Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-04-03
2001-04-24
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S274000
Reexamination Certificate
active
06221852
ABSTRACT:
The present invention relates to certain enzyme inactivators which are especially useful for co-administration with other therapeutic compounds such as antiviral compounds in order to provide an improved therapeutic index by reducing the toxic side-effects.
A therapeutic nucleoside analogue that has been found to have a particularly beneficial clinical effect against a spectrum of conditions associated with Human Immunodeficiency Virus (HIV) infections such as Acquired Immune Deficiency Syndrome (AIDS), AIDS-related complex (ARC) and asymptotomatic infections, is the compound 3′-azido-3′-deoxythymidine having the approved name zidovudine. This compound at low doses is generally very well tolerated by patients and is now widely used in the treatment of HIV infections. However, in certain patients treated with zidovudine, some haematogical suppression including anaemia and neutropenia may be observed, presumably arising from a certain limited level of toxicity of zidovudine observed towards stem cells. Other less commonly observed side-effects have been described such as myopathy which may be related to intracellular activity of zidovudine.
It has now been found that the stem cell and haematological toxicity of zidovudine can be reduced by co-administration of an inactivator of the enzyme uracil reductase (dihydropyrimidine dehydrogenase, EC 1.3.1.2) which reduces the degradation of uracil.
The present invention is thus based on the discovery that the use of an inactivator of uracil reductase in combination with zidovudine reduces the cellular toxicity of zidovudine.
According to the present invention therefore we provide a uracil reductase inactivator for use in medical therapy, especially in combination with zidovudine or a pharmaceutically acceptable salt or ester thereof, for example in the treatment or prophylaxis of HIV infections such as AIDS, ARC and asymptomatic infections.
The present invention further provides:
a) a combination of a uracil reductase inactivator and zidovudine or a pharmaceutically acceptable salt or ester thereof;
b) a method for the treatment or prophylaxis of an HIV infection in a human which comprises administering to the said human an effective anti-HIV amount of zidovudine or a pharmaceutically acceptable salt or ester thereof in combination with a uracil reductase inactivator.
It should be noted that the references herein to uracil reductase inactivators refer to compounds that inactivate the uracil reductase enzyme, effectively acting as suicide substrates, in contrast to compounds that merely have an inhibiting effect on the enzyme.
It has been found that particularly beneficial effects in reducing the toxicity of zidovudine have been achieved using as a uracil reductase inactivator a 5-substituted uracil compound, particularly a uracil compound substituted in the 5-position by a halogen atom e.g. iodine or bromine; a C
2-4
alkenyl group (e.g. vinyl) optionally substituted by halogen e.g. 2-bromovinyl, 1-chlorovinyl or 2-bromo-1-chlorovinyl; a C
2-6
alkynyl group optionally substituted by a halogen (e.g. bromine) atom; a cyano group; or a C
1-4
alkyl group substituted by halogen e.g. trifluoromethyl. Particularly preferred inactivators of uracil reductase for use in accordance with the invention are 5-ethynyluracil and 5-propynyluracil. Other inactivators for such use include:
5-ethynyluracil
5-cyanouracil
5-propynyluracil
5-bromoethynyluracil
5-(1-chlorovinyl)uracil
5-iodouracil
5-bromovinyluracil
5-hex-1-ynyluracil
5-vinyluracil
5-trifluorouracil
5-bromouracil
5-(2-bromo-1-chlorovinyl)uracil
In experiments in mice, it has been found that red-blood cell anaemia induced by treatment with zidovudine could be at least partially prevented by treatment with 5-ethynyluracil.
The above 5-propynyluracil is a novel compound and represents a further feature of the present invention.
Other uracil reductase inactivators which may be employed in accordance with the present invention include compounds which generate the above uracil compounds in vivo. Such compounds include nucleoside derivatives which contain a nucleobase corresponding to the above 5-substituted uracil compounds, for example nucleoside derivatives containing a ribose, 2′-deoxyribose, 2′,3′-dideoxyribose, arabinose or other cleavable sugar portion, which may additionally contain a 2′- or 3′-substituent such as halo, for example fluoro. Specific examples of such nucleoside derivatives are 1-(&bgr;-D-arabinofuranosyl)-5-prop-1-ynyluracil and 2′,3′-dideoxy-5-ethynyl-3′-fluorouridine.
Zidovudine or a pharmaceutically acceptable salt or ester thereof and the said uracil reductase inactivator may be employed in combination in accordance with the invention by administration of the components of the combination to an appropriate subject either concomitantly, for example in a unitary pharmaceutical formulation, or, more preferably, separately, or sequentially within a sufficient time period whereby the desired therapeutic effect of the combination is achieved.
Zidovudine or a pharmaceutically acceptable salt or ester thereof and the uracil reductase inactivator may be administered respectively for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal); the oral route is especially preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and other clinical factors.
In general a suitable dose of zidovudine or a pharmaceutically acceptable salt or ester thereof will be in the range of 1.0 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 2 to 30 mg per kilogram body weight per day and most preferably in the range of 5 to 20 mg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throught the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
Experiments with 3′-azido-3′-deoxythymidine suggest that a dose should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 &mgr;M, preferably about 2 to 50 &mgr;M, most preferably about 3 to about 30 &mgr;M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 100 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
The uracil reductase inactivator may be administered in a dosage in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.01 to 10 mg per kilogram body weight per day, most preferably in the range of 0.01 to 0.4 mg per kilogram body weight per day; an alternative preferred administration regime is 0.5 to 10 mg/kg once per week.
The desired dose is preferably presented as one, two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms for example containing 1 to 200 mg, preferably 2 to 100 mg, most preferably 2 to 50 mg of the uracil reductase inactivator.
Zidovudine and the uracil reductase inactivator are employed in an appropriate ratio whereby the above-mentioned toxic effects of zidovudine are reduced or obviated without significant reduction of the therapeutic effect of zidovudine; such a ratio (based on the respective weights of zidovudine and uracil reductase inactivator) is generally in the range 1:1 to 1000:1, preferably in the range 5:1 to 500:1 an
Porter David J. T.
Rahim Saad George
Spector Thomas
Glaxo Wellcome Inc.
Jarvis William R. A.
Lemanowicz John L.
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