US2965542A - Pharmaceutical product for reducing the proportion of cholesterol in the blood - Google Patents
Pharmaceutical product for reducing the proportion of cholesterol in the blood Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- the object of my invention is the manufacture of a medicine which will reduce the excess of lipides in the blood and especially to reduce the proportion of cholesterol.
- certain proteins, polypeptides, peptides, amino acids and certain more or less complex combinations of these substances have a clarifying power on the blood serum and a certain action on the lipide metabolism. This action is accompanied by favorable effects on the vascular troubles which almost always accompany lipemia. This action has been verified by many laboratory experiments and a great many clinical tests which have enabled me to determine the proper mode of application and effective doses of the medicine of which I have discovered the therapeutic value.
- the decreases recorded are of the order of 12 to 15% in normal subjects and attain clearly significant values of the order of in hyperlipedemic subjects. Subl stantial drops in the Kunkel test are often associated with these changes.
- protamine sulfate as an anti-cholesterol in accordance with present techniques is not advisable. In fact this substance can be administered only intravenously (the intramuscular method is painful and the substance is ineffective when administered orally).
- the protamine was accordingly fractioned by means of V a chromatographic process of separation derived from Zahns (Textilpraxis, 1951, page 127). This method permits the isolation of a certain number of hydrolyzation products, the clarifying effects of which on blood serum were studied in vitro.
- the remaining peptide is composed of 5 amino acids and represents an interesting stage in the search for an agent which is therapeutically useful for inducing hypocholesteremia.
- this molecule was still large enough to permit concern over the possibility ofanaphylactic accidents.
- this method of isolation led to a cost of production which results in a very expensive drug.
- the mixture secured by starting with the 5 amino acids is easy to produce in a consistent manner and may be utilized under proper toxicological control without danger. Moreover, its clarifying power permitted the hope that it was also endowed with an anticholesterol action.
- the procedure which I adopted consists in comparing a lot of :4 control animals subjected each day, like the test animals, to an intramuscular injection comprising only the solvents to the active product (isotonic chloride serum), to six animals subjected each day at the same time to an intramuscular injection of the pharmaceutical product contuated, after centrifuging, by decanting.
- the dose of the substance injected was calculated in proportion by weight to the dose used on men, that is to say, 1 ml. of a 2% solution per keg.
- the biological controls for the serum were eifectuated in the morning, a minimum of 12 hours after the withdrawal, at a fixed hour each evening, of the food remaining in the cage.
- the rabbits were killed and their aortas macroscopically and microscopically examined.
- the weights of the rabbits are given in grams and the percentages of cholesterol in grams per liter of blood serum.
- the average amount of cholesterol decreased from 4.32 g. before treatment to 2.51 g. after treatment, for a total drop of 1.81 g. and by percent a drop of 41.9%.
- the average percentage of cholesterol went from 3.58 g. before treatment to 2.14 g. after treatment, for a total decrease of 1.44 g. and by percentage an average drop of 40%.
- Example 1 As shown in col. 2, line 60, has thus far proven the most satisfactory from the point of view of perfect tolerance by the patients, and the most consistent effect on the lipide metabolism and on the difiiculties which accompany imbalances of this metabolism.
- EXAMPLE IV The fourth fraction having shown itself to be the most effective from the point of view of clarifying power in vitro, we then followed up by studying it in vivo, first on animals, and then on men.
- EXAMPLE V This formula is like that of Example 1, except that the glycine is omitted and the percentage of concentration of the amino mixture has been changed to 2%.
- EXAMPLE VI This formula is like that of Example 1, except that we eliminated the isoleucine and changed the concentration of amino acids in the solution to 2%.
- Series B comprised oral administration (per es) of ml. per day of a 10% solution of alanine, for 10 days.
- Example XI The formula of Example I has been used in combination with certain other therapeutic agents.
- Example I having shown itself to be effective when administered perlingually at the rate of 3 tablets of 100 mg. per day for three weeks, we utilized it in the same way in association with heparin. We have thus far only observed 6 patients treated by this method, and thus cannot state a final conclusion, but it may nevertheless be said that of these 6 patients, the treatment has already proven successful with 4.
