CA1340246C - Use of pyridoxine derivatives in the prevention and treatment of hyperlipidaemia and athersclerosis - Google Patents
Use of pyridoxine derivatives in the prevention and treatment of hyperlipidaemia and athersclerosisInfo
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- CA1340246C CA1340246C CA000559285A CA559285A CA1340246C CA 1340246 C CA1340246 C CA 1340246C CA 000559285 A CA000559285 A CA 000559285A CA 559285 A CA559285 A CA 559285A CA 1340246 C CA1340246 C CA 1340246C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
A description is given of the use of pyridoxine derivatives and salts thereof, more particularly pyridoxal, pyridoxal phosphate, pyridoxamine and pyridoxamine phosphate, in the prevention and treatment of hyperlipidaemia and atherosclerosis. This excludes pyridoxine-5'-phosphoric acid ester glutamate and aspartate which are described in DE
24 61 742 C2. The resulting substances are natural, well tolerated, with a clearly defined chemical composition, sufficiently stable, and effective in long-term treatment.
The buccal application form and the form resistant to gastric juice are especially advantageous.
24 61 742 C2. The resulting substances are natural, well tolerated, with a clearly defined chemical composition, sufficiently stable, and effective in long-term treatment.
The buccal application form and the form resistant to gastric juice are especially advantageous.
Description
13~02~
Use of Pyridoxine Derivatives in the Prevention and Treatment of Hyperlipidaemia and Atherosclerosis Description The invention relates to the use of pyridoxine derivatives in the prevention and treatment of hyperlidpidaemia and atherosclerosis. This does not include pyridoxine-5'-phosporic acid ester glutamate and aspartate, which are described in DE 24 61 742 C2.
Athersclerosis is one of the most frequent diseases and causes of death (atherosclerosis of the coronaries) in industrialised countries. Atherosclerosis is usually a slow process comprising complex changes in the structure and function of blood vessels and ending in clearly visible clinical diseases such as angina pectoria and cardiac infract through constriction and blockage of coronary vessels, reduced perfusion of the extremities, or brain infarct. The dramatic final stage of the disease is often preceded by long years of severe discomfort and chronic illness. The possibilities of treatment in the advanced stage are very limited, expensive and invasive, e.g. the open-heart operation or amputation of extremeties.
Apart from relatively rare cases of severe hereditary metabolic disturbances, atherosclerosis is to a large extent a disease of civilisation. The risk of atherosclerosis is increased particularly by smoking (nicotine). Other risk factors are e.g. high blood pressure, insufficient physical activity, diabetes mellitus and renal insufficiency. A critically important step in the prevention of atherosclerosis was the recognition of the connection between high blood lipid .-,, .~., concentration and increased rlsk of atheroscle ~ S31S
including increased risk of death through cardiac infarct (compare Dayton, S., Chapman J., Pearce M., Popiak G., Cholesterol, atherosclerosis, ischaemic heart disease, and stroke, Am. J. Med. 72, 97 (1970).
Cholesterol-rich food and a high content of animal fat (saturated fatty acids ) in food produce an undesirable increase in the content of lipoproteins in the blood, resulting in accelerated development of atherosclerotic lesions.
Since cholesterol is the main substance found in atheromatous plaques, a connection between an elevated cholesterol level and atherosclerosis appears certain.
Lipids, which are insoluble in water, are conveyed in the blood by lipoproteins. A distinction is made between LDL (low-density lipoproteins) and HDL (high-density lipoproteins). LDL-cholesterol is of critical importance in atherogenesis. HDL-cholesterol, on the other hand, conveys excess cholesterol from the periphery back to the liver.
Its effects, if anything, is protective.
Consequently, the accumulation of cholesterol in the median cells of the atherial walls depends not only on the total concentration of cholesterol in the serum but also on the ratio of LDL to HDL.
Elevated blood lipid concentrations, more particularly elevated LDL concentrations in the blood, increase the deposition of lipids in the arterial walls, which in turn initiates or at any rate intensifies other atherosclerotic changes.
13~02~6 The aim of prevention of atherosclerosis, therefore, has increasingly been to reduce the blood lipid concentrations in general and the LDL cholesterol concentrations in particular.
This aim can be achieved in various ways:
Some cholesterol and saturated fatty acids (likewise undesirable) are supplied in food. Consequently a diet containing little cholesterol or animal fats is the first condition for successful treatment or prevention of atheroschlerosis.
However, keeping to a diet is often difficult and also insufficient. The reason is that atherogenic lipids are not only ingested in food but also formed in the body. In order to reduce the conentration of endogenic lipids in the blood, also, or at least to reduce their atherogenic effect, a large number of drugs have been developed or recommended for this purpose during the last 20 years.
A simple and relatively harmless method of lowering the cholesterol concentration in the blood is to start with the elimination mechanism thereof. In the liver, cholesterol is converted into bile acids, in which form it enters the intestine. Bile acids are largely reabsorbed and re-used.
This enterohepatic circulation can be interrupted if bile acids are retained in the intestine by non-absorbable substances.
Examples of such substances are solid ion-exchangers, certain swelling agents such as guar, and also normal constituents of food such as fibrous materials. These cause the liver to covert more cholesterol into bile acids, thus .._._. ,~
- ~4~ n 2 eliminating it more quickly. A disadvantage of this method of treatment ist the extremely high dosage of the preparations in question (8 - 24 g/day) and the inconvenience of taking them.
A number of systematically acting "lipid-lowering agents"
have also been introduced into treatment, e.g. derivatives of clofibric acid, which inhibit the synthesis of cholesterol in the liver. Owing to the serious side-effects and the required duration of treatment clofibrates are used only for severe disturbances in lipid metabolism (compare Scheffler W. and Schwartzkopff, W., Frequently used lipid-lowering drugs have no guaranteed effect. Artery 8, 120 -127 1980)).
However, other synthetic or even natural drugs (nicotinic acid derivatives) sometimes cause unacceptable side-effects, or the dosage has to be so high, particularly in the case of long-term treatment of elderly patients or with kidney of liver disease, that they place an unacceptable burden on metabelism.
