CA2388103A1 - Medicament and combination of compatible medicaments - Google Patents
Medicament and combination of compatible medicaments Download PDFInfo
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- CA2388103A1 CA2388103A1 CA002388103A CA2388103A CA2388103A1 CA 2388103 A1 CA2388103 A1 CA 2388103A1 CA 002388103 A CA002388103 A CA 002388103A CA 2388103 A CA2388103 A CA 2388103A CA 2388103 A1 CA2388103 A1 CA 2388103A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to a medicament or a combination of compatible medicaments for combined administration. Said medicament or combination of medicaments contains at least one active agent and at least one antagonist of said active agent.
Description
Medicament and mutually coordinated co~obiaatioa of medicaments The invention relates to a medicament and to a mutually coordinated combination of medicaments. The invention additionally relates to the use of an active ingredient and of an antagonist of this active ingredient.
Medicaments having at least one active ingredient are known in the prior art.
By active ingredient is meant chemical elements, chemical compounds and mixtures thereof which, in defined dose, interact with a biosystem and thus exert a desired effect on the system. Active ingredients generally act in a biosystem via specific receptors.
An antagonist is a substance or mixture of substances which counteracts the effect of an active ingredient or the effect of an endogenous substance.
It is known to administer antagonists as active ingredients in order thus to influence a biosystem.
Examples of such antagonists are H1 and H2 receptor blockers which inhibit the effect of histamine.
Antagonists are also administered in order to abolish the effect of overdosed active ingredients. Thus, a morphine intoxication is treated with a morphine antagonist such as naloxone.
It is also known to counteract the anticoagulant effect of coumarin derivatives such as phenprocoumon or warfarin by vitamin K. This may be indicated, for example, in the event of overdosage of coumarin derivatives or of poisoning with rat poison containing coumarin derivatives. Thijsen et al., Br. J. Haematol.
84 (1993), pages 681-685 disclose the administration of vitamin K1 to a patient in whom blood coagulation was inhibited long-term with phenprocoumon and in whom hemorrhages occurred. Am. J. lin. Nutr. 1987, 45(4), 847 describes the effect of simultaneous intake of warfarin and vitamin K1.
Active ingredients normally act in the body above a particular therapeutically effective concentration. The concentration of an active ingredient in the blood is normally stated in the form of blood levels or plasma levels. The intention during therapy is to stay within a particular range of blood levels. This range is referred to as the "therapeutic range". It proves to be disadvantageous for the blood level of the active ingredients administered during therapy occasionally to be above or below the therapeutic range. Blood levels above the therapeutic range are not desired because they frequently cause unwanted side effects. Blood levels below the therapeutic range do not lead to the desired therapeutic effect.
Even with blood levels which are within the therapeutic range of the active ingredient it is possible for the active ingredient to be subject to variations in its availability or efficacy. Variations in the efficacy may occur if the effect of the active ingredient is influenced by other factors. The blood glucose-lowering effect of insulin may vary for example as a function of endogenous glucagon. A variation caused by diet in the efficacy is disclosed by Pedersen et al., J. Intern.
Med. 229 (1991), pages 517-520. This describes the influence of vitamin K consumed with the diet on the anticoagulant effect of warfarin. Variations in availability occur for example with plasma protein-bound active ingredients if factors influence release from the plasma protein. Thus, for example, a plasma protein-bound coumarin derivative may be displaced from its binding site on the plasma protein by sulfonamides.
Thus, while the blood levels are constant, the availability of the coumarin derivatives increases on simultaneous treatment with sulfonamides.
Excursions outside the therapeutic range, and variations in the availability and efficacy may be related to diet or physiological/metabolic, physical/
endogenous or therapeutic factors. The therapeutic range, the availability and the efficacy of a medicament moreover vary between individuals. A part is played in this by individual factors such as height, proportion of body fat, metabolism etc.
It is an object of the invention to eliminate the disadvantages of the prior art. In particular, it is intended to provide a medicament or a mutually coordinated combination of medicaments with an efficacy which is as constant as possible. The undesired effect of dietary, physiological/metabolic, physical/
endogenous or therapeutic factors on the efficacy is to be reduced. The medicament or the mutually coordinated combination of medicaments is to have similar efficacy in different people despite individual differences. The aim is to increase the reliability of the therapeutic effect .