- a new pharmaceutical product for reducing an excess of the lipides of the blood and especially for reducing the proportion of cholesterol therein which comprises a mixture containing at least 6% by weight of each of the following racemic amino acids: alanine, isoleucine, valine, serine and glycine.
- a new pharmaceutical product as claimed in claim 1 which comprises said amino acids in the following proportions by weight:
- a new pharmaceutical product for reducing an excess of the lipides of the blood and especially for reducing the proportion of cholesterol therein which comprises a mixture containing alanine, glycine, isoleucine, valine and serine as its only active ingredients, said alanine and serine each constituting at least 6% by weight of said active ingredients, and each of the remaining ingredients constituting at least 20% by weight of said active ingredients.
- the method of reducing the proportion of cholesterol in the blood of a human being which comprises the step of administering to said human being a mixture containing alanine, glycine, isoleucine, valine and serine as its only active ingredients, said alanine and serine each constituting at least 6% by weight of said active ingredients, and each of the remaining ingredients constituting at least 20% by weight of said active ingredients.
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Description
United States Patent PHARMACEUTICAL PRODUCT FOR REDUCING gilgQgROPORTION OF CHOLESTEROL IN THE Albert Castaigne, 40 Rue dAubuisson, Toulouse, Haute-Garonne, France No Drawing. Filed Feb. 12, 1958, Ser. No. 714,691
9 Claims. (Cl. 167----65) It is presently believed that the greater part of the arterial maladies which lead to such heart troubles as infarction of the myocardium, cerebral hemorrhages, and a number of other serious difficulties are due to an excess of lipides, and especially cholesterol, in the blood.
While a large number of laboratories and hospitals throughout the world have searched for medicaments capable of affecting the lipide metabolism of the blood, no product has been found which has shown a constant and certain effect. On the other hand, the dietary regimes imposed on such patients are also frequently without effect.
The object of my invention is the manufacture of a medicine which will reduce the excess of lipides in the blood and especially to reduce the proportion of cholesterol. I have established that certain proteins, polypeptides, peptides, amino acids and certain more or less complex combinations of these substances have a clarifying power on the blood serum and a certain action on the lipide metabolism. This action is accompanied by favorable effects on the vascular troubles which almost always accompany lipemia. This action has been verified by many laboratory experiments and a great many clinical tests which have enabled me to determine the proper mode of application and effective doses of the medicine of which I have discovered the therapeutic value.
The discovery that the effect of sulfate of protamine at relatively high concentrations (more than 2000 (l' =0.0O1 mg.) acting in vitro on the serum is an immediate opacification of the serum, presumably by fiocculation of a protein, followed by a secondary clarification brought about by redissolution of this flocculate has led me to study this secondary clarification more closely.
The singularity of this action which is neutralized in serum heated to 56 C., in aged serums and in jaundice serums, by retention, appears to be finally completed by a final slight but indisputable clarification of the fresh blood serum taken from individuals who have not recently eaten. This clarification appears the more clearly when the original serum was the more turbid, even lactescent.
It will be understood that this clarification indicates, with respect to the clarification by the lipase lipoprotein, only an optical analogy of regression of optical density,
lCC
limited but significant in fresh serums taken from dogs, men, and rabbits, continues progressively up to the fourth hour and is still present at the 24th hour.
It is associated with a constant decrease, even in normal subjects, in the total lipides and the total cholesterol, measured by the Grigault method, and of the esterified cholesterol after precipitation and elimination of the free cholesterol by digitonin according to Delsalles technique.
The decreases recorded are of the order of 12 to 15% in normal subjects and attain clearly significant values of the order of in hyperlipedemic subjects. Subl stantial drops in the Kunkel test are often associated with these changes.
The use of protamine sulfate as an anti-cholesterol in accordance with present techniques is not advisable. In fact this substance can be administered only intravenously (the intramuscular method is painful and the substance is ineffective when administered orally).
But the intravenous administration of protamine in the required doses may well provoke anaphylactic shocks, shocks which are the more serious because the anticholesterol medication is in principle designed for use against vascular disease.