Some derivatives of pyridoxine phosphate are described in DE 24 61 742 C2 as lipid-lowering and anti-atherosclerotic active principles. These substances are pyridoxine-5'- phosphoric acid ester glutamate and asparates. Their effect is attributed to the combination of pyridoxine phosphate and glutamic acid or aspartic acid. In spite of their undoubted efficiency, the known substances also have appreciable disadvantages. They are not strictly natural remedies, their chemistry is ill-defined, their stability is questionable, even when very small quantities of moisture are added, and non-existent in vivo, e.g. during ~5~ 1 3 ~ 2 ib absorption, and the doses have to be relatively high. As a resulut of their instability, the active principles listed in DE 24 61 742 C2 also cannot be administered in the form of infusions or ampoules for drinking or solutions of other kinds. However, ingestion in liquid form is particularly convenient, particularly for patients who are usually elderly.
Under unfavorable conditions, individual constituents of the substances described in DE 24 61 742 C2 may even have an unfavourable effect on treatment of the patients.
Since therefore the patients are usually elderly, suffer from a number of diseases and often have to take lipid-lowering drugs as long as they live, it is desirable to have a natural well-tolerated drug to be taken in low doses. The drug also needs to have a well-defined chemical composition, to be resistant to external influences and to be substantially unchanged and completely resorbable after oral administrations. The drug should alter the metabolic situation in a manner which, other things being equal, results in reduced deposition of lipids in the arterial wall and thus delays, interrupts or even reverses atherosclerotic changes.
The object of the invention therefore is to provide a novel means for prevention and treatment of hyperlipidaemia and atherosclerosis and having the aforementioned properties. The substance should also be of use for treating persons who have high blood lipid concentrations even when on a diet.
During the search for a suitable active principle it was found that certain derivatives of pyridoxine, more ~,, 13~02~6 particularly pyridoxal, pyridoxal phosphate, pyridoxamine and pyridoxamine phosphate and precursors and their metabolites, unexpectedly have an aforementioned lipig-lowering, anti-atherosclerotic activity. This was explicitly queried in DE 24 61 742 C2 (column 3, lines 35 ff). On the other hand pyridoxine, often also called vitamin B6, does not have any strong action in this respect.
Pyridoxine was used separately in earlier experiments on animals in conjunction with lipid metabolism (see Frolova, J.A.: Vitamin B6 and lipid metabolism; Vorpr.med.Khim. 89, 18. 339 346 (1972)). Its effect, however, is weak. In our experiments, pyridoxine in rats was ineffective at a dose of 79 mg/kg body weight, although a positive control showed the expected effect in the same experiment.
Various pyridoxine derivatives occur in metabolism and to some extent are convertible into one another. These, in addition to pyridoxine itself, include e.g. pyridoxamine, pyridoxal, pyridoxal phosphate and pyridoxic acid. It is generally recognized that the pool of pyridoxal and derviatives thereof is correspondingly increased by oral administration of pyridoxine.
It has now surprisingly been found that oral administration of certain pyridoxine derivatives, more particularly pyridoxal phosphate, pyridoxal, pyridoxamine phosphate and pyridoxamine or precursors thereof, results in a marked reduction in serum lipids, particularly LDL cholesterol, which has such a disastrous effect on atherogenesis.
Another effect, apparently independent of the reduction of serum lipids, is the reduced deposition of lipids in the arterial walls. Both actions guarantee preventive and therapeutic treatment of atherosclerosis which is effective . . . , ~ ~ ~ .
_7_ 13~2~
and, on present knowledge, attacks the causes. The treatment is all the more valuable in that it is not offset by any recognizable side-effects. The toxicity of the aforementioned vitamin B6 derivatives is extremely low, and they are therefore extremely well tolerated at the doses used for human treatment. More particularly, there is no toxic effect on the liver, in contrast to most other lipid-lowering agents, which cause a marked increase in the liver weight of experimental animals after only a short period of treatment.
In addition to the mentioned pyridoxine derivatives occurring in metabolism, also useful in this invention are derivatives having -CH2NRIRII in the 4-position, wherein RI and RII independently are H, lower alkyl, lower alkenyl, hydroxy or hydroxy(lower)alkyl, where lower means up to about 6 C-atoms, e.g., the mentioned pyridoxamine compounds where the amino group is substituted by RI/RII. Such compounds can be prepared by conventional amino substitution reactions.
~ Also useful are compounds preparable by conventional reactions between pyridoxal compounds and amino acids or primary amines, e.g., ~C~ 'j\c~ 2 X0-CH2 ~~ H2NR2 ~> X0CH2 ~ 0H
N CH3'~~N ~ CH3 X=H, (OH)20P
wherein R1 is H, lower alkyl, lower alkenyl, hydroxy or -- ~ ~ v ,r' ~, -8- 13~2~6 hydroxy(lower)alkyl, wherein lower means up to about 6 C-atoms, and R2 is (a) an Rl group (amines), /R
(b) -CH~ (amino acids) (CH2 ) n-COOH
n = 0-6, ~ ( CH2 ) n-COOH
(c) -CH (monoaminodicarboxylic acids) COOH
n ~ 0-6 ~e.g., aspartic or glutamic acids), or ( CH2 ) n-NH2 (d) -CH ~ (diaminomonocarboxylic acids) COOH
n = 0-6.
As mentioned above, any compound which is metabolized to produce one of the foregoing compounds of this invention can also be used. Such compounds, for example, have substituents which are removed upon metabolization. In this sense, some of the foregoing compounds are precursors and/or metabolites of others.
For example, in the course of metabolism in the human body pyridoxine is oxidized to pyridoxal, which is enzymatically (pyridoxalkinase) converted to pyridoxal-5-phosphate:
pyridoxal + ATP - pyridoxal-5-phosphate + ADP
Useful salts of the compounds of this invention are the usual pharmaceutically acceptable salts, e.g, acid addition salts and are conventionally prepared from conventionally employed acids. Such acids include, for example, inorganic acids, e.g. hydrochloric acid, nitric t, ~
-9- 134~246 acid, phosphoric acld, sulfuric acid, hydrobromic acld, hydriodic acid, nitrous acid or phosphorous acid, or organic acids, such as, for example, aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids, or alkenedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids.