This object is achieved by the features of claims 1 and 8. Expedient developments of the invention are evident from the features of claims 2 to 7 and 9 to 13.
This object is achieved by the presence of at least one antagonist of this active ingredient. It is likewise achieved by a mutually coordinated combination of two medicaments, where a first medicament comprises at least one active ingredient and a second medicament comprises at least one antagonist of this active ingredient.
The antagonist brings about an increase in the therapeutically effective concentration of the active ingredient. Thus, in order to achieve a particular therapeutic effect, the dose employed of active ingredient must be higher than without the antagonist.
The effects of interfering factors or individual factors on the efficacy of the active ingredient administered in increased dosage are proportionately less than with an active ingredient in a conventional dose. A higher antagonist dose means a higher therapeutically effective concentration of the active ingredient and a smaller effect of interfering factors or individual factors on the efficacy of the active ingredient. The desired therapeutic effect is achieved with greater certainty using the medicament according to the invention or the mutually coordinated combination of medicaments compared with conventional medicaments. The patient is less restricted during therapy with the medicament according to the invention.
Thus, for example, he needs to comply with diets less strictly than during therapy with conventional medicaments. Medication with a medicament according to the invention is simpler for the physician than with a conventional medicament because he needs to take less account of individual differences between various patients. The medicament according to the invention moreover opens up new therapeutic possibilities. The influence of other medicaments on the medicament according to the invention is less than with conventional medicaments. The physician is able to combine with one another active ingredients which cannot be administered together in the case of conventional medication.
In an advantageous development of the medicament according to the invention or of the mutually coordinated combination, according to the invention, of medicaments, the active ingredient and the antagonist are present in amounts such that a therapeutically effective concentration of the active ingredient is reached during therapy. The choice of suitable amounts and thus of a particular ratio of amounts of active ingredient and antagonist makes it possible to determine the efficacy of the medicament according to the invention. Medicaments according to the invention with identical combination of active ingredient and antagonist can be provided for diverse applications with different efficacies.
A medicament according to the invention or a mutually coordinated combination, according to the invention, of medicaments is particularly advantageous when the antagonist is present in an amount which increases the therapeutically effective concentration of the active ingredient during therapy to an extent such that external or endogenous interfering variables or individual factors are substantially unable to influence the effect of the active ingredient. The influence which said interfering variables or factors can exert decreases as the therapeutically effective concentration of the active ingredient increases. The increase in the therapeutically effective concentration of the active ingredient until interfering variables and individual factors are substantially unable to influence its effect increases the reliability of the medicament.
In a preferred development of the medicament according to the invention and of the mutually coordinated combination, according to the invention, of medicaments, the affinity of the active ingredient for one of its specific binding partners at the site of action differs from that of the antagonist for one of its specific binding partners. It is possible in this case for the specific binding partner of the active ingredient and that of the antagonist to be identical.
This is the case, for example, when the active ingredient and the antagonist compete for binding to one and the same receptor. The different affinities permit an equilibrium to be set up between antagonist and active ingredient, which equilibrium is able to "buffer" the influence of interfering variables. The dose of active ingredient in a system which can be influenced by a medicament according to the invention and in which, for example, the antagonist has a higher affinity than the active ingredient itself for the receptor of the active ingredient is high. Only a sufficiently high dose of active ingredient is able to displace such an antagonist from the receptor and thus display its effect. If there is also for example an endogenous interfering factor which competes with similar affinity as the active ingredient for binding to the same receptor in this system, its influence on the system is small because of the high dose of active ingredient.
In a further development, vitamin K is present as antagonist, and at least one vitamin K antagonist is present as active ingredient. The vitamin K antagonist may in this case be selected from the group of coumarin derivatives. Examples thereof are dicoumarol, phenprocoumon (Marcumar~), acenocoumarol (Sintrom~) and warfarin (Coumadin~). A medicament according to the invention preferably comprises from 0.1 to 10 mg of vitamin K and from 3 to 10 mg of phenprocoumon, preferably 0.5 to 3 mg of vitamin K and 4.5 to 7.5 mg of phenprocoumon, in particular 0.5 to 1.5 mg of vitamin K and 5 to 7 mg of phenprocoumon. The medicament can be administered one to four times a day.
