Therapeutic Essay - Retinopathy and OPC
When we see what appears in the pharmacological arsenal "vasculo-protectors," we hope to prevent or at least ease certain forms of exsudative retinopathies, hemorrhaging or ischemia of a particularly severe prognostic.
However, if the prescription of such substances in which there exists multiple specialized forms becomes more frequent if not habitual many of us will doubt the validity or the efficiency of these derivatives. It is therefore necessary to explain why certain medications donÕt live up to the hopes we have in them and how the progress of biochemistry permits us to discount the best results by putting in our reach the most active substances.
The Notion of "P" Factor - Its Nature
Old experiments have already confirmed that ascorbic acid alone is incapable of preventing or curing scurvy in a guinea pig. It can only be treated efficiently with the adjunct of vegetable substances belonging to the polyphenol group, i.e. Szent Gyorgyi citrine and what we call bioflavanoid or P factor vitamins.
Thus was brought to light a second anti-scurvy factor (the first being ascorbic acid) necessary, but insufficient because it was inactive due to the absence of the first factor, of curing or preventing scurvy.
The P factor has not yet been isolated with certainty. The chromatograms of etherophophate extracts from a normally nourished guinea pig liver shows us an always identical stain that is absent in the extracts from animals on deficient diets. The stain is connected to the flavones with 3 hydroxyl in 3.5 and 7 in which the last two were substituted.
We have, on the other hand, a multitude of profactors of vegetable origin and whose efficiency is variable. Here are the chemical classifications of these derivatives. These natural P factors were imperfect because they polymerized. This molecular condensation not only slows the inactivity of the product but also of the appearance of the antifactors due to inverse biological properties. It must also be said that by mistake we retained in this group the derivatives of the benzopyrone chemical family like Escoletaol. However, when the lateral cycle defaults there is no P type action.
We ultimately believed that by utilizing a purer and more stable derivative we could turn around the problem of polymerization. We therefore prepared the leucoanthocyan or hydroxyflavan 3-4 diol, neighbor components of catechine but in this application does not give complete satisfaction. The derivative monomer was unstable under normal conditions.
We demonstrated that active substances made up a molecular structure with two links that phytochemists call a procyanidol dimer.
It was noted that in this dimer the leucocyanidol only exists in a virtual state. It is found under the form of catechine. It is only through hydrolysis the flavane diol 3-4 comes to light.
Of course in vegetables we find these dimers side by side together with neighboring structures that we group together under the name flavanic oligomers. In effect, each link of these chains has a stereoisometric that is their own which creates a great diversity among natural products. We can say that each plant has therefore has its own personal identity if we refer to its flavanolic components.
The extraction of the total oligomer flavanoids from a vegetal is a great technological breakthrough when viewed in light of the imprecise information of the last few years. What's more, this progress has a direct effect on the therapeutic use of these components.
We are presently using the following advantages:
* Analytical procedures permit us to define in a satisfactory manner the diverse extracts obtained.
* The products thus prepared are more stable and better conserved than extracts obtained in the past.
This is because they only close up around those components in which the structure itself rejects polymerization, an essential cause of the older extracts.
* Finally, the molecular weight of these oligomers is in the optimal zone. It is heavy enough to increase the affinity of these substances vis-^-vis the proteins that show themselves to be superior to those of the flavones and the catechine monomers. It is low enough to in any case to avoid all risk of toxicity, especially catabolic hepatitis.
We now need to explain why these new derivatives can be active.
They act like the economizing factors of ascorbic acid with the secondary concret of the vascular walls. The oxide reduction process, the carrying of the SH ions, and the interference with hyaluronidase are conditioned by these substances which are more active than they are givers of hydrogen. It must be said again that these products come into competition with the catechol enzyme ortho-methyl-transferase (C.O.M.T.) in such a way that the catecholamines are less easily destroyed thus prolonging the vascular protecting activities.
To sum up, the fact that the stable, non spontaneously degradable products, active on the vascular walls at their junction level, explains the superiority of the stable flavanoids of the third generation.
Among these, the OPC grape extracts are easily metabolized. It was proven that that they affix themselves selectively in the tissues rich in glycosaminoglycanes by using the marked products.