It thus became necessary to determine whether the anticholesterol action of the protamine was the effect of the entire molecule of this substance or that of its components (amino acids or combination of amino acids). In the latter case it could be hoped that a more simple formula than that of protamine might be arrived at, which would not run the risk of anaphylactic accidents.
The protamine was accordingly fractioned by means of V a chromatographic process of separation derived from Zahns (Textilpraxis, 1951, page 127). This method permits the isolation of a certain number of hydrolyzation products, the clarifying effects of which on blood serum were studied in vitro.
and that it is in any case equivocal to equate this phenomenon to the clarification accomplished by the product sold under the name of Heparin, that is to say, by hydrolysis of the triglycerides, which has not yet been proven. It is, however, certain that this action produces a certain effect on the lipoproteins of the system, as this was revealed by substantial modifications of the lipidic electrophoresis (acceleration of migration of the lipoproteins) and perceptible decreases in Kunkels phenolic test.
These discoveries relating to the action in vitro of protamine sulfate have led me to study its action in vivo, a study which has enabled me to demonstrate the and its clarifying effect thereon.
.The hydrolyzation process following the chromatographic separation, repeated several times, showed that a certain fraction of protarnine, always the same, is endowed with the clarifying power of the entire molecule.
The chromatographic study of this fraction after a more extended hydrolyzation revealed that it is composed of alanine, valine, glycine, serine, and isoleucine. The arginine and proline of the protamine have thus been eliminated and the molecule is much smaller than that of the protamine, since the arginine represents the greater part of the molecular weight of this substance.
The remaining peptide is composed of 5 amino acids and represents an interesting stage in the search for an agent which is therapeutically useful for inducing hypocholesteremia. However, this molecule was still large enough to permit concern over the possibility ofanaphylactic accidents. Moreover, this method of isolation led to a cost of production which results in a very expensive drug. Finally, there was no assurance that the substance prepared would always be exactly the same.
I have accordingly carried out not only the qualitative but also the quantitative analysis of this amino complex.
Several tests showed the following composition:
I then reconstituted this formula by the simple mixture of these racemic amino acids in these same proportions and studied comparatively the clarifying effect of protamine, the amino complex obtained by hydrolysis of the amino mixture which reproduces its formula, and separately, the 5 amino acids.
I determined that the protamine, the amino complex, and the amino mixture, were all three endowed with the same clarifying power, which was superior to that of the 5 amino acids taken separately.
The mixture secured by starting with the 5 amino acids is easy to produce in a consistent manner and may be utilized under proper toxicological control without danger. Moreover, its clarifying power permitted the hope that it was also endowed with an anticholesterol action.
I first tested on rabbits the pharmaceutical product having the foregoing formula.
As in the previous experiments in which an excess of cholesterol was induced in rabbits by a diet rich in cholesterol (experiments which have been carried out on a large scale in English speaking countries) which are facilitated by the feeble resistance of this animal to exogenous cholesterol, I adopted the substantial-1y conventional technique consisting of adding 1% of cholesterol which has been dissolved in ether and distributed as homogeneously as possible through a food base which is composed of agglomerated vegetable tablets. The animals all had the same heredity. They were all male and were all of substantially the same age and weight. The procedure which I adopted consists in comparing a lot of :4 control animals subjected each day, like the test animals, to an intramuscular injection comprising only the solvents to the active product (isotonic chloride serum), to six animals subjected each day at the same time to an intramuscular injection of the pharmaceutical product contuated, after centrifuging, by decanting.
Such interfering factors as the conditions of light, temperature, order of feeding and beverages were standardized, as far as possible by mixing the treated and control animals indiscriminately when they were distributed into 5 their cages, their order of selection not depending on their number.
The dose of the substance injected was calculated in proportion by weight to the dose used on men, that is to say, 1 ml. of a 2% solution per keg.
10 The biological controls for the serum were eifectuated in the morning, a minimum of 12 hours after the withdrawal, at a fixed hour each evening, of the food remaining in the cage.
The biological controls were effectuated by:
(1) Direct estimate of the lactescence of the serum placed on a photographic film which had not yet been developed;
(2) Through the total proportion of cholesterol, following Grigaults technique;
(3) Through the total proportion of proteins;
(4) By Kunkels test.