The invention additionally relates to the use of an active ingredient and of an antagonist of this active ingredient for producing a medicament or a mutually coordinated combination of medicaments for combined administration.
The invention also encompasses the therapy of a patient by administering the medicament or a correspondingly constituted combination of medicaments. The medicament _ 7 _ or combination of medicaments is in this case provided with written instructions for the patient; the written instructions contain, in the case of the combination, information about the amounts and the maximum time interval for taking the medicaments. The invention further encompasses a composition of matter comprising at least one therapeutic active ingredient and at least one antagonist of this active ingredient. Concerning advantageous developments of the active ingredient and of the material, reference is made to the preceding statements.
The features which have been mentioned and are to be explained below can be used not only in the particular combinations indicated but also in other combinations or alone. Further advantages are evident from the following example and in connection with the drawing.
This shows in Fig. 1 a diagrammatic representation of the effect of a coumarin derivative on the vitamin K cycle and on blood coagulation, Fig. 2 a diagrammatic representation of the thera-peutic range and of the plasma level of phenprocoumon, and of the variations in the anticoagulant effect of phenprocoumon on administration with a medicament according to the prior art and Fig. 3 a diagrammatic representation of the thera-peutic range and of the plasma level of phenprocoumon, and of the variations in the anticoagulant effect of phenprocoumon on administration with a medicament according to the invention.
The decarboxylated coagulation factors identified in Fig. 1 are those coagulation factors which are activated by carboxylation. Activation renders them capable of inducing blood coagulation. Decarboxylated coagulation factors which may be present are:
factor VII, protein C, factor IX, protein S, factor X
and prothrombin. The carboxylation is catalyzed by the enzyme 'y-glutamyl-carboxylase. In this case, vitamin K
hydroquinone is converted as cofactor into vitamin K
epoxide in stoichiometric amounts. Most of the vitamin K hydroquinone is recovered from vitamin K
epoxide with the aid of the enzyme vitamin K epoxide reductase (VKER). Less than 1$ of the vitamin K
hydroquinone is formed from newly consumed vitamin K.
The daily vitamin K requirement is 0.03 - 1.5 ~glkg of body weight. VKER can be inhibited by coumarin derivatives such as warfarin or phenprocoumon. The resulting inhibition of vitamin K hydroquinone production and thus of carboxylation of the.
decarboxylated coagulation factors leads to inhibition of blood coagulation. If the dosage of coumarin derivatives is sufficiently high, recovery of vitamin K
hydroquinone from vitamin K epoxide can be substantially suppressed. Vitamin K hydroquinone production and blood coagulation then depend mainly on the vitamin K intake.
The amounts of vitamin K present in foodstuffs vary.
The anticoagulant effect of coumarin derivatives varies depending on the amount of vitamin K consumed with the diet. This is shown by way of example for the active ingredient phenprocoumon administered with a conventional medicament in Fig. 2. The limits of the therapeutic range of phenprocoumon are represented here by broken lines. It is in the range between 0.02 and 0.05 ~.g of phenprocoumon per m1 of plasma. After taking the medicament, a phenprocoumon plasma level within the therapeutic range is set up as shown by the dotted line. The plasma level scale is on the Y axis at the left. The anticoagulant effect is represented by the full line. It is indicated in arbitrary units, for _ g _ which the scale is on the Y axis at the right. Since carboxylated coagulation factors are initially still present in the body, the anticoagulant effect has its onset only after they have been consumed. The latency period is about 6 hours, and the full effect does not occur until after 36 to 72 hours. However, the anticoagulant effect does not remain relatively constant like the plasma level. The repeated large decrease in the anticoagulant effect depicted here is caused in each case by intake of vitamin K with the diet. The anticoagulant effect increases again only after the plasma level of vitamin K, which is not depicted here, has fallen.