Particular Problems of Opthalmology
A number of retinopathies manifest themselves through hemorrhaging and exsudation that cover most of the back of the eye. Their seriousness comes from the possible destruction of the macula. This zone which conditions the visual acuteness by the high density of cones that it contains (148,200/mm2) is altered as soon as the suffusions station themselves in a prolonged fashion, probably because they are constantly recreating themselves. The angiograph fluoresceinic has revealed the importance of exsudative and hemorrhaging leaks and the extension of the avascular zones. This ischemia caused by insufficient perfusion carries the waste away which are as important as those products coming from the flooding of neighboring tissues.
This is why we give an angiograph systematically before each treatment. The leaky zones and the edges of the hypoxide zones are photocoagulated by laser. Of course we exclude from this treatment all space interpapialo-macular because of the risk of definite scotoms. If things are executed correctly in the beginning there is nothing left to do but prescribe a continuous medical treatment and monitor its effects. This can be verified through biology and ophtalmological exams.
STUDY OF CONTROL OPHTALMOLOGICAL DISEASES
All of the patients (147) undergo a measure of visual acuteness, near or far, a Goldmann visual field, a static perimeter, a study of the chromatic sense of Farnsworth and a measure of dynamic visual acuteness. This exam, finalized in Bordeaux, objectifies itself by a level of mesopic visual acuteness and a numbered index at each level of acuteness. It is therefore easy to establish comparisons.
Finally, the electroretinogram and the visual potentials evoked are registered for each subject.
By these techniques we can evaluate the importance of the deficits, even infra-clinic which means unperceived by the patient and compare the eventual efficiency of a medication. A control by placebo can also be done. The product and the placebo are given following a directive unknown to the person handing them out. The exams take place each month with a month's interval separating each of the two products tested in order to foresee any interference of after-imaging.
We will detail the biological controls later on.
Diabetic Retinitis
As we have already said the average evolutionary form implicates the necessity of an opthamological surveillance every three months with fluoresceinic angiographs performed repeatedly. At these regular intervals, once weÕve established a leak, we perform a photocoagulation in order to prevent oedemas flooding.
We keep these photocoagulation that are aggravating very rapidly in the young subjects in order to try and save a little of the central vision. ItÕs only in the case of fulminante evolution that we advise the use of antehypophese under the control of micro surgical techniques and introduced via endonasal.
Thirty-seven patients previously brought into balance with the diet of sulfamides hypoglycemiants for 28, insulin for the other 9 were carriers of the average forms of diabetic retinopathy exsudative and symmetric hemorrhaging.
They showed all the venous dilations and a number of micro aneurysms. Every patient underwent laser photocoagulation on all the leakage zones and all the extrications non interpapillo-macular.
After an angiographic control we prescribed in a continuous fashion for a period of one year 2 pills (50 mg each) of OPC to those subjects aged between 22 and 70 years old.
Here are the following results:
* Out of 72 eyes (37 patients, 2 with one eye each) the visual acuteness was maintained in 52, improved in 16 and became aggravated in 4.
* Aggravation is the consequence of intravitrous hemorrhaging. These hemorrhages had a resolvent tendency but the final evolution was not observed.
* The peripheral visual field remained without modification. A concentration of central isopters was observed in four of the patients and three other patients because of the evolution of a crystalline opacity.
* From an anatomical point of view the micro-aneurysms remained the same number in 51 patient, decreased in 18 and were more numerous in 3.
* Retinal hemorrhaging is possible despite the treatment. In any case they appeared to us to be less frequent and less serious. Retinal hemorrhaging decreased in 38 eyes transforming into something discolored. In 25 eyes it stayed unchanged. Finally, 9 times they increased in number.
* On the contrary, the exsudations appeared less sensitive to the medication perhaps because of the number of hemorrhages that discolor and are subsequently ticketed as being under this term. This would explain their supplementary appearance 25 times, their modification 40 times and their regression 8 times.
* It appears then that this treatment merits the highest interest in association with photocoagulation. Given the extreme seriousness of the retinopathies, OPC appears to be the choice of the patients.
Venous Thrombosis of the Retina
Whatever the assembled factors (diabetes, hypertension, etc.) it appeared to us that the venous thrombosis, particularly those in the branches, get the greatest profit from a prolonged and continuous treatment. Of course the photocoagulation is necessary before all other extravasations. In any case, while the anticoagulant prescription is impossible because of the level of arterial tension OPC was given instead (2 or 3 pills) for at least a year. 12 patients carrying partial thrombosis to the end of the treatment recuperated visual acuteness between 3 and 8/10.