In order to check the accuracy of my results I have made duplicate sets of tests on two groups of ten rabbits.
At the end of the tests the rabbits were killed and their aortas macroscopically and microscopically examined.
The results are shown in the following table:
CONTROL RABBITS Weight Choles- Weight Choles- Weight Oholes- Weight Choles- (grams) terol (grams) terol (grams) terol (grams) terol 1st week 2, 400 0. 33 2,600 0. 4O 2, 500 0.35 2, 600 0. 60 2nd week". 2, 800 0. 50 2, 800 0.60 2,500 0.50 2, 950 0.90 4th Week 2, 900 8. 50 2, 850 2.00 2, 400 4. 25 3, 100 8. 30 6th Week..- 2, 900 8. 00 2, 950 9. 50 2,500 9. 00 3, 100 8. 50 8th week- 3,000 7.00 3,100 9.50 2, 800 11.00 3, 300 9. 00 10th week- 3, 400 7. 30 3, 350 8.50 3, 000 11.00 3, 700 8.00 12th week 3, 400 10. 60 3, 150 11. 2, 950 16, 60 3, 650 8. 40 14th week 3,230 14.40 3,220 17. 3, 200 22 00 2, 730 11.80 16th week 3,350 26.00 3, 550 23. 20 3, 900 20.00 18th week 3,300 22.00 3, 500 20 00 4,000 16.00
Anti-ather-omatous eflect.
1 The rabbits were not left without food and drink.
stituting my invention, in the same volume of the aforesaid solvent.
I subjected all of the animals, each kept in its individual cage, to the same regime of excess cholesterol for a period of 18 weeks.
In the foregoing and in each of the following summaries of the results of tests, the weights of the rabbits are given in grams and the percentages of cholesterol in grams per liter of blood serum.
TEST RABBITS Weight Choles- Weight Choles- Weight Oholes- Weight Oholes- Weight Choles- Weight Cholesterol terol terol terol terol terol 1st week. 2, 400 0. 40 2, 330 0.35 1, 500 0. 50 2, 400 0. 40 2, 400 0 35 2, 650 0.35 2nd Week- 2, 400 0.45 2, 550 0. 35 2, 050 0. 55 2, 450 0.50 2, 100 0. 50 2, 600 0.55 4th week 2, 550 5. 80 2, 550 12. 10 2, 450 12.30 2, 750 3. 75 2, 250 1. 25 3, 150 3. 12 6th Week 1 2, 600 6. 2,700 15.00 2, 600 11. 00 3, 000 2.00 2,600 1. 50 3, 300 4. 50 8th week 2,700 5. 00 3, 150 15. 00 2, 750 14. 80 3, 250 1. 80 2,750 1. 50 3, 300 4. 50 10th Week. 3,100 5. 50 3, 400 16 40 3,150 12.00 3, 600 2. 3,250 1.80 3, 900 1. 12th Week... 3, 5. 70 3, 400 16 40 3, 150 18. 60 3, 550 4. 00 3, 400 2. 80 3, 900 5.80 14th week-.- 3,270 6. 00 3,630 30 00 3. 25.00 3, 700 6. 00 320 3. 20 3,970 6.00 16th Week 3,400 6. 00 3,800 34 00 3,250 25.00 3, 700 8.00 3,450 5.00 3, 980 9. 50 18th week 3, 450 6. 00 3,800 28 00 3, 300 18.00 3,750 5.00 3,500 5. 00 4,000 9. 60
Anti-Atheromatous efiect.
'lihe rabbits were not left without food and drink.
The value of these results appeared to me to be highly significant by reason of the average and the frequency of the results obtained as well as the eliminating of interfering factors.
The animals increased steadily in weight and the results showed no significant diiferences therein between the two lots.
I have since repeated this experiment on a number of lots of rabbits and the results hereinbefore described were again confirmed.
On the other hand, I have also carried out clinical tests on many patients. The results obtained by subjecting 15 patients to intravenous injections of 5 cc. of a 2% solution of the product constituting my invention are shown in the following table.