Physiologically acceptable salts of these acids are, therefore, e.g., the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene-sulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ~-hydroxybutyrate, glycolate, malate, tartate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate or napthalene-2-sulfonate.
The newly discovered efficacy of the aforementioned pyridoxine derviatives is all the more surprising in that these compounds, which have a simple structure, were thought to have a low activity and it was expected to obtain effective drugs only by very complex molecules derived from pyridoxal phosphate as described e.g. in the cited DE 24 61 742 C2.
The main substances for clinical use according to the invention are the four aforementioned pyridoxine derivates -lO- 13~0~46 (pyridoxal, pyridoxamine, pyridoxal phosphate and pyridoxamine phosphate) and suitable mixtures thereof. Of course, all other substances are suitable which liberate the aforementioned pyridoxine derivatives in vitro or more particularly in vivo. The pyridoxine derivatives may also be used in conjunction with other measures for stabilizing lipid metabolism (e.g. diet) or treatment (e.g. bile acid adsorbing agents). A preferred combination is with lipid-lowering agents which act on metabolism at a different point from the aforementioned pyridoxine derivatives.
Combinations with drugs for treatment of diseases frequently accompanying atherosclerosis (high blood pressure, diabetes, etc.) may also be advantageous. Since the aforementioned pyridoxine or vitamin B6 derivatives are very well tolerated, they are particularly suitable for patients with numerous underlying or accompanying diseases.
On the other hand pyridoxine itself, which is preferably used under the name of vitamin B6, is not suitable.
In practice, treatment is preferably by oral administration of the active principles for a prolonged period. A maximum effect is not expected before two months or longer treatment. Treatment must be continuous, since if the preparations are discontinued the resulut is a very rapid decrease in the effect, an increase in serum lipids and a worsening of atherosclerosis.
In exceptional cases the active principles used according to the invention may also be administered parenterally, e.g. by intravenous infusion of the aqueous solutions or intramuscular injection thereof.
, ..
-11- 13 ~ 6 In oral therapy the daily amount is administered either in one dose or in two or three doses.
The daily amount can be between 20 mg and 1000 mg, preferably between 50 and 500 mg of the aforementioned vitamin B6 derivatives.
The substances according to the invention, as compared with most other drugs used for prevention and treatment of atherosclerosis, have the important advantage of having a neutral or at least acceptable taste and of being easy to dissolve in water and thus not causing any problems of consistency.
Furthermore, the good taste and good solubility of the inventive compounds allow to take advantages of the improved bioavailability in case of buccal adsorption. In this case the bioavailability is much better in comparison with the metabolic degradation in the intestine and liver.
The very widely-used clofibrates, on the other hand, are nauseously bitter, and substances for adsorbing bile acid are coarse-grained or form voluminous gels.
The invention also relates to use of pyridoxine derivatives or salts thereof for producing a drug for prevention and treatment of hyperlipidaemia and atherosclerosis.
Since the substances according to the invention are soluble in water and chemically stable, elderly patients can also easily take them in the form of a powder or granulate or dissolved in water or a drink. The individual dose may also be administered in the form of a tablet, capsule or dragee, '~
.
.. .... . .
' -12- 13~246 and the dissolution of each of these forms and the liberation of active principle can be delayed and controlled by methods known to the skilled addressee. One particularly noteworthy method is a coating resistant to gastric juices, which does not liberate the active principle until it reaches the intestine and protects it from stomach acid. It may be advantageous to add flavourings when taken as a powder, granulate, solution or tablet for sucking.
Otherwise the active principles can be used in conventional manner as salts, e.g. pyridoxal hydrochloride, or in conjunction with other physiologically acceptable acids or bases, or with use of conventional pharmaceutical adjuvants, stabilizers, buffers, etc.
The following table shows the values for the decrease of the concentrations of certain compounds found in hyperlipaemic rabbits after 10 weeks of treatment with pyridoxamine. The values are mean values of 18 rabbits and measured relative to a basis of non-treated rabbits. The control group received a diet comprising 2% of cholesterol. In the group under treatment each rabbit received additionally 120 mg pyridoxamine ~ 2HCl/kg body weight. At the end of the test the aortae of the rabbits from the heart to the branch of the kidney arteriae were withdrawn and examined:
dry weight - 8 %
lipids(total) - 18 %
cholesterol - 27 %
triglcerides - 17 %
calcium - 31 %
Thus, pyridoxamine ~ 2 HCl after a treatment of only 10 weeks shows a substantial decrease of those changes that are characteristic for artherosclerosis: thickening of the '- '''~j;~F' -13- 134~L6 walls (measured as dry weight), lipid inclusion and calcium inclusion.
Examples 1. Capsules a) 500 mg of pyridoxal ~ HCl or pyridoxamine ~ 2 HC
were homogenously mixed with 1000 g lactose and 150-mg portions thereof were poured into gelatin capsules. The capsule halves were stuck or welded together. One capsule is taken three times a day at meals.
b) 300 mg pyridoxal ~ HCl or pyridoxamine ~ 2 HCl was welded in gelatin capsules. To be taken once every evenlng .
Use of Pyridoxine Derivatives in the Prevention and Treatment of Hyperlipidaemia and Atherosclerosis Description The invention relates to the use of pyridoxine derivatives in the prevention and treatment of hyperlidpidaemia and atherosclerosis. This does not include pyridoxine-5'-phosporic acid ester glutamate and aspartate, which are described in DE 24 61 742 C2.