Retinopathies of Juhnius Kunht
The detachment exsudative and hemorrhaging in the eldery is serious. After temporal photocoagulation of the macula, the prescription is called for but the results are less pronounced. Out of 14 patients 2 noted a recuperation of 3/10, the others preserved their central scotom. However, the performance of those unscathed got better in a systematic fashion, the visual mesopic acuteness went up from 2 to 4/10. No other supplemental disorder appeared during these fourteen mounths.
Inflamed Retinitis
In the juxta-maculaire leaks in the young subjects where we can't photocoagulate because of their situation the results looked to us to be interesting as a maintenance treatment after cortico therapy. Out of 4 patients only one fell back after 8 months of treatment with 2 pills.
Retinal Degeneration
Prescribing OPC in a continuous fashion is perhaps indicated in the maculopathies of the Stargardt type. It is difficult to come to any conclusion even if nothing bad happened to the 5 patients after one year of treatment. It is the same for 3 pigmentary retinitis in which the visual field is unchanged.
Myopic Retinopathies
Exsudation in the immediate proximity of the macula is always something to fear. 31 myopics received on a regular basis for 11 to 14 months 2 daily pills. A preliminary photocoagulation on 8 out of the 31 at the level of the posterior pole. Not one maculopathy appeared. Dynamic visual acuteness and static perimetric went unchanged in 21 subjects. We observed one infra-clinical aggravation and 8 improvements. Given the extreme frequency of complicated myopia this therapy merits being systematically instituted.
Arterioscleroses Retinopathy
These dry lesions are extremely frequent. We see on the level of the posterior pole deep yellow nodules between the choroid and the retina. The evolution can be fearsome with the parietal ulceration being produced, the choroid fluids diffuse and injure the noble structures in a number of cases.
It was therefore appropriate to give an angiograph to all of the subjects who were carriers and to photocoagulate each case of transsudation. 41 patients who were treated were given OPC continuously for one year. No damage was observed either from an objective point of view or from the infra-clinic exams.
11 patients showed an improvement from the point of the static perimetric and 17 obtained a better visual acuteness mesopic.
The results confirm that which was obtained in the double blind test. The placebo never cured the dynamic visual acuteness while this was better or the same in 29 out of 30 cases.
To recapitulate, it is especially retinopathy ischemias that benefit from a prolonged treatment in eventual association with photocoagulation. The results are far from being negligible in exsudations and serious hemorrhaging.
COMPLIMENTARY BIOLOGICAL EXAMS
All the subjects underwent an objective study of their blood in order to control the eventual action of the treatment.
In 147 patients a study was done using a Hess viscometer: one measure of the conjunctival capillary resistance according to the Frezotti technique and one according to the Landis.
Viscosity Study
The Hess viscometer only gives relative results. 85 subjects experienced an improvement in viscosity, 59 had no change at all and 3 experienced aggravation. The other two methods appeared more reliable and more objective.
Study of the micro suction of the R.C.
This study was closely conducted using the Frezotti technique. The micro suction is a cylindrical glass tube with an outside diameter of 6mm. The end of the tube which is in contact with the ocular conjunctive has an enlarged outside diameter of 10mm in order to insure the proper adhesion without risking traumatizing the mucus and itÕs vessels. The inside diameter however is reduced (4.5mm as opposed to 6mm used in the Thomas model). The same for the contact surface (15.9mm2 as opposed to 28.32 as used by Thomas). This is done in order to avoid or limit the risks of scratching or ruining the conjunctive during the application of strong negative pressure. The other end is hermetically sealed by an optical device composed of an ocular lens with a plane surface allowing us to observe the conjunctive during the suction using a biomicroscope lens with a optic magnification of 10 and 16). This optical device allows us to pinpoint the initial appearance of minor hemorrhaging. On the lateral part is attached plastic tubing attached to a vacuum generator graduated in Hg cm. In order to avoid traumatisms to the conjunctive which can happen during a too rapid of a return to normal pressure we judged it necessary to install between the micro suction and the vacuum generator a three way regulator allowing an easy and progressive return to normal pressure. Thanks to these technical improvements we could therefore refine our observation, work in weaker negative pressure zones and limit the number of capillary ruptures that were directly linked to strong negative pressure. We eliminated the interference of mechanical or traumatic factors such that ischemia, the compression of the smaller venous vessels and tissue mechanical traumatisms.
