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Important Features of Reparil Gel N, Dragees:
   
  1- Composition.
  2- Mechanism of Action.
  3- Absorption.
  4- Secretian & metabolism.
  5- Indications.
  6- Contra-indications.
  7- Dosage.
  8- Clinical Trials.
   
  COMPOSITION: Top
   
 

Reparil gel N

Reparil Dragees

 Each 100 g gel contain :

Aescin                                      1.0 g

Diethylamine salicylate               5.0 g

Each Tablet contains :

Amorphous aescin                       20 mg

   
  MECHANISM OF ACTION AESCIN: Top
 
Aescin acts as a selective antiodematous and anti-inflammatory agent, its action is not necessarily related to its presence inside the tissues (action selective on the capillary membrane).

The mechanism of action of aescin is roughly as illustrated in the following diagrams:

Water exchange between the intracapillary and extracapillary space under normal conditions (Fig. 1):
Along the first part of the capillary water molecules (depicted as black dots) are passing from the capillary bed into the extracellular and intracellular spaces. The force responsible for expelling water from the capillary is the intracapillary hydrostatic pressure (blood pressure). In the terminal part of the capillary colloid-osmotic pressure is greater than hydrostatic pressure, and water is therefore sucked out of the extracapillary space into the capillary. There is an equilibrium between the amount of water leaving the capillary and the amount re-entering it. Along the capillary wall there is a permeability gradient arranged in such a way that the number of membrane pores and leaks in the first part of the capillary (left) is less than in the terminal part.

 Fig 1
 
   
Established oedema (Fig. 2)

The oedema is conceived as being a steady state (dynamic equilibrium), i.e. the cells and the intracellular space contain an abnormally large amount of fluid, but this undergoing continuous exchange with the plasma. Before reaching this steady state, the outflow from the capillary bed had for some time exceeded the backflow of fluid from the tissues into the capillaries, the result being abnormal shift in the relation between intracapillary and extracapillary fluid (odema). The oedema is represented in the diagram by extra large cells and intercellular spaces.



 Fig 2
   
 
   
Mechanism of action of aescin (Fig. 3)

Along the capillary there is permeability gradient arranged in such a way that there are fewer membrane pores in the first part of the capillary (left) than in the terminal part (right). This means that in the first part of the capillary the surface area available for water and solute exchange is not as great as in the terminal part. Aescin (depicted by yellow dots) acts by diminishing the number and/or of the opening in the capillary wall. Because of the permeability gradient, this sealing effect is more pronounced in the first part of the capillary than in the terminal part. The result is a reduction in the outflow of fluid from the first part of the capillary into the surrounding tissues. Macroscopically, this is apparent in a decrease in the oedema.



 Fig 3
   
 
   
After elimination of oedema (Fig. 4)

The outflow of water from the first part of the capillary into the tissues and the backflow from the tissues into the terminal part of the capillary are now stabilized at a lower level than in the earlier stages. The decrease in the oedema is represented in the diagram by making the cells smaller and narrowing the intercellular space to the normal width.



 Fig 4
   
  Absorption after oral adminstration Top
 

Aescin in doses of 0.06 -0.25 mg/kg was administered to rats and mice by installation into the stomach through an oesophageal tube. The blood level was followed in mice for 48 hours, while excretion in bile and urine was followed for the same period in rats. Mice absorbed 13.5 % of the dose, calculated in terms of non – volatile radioactivity. During this period rats excreted 16 % of the dose in the form of nonvolatile radioactivity and 4 % as volatile radioactivity.
Thin layer chromatography of blood, bile, and urine showed that when aescin is given by mouse the proportion which is metabolized is very much higher than after I.V. injection. In mice, for example, only one third to one quarter of the non volatile radioactivity in the blood consisted of unchanged aescin. In rats only one sixth to one seventh of the absorbed dose was excreted unchanged. Fig. 5
   
 
 
Excretion of aescin and non volatile aescin metabolites after oral administration of aescin (0.063 mg/kg) in rats. The results are expressed as percentages of the dose. Cumulative values of radioactivity excreted in bile and urine. Mean readings from 3-8 rats.
 
   
  Absorption after local application:
  Topical application of aescin clearly produces significant concentration in the cutis and sub-cutis beneath the application site, and there is evidence of a definite concentration gradient from cutis to subcutis to subcutaneous fat.

