Note: Descriptions are shown in the official language in which they were submitted.
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WO 01/37818 PCT/DE00/03977
1
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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