HUMAN CLINICAL TESTS Cholesterol Percent Decrease Number of Days Numbers of Injections Before, g. After, g. Total, g. Percent In another group of clinical tests on 38 patients treated intravenously with an average of 5 to 6 injections of 2% strength, the results were as follows:
The average amount of cholesterol decreased from 4.32 g. before treatment to 2.51 g. after treatment, for a total drop of 1.81 g. and by percent a drop of 41.9%. In another group of patients treated orally the average percentage of cholesterol went from 3.58 g. before treatment to 2.14 g. after treatment, for a total decrease of 1.44 g. and by percentage an average drop of 40%.
- I have, moreover, been able to follow for more than 6 months the progress of a number of patients who have undergone the treatment which has just been described. This has enabled me to make the following observations:
(1) In certain patients in which the percentage of cholesterol had been brought down to nearly normal figures this percentage remained normal several months after the termination of the treatment.
(2) In other patients this percentage rose gradually, at about .20 g. per month.
(3) In still other patients the percentage of cholesterol returned rapidly to its original figure (in between 1 and 2 months).
(4) When such an increase occurred, the percentage of cholesterol remained responsive to this treatment and could be controlled by the periodic oral administration of the medicament constituting my invention.
The formula of Example 1, as shown in col. 2, line 60, has thus far proven the most satisfactory from the point of view of perfect tolerance by the patients, and the most consistent effect on the lipide metabolism and on the difiiculties which accompany imbalances of this metabolism.
To arrive at this choice it has been necessary to compare the action of the formula of Example 1 to that of other formulas, and we have consequently carried out a long series of tests, several examples of which are given below:
6 EXAMPLE II t 1 solution of protamine (salmine) in physiological serum This solution has shown itself to be effective both in vitro and in vivo. In vitro, it brings about the clarification of hyperlipemic serums. In vivo, in the cases of 25 hyperlipemic patients treated by intravenous injections of 10 ml. per day of this solution, for from 4 to 7 days, we obtained in of the cases, very substantial decreases in the percentages of cholesterol, of total lipides, and of Kunkels phenolic test.
We have, however, abandoned the intramuscular method of administration because it is painful and less effective.
EXAMPLE III Hydrolysate of sa lmine After having hydrolyzed salmine by heat, in the presence of hydrochloric acid, and after having eliminated the hydrochloric acid, we experimented with the hydrolysate obtained, in a concentration corresponding to 1% of salmine in physiological serum.
The following results were obtained: In vitro, there was a clarification of hyperlipemic serums. In vivo, of 10 hyperlipemic patients treated by intravenous injection of 10 ml. per day for 6 days, we obtained in 8 cases substantial decreases in the percentages of cholesterol, of total lipides, and of Kunkels phenolic test.
We studied the different fractions of salmine obtained by acid hydrolysis followed by chromatographic separation, that is to say, hydrolyzed by HCl, 2N at C., for 3 hours, followed by separation of the fractions obtained by passage through a column of Dowex 50 to separate the arginine and the peptides from the neutral amino acids and their peptides.
By again chromatographing these fractions on a column of cellulose we obtained four fractions, the clarifying power of which we first studied in vitro.
EXAMPLE IV The fourth fraction having shown itself to be the most effective from the point of view of clarifying power in vitro, we then followed up by studying it in vivo, first on animals, and then on men.
Among 10 hyperlipemic patients treated for 6 days with daily injections of 10 ml. of a 1% solution of this fraction, 9 were very clearly successful. These treatments could be made by intramuscular injections, which were practically painless.
The formula of this fourth fraction is essentially the same as that of Example -1. It nevertheless involves a difierent substance, since some of the amino acids are still combined with each other in the form of peptides.
Having once obtained and tested the formula of Exampic I, as already given, we proceeded with tests on the mixtures obtained, by varying the proportions of the respective amino acids, and by eliminating some of them.
EXAMPLE V This formula is like that of Example 1, except that the glycine is omitted and the percentage of concentration of the amino mixture has been changed to 2%.
