Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-04
2001-09-18
Harrison, Robert H. (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S565000, C514S682000, C514S895000
Reexamination Certificate
active
06291488
ABSTRACT:
The present invention relates to synergistic combinations of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (atovaquone) and proguanil which have anti-parasitic activity. More particularly, the invention is concerned with pharmaceutical compositions containing said combinations, their use in the treatment of protozoal parasitic infections such as malaria and toxoplasmosis and their use in the treatment of infections caused by
Pneumocystis carinii.
The compound 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone (atovaquone) has previously been disclosed, for example in European Patent No. 123,238 which relates to 2-substituted-3-hydroxy-1,4-naphthoquinone of formula (I)
wherein either R
1
is hydrogen and R
2
is selected from C
1-6
alkoxy, aralkoxy,C
1-6
alkyl-C
1-6
alkoxy, phenyl substituted by one or two groups selected from halogen and C
1-6
alkyl, halogen and perhalo-C
1-6
alkyl or R
1
and R
2
are both C
1-6
alkyl or phenyl, and n is zero or 1, and physiologically acceptable salts thereof. The compounds are said to have antiprotozoal activity. Specifically, compounds of formula. (I) wherein n is zero are said to be active against the human malaria parasite
Plasmodium falciparum
and also against Eimeria species such as
E. tenella
and
E. acervulinam
which are causative organisms of
coccidiosis
and compounds of formula where n is 1 are said to be active against protozoa of the genus Theileria, in particular
T. annulata
or
T. parva
. Amongst the compounds specifically named and exemplified is the compound of formula (I) wherein n is zero, R
1
hydrogen and R
1
is 4-chlorophenyl, i.e. atovaquone.
Proguanil is a well-known drug for prophylaxis, but not treatment, of malaria. It is one of the safest antimalarial drugs and may be given to young children and pregnant women. However resistance of
P. falciparum
to proguanil has appeared particularly in South East Asia, and is an increasing problem.
In order to combat drug resistance it is becoming standard practice to use combinations of more than one antimalarial, either simultaneously or sequentially. However, many such combinations are antagonistic, resulting in less effective treatment and the dosage regimens are often complicated, increasing the likelihood of patients failing to complete the treatment. Accordingly, it was an object of the present invention to provide a combination of antimalarial drugs which was not antagonistic and which did not require a complex dosing regimen.
It has now surprisingly, been found that by combining, either concomitantly or sequentially, atovaquone, represented in this specification by formula (II):
and proguanil, potentiation of antiparasitic and particularly antimalarial activity is achieved. Furthermore a potentiating combination of the compound of formula (II) and proguanil can be simply presented in a single pharmaceutical formulation.
In a first aspect, the present invention provides a method for the treatment and/or prophylaxis of a protozoal parasitic infection, e.g. malaria or toxoplasmosis, or an infection caused by
P.Carinii
in mammals, including humans, which comprises administering an effective amount of atovaquone or a physiologically acceptable salt thereof and concomitantly or sequentially administering an effective amount of proguanil.
In a second aspect, the present invention provides atovaquone for use in the manufacture of a medicament, for administration either concomitantly or sequentially with proguanil, for treatment and/or prophylaxis of a protozoal parasitic infection, e.g. malaria or toxoplasmosis or an caused by
P. carinii
, in mammals, including humans.
Preferably the compound of formula (B) and proguanil are administered concomitantly. Most preferably the compound of formula (II) and proguanil are administered in a potentiating ratio.
Thus, according to a further aspect of the present invention, there is provided a combination of atovaquone, or a pathologically acceptable salt thereof, and proguanil wherein atovaquone, or its salt, and proguanil are present in a potentiating ratio.
The term ‘potentiating ratio’ is used herein to indicate that atovaquone and proguanil are present in a ratio such that the antiparasitic activity of the combination is greater than that of either atovaquone or proguanil alone or of the additive activity that would be predicted for the combination based on the activities of the individual components. Thus the individual components act synergistically in combination provided they are present in a potentiating ratio.
A potentiating ratio, which may be successfully used to treat malaria, including hydroxynaphthoquinone resistant strains of malaria is in the range 1:0.1-1:100 of proguanil: atovaquone. Suitably, the potentiating ratio is in the range 1:0.2-1.10.
A particularly preferred potentiating ratio is in the range 1:1-1:3.
The present invention also provides in another aspect a method for the treatment and/or prophylaxis of malaria in mammals, including humans, which comprises administering an effective amount of a combination of atovaquone, or a physiologically acceptable salt thereof and proguanil.
The hydroxyl group of atovaquone may form salts with appropriate bases, and physiologically acceptable salts of atovaquone include inorganic base salts such as alkali metal (e.g. sodium and potassium) salts and alkaline earth metal (e.g. calcium salts: organic base salts e.g. phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine and diethanolamone salts: and amino acid salts e.g. lysine and arginine.
It will be appreciated that the compound of formula (II) may exist as the cis or trans isomer, that is to say that the cyclohexyl ring any be cis or trans substituted by the naphthoquinone nucleus and the chlorophenyl group. Both cis and trans isomers and mixtures thereof in any ratio may be used in accordance with the present invention. In general mien the compound is in the form of a mixture of isomers the trans isomer will be present in an amount of about 50% or will be the predominant isomer but the use of mixtures in which the cis isomer predominates is also included within the scope of the invention. The specific ratio of isomers may be varied as required; typical mixtures include those in which cis/trans isomer ratio is about 1:1,40:60 and 5:95. For use according to the present invention the trans isomer of the compound of formula (II), or a mixture of its cis and trans isomers containing at least 95% e.g. 99% of the trans isomer, is preferred.
The compound of formula (II) may also exist in a tautomeric form in which the hydroxyl group donates its proton to one of the one groups and the use of such tautomeric forms is included within the scope of this invention. However, it is believed that the stable form is that shown in formula (II).
The amount of a combination of atovaquone and proguanil required to be effective as an antiparasitic agent will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the route of administration and nature of the formulation, the mammal's bodyweight, age and general condition and the nature and severity of the disease to be treated. In general, a suitable effective dose for administration to man for treatment of malaria is in the range of 2.0 mg to 30 mg of proguanil per kilogram bodyweight per day and 0.5 mg to 30 mg of atovaquone per kilogram bodyweight per day, for example from 3 to 20 mg/kg/day of proguanil and 1 to 20 mg/kg/day of atovaquone, particularly 5 to 15 mg/kg/day of proguanil and 3 to 15 mg/kg/day of atovaquone.
At suitable effective dose for administration to man for prophylaxis of malaria is in the range of from 3 to 20 mg per kilogram bodyweight per week of each of proguanil and atovaquone for example from 6 mg/kg/week to 10 mg/kg/week of each of proguanil and atovaquone.
It should be understood that the dosages referred to above are calculated in terms of the drip per se.
For use according to the present invention the com
Gutteridge Winston Edward
Hutchinson David Brian Ashton
Latter Victoria Susan
Pudney Mary
Glaxo Wellcome Inc.
Harrison Robert H.
Nixon & Vanderhye
LandOfFree
Preventing protozoal infections does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preventing protozoal infections, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preventing protozoal infections will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2447304