Athersclerosis is one of the most frequent diseases and causes of death (atherosclerosis of the coronaries) in industrialised countries. Atherosclerosis is usually a slow process comprising complex changes in the structure and function of blood vessels and ending in clearly visible clinical diseases such as angina pectoria and cardiac infract through constriction and blockage of coronary vessels, reduced perfusion of the extremities, or brain infarct. The dramatic final stage of the disease is often preceded by long years of severe discomfort and chronic illness. The possibilities of treatment in the advanced stage are very limited, expensive and invasive, e.g. the open-heart operation or amputation of extremeties.
Apart from relatively rare cases of severe hereditary metabolic disturbances, atherosclerosis is to a large extent a disease of civilisation. The risk of atherosclerosis is increased particularly by smoking (nicotine). Other risk factors are e.g. high blood pressure, insufficient physical activity, diabetes mellitus and renal insufficiency. A critically important step in the prevention of atherosclerosis was the recognition of the connection between high blood lipid .-,, .~., concentration and increased rlsk of atheroscle ~ S31S
including increased risk of death through cardiac infarct (compare Dayton, S., Chapman J., Pearce M., Popiak G., Cholesterol, atherosclerosis, ischaemic heart disease, and stroke, Am. J. Med. 72, 97 (1970).
Cholesterol-rich food and a high content of animal fat (saturated fatty acids ) in food produce an undesirable increase in the content of lipoproteins in the blood, resulting in accelerated development of atherosclerotic lesions.
Since cholesterol is the main substance found in atheromatous plaques, a connection between an elevated cholesterol level and atherosclerosis appears certain.
Lipids, which are insoluble in water, are conveyed in the blood by lipoproteins. A distinction is made between LDL (low-density lipoproteins) and HDL (high-density lipoproteins). LDL-cholesterol is of critical importance in atherogenesis. HDL-cholesterol, on the other hand, conveys excess cholesterol from the periphery back to the liver.
Its effects, if anything, is protective.
Consequently, the accumulation of cholesterol in the median cells of the atherial walls depends not only on the total concentration of cholesterol in the serum but also on the ratio of LDL to HDL.
Elevated blood lipid concentrations, more particularly elevated LDL concentrations in the blood, increase the deposition of lipids in the arterial walls, which in turn initiates or at any rate intensifies other atherosclerotic changes.
13~02~6 The aim of prevention of atherosclerosis, therefore, has increasingly been to reduce the blood lipid concentrations in general and the LDL cholesterol concentrations in particular.
This aim can be achieved in various ways:
Some cholesterol and saturated fatty acids (likewise undesirable) are supplied in food. Consequently a diet containing little cholesterol or animal fats is the first condition for successful treatment or prevention of atheroschlerosis.
However, keeping to a diet is often difficult and also insufficient. The reason is that atherogenic lipids are not only ingested in food but also formed in the body. In order to reduce the conentration of endogenic lipids in the blood, also, or at least to reduce their atherogenic effect, a large number of drugs have been developed or recommended for this purpose during the last 20 years.
A simple and relatively harmless method of lowering the cholesterol concentration in the blood is to start with the elimination mechanism thereof. In the liver, cholesterol is converted into bile acids, in which form it enters the intestine. Bile acids are largely reabsorbed and re-used.
This enterohepatic circulation can be interrupted if bile acids are retained in the intestine by non-absorbable substances.
Examples of such substances are solid ion-exchangers, certain swelling agents such as guar, and also normal constituents of food such as fibrous materials. These cause the liver to covert more cholesterol into bile acids, thus .._._. ,~
- ~4~ n 2 eliminating it more quickly. A disadvantage of this method of treatment ist the extremely high dosage of the preparations in question (8 - 24 g/day) and the inconvenience of taking them.
A number of systematically acting "lipid-lowering agents"
have also been introduced into treatment, e.g. derivatives of clofibric acid, which inhibit the synthesis of cholesterol in the liver. Owing to the serious side-effects and the required duration of treatment clofibrates are used only for severe disturbances in lipid metabolism (compare Scheffler W. and Schwartzkopff, W., Frequently used lipid-lowering drugs have no guaranteed effect. Artery 8, 120 -127 1980)).
However, other synthetic or even natural drugs (nicotinic acid derivatives) sometimes cause unacceptable side-effects, or the dosage has to be so high, particularly in the case of long-term treatment of elderly patients or with kidney of liver disease, that they place an unacceptable burden on metabelism.
Some derivatives of pyridoxine phosphate are described in DE 24 61 742 C2 as lipid-lowering and anti-atherosclerotic active principles. These substances are pyridoxine-5'- phosphoric acid ester glutamate and asparates. Their effect is attributed to the combination of pyridoxine phosphate and glutamic acid or aspartic acid. In spite of their undoubted efficiency, the known substances also have appreciable disadvantages. They are not strictly natural remedies, their chemistry is ill-defined, their stability is questionable, even when very small quantities of moisture are added, and non-existent in vivo, e.g. during ~5~ 1 3 ~ 2 ib absorption, and the doses have to be relatively high. As a resulut of their instability, the active principles listed in DE 24 61 742 C2 also cannot be administered in the form of infusions or ampoules for drinking or solutions of other kinds. However, ingestion in liquid form is particularly convenient, particularly for patients who are usually elderly.
Under unfavorable conditions, individual constituents of the substances described in DE 24 61 742 C2 may even have an unfavourable effect on treatment of the patients.
Since therefore the patients are usually elderly, suffer from a number of diseases and often have to take lipid-lowering drugs as long as they live, it is desirable to have a natural well-tolerated drug to be taken in low doses. The drug also needs to have a well-defined chemical composition, to be resistant to external influences and to be substantially unchanged and completely resorbable after oral administrations. The drug should alter the metabolic situation in a manner which, other things being equal, results in reduced deposition of lipids in the arterial wall and thus delays, interrupts or even reverses atherosclerotic changes.
The object of the invention therefore is to provide a novel means for prevention and treatment of hyperlipidaemia and atherosclerosis and having the aforementioned properties. The substance should also be of use for treating persons who have high blood lipid concentrations even when on a diet.