The patient was seated in order to permit a correct observation using the microscope lens:
1. A local anesthetic was used, 0.4% Novesine.
2. The application of the micro suction, previously heated to a temperature of 37 degrees Celsius on the temporal zone of the conjunctive ocular.
3. Initial depression of 5 cm Hg maintained for one minute.
4. If we observe the appearance of any tiny hemorrhaging we move to Š10 cm Hg for one minute.
5. We increase the negative pressure in gradations of Š5 cm Hg each minute until we see the appearance of the first tiny hemorrhaging. This value determines the R.C.C. for the eye being studied.
6. The test is immediately run on the other eye, but applying this time an initial negative pressure lesser than Š5 cm Hg obtained during the first exam. We then increase the negative pressure by Š1 cm Hg each minute up until we observe the first tiny hemorrhaging.
By using this angiosterrometric method on presumably normal subjects we considered the number from Š30 to Š40 cm Hg as a normal value of R.C.C. which had previously been proposed by Gerard in 1961. The conjunctival capillary resistance is increased starting on the fourth day, the maximum being attained the third month. The global increase in the capillary resistance was observed in 111 patients. The results were insignificant or nil in 36.
Landis Test
It was in 1932 that Landis proposed his personal method for studying capillary permeability. We will see further on the precise modes of execution for this method but letÕs now look at the larger principles. By affixing a constricting link on an upper limb we hope to obtain an increase in the hydrostatic pressure in the capillaries and an increase in the venous pressure. The Starling balance, as well as we know it, is thrown off and we get the conditions of a water leak in the middle circulating towards the lacunar spaces et eventually a leak of proteins in the same sense. This must result in at the level of the compressed arm modifications in the composition of the blood, notably in the composition of the hematies and in the proteins. Starting with the study of these of these modifications, by 100 for the initial blood for the water leak and the protein leak determined by the compression. The optimum compression is 80mm Hg for 30 minutes. The water leak is calculated by measuring the comparative hematocrites in the blood of both arms. There have been a number of critics of this method. If done precisely this method can bring in very useful information on capillary permeability and whatÕs more allows us to enumerate the results.
Landis Test Techniques
Blood samples were taken between 7:30 and 8:30 in the morning. The patients were lying down and had been fasting since the night before. Starting Time Zero a pneumatic armband of the type Vaquez or Pachon was placed just above the elbow. The armband was inflated to 8 cm Hg and maintained in place for 30 minutes. This pressure of 8 cm Hg brings on an important water leak and allows us to decelerate the flow of proteins. This pressure of 8 cm Hg being less than the systolic arterial pressure in all of the examined patients it there cannot be used as a garrot on arterial flow. After 30 minutes of the arm being perfectly still we simultaneously take 5 ml of blood from each arm for protein dosage. In certain patients in which due to certain circumstances we canÕt take blood from both arms we take blood from the same arm with the first drawing taking place without the armband. Whenever possible blood was drawn without the garrot in order to avoid creating compression. However, in view of the difficulty in drawing blood from certain patients we had to put a garrot in place for a few seconds in order to see the vein. Immediately after drawing the blood the samples were taken to the laboratory and the hematocrites were evaluated after being in the centrifuge for three minutes. The first values were determined simultaneously by micromethod in the hematocrite tubes, which measured 10cm long by 4cm in diameter, which were put into the centrifuge for 30 minutes. The obtained results from these two methods were always superposable which led us to believe the only method to use was the micromethod proven to be more precise and quicker. The Landis test improved in 91 patients unchanged in 39 and aggravated in 7.
CONCLUSION
The importance of the seriousness of the depredations of the central retina legitimizes the use of medications objectively active on the various disorders observed. OPC, a perfectly defined substance non polymerisable represents a therapeutic trump in all the exsudations of a diabetic origin, arteriosclerosis, inflammation, degenerative and myopic accompanied by ischemia as seen in the systematic fluoresceinics. The laser treatment for coagulation leaks must be done previously. The study of the test using the Landis suction, objectively controlling the therapeutic action demonstrates the great value of this new medication.