The broken lines in Fig. 3 also represent the limits of the therapeutic range of phenprocoumon. The dotted line shows the phenprocoumon plasma level and the full line shows the anticoagulant effect of phenprocoumon. The axis scales are identical to those in Fig. 2. In the example depicted in Fig. 3, a medicament according to the invention is used to supply a defined amount of vitamin K in addition to phenprocoumon. The simultaneous supply of vitamin K shifts the therapeutic range of phenprocoumon to a higher plasma level. In this case it is between 0.07 and 0.1 ~g of phenprocoumon per ml of plasma. The medicament according to the invention therefore contains a larger amount of phenprocoumon compared with a conventional phenprocoumon medicament. A substantial blockade of VKER by phenprocoumon means that the vitamin K
administered with the medicament is the essential source for generating vitamin K hydroquinone. The dose thereof is such that blood coagulation is inhibited but is maintained to an extent such that no unwanted hemorrhages occur in the patient. After the medicament according to the invention is taken, a phenprocoumon plasma level within the therapeutic range is set up.
The anticoagulant effect remains relatively stable even after intake of vitamin K with the diet. The amount of - 1~ -vitamin K supplied with the diet represents only a small proportion of the total intake of vitamin K. It thus has a much weaker effect on the inhibition of blood coagulation than during therapy with a phenprocoumon medicament according to the prior art, as depicted in Fig. 2. The medicament according to the invention brings about a stabilization of the anticoagulant effect of phenprocoumon.
Medicaments having at least one active ingredient are known in the prior art.
By active ingredient is meant chemical elements, chemical compounds and mixtures thereof which, in defined dose, interact with a biosystem and thus exert a desired effect on the system. Active ingredients generally act in a biosystem via specific receptors.
An antagonist is a substance or mixture of substances which counteracts the effect of an active ingredient or the effect of an endogenous substance.
It is known to administer antagonists as active ingredients in order thus to influence a biosystem.
Examples of such antagonists are H1 and H2 receptor blockers which inhibit the effect of histamine.
Antagonists are also administered in order to abolish the effect of overdosed active ingredients. Thus, a morphine intoxication is treated with a morphine antagonist such as naloxone.
It is also known to counteract the anticoagulant effect of coumarin derivatives such as phenprocoumon or warfarin by vitamin K. This may be indicated, for example, in the event of overdosage of coumarin derivatives or of poisoning with rat poison containing coumarin derivatives. Thijsen et al., Br. J. Haematol.
84 (1993), pages 681-685 disclose the administration of vitamin K1 to a patient in whom blood coagulation was inhibited long-term with phenprocoumon and in whom hemorrhages occurred. Am. J. lin. Nutr. 1987, 45(4), 847 describes the effect of simultaneous intake of warfarin and vitamin K1.
Active ingredients normally act in the body above a particular therapeutically effective concentration. The concentration of an active ingredient in the blood is normally stated in the form of blood levels or plasma levels. The intention during therapy is to stay within a particular range of blood levels. This range is referred to as the "therapeutic range". It proves to be disadvantageous for the blood level of the active ingredients administered during therapy occasionally to be above or below the therapeutic range. Blood levels above the therapeutic range are not desired because they frequently cause unwanted side effects. Blood levels below the therapeutic range do not lead to the desired therapeutic effect.
Even with blood levels which are within the therapeutic range of the active ingredient it is possible for the active ingredient to be subject to variations in its availability or efficacy. Variations in the efficacy may occur if the effect of the active ingredient is influenced by other factors. The blood glucose-lowering effect of insulin may vary for example as a function of endogenous glucagon. A variation caused by diet in the efficacy is disclosed by Pedersen et al., J. Intern.
Med. 229 (1991), pages 517-520. This describes the influence of vitamin K consumed with the diet on the anticoagulant effect of warfarin. Variations in availability occur for example with plasma protein-bound active ingredients if factors influence release from the plasma protein. Thus, for example, a plasma protein-bound coumarin derivative may be displaced from its binding site on the plasma protein by sulfonamides.
Thus, while the blood levels are constant, the availability of the coumarin derivatives increases on simultaneous treatment with sulfonamides.