During the search for a suitable active principle it was found that certain derivatives of pyridoxine, more ~,, 13~02~6 particularly pyridoxal, pyridoxal phosphate, pyridoxamine and pyridoxamine phosphate and precursors and their metabolites, unexpectedly have an aforementioned lipig-lowering, anti-atherosclerotic activity. This was explicitly queried in DE 24 61 742 C2 (column 3, lines 35 ff). On the other hand pyridoxine, often also called vitamin B6, does not have any strong action in this respect.
Pyridoxine was used separately in earlier experiments on animals in conjunction with lipid metabolism (see Frolova, J.A.: Vitamin B6 and lipid metabolism; Vorpr.med.Khim. 89, 18. 339 346 (1972)). Its effect, however, is weak. In our experiments, pyridoxine in rats was ineffective at a dose of 79 mg/kg body weight, although a positive control showed the expected effect in the same experiment.
Various pyridoxine derivatives occur in metabolism and to some extent are convertible into one another. These, in addition to pyridoxine itself, include e.g. pyridoxamine, pyridoxal, pyridoxal phosphate and pyridoxic acid. It is generally recognized that the pool of pyridoxal and derviatives thereof is correspondingly increased by oral administration of pyridoxine.
It has now surprisingly been found that oral administration of certain pyridoxine derivatives, more particularly pyridoxal phosphate, pyridoxal, pyridoxamine phosphate and pyridoxamine or precursors thereof, results in a marked reduction in serum lipids, particularly LDL cholesterol, which has such a disastrous effect on atherogenesis.
Another effect, apparently independent of the reduction of serum lipids, is the reduced deposition of lipids in the arterial walls. Both actions guarantee preventive and therapeutic treatment of atherosclerosis which is effective . . . , ~ ~ ~ .
_7_ 13~2~
and, on present knowledge, attacks the causes. The treatment is all the more valuable in that it is not offset by any recognizable side-effects. The toxicity of the aforementioned vitamin B6 derivatives is extremely low, and they are therefore extremely well tolerated at the doses used for human treatment. More particularly, there is no toxic effect on the liver, in contrast to most other lipid-lowering agents, which cause a marked increase in the liver weight of experimental animals after only a short period of treatment.
In addition to the mentioned pyridoxine derivatives occurring in metabolism, also useful in this invention are derivatives having -CH2NRIRII in the 4-position, wherein RI and RII independently are H, lower alkyl, lower alkenyl, hydroxy or hydroxy(lower)alkyl, where lower means up to about 6 C-atoms, e.g., the mentioned pyridoxamine compounds where the amino group is substituted by RI/RII. Such compounds can be prepared by conventional amino substitution reactions.
~ Also useful are compounds preparable by conventional reactions between pyridoxal compounds and amino acids or primary amines, e.g., ~C~ 'j\c~ 2 X0-CH2 ~~ H2NR2 ~> X0CH2 ~ 0H
N CH3'~~N ~ CH3 X=H, (OH)20P
wherein R1 is H, lower alkyl, lower alkenyl, hydroxy or -- ~ ~ v ,r' ~, -8- 13~2~6 hydroxy(lower)alkyl, wherein lower means up to about 6 C-atoms, and R2 is (a) an Rl group (amines), /R
(b) -CH~ (amino acids) (CH2 ) n-COOH
n = 0-6, ~ ( CH2 ) n-COOH
(c) -CH (monoaminodicarboxylic acids) COOH
n ~ 0-6 ~e.g., aspartic or glutamic acids), or ( CH2 ) n-NH2 (d) -CH ~ (diaminomonocarboxylic acids) COOH
n = 0-6.
As mentioned above, any compound which is metabolized to produce one of the foregoing compounds of this invention can also be used. Such compounds, for example, have substituents which are removed upon metabolization. In this sense, some of the foregoing compounds are precursors and/or metabolites of others.
For example, in the course of metabolism in the human body pyridoxine is oxidized to pyridoxal, which is enzymatically (pyridoxalkinase) converted to pyridoxal-5-phosphate:
pyridoxal + ATP - pyridoxal-5-phosphate + ADP
Useful salts of the compounds of this invention are the usual pharmaceutically acceptable salts, e.g, acid addition salts and are conventionally prepared from conventionally employed acids. Such acids include, for example, inorganic acids, e.g. hydrochloric acid, nitric t, ~
-9- 134~246 acid, phosphoric acld, sulfuric acid, hydrobromic acld, hydriodic acid, nitrous acid or phosphorous acid, or organic acids, such as, for example, aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids, or alkenedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids.
Physiologically acceptable salts of these acids are, therefore, e.g., the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene-sulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ~-hydroxybutyrate, glycolate, malate, tartate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate or napthalene-2-sulfonate.
The newly discovered efficacy of the aforementioned pyridoxine derviatives is all the more surprising in that these compounds, which have a simple structure, were thought to have a low activity and it was expected to obtain effective drugs only by very complex molecules derived from pyridoxal phosphate as described e.g. in the cited DE 24 61 742 C2.
The main substances for clinical use according to the invention are the four aforementioned pyridoxine derivates -lO- 13~0~46 (pyridoxal, pyridoxamine, pyridoxal phosphate and pyridoxamine phosphate) and suitable mixtures thereof. Of course, all other substances are suitable which liberate the aforementioned pyridoxine derivatives in vitro or more particularly in vivo. The pyridoxine derivatives may also be used in conjunction with other measures for stabilizing lipid metabolism (e.g. diet) or treatment (e.g. bile acid adsorbing agents). A preferred combination is with lipid-lowering agents which act on metabolism at a different point from the aforementioned pyridoxine derivatives.
Combinations with drugs for treatment of diseases frequently accompanying atherosclerosis (high blood pressure, diabetes, etc.) may also be advantageous. Since the aforementioned pyridoxine or vitamin B6 derivatives are very well tolerated, they are particularly suitable for patients with numerous underlying or accompanying diseases.
On the other hand pyridoxine itself, which is preferably used under the name of vitamin B6, is not suitable.