To assess percutaneous absorption of DEAS of Reparil Gel N, 14C-diethylamin salicylate was applied to the skin of the back of male rats. The proportion absorbed was ascertained from controls of 14C-radioactivity excreted in the urine and bile. Further measurements included the concentration in plasma and in various organs and tissues, together with the study of the metabolism of 14C-diethylamin salicylate. The average amount absorbed – measured in terms of amount excreted over 48 hours – was 15 %. High levels of radioactivity were noted in the skin area which had been treated, whereas 14C counts in organs and tissues at various times after application were low.
This effect is regarded as desirable from therapeutic and toxicological standpoints alike

   
  Secretion and metabolism: Top
   
 
In rats and pigs aescin is excreted via the kidneys and the liver. There are wide individual differences between animals in the relative importance of these two routes of excretion. However, in general more aescin is excreted via the liver than via the kidneys. As would be expected from the step fall in blood concentration in the first few hours after an injection, the elimination rate during the first few hours is very high, though it subsequently becomes less.
Thin-layer chromatography of urine and bile has shown that after an intravenous injection of aescin only a small proportion is metabolized. This process produces metabolites some of which are more polar and some less polar than aescin itself, and a small proportion of volatile radioactivity. In all, approximately 70-80 % of the injected dose is excreted unchanged in the urine and bile.
   
  Indications: Top
 
Reparil tab.
:
Traumatic swellings, tenosynovitis, painful lesions of the vertebral column (cervical syndrome, lumbago and sciatica), varicose veins, leg ulcers, hemorrhoids, thrombophlebitis, inflammatory oedema secondary to infections e.g. follicular tonsillitis, otitis externa, cellulites, mastitis, ECT.
Reparil gel N:
In cases of contusions, crush injuries, sprains, strains, bruises, haematoma, tenosynovitis, tendonitis, painful conditions of vertebral column, superficial thrombophlebitis, varicose veins and for care of veins after injections or infusions
   
  Dosage: Top
   
  Reparil Tab.

Treatment should be commenced with 2 dragees 3 times daily, taken with fluids after meals, in milder cases an as a maintenance dose 1 dragee should be taken 3 times daily.

For children 1 dragee taken 2-3 times daily after meals.

Reparil Gel N

Spread a thin layer of the gel onto the skin of the affected area once daily or more frequently. It is not necessary to rub the gel into the skin, but his may be done if desired.

   
  Contra-indications: Top
   
  Reparil Tab.

Pre-existing renal damage, renal failure, renal insufficiency, Rhesus incompatibility in pregnancy.

Although animal experiments with aescin have shown no evidence of teratogenic action, in conformity with general medical consideration Reparil tab. should not be given during the first months of pregnancy.

Reparil gel N

Reparil gel N should not be applied to broken skin, mucous membranes, or skin areas exposed to radiotherapy (the burning sensation is reversible).

     
  Clinical Trials: Top
 

Action of aescin

The pharmacological effect of aescin have been investigated in a wide range of experimental studies. Including the toxological trails these comprised many thousands of experiments.
Much work has been devoted to investigating the influence of aescin on various kinds of inflammatory oedema – ranging from pure transudation to severe tissue necrosis – provoked by the following agents: ovalbumin, dextran, local Arthus phenomenon, carrageen, hyaluronidase, bradykinin, compound 48/80, serotonin, histamine,aerosil, kaolin, bee venom, baker's yeast and formalin, the experimental model employed through out this work was the easily measurable oedema of the rat's foot-pad. The most potent inhibitory effect was noted in those forms of oedema in which transudation of fluid from the blood into the extra capillary space is the main feature. Apart from rat's foot-pad oedema, aescin also inhibits pulmonary oedema in guinea –pigs induced by ovalbumin or histamine. Traumatic oedema of the rat's foot-pad produced by artificial local ischaemia is closely comparable with the conditions existingin man. Fig. 6
   
 
 
Fig. 6
 
Traumatic oedema (rat's foot pad) increase in volume as percentage of initial volume:untreated and after Reparil (0.3 mg/kg) (VOGEL et al.)
 

The anti-inflammatory action of aescin has been demonstrated in experimental peritonitis induced by intraperitoneal administration of formalin to rats and in exudative pleurisy provoked by itraperitoneal injection of Evans' Blue or carrageen. The increase in vascular permeability in the peritoneum and the pleura occurring in the course of inflammation leads to accumulation of exudates and increase in the amount of protein in both these areas aescin inhibited exudates formation and reduced the increased passage of protein molecules from thr blood vessels to the site of inflammation (ROTHKOPF and VOGEL).
Pleural exudation produced in rats by phenyl isothiocyanate was blocked to a great extend by aescin (ROTHKOPF-ISCHEBECK).
The efficacy of aescin as protective agent against oedema has recently been confirmed by FELIX, using as experimental model the oedema of the endothelium of the terminal capillary pathway caused by polidocanol. According to HAMMERSEN this oedema is due to a non inflammatory increase n capillary permeability (morphological oedema).
After pretreatment with aescin a significant oedema – protective effect was demonstrable, more especially as regards the escape of protein into the skin and muscles (Fig. 7).
   
 
 
Fig. 7    Control    0.1 mg/kg 1 h    0.3 mg/kg 1 h    0.1 mg/kg 16h
   
Oedema induced by polidocanol in the cat's hind leg. Aescin checks the escape of plasma protein (FELIX).
 