Excursions outside the therapeutic range, and variations in the availability and efficacy may be related to diet or physiological/metabolic, physical/
endogenous or therapeutic factors. The therapeutic range, the availability and the efficacy of a medicament moreover vary between individuals. A part is played in this by individual factors such as height, proportion of body fat, metabolism etc.
It is an object of the invention to eliminate the disadvantages of the prior art. In particular, it is intended to provide a medicament or a mutually coordinated combination of medicaments with an efficacy which is as constant as possible. The undesired effect of dietary, physiological/metabolic, physical/
endogenous or therapeutic factors on the efficacy is to be reduced. The medicament or the mutually coordinated combination of medicaments is to have similar efficacy in different people despite individual differences. The aim is to increase the reliability of the therapeutic effect .
This object is achieved by the features of claims 1 and 8. Expedient developments of the invention are evident from the features of claims 2 to 7 and 9 to 13.
This object is achieved by the presence of at least one antagonist of this active ingredient. It is likewise achieved by a mutually coordinated combination of two medicaments, where a first medicament comprises at least one active ingredient and a second medicament comprises at least one antagonist of this active ingredient.
The antagonist brings about an increase in the therapeutically effective concentration of the active ingredient. Thus, in order to achieve a particular therapeutic effect, the dose employed of active ingredient must be higher than without the antagonist.
The effects of interfering factors or individual factors on the efficacy of the active ingredient administered in increased dosage are proportionately less than with an active ingredient in a conventional dose. A higher antagonist dose means a higher therapeutically effective concentration of the active ingredient and a smaller effect of interfering factors or individual factors on the efficacy of the active ingredient. The desired therapeutic effect is achieved with greater certainty using the medicament according to the invention or the mutually coordinated combination of medicaments compared with conventional medicaments. The patient is less restricted during therapy with the medicament according to the invention.
Thus, for example, he needs to comply with diets less strictly than during therapy with conventional medicaments. Medication with a medicament according to the invention is simpler for the physician than with a conventional medicament because he needs to take less account of individual differences between various patients. The medicament according to the invention moreover opens up new therapeutic possibilities. The influence of other medicaments on the medicament according to the invention is less than with conventional medicaments. The physician is able to combine with one another active ingredients which cannot be administered together in the case of conventional medication.
In an advantageous development of the medicament according to the invention or of the mutually coordinated combination, according to the invention, of medicaments, the active ingredient and the antagonist are present in amounts such that a therapeutically effective concentration of the active ingredient is reached during therapy. The choice of suitable amounts and thus of a particular ratio of amounts of active ingredient and antagonist makes it possible to determine the efficacy of the medicament according to the invention. Medicaments according to the invention with identical combination of active ingredient and antagonist can be provided for diverse applications with different efficacies.
A medicament according to the invention or a mutually coordinated combination, according to the invention, of medicaments is particularly advantageous when the antagonist is present in an amount which increases the therapeutically effective concentration of the active ingredient during therapy to an extent such that external or endogenous interfering variables or individual factors are substantially unable to influence the effect of the active ingredient. The influence which said interfering variables or factors can exert decreases as the therapeutically effective concentration of the active ingredient increases. The increase in the therapeutically effective concentration of the active ingredient until interfering variables and individual factors are substantially unable to influence its effect increases the reliability of the medicament.
In a preferred development of the medicament according to the invention and of the mutually coordinated combination, according to the invention, of medicaments, the affinity of the active ingredient for one of its specific binding partners at the site of action differs from that of the antagonist for one of its specific binding partners. It is possible in this case for the specific binding partner of the active ingredient and that of the antagonist to be identical.
This is the case, for example, when the active ingredient and the antagonist compete for binding to one and the same receptor. The different affinities permit an equilibrium to be set up between antagonist and active ingredient, which equilibrium is able to "buffer" the influence of interfering variables. The dose of active ingredient in a system which can be influenced by a medicament according to the invention and in which, for example, the antagonist has a higher affinity than the active ingredient itself for the receptor of the active ingredient is high. Only a sufficiently high dose of active ingredient is able to displace such an antagonist from the receptor and thus display its effect. If there is also for example an endogenous interfering factor which competes with similar affinity as the active ingredient for binding to the same receptor in this system, its influence on the system is small because of the high dose of active ingredient.