In practice, treatment is preferably by oral administration of the active principles for a prolonged period. A maximum effect is not expected before two months or longer treatment. Treatment must be continuous, since if the preparations are discontinued the resulut is a very rapid decrease in the effect, an increase in serum lipids and a worsening of atherosclerosis.
In exceptional cases the active principles used according to the invention may also be administered parenterally, e.g. by intravenous infusion of the aqueous solutions or intramuscular injection thereof.
, ..
-11- 13 ~ 6 In oral therapy the daily amount is administered either in one dose or in two or three doses.
The daily amount can be between 20 mg and 1000 mg, preferably between 50 and 500 mg of the aforementioned vitamin B6 derivatives.
The substances according to the invention, as compared with most other drugs used for prevention and treatment of atherosclerosis, have the important advantage of having a neutral or at least acceptable taste and of being easy to dissolve in water and thus not causing any problems of consistency.
Furthermore, the good taste and good solubility of the inventive compounds allow to take advantages of the improved bioavailability in case of buccal adsorption. In this case the bioavailability is much better in comparison with the metabolic degradation in the intestine and liver.
The very widely-used clofibrates, on the other hand, are nauseously bitter, and substances for adsorbing bile acid are coarse-grained or form voluminous gels.
The invention also relates to use of pyridoxine derivatives or salts thereof for producing a drug for prevention and treatment of hyperlipidaemia and atherosclerosis.
Since the substances according to the invention are soluble in water and chemically stable, elderly patients can also easily take them in the form of a powder or granulate or dissolved in water or a drink. The individual dose may also be administered in the form of a tablet, capsule or dragee, '~
.
.. .... . .
' -12- 13~246 and the dissolution of each of these forms and the liberation of active principle can be delayed and controlled by methods known to the skilled addressee. One particularly noteworthy method is a coating resistant to gastric juices, which does not liberate the active principle until it reaches the intestine and protects it from stomach acid. It may be advantageous to add flavourings when taken as a powder, granulate, solution or tablet for sucking.
Otherwise the active principles can be used in conventional manner as salts, e.g. pyridoxal hydrochloride, or in conjunction with other physiologically acceptable acids or bases, or with use of conventional pharmaceutical adjuvants, stabilizers, buffers, etc.
The following table shows the values for the decrease of the concentrations of certain compounds found in hyperlipaemic rabbits after 10 weeks of treatment with pyridoxamine. The values are mean values of 18 rabbits and measured relative to a basis of non-treated rabbits. The control group received a diet comprising 2% of cholesterol. In the group under treatment each rabbit received additionally 120 mg pyridoxamine ~ 2HCl/kg body weight. At the end of the test the aortae of the rabbits from the heart to the branch of the kidney arteriae were withdrawn and examined:
dry weight - 8 %
lipids(total) - 18 %
cholesterol - 27 %
triglcerides - 17 %
calcium - 31 %
Thus, pyridoxamine ~ 2 HCl after a treatment of only 10 weeks shows a substantial decrease of those changes that are characteristic for artherosclerosis: thickening of the '- '''~j;~F' -13- 134~L6 walls (measured as dry weight), lipid inclusion and calcium inclusion.
Examples 1. Capsules a) 500 mg of pyridoxal ~ HCl or pyridoxamine ~ 2 HC
were homogenously mixed with 1000 g lactose and 150-mg portions thereof were poured into gelatin capsules. The capsule halves were stuck or welded together. One capsule is taken three times a day at meals.
b) 300 mg pyridoxal ~ HCl or pyridoxamine ~ 2 HCl was welded in gelatin capsules. To be taken once every evenlng .
2. Tablets for buccal application 1000 g pyridoxal phosphate magnesium salt was homogenously mixed with 3 000 g lactose and 15 g magnesium stearate, granulated and moulded into tablets each weighing 301.5 mg. One tablet to slowly dissolve in the mouth morning and evening.
3. Tablets resistant to gastric juice 1000 g pyridoxal ~ HCl or pyridoxamine ~ 2 HCl was uniformly mixed with 2 000 g tablettose (special lactose) and 15 g magnesium stearate, granulated and moulded into approximately round tablets weighing 150 and 75 mg. 20 coatings of cellulose acetate succinate (9), diemethyl phthalate (3, 4), acetic acid ester (84,
4) and acetone (84, 4) were applied, using talcum as a .;
-14- 13~02~6 dispersion agent. One or two tablets to be taken three times a day before meals.
4. Effervescent tablets 500 g pyridoxal phosphate, 600 g citric acid and 280 g sodium carbonate were mixed with 2 000 g lactose and moulded when dry into 338-mg units. One or two tablets dissolved in a little water to be taken at meals.
-14- 13~02~6 dispersion agent. One or two tablets to be taken three times a day before meals.
4. Effervescent tablets 500 g pyridoxal phosphate, 600 g citric acid and 280 g sodium carbonate were mixed with 2 000 g lactose and moulded when dry into 338-mg units. One or two tablets dissolved in a little water to be taken at meals.
5. Granulate 1000 g pyridoxal ~ HCl was granulated with 1 000 g citric acid and 8 000 g lactose, after which the granulate was screened to obtain a uniform particle size of about 1 mm. The granulate was thoroughly dried and welded in aluminum foil. The individual dose per bag was 500 mg or 1 g. The contents of the bag is dissolved in water of fruit juice when taken. To increase the effect, a conventional commercial guar preparation or other lipig-lowering drug can be added, preferably a product in which the active principle is not absorbable or has a supplementary mechanism of action, the drug being optionally dissolved when taken.
. ~ ~ ~
. ~ ~ ~
Claims (8)
1. Use for prevention and treatment of hyperlipidemia and atherosclerosis of a compound of the formula where R I and R II independently are H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, and X is H or (OH)2OP, or of the formula wherein X is H or (OH)2OP, and R2 is (a) an R1 group, , , or , and R1 is H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, or a salt thereof, provided that when both R I and R II are H or one is H and the other alkyl, X is not (OH)2OP and the compound is not used with clofibric acid or an ester of salt thereof and provided that when =N-R2 is derived from glutamic or aspartic acid, X is not (OH)2OP.