This formula has given satisfactory results in vivo. In 12 hyperlipemic patients a series of 5 intramuscular injections at the rate of one a day has in six cases resulted in decreases in the percentages of cholesterol, of total lipides, and of Kunkels test. But these decreases have been proportionally less frequent and less substantial than when the formula of Example I was used. Moreover, it seemed to us that the effect on the subjective symptoms was less clear.
EXAMPLE VI This formula is like that of Example 1, except that we eliminated the isoleucine and changed the concentration of amino acids in the solution to 2%.
7 When tested on 10 patients this new formula showed itself to be eflicacious, as in the case of Example V, but less so than the formula of Example I.
EXAMPLE VII The results of tests carried out in vitro led us to think that, in the formula of Example I, the alanine was the most effective constituent. We therefore proceeded with two series of tests using this amino acid alone.
Series A consisted of intramuscular injections of 5 ml. of a 5% solution.
Series B comprised oral administration (per es) of ml. per day of a 10% solution of alanine, for 10 days.
These tests were made on patients by intramuscular injection and 18 by oral administration.
The results obtained by intramuscular injection were often brilliant, but less consistent than with the formula of Example 1. Only 5 clearly favorable results were secured in 15 cases.
The results obtained by oral administration were almost as consistent and clear as with the formula of Example I administered in the same manner. Out of 18 cases, we secured very favorable results in 12, but these were not accompanied by subjective improvements as consistently as with the formula of Example I.
EXAMPLE VIII We tried on 6 patients a formula identical to that of Example I from the point of view of composition by weight, but replaced the racemic amino acids with the same levo'gyric amino acids.
The results obtained were clearly not as good and some patients, moreover, were weakened by the treatment.
EXAMPLE IX For the same reasons it was necessary to abandon the opposite formula, that is to say, a formula identical to that of Example I, but composed of dextrogyric amino acids.
EXAMPLE X We began with a hydrolysate of casein, from which we eliminated all but the neutral amino acids or their peptides. We thus obtained a formula very close to that of fraction 4 of the hydrolysate of p-rotamine.
This formula, when intravenously administered to animals resultedin shocks. Consequently, it was administered to men-only in'an oral manner, at the rate of .50 gram per day in a 2% solution, for 15 days. A significant proportion of very good results was obtained.
EXAMPLE XI The formula of Example I has been used in combination with certain other therapeutic agents.
The formula of Example I having shown itself to be effective when administered perlingually at the rate of 3 tablets of 100 mg. per day for three weeks, we utilized it in the same way in association with heparin. We have thus far only observed 6 patients treated by this method, and thus cannot state a final conclusion, but it may nevertheless be said that of these 6 patients, the treatment has already proven successful with 4.
What I claim is:
1. A new pharmaceutical product for reducing an excess of the lipides of the blood and especially for reducing the proportion of cholesterol therein, which comprises a mixture containing at least 6% by weight of each of the following racemic amino acids: alanine, isoleucine, valine, serine and glycine.
2. A new pharmaceutical product as claimed in claim 1 which comprises said amino acids in the following proportions by weight:
Percent Alanine 6.7 Glycine 22.0 Isoleucine 29.0 Valine 34.6 Serine 7.7
Percent Alanine 6.7 Glycine 22.0 Isoleucine 29.0 Valine 34.6 Serine 7.7
5. The method claimed in claim 4 in which said mixture is administered by intravenously injecting at least the amount thereof contained in 25-30 cc. of a 2% strength solution in physiological serum, said amount being divided into a plurality of doses administered over a period of days.
6. The method claimed in claim 3 in which a total of at least 6 grams of said mixture is administered orally in a plurality of doses at the rate of less than 1 gram per day.
7. The method claimed in claim 3 in which at least the amount contained in ml. of a 1% solution of said mixture is administered by intramuscular injection in a plurality of doses spread over a period of days.
8. A new pharmaceutical product for reducing an excess of the lipides of the blood and especially for reducing the proportion of cholesterol therein which comprises a mixture containing alanine, glycine, isoleucine, valine and serine as its only active ingredients, said alanine and serine each constituting at least 6% by weight of said active ingredients, and each of the remaining ingredients constituting at least 20% by weight of said active ingredients.