In a further development, vitamin K is present as antagonist, and at least one vitamin K antagonist is present as active ingredient. The vitamin K antagonist may in this case be selected from the group of coumarin derivatives. Examples thereof are dicoumarol, phenprocoumon (Marcumar~), acenocoumarol (Sintrom~) and warfarin (Coumadin~). A medicament according to the invention preferably comprises from 0.1 to 10 mg of vitamin K and from 3 to 10 mg of phenprocoumon, preferably 0.5 to 3 mg of vitamin K and 4.5 to 7.5 mg of phenprocoumon, in particular 0.5 to 1.5 mg of vitamin K and 5 to 7 mg of phenprocoumon. The medicament can be administered one to four times a day.
The invention additionally relates to the use of an active ingredient and of an antagonist of this active ingredient for producing a medicament or a mutually coordinated combination of medicaments for combined administration.
The invention also encompasses the therapy of a patient by administering the medicament or a correspondingly constituted combination of medicaments. The medicament _ 7 _ or combination of medicaments is in this case provided with written instructions for the patient; the written instructions contain, in the case of the combination, information about the amounts and the maximum time interval for taking the medicaments. The invention further encompasses a composition of matter comprising at least one therapeutic active ingredient and at least one antagonist of this active ingredient. Concerning advantageous developments of the active ingredient and of the material, reference is made to the preceding statements.
The features which have been mentioned and are to be explained below can be used not only in the particular combinations indicated but also in other combinations or alone. Further advantages are evident from the following example and in connection with the drawing.
This shows in Fig. 1 a diagrammatic representation of the effect of a coumarin derivative on the vitamin K cycle and on blood coagulation, Fig. 2 a diagrammatic representation of the thera-peutic range and of the plasma level of phenprocoumon, and of the variations in the anticoagulant effect of phenprocoumon on administration with a medicament according to the prior art and Fig. 3 a diagrammatic representation of the thera-peutic range and of the plasma level of phenprocoumon, and of the variations in the anticoagulant effect of phenprocoumon on administration with a medicament according to the invention.
The decarboxylated coagulation factors identified in Fig. 1 are those coagulation factors which are activated by carboxylation. Activation renders them capable of inducing blood coagulation. Decarboxylated coagulation factors which may be present are:
factor VII, protein C, factor IX, protein S, factor X
and prothrombin. The carboxylation is catalyzed by the enzyme 'y-glutamyl-carboxylase. In this case, vitamin K
hydroquinone is converted as cofactor into vitamin K
epoxide in stoichiometric amounts. Most of the vitamin K hydroquinone is recovered from vitamin K
epoxide with the aid of the enzyme vitamin K epoxide reductase (VKER). Less than 1$ of the vitamin K
hydroquinone is formed from newly consumed vitamin K.
The daily vitamin K requirement is 0.03 - 1.5 ~glkg of body weight. VKER can be inhibited by coumarin derivatives such as warfarin or phenprocoumon. The resulting inhibition of vitamin K hydroquinone production and thus of carboxylation of the.
decarboxylated coagulation factors leads to inhibition of blood coagulation. If the dosage of coumarin derivatives is sufficiently high, recovery of vitamin K
hydroquinone from vitamin K epoxide can be substantially suppressed. Vitamin K hydroquinone production and blood coagulation then depend mainly on the vitamin K intake.
The amounts of vitamin K present in foodstuffs vary.
The anticoagulant effect of coumarin derivatives varies depending on the amount of vitamin K consumed with the diet. This is shown by way of example for the active ingredient phenprocoumon administered with a conventional medicament in Fig. 2. The limits of the therapeutic range of phenprocoumon are represented here by broken lines. It is in the range between 0.02 and 0.05 ~.g of phenprocoumon per m1 of plasma. After taking the medicament, a phenprocoumon plasma level within the therapeutic range is set up as shown by the dotted line. The plasma level scale is on the Y axis at the left. The anticoagulant effect is represented by the full line. It is indicated in arbitrary units, for _ g _ which the scale is on the Y axis at the right. Since carboxylated coagulation factors are initially still present in the body, the anticoagulant effect has its onset only after they have been consumed. The latency period is about 6 hours, and the full effect does not occur until after 36 to 72 hours. However, the anticoagulant effect does not remain relatively constant like the plasma level. The repeated large decrease in the anticoagulant effect depicted here is caused in each case by intake of vitamin K with the diet. The anticoagulant effect increases again only after the plasma level of vitamin K, which is not depicted here, has fallen.
