)
2) PLOMTEUX, G. A., ALBERT, A., HEUSGHEM, G. IRCS Medical Science
9, 259 (1977)
In all the Legalon trials there has been evidence that Legalon significantly
curtails the duration of illness and produces considerable improvement
in clinical state. |
| Legalon in chronic hepatitis |
Because of wide individual fluctuations
in the course of the disease, assessment of any therapeutic agent
for chronic hepatitis presents great problems. Thaler14) carried out
two double-blind trials of silymarin in
chronic aggressive hepatitis. Statistical analysis showed that silymarin
was significantly better than placebo in terms of improvement in mesenchymal
inflammatory reactions within the hepatic parenchyma. Thaler also
found indications pointing to the superiority of Legalon in terms
of the following histological parameters:
a) parenchymatous changes.
b) portal inflammatory reaction
c) piecemeal necrosis
The results of the double-blind trial carried out by Berenguer and
Carrasco 3) likewise indicated a definite effect from Legalon in
various forms of chronic hepatitis. This effect was demonstrated
most clearly in histological terms. After as short a time as 6 months
the frequency of improvement in piecemeal necrosis and fibrosrswas
significantly higher than in the placebo group (p < 0.02). |
| Legalon in hepatic cirrhosis |
A long-term double-blind trial2)
was carried out in four different hospitals to ascertain the effect
of Legalon on the fate of patients with cirrhosis. The main criterion
was survival time. After a mean observation period of 50 months
the survival rate among patients treated with silymarin was 76 %
as against 53 % in the placebo group (p < 0.02). Analysis of
the subgroups showed that the treatment was most effective in patients
with alcoholic cirrhosis (p < 0.01). These results indicate that
treatment with silymarin can lower mortality among patients with
cirrhosis. |
| Legalon in liver damage of toxic
metabolic origin |
In patients with liver damage caused
by exogenous poisons (alcohol, drugs) or by metabolic disorders
due to other primary diseases (diabetes mellitus) the main finding
is usually fatty change, while the biochemical results are frequently
within the normal range or only slightly outside it.
The efficacy of silymarin in the treatment of alcohol-induced liver
diseases has been substantiated by numerous trials. For example,
there have been four randomized double-blind trials of the efficacy
of Legalon in all forms of alcohol-induced liver disease: fatty
liver, alcoholic hepatitis and alcoholic cirrhosis.
1) V ARIS, K., SALMI, H. A., SIURALA, M.
Akt. Hepatol. III. Int. Symp. K61n 1978/Hans. Verl.-Kontor, Lubeck
1979
p.42
2) 01 MARIO, F. et al.
Hepatology (VI) 364 (1980)
3) FINTELMANN, V., ALBERT, A.
Therapiewoche 30, 5589 (1980)
4) SALMI, H. A., SARNA, S.
Scand. J. Gastroenterol. 17, 517 (1982)
In all these studies there was significant improvement in biochemical
indices among the patients treated with Legalon as compared with
the placebo group. Signs of histological improvement were also significantly
more frequent in the treatment group (p < 0.01).
There is also evidence that Legalon can diminish
or prevent liver damage due to certain drugs. Certain antiepileptics,
sedatives, antidepressives, anaesthetics, antidiabetics, antibiotics,
tuberculostatics, antimetabolites and antimalarials are known to
be capable of producing morphological changes in the liver: some
liver function tests may then give abnormal results, and intrahepatic
cholestasis may develop as a result of exposure to such drugs.
In a controlled trial, Saba 22) demonstrated that Legalon produces
significant improvement in the abnormalities of the principal liver
function tests caused by psychotropic drugs, even though the drugs
which were causing the liver damage were still being administered.
Lahtinen et al..16), in a double-blind trial, found evidence that
Legalon exerted beneficial effects on liver function tests after
cholecystectomy under general anaesthesia.
The pharmacological attributes of silymarin have thus been borne
out in clinical practice. Silymarin is capable of protecting the
liver cell from toxic agents.
In the light of this clinical documentation -now extremely extensive
- emphasis must be laid on the clear evidence of the clinical efficacy
of Legalon in the majority of liver diseases, and on the precision
and objectivity of the research methods employed. As compared with
other drugs for the treatment of liver disease, Legalon may reasonably
be described as the best documented pharmaceutical agent for liver
disease at present available. |
| Summary of clinical results |
1. The results obtained
with silymarin in animal experiments clearly justify therapeutic
administration of Legalon to human patients.
2. After treatment with Legalon, improvement in pathological changes
amounted to more than 60 %. This figure is based on observations
of clinical symptoms and signs, biochemical indices and biopsy results.
3. Among patients treated with Legalon improvement in the main liver
function tests was twice as rapid as in a control group receiving
conventional treatment.
4. Those indices which reflect the state of hepatocellular function
returned to normal.
5. Legalon exercises comprehensive effects on the liver cell by
virtue of its power to protect the structures of the liver cell.
6. Legalon is nontoxic and does not produce side effects of any
kind. |
| Good evidence of the efficacy of Legalon is
provided by statistical data: |
-Its intracellular action on the mitochondria within
the liver cell and on all the intracellular membranes has been irrefutably
demonstrated by electron microscope studies.
-Its power of counteracting destructive intracellular lesions caused
by toxins has been measured with the Zeiss Videomat microscope.
-Clear evidence of its effect has been provided by experimental models
of liver damage.
-Its clinical efficacy has been demonstrated it:
-in large numbers of cases.
-by comparison with a placebo.
-by comparison with other products
-by liver biopsy
-by statistical analysis of the results
-by use in the treatment of outpatients, among whom there was no.
possibility of checking compliance with diet or bed rest
-Its biological effects have been the subject of numerous statistical
trials, and there are approximately 6,000 individual results which
provide evidence of the biological effects of Legalon treatment.
Out of the large number of cases which have been treated with legalon,
we wish to present this example, which provides unmistakable evidence
of its therapeutic effect.
Fatty liver with mesenchymal reaction.
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| Biopsy after 8 weeks' treatment: regression of fatty
infiltration and mesenchymal reaction (original by courtesy of WilHELM)
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There is one important point in which Legalon clearly differs from
other products: its efficacy has been proved. Seldom, if ever, have
so many objective trials been carried out in the field of liver
disease. Throughout all stages of testing, the efficacy of Legalon
has been established by objective criteria and not by hypotheses
or assumptions.
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