2. Use according to claim 1, wherein physiologically unobjectionable pharmaceutical excipients and adjuvants are added to the compound.
3. Use according to claim 1, wherein the compound is used in combination with another active principle likewise used to treat hyperlipidemia and atherosclerosis or an accompanying disease.
4. Use for producing a drug for prevention and/or treatment of hyperlipidemia and/or atherosclerosis of a compound of the formula where R I and R II independently are H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, and X is H or (OH)2OP, or of the formula wherein X is H or (OH)2OP, and R2 is (a) an R1 group, , , or , and R1 is H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, or a salt thereof, provided that when both R I and R II are H or one is H and the other alkyl, X is not (OH)2OP and the compound is not used with clofibric acid or an ester of salt thereof and provided that when =N-R2 is derived from glutamic or aspartic acid, X is not (OH)2OP.
5. Use according to claim 4, wherein the compound is produced in solid form or as an aqueous solution together with pharmaceutically safe excipients and/or adjuvants.
6. Use according to claim 1, wherein the compound is prepared with physiologically unobjectionable pharmaceutical carriers and adjuvants for buccal application.
7. Use according to claim 1, wherein the compound is prepared with physiologically unobjectionable pharmaceutical carriers and adjuvants in a form resistant to gastric juice.
8. A compound for prevention and treatment of hyperlipidemia and atherosclerosisof the formula where R I and R II independently are H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, and X is H or (OH)2OP, or of the formula wherein X is H or (OH)2OP, and R2 is (a) an R1 group, , , or , and R1 is H, C1-6-alkyl, C2-6-alkenyl, hydroxy or hydroxy-C1-6-alkyl, or a salt thereof, provided that R I and R II are not both hydrogen, that X is not (OH)2OP when one of R I and R II is H and the other alkyl or when =N-R2 is derived from glutamic acid, aspartic acid or an S-containing amino acid, and that when X is H and one of R I and R II is H, the other is not butyl.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19873705549 DE3705549A1 (en) | 1987-02-18 | 1987-02-18 | USE OF PYRIDOXINE DERIVATIVES IN THE PROPHYLAXIS AND THERAPY OF HYPERLIPIDAEMIA AND ATHEROSCLEROSIS |
DEP3705549.6 | 1987-02-18 |
Publications (1)
Publication Number | Publication Date |
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CA1340246C true CA1340246C (en) | 1998-12-15 |
Family
ID=6321453
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Application Number | Title | Priority Date | Filing Date |
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CA000559285A Expired - Fee Related CA1340246C (en) | 1987-02-18 | 1988-02-18 | Use of pyridoxine derivatives in the prevention and treatment of hyperlipidaemia and athersclerosis |
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EP (1) | EP0282696B1 (en) |
JP (2) | JPH0710777B2 (en) |
KR (1) | KR950009094B1 (en) |
AT (1) | ATE82125T1 (en) |
CA (1) | CA1340246C (en) |
DE (2) | DE3705549A1 (en) |
DK (1) | DK55888A (en) |
EG (1) | EG18335A (en) |
ES (1) | ES2052609T3 (en) |
GR (1) | GR3006693T3 (en) |
HU (1) | HUT47850A (en) |
ZA (1) | ZA88577B (en) |
Cited By (1)
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WO2017002034A1 (en) * | 2015-06-30 | 2017-01-05 | Assistance Publique-Hopitaux De Paris | Effervescent formulation based on pyridoxal-5-phosphate |
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US6716858B1 (en) | 1995-08-28 | 2004-04-06 | Kansas University Medical Center | Methods for inhibiting diabetic complications |
US6228858B1 (en) | 1995-09-12 | 2001-05-08 | University Of Kansas Medical Center | Advanced glycation end-product intermediaries and post-amadori inhibition |
US6740668B1 (en) | 1995-08-28 | 2004-05-25 | Kansas University Medical Center | Methods for inhibiting diabetic complications |
US5744451A (en) | 1995-09-12 | 1998-04-28 | Warner-Lambert Company | N-substituted glutamic acid derivatives with interleukin-1 β converting enzyme inhibitory activity |
US6730686B1 (en) | 1995-09-12 | 2004-05-04 | Kansas University Medical Center | Methods for inhibiting oxidative modification of proteins |
US6750209B1 (en) | 1995-09-12 | 2004-06-15 | Kansas University Medical Center | Advanced glycation end-product intermediaries and post-amadori inhibition |
US7030146B2 (en) | 1996-09-10 | 2006-04-18 | University Of South Carolina | Methods for treating diabetic neuropathy |
US6043259A (en) * | 1998-07-09 | 2000-03-28 | Medicure Inc. | Treatment of cardiovascular and related pathologies |
AU1444600A (en) * | 1998-10-09 | 2000-05-01 | Kansas University Medical Center | Methods for inhibiting oxidative modification of proteins |
ATE306489T1 (en) | 1999-03-08 | 2005-10-15 | Medicure Inc | PYRIDOXAL ANALOGUE FOR THE TREATMENT OF DISORDERS CAUSED BY VITAMIN B6 DEFICIENCY |
CA2376029A1 (en) | 1999-07-13 | 2001-01-18 | Medicure Inc. | Use of pyridoxin derivatives for the treatment of diabetes and related complications |
JP2003507418A (en) | 1999-08-24 | 2003-02-25 | メディキュア インターナショナル インコーポレイテッド | Treatment of cardiovascular disease and related diseases |
WO2001064692A1 (en) | 2000-02-29 | 2001-09-07 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
US6586414B2 (en) | 2000-03-28 | 2003-07-01 | Medicure International Inc. | Treatment of cerebrovascular disease |
US6548519B1 (en) | 2001-07-06 | 2003-04-15 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: novel uses |
AU2001272263B2 (en) | 2000-07-07 | 2005-12-15 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: cardiovascular therapeutics |
US6897228B2 (en) | 2000-07-07 | 2005-05-24 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
WO2004084895A2 (en) * | 2003-03-27 | 2004-10-07 | Medicure, Inc. | Modulation of cell death |
CA2585165A1 (en) | 2004-10-28 | 2006-05-18 | Medicure International Inc. | Dual antiplatelet/anticoagulant pyridoxine analogs |
US7375112B2 (en) * | 2005-01-05 | 2008-05-20 | Medicure International Inc. | Compounds and methods for regulating triglyceride levels |
WO2020003363A1 (en) * | 2018-06-25 | 2020-01-02 | 学校法人近畿大学 | Nutrition supplement or pharmaceutical composition for preventing deterioration in blood vessels due to the impact of ingesting nicotine |
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FR3373E (en) | 1904-02-26 | 1904-10-27 | Joseph Louis Felix Garrigou | Process for treating emptying and organic waste, and overall apparatus for its implementation |
FR6707M (en) * | 1966-04-29 | 1969-02-17 | ||
GB1070120A (en) * | 1966-05-06 | 1967-05-24 | Tanabe Seiyaku Co | Pyridoxine derivative and the preparation thereof |
FR7238M (en) * | 1968-03-27 | 1969-09-01 | ||
FR2035765A1 (en) * | 1969-03-06 | 1970-12-24 | Inst Rech Scient | Medicaments contg pyridoxine heparinates or - other vitamin b6 heparinates |
JPS5347110B2 (en) * | 1971-11-02 | 1978-12-19 | ||
FR2176509A2 (en) * | 1972-03-21 | 1973-11-02 | Inst Rech Scient | Pyridoxine p-chlorophenoxyisobutyrate prodn - giving very pure product from corresp acid and pyridoxine |
JPS5018470A (en) * | 1973-05-31 | 1975-02-26 | ||
FR2260330A1 (en) | 1974-02-07 | 1975-09-05 | Innothera Lab Sa | Pyridoxine N-oxy nicotinate - hypolipaemiant and hypocholesterolemiant of good therapeutic index |
CH607773A5 (en) * | 1974-12-24 | 1978-10-31 | Steigerwald Arzneimittelwerk | Process for the preparation of novel pyridoxine derivatives |
DE2461742C2 (en) * | 1974-12-28 | 1983-01-27 | Steigerwald Arzneimittelwerk Gmbh, 6100 Darmstadt | Pyridoxine-5'-phosphoric acid ester derivatives and their preparation and pharmaceuticals containing these compounds |
FR2349330A1 (en) * | 1976-04-29 | 1977-11-25 | Savini Emile | Compsns. contg. pyridoxine and an antioxidant esp. tocopherol - used for treatment of hyperlipidaemia |
JPS5347110A (en) * | 1976-10-12 | 1978-04-27 | Osaka Bosui Kensetsusha Kk | Impermeable wall forming method |
-
1987
- 1987-02-18 DE DE19873705549 patent/DE3705549A1/en not_active Withdrawn
-
1988
- 1988-01-20 ES ES88100747T patent/ES2052609T3/en not_active Expired - Lifetime
- 1988-01-20 AT AT88100747T patent/ATE82125T1/en not_active IP Right Cessation
- 1988-01-20 DE DE8888100747T patent/DE3875760D1/en not_active Expired - Fee Related
- 1988-01-20 EP EP88100747A patent/EP0282696B1/en not_active Expired - Lifetime
- 1988-01-28 ZA ZA880577A patent/ZA88577B/en unknown
- 1988-02-01 EG EG53/88A patent/EG18335A/en active
- 1988-02-03 DK DK055888A patent/DK55888A/en not_active Application Discontinuation
- 1988-02-16 HU HU88723A patent/HUT47850A/en unknown
- 1988-02-17 KR KR1019880001692A patent/KR950009094B1/en not_active IP Right Cessation
- 1988-02-17 JP JP63032943A patent/JPH0710777B2/en not_active Expired - Lifetime
- 1988-02-18 CA CA000559285A patent/CA1340246C/en not_active Expired - Fee Related
-
1992
- 1992-12-28 GR GR920403159T patent/GR3006693T3/el unknown
-
1994
- 1994-09-02 JP JP6209830A patent/JP2588686B2/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017002034A1 (en) * | 2015-06-30 | 2017-01-05 | Assistance Publique-Hopitaux De Paris | Effervescent formulation based on pyridoxal-5-phosphate |
FR3038227A1 (en) * | 2015-06-30 | 2017-01-06 | Assist Publique - Hopitaux De Paris | EFFERVESCENT FORMULATION BASED ON PYRIDOXAL-5-PHOSPHATE |
US10195221B2 (en) | 2015-06-30 | 2019-02-05 | Assistance Publique-Hopitaux De Paris | Effervescent formulation based on pyridoxal-5-phosphate |
US10960015B2 (en) | 2015-06-30 | 2021-03-30 | Assistance Publique-Hopitaux De Paris | Effervescent formulation based on pyridoxal-5-phosphate |
Also Published As
Publication number | Publication date |
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DE3875760D1 (en) | 1992-12-17 |
DK55888A (en) | 1988-08-19 |
JP2588686B2 (en) | 1997-03-05 |
DK55888D0 (en) | 1988-02-03 |
ZA88577B (en) | 1988-07-28 |
EP0282696A3 (en) | 1989-06-14 |
JPH07238020A (en) | 1995-09-12 |
EP0282696B1 (en) | 1992-11-11 |
GR3006693T3 (en) | 1993-06-30 |
ES2052609T3 (en) | 1994-07-16 |
JPS63203621A (en) | 1988-08-23 |
EP0282696A2 (en) | 1988-09-21 |
HUT47850A (en) | 1989-04-28 |
EG18335A (en) | 1992-09-30 |
JPH0710777B2 (en) | 1995-02-08 |
KR950009094B1 (en) | 1995-08-14 |
KR880009649A (en) | 1988-10-04 |
ATE82125T1 (en) | 1992-11-15 |
DE3705549A1 (en) | 1988-09-01 |
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