The broken lines in Fig. 3 also represent the limits of the therapeutic range of phenprocoumon. The dotted line shows the phenprocoumon plasma level and the full line shows the anticoagulant effect of phenprocoumon. The axis scales are identical to those in Fig. 2. In the example depicted in Fig. 3, a medicament according to the invention is used to supply a defined amount of vitamin K in addition to phenprocoumon. The simultaneous supply of vitamin K shifts the therapeutic range of phenprocoumon to a higher plasma level. In this case it is between 0.07 and 0.1 ~g of phenprocoumon per ml of plasma. The medicament according to the invention therefore contains a larger amount of phenprocoumon compared with a conventional phenprocoumon medicament. A substantial blockade of VKER by phenprocoumon means that the vitamin K
administered with the medicament is the essential source for generating vitamin K hydroquinone. The dose thereof is such that blood coagulation is inhibited but is maintained to an extent such that no unwanted hemorrhages occur in the patient. After the medicament according to the invention is taken, a phenprocoumon plasma level within the therapeutic range is set up.
The anticoagulant effect remains relatively stable even after intake of vitamin K with the diet. The amount of - 1~ -vitamin K supplied with the diet represents only a small proportion of the total intake of vitamin K. It thus has a much weaker effect on the inhibition of blood coagulation than during therapy with a phenprocoumon medicament according to the prior art, as depicted in Fig. 2. The medicament according to the invention brings about a stabilization of the anticoagulant effect of phenprocoumon.
Claims (13)
1. A medicament having at least one active ingredient, characterized in that at least one antagonist of this active ingredient is present.
2. A mutually coordinated combination of two medicaments, where a first medicament comprises at least one active ingredient and a second medicament comprises at least one antagonist of this active ingredient.
3. A medicament or mutually coordinated combination of medicaments as claimed in claim 1 or 2, characterized in that the active ingredient and the antagonist are present in amounts such that a therapeutically effective concentration of the active ingredient is reached during therapy.
4. A medicament or mutually coordinated combination of medicaments as claimed in any of the preceding claims, characterized in that the antagonist is present in an amount which increases the therapeutically effective concentration of the active ingredient during therapy to an extent such that external or endogenous interfering variables or individual factors are substantially unable to influence the effect of the active ingredient.
5. A medicament or mutually coordinated combination of medicaments as claimed in any of claims 1 to 4, characterized in that the affinity of the active ingredient for its specific binding partner at the site of action differs from that of the antagonist for its specific binding partner.
6. A medicament or mutually coordinated combination of medicaments as claimed in any of claims 1 to 5, characterized in that vitamin K is present as antagonist, and at least one vitamin K antagonist, in particular a coumarin derivative, in particular dicoumarol, phenprocoumon, acenocoumarol or warfarin, is present as active ingredient.
7. A medicament or mutually coordinated combination of medicaments as claimed in any of claims 1 to 6, characterized in that from 0.1 to 10 mg of vitamin K and from 3 to 10 mg of phenprocoumon, preferably 0.5 to 3 mg of vitamin K and 4.5 to 7.5 mg of phenprocoumon, in particular 0.5 to 1.5 mg of vitamin K and 5 to 7 mg of phenprocoumon, are present therein.
8. The use of at least one active ingredient and of at least one antagonist of this active ingredient for producing a medicament or a mutually coordinated combination of medicaments.
9. The use as claimed in claim 8, characterized in that the active ingredient and the antagonist are present in the medicament or the mutually co-ordinated combination of medicaments in amounts such that a therapeutically effective con-centration of the active ingredient is reached during therapy.