9. The method of reducing the proportion of cholesterol in the blood of a human being which comprises the step of administering to said human being a mixture containing alanine, glycine, isoleucine, valine and serine as its only active ingredients, said alanine and serine each constituting at least 6% by weight of said active ingredients, and each of the remaining ingredients constituting at least 20% by weight of said active ingredients.
References Cited in the file of this patent Frost: Chem. Products, 15:1, January 1952, pp. 6-12.
Landat: Arch. int. PharmacodyL, 1956, CVIII, No. 2, pp. 192-199.
Comptes Rendus, Soc. de Biol. (Fr.), vol. 148, 1954, pp. 1961-1963.
Comptes Rendus, Soc. de Biol. (FL), vol. 149, 1955, pp. 648-651.
J. Biol. Chem, vol. 191, 1951, pp. 233-238.
Handbook of Biological Data, 1956, pp. 50, 52, 60. W. B. Saunders Co., Phila., Pa.
Claims (1)
1. A NEW PHARMACEUTICAL PRODUCT FOR REDUCING AN EXCESS OF THE LIPIDES OF THE BLOOD AND ESPECIALLY FOR REDUCING THE PROPORTION OF CHOLESTEROL THEREIN, WHICH COMPRISES A MIXTURE CONTAINING AT LEAST 6% BY WEIGHT OF EACH OF THE FOLLOWING RACEMIC AMINO ACIDS: ALANINE, ISOLEUCINE, VALINE, SERINE AND GLYCINE.
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3182064A (en) * | 1961-05-24 | 1965-05-04 | Us Vitamin Pharm Corp | alpha-[2-(4-pyridyl)ethyl]aminopropionic acid derivatives |
US3412190A (en) * | 1968-01-11 | 1968-11-19 | Enzomedic Lab Inc | Lowering blood lipids and treating rheumatoid arthritis with diphosphopyridine nucleotide |
US3532742A (en) * | 1963-09-26 | 1970-10-06 | Mead Johnson & Co | Octalone carboxylic acids and their derivatives |
WO1988001872A1 (en) * | 1986-09-10 | 1988-03-24 | Dudrick Medical Research Fund I, Ltd. | Method and substrate composition for treating atherosclerosis |
WO1991007188A1 (en) * | 1989-11-22 | 1991-05-30 | Adrian Barbul | Method for reducing blood cholesterol using arginine |
US5032608A (en) * | 1986-09-10 | 1991-07-16 | Dudrick Stanley J | Method and substrate composition for treating atherosclerosis |
US5248688A (en) * | 1986-09-10 | 1993-09-28 | Dudrick Medical Research Fund I, Ltd. | Method and substrate composition for treating atherosclerosis |
-
1958
- 1958-02-12 US US714691A patent/US2965542A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3182064A (en) * | 1961-05-24 | 1965-05-04 | Us Vitamin Pharm Corp | alpha-[2-(4-pyridyl)ethyl]aminopropionic acid derivatives |
US3532742A (en) * | 1963-09-26 | 1970-10-06 | Mead Johnson & Co | Octalone carboxylic acids and their derivatives |
US3412190A (en) * | 1968-01-11 | 1968-11-19 | Enzomedic Lab Inc | Lowering blood lipids and treating rheumatoid arthritis with diphosphopyridine nucleotide |
WO1988001872A1 (en) * | 1986-09-10 | 1988-03-24 | Dudrick Medical Research Fund I, Ltd. | Method and substrate composition for treating atherosclerosis |
US5032608A (en) * | 1986-09-10 | 1991-07-16 | Dudrick Stanley J | Method and substrate composition for treating atherosclerosis |
US5248688A (en) * | 1986-09-10 | 1993-09-28 | Dudrick Medical Research Fund I, Ltd. | Method and substrate composition for treating atherosclerosis |
WO1991007188A1 (en) * | 1989-11-22 | 1991-05-30 | Adrian Barbul | Method for reducing blood cholesterol using arginine |
US5157022A (en) * | 1989-11-22 | 1992-10-20 | Adrian Barbul | Method for reducing blood cholesterol using arginine |
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