 
Abnormal capillary resistance or fragility is also largely corrected by Reparil. It raises capillary resistance in scorbutic guinea – pig, the increase being proportional to the dose. Particularly convincing experimental results were obtained in studies of capillary permeability in which the escape of fluid through the capillary wall is measured.
As an example from the wide range of experiments the measurements of permeability by means of dye diffusion is illustrated in Figure 8
   
 
 
Fig. 8
 
 
The effect of Reparil on capillary permeability measured in terms of dye diffusion into the tissues (rat's foot-pad) under normal conditions and in abnormal permeability states induced by anaphylactic shock (from GIRERD et al)
 
   
 

Relevant to the mechanism of action of aescin is the fact that the transudation which follows implantation of an absorbent plastic foreign body can be inhibited by aescin. However, the formation of granulation tissue after introduction of croton oil or cotton wool into the tissue and immunologically induced experimental arthritis in rats are not inhibited.
Aescin thus blocks all trans-capillary transudation process – characteristic of the initial exudative stage of inflammation – while having no effect on the reparative fibroblast reaction with granulation tissue formation characteristic of the late stage of inflammation.

Aescin can hence be regarded as a genuine capillary sealing agent. To confirm this hypothesis, the following experiments were carried out on the rabbit's hind leg. One of the lymphatic situated between the femoral artery and vein was cannulated in order to collect lymph, the idea being that this region is characterized by uniform permeability conditions, whereas cannulation of the thoracic duct yields mixed lymph from a variety of organs with different grades of permeability, the capillary wall located between lymph and plasma is the main component of the plasma lymph barrier. By studying lymph flow, the permeability of the capillary wall to water and small molecules can be investigated. Polyvinylpyrrolidone (PVP) was used as a test molecule and its passage into the lymph provided an index of the permeability to macro-molecules. As the plasma-lymph barrier of the rabbit's hind leg is not permeable to high molecular weight PVP – unlike those of liver and kidney – PVP outflow from the blood vessels into the lymph can be used to measure the raised permeability of the vascular wall. In intact animals aescin is a potent suppressor of lymph flow, it reduces the number and/or diameter of the small pores in the capillary wall through which water and dissolved crystalloids emerge.
As the condition in healthy animals are not necessarily comparable with those existing in human disease, a patho-physiological model of increased capillary permeability was set up by infusing the plasma kinin bradykinin for 30 min by intra-arterial route to rabbits. This substances is known to produce an isolated rise in capillary permeability without causing any haemodynamic changes.

   
 
 
Fig. 9   Before bradykinin   During bradykinin   30 min after bradykinin
 
The effect of Reparil in suppressing the response to bradykinin, as measured by changes in lymph flow in the rabbit's hind leg (from VOGEL).
 

As shown in Fig. 9 an infusion of 100 ng/kg/min caused an approximate 200 % increase in lymph flow. After pre-treatment with aescin (0.3 mg/kg) the same dose of bradykinin produces an increase in lymph flow of only 80 %. With a larger dose of aescin (1.0 mg/kg) the increase in lymph flow is even less – only 35 %. Aescin has the capability of brining the increased permeability caused by bradykinin back to normal.
   
  The concerted action of aescin and DEAS:
   
 
The mechanism underline the action of Reparil N gel depends first on inhibition of the synthesis of inflammatory mediators (DEAS) and secondly on its effect on capillary permeability and on the action of the pain inducing inflammation mediator Bradykinin.
During the course of the inflammatory lesions, both post-traumatic and rheumatic, inflammatory mediators are released. Besides increasing capillary permeability, these are also responsible for stimulation of pain receptors. Because there is now an increase in the number and/or diameter of the pores in the capillaries, larger amounts of fluids escape into the tissues, and the outcome is local swelling or oedema. Stimulation of pain receptors explains why it is that we feel pain.
The oedema arising in this way tends to aggravate the inflammatory reaction, thus intensify the pathological reactions already in progress.
The vicious circle initiated by the injury can be broken by Reparil acting simultaneously at two different levels.

1. The action of DEAS depends on it's power to inhibit the synthesis of prostaglandin and other mediators of inflammation. In this way it suppresses the liberation of mediators and hence ameliorates all the signs and symptoms of inflammation such as swelling (oedema), pain, redness, heat and loss of function
The action of aescin commences one stage further on :

2. By a direct influence on the number and or diameter of the pores in the capillary wall, aescin exerts a capillary sealing action which diminished fluid outflow into the tissues and hence reduces oedema. In addition aescin blocks the pain inducing inflammatory mediators bradykinin, thus alleviating pain as well.
By using these two complementary mechanisms in conjunction it is therefore possible effectively to reduce local swelling and at the same time to alleviate pain and break the vicious circle of inflammation.