10. The use as claimed in either of claims 8 or 9, characterized in that the antagonist is present in the medicament or the mutually coordinated combination of medicaments in an amount which increases the therapeutically effective concentration of the active ingredient during therapy to an extent such that external or endogenous interfering variables or individual factors are substantially unable to influence the effect of the active ingredient.
11. The use as claimed in any of claims 8 to 10, characterized in that the affinity of the active ingredient for its specific binding partner at the site of action differs from that of the antagonist for its specific binding partner.
12. The use as claimed in any of claims 8 to 11, characterized in that vitamin K is present as antagonist, and at least one vitamin K antagonist, in particular a coumarin derivative, in particular dicoumarol, phenprocoumon, acenocoumarol or warfarin, is present as active ingredient.
13. The use as claimed in any of claims 8 to 12, characterized in that from 0.1 to 10 mg of vitamin K and from 3 to 10 mg of phenprocoumon, preferably 0.5 to 3 mg of vitamin K and 4.5 to 7.5 mg of phenprocoumon, in particular 0.5 to 1.5 mg of vitamin K and 5 to 7 mg of phenprocoumon, are present in the medicament or the mutually coordinated combination of medicaments.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19955607.5 | 1999-11-19 | ||
| DE19955607A DE19955607A1 (en) | 1999-11-19 | 1999-11-19 | Drug or coordinated combination of drugs |
| PCT/DE2000/003977 WO2001037818A2 (en) | 1999-11-19 | 2000-11-16 | Medicament and combination of compatible medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2388103A1 true CA2388103A1 (en) | 2001-05-31 |
Family
ID=7929548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002388103A Abandoned CA2388103A1 (en) | 1999-11-19 | 2000-11-16 | Medicament and combination of compatible medicaments |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1235569B1 (en) |
| JP (1) | JP2003514849A (en) |
| AT (1) | ATE259229T1 (en) |
| AU (1) | AU2502301A (en) |
| CA (1) | CA2388103A1 (en) |
| DE (2) | DE19955607A1 (en) |
| WO (1) | WO2001037818A2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2286070T3 (en) | 2000-05-12 | 2007-12-01 | Nattopharma Asa | FOOD PRODUCT CONTAINING VITAMIN K2. |
| GB0220182D0 (en) * | 2002-08-30 | 2002-10-09 | Cardiovascular Res Inst Maastr | Organic compounds |
| WO2008082542A1 (en) * | 2006-12-19 | 2008-07-10 | Institute For Therapeutic Research, Inc. | Combination of vitamin k and vitamin k antagonist such as r-isomer of warfarin, phenprocoumon or r-isomer of phenprocoumon as anticoagulant therapy |
| SE533680C2 (en) * | 2009-04-07 | 2010-11-30 | Per Ola Andersson | Method and apparatus for detecting drugs in a sample |
-
1999
- 1999-11-19 DE DE19955607A patent/DE19955607A1/en not_active Withdrawn
-
2000
- 2000-11-16 DE DE50005282T patent/DE50005282D1/en not_active Expired - Fee Related
- 2000-11-16 EP EP00988591A patent/EP1235569B1/en not_active Revoked
- 2000-11-16 AT AT00988591T patent/ATE259229T1/en not_active IP Right Cessation
- 2000-11-16 CA CA002388103A patent/CA2388103A1/en not_active Abandoned
- 2000-11-16 JP JP2001539433A patent/JP2003514849A/en active Pending
- 2000-11-16 WO PCT/DE2000/003977 patent/WO2001037818A2/en not_active Application Discontinuation
- 2000-11-16 AU AU25023/01A patent/AU2502301A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE50005282D1 (en) | 2004-03-18 |
| JP2003514849A (en) | 2003-04-22 |
| EP1235569B1 (en) | 2004-02-11 |
| EP1235569A2 (en) | 2002-09-04 |
| ATE259229T1 (en) | 2004-02-15 |
| AU2502301A (en) | 2001-06-04 |
| WO2001037818A2 (en) | 2001-05-31 |
| WO2001037818A3 (en) | 2002-06-20 |
| DE19955607A1 (en) | 2001-06-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |