Therapeutic combinations

Details Therapeutic combinations Therapeutic combinations

1997-03-20

2001-01-23

Travers, Russell (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S049000, C514S050000

Reexamination Certificate

active

06177435

ABSTRACT:

The present invention relates to therapeutic combinations for the treatment of Human Immunodeficiency Virus (HIV) infections comprising zidovudine and an agent serving to enhance the antiviral activity of zidovudine against HIV populations otherwise resistant to attack by zidovudine.
Zidovudine, which has the chemical name 3′-azido-3′-deoxythymidine, is now well established as an important and useful chemotherapeutic agent for the treatment or prophylaxis of HIV-infections including related clinical conditions such as Acquired Immune Deficiency Syndrome (AIDS), AIDS-related complex (ARC) and also for the treatment of patients who have an asymptomatic HIV infection or who are anti-HIV antibody-positive.
Following the widespread clinical use of zidovudine in the therapy of such infections and conditions, it has been observed that in certain instances following prolonged treatment, the virus may develop a certain level of resistance to zidovudine and therefore a loss of sensitivity to the drug.
Other anti-HIV chemotherapeutic agents have been proposed and investigated, though very few of these agents have the combination of efficacy and safety possessed by zidovudine. Among these agents are various classes of non-nucleoside inhibitors of HIV reverse transcriptase which have been found to have potent anti-HIV activity in vitro. In contrast to nucleoside inhibitors these compounds do not need to be phosphorylated in vivo to exert their inhibitory effect but it has been found that their use rapidly induces resistance by the virus, i.e. loss of antiviral sensitivity to the compound by the virus. Other agents include antiviral nucleoside analogues containing an oxathiolane residue in place of the sugar residue for example nucleosides as described in European Patent Specification No. 382526 particularly (−)-2′,3′-dideoxy-3′-thiacytidine, otherwise known as 3TC or lamivudine, and PCT Patent Specification No. WO 92/14743 particularly (−)-2′3′-dideoxy-5-fluoro-3′-thiacytidine otherwise known as FTC. These compounds may be prepared as described in the above relevant Patent Specification.
We have now discovered a solution to the problem encountered in anti-HIV therapy of the development of resistance to zidovudine by the virus. In particular, we have found that the development and maintenance of resistance by HIV populations can be reduced or prevented, i.e. the sensitivity of such populations to zidovudine can be enhanced, by treating the virus population with an inhibitor of HIV-reverse transcriptase (HIV-RT) which induces a mutation in the RT coding sequence (a) in which the tyrosine residue at position 181 is replaced by a cysteine residue; or (b) in which the methionine residue at position 184 is replaced by a valine or isoleucine residue; such an inhibitor will be referred to hereinafter as “a mutation-inducing HIV-RT inhibitor”.
Examples of an HIV-RT inhibitor inducing a mutation of type (a) above include non-phosphorylated HIV-RT inhibitors, ie. inhibitors which are not required to be phosphorylated in vivo to be able to effect inhibition of HIV-RT.
Examples of an HIV-RT inhibitor inducing a mutation of type (b) above include oxathiolane nucleosides of the above types.
According to the present invention therefore we provide:
(a) a mutation-inducing HIV-RT inhibitor for use in enhancing or maintaining the antiviral sensitivity of an HIV population to zidovudine or a physiologically functional derivative thereof;
b) a therapeutic combination for the treatment or prophylaxis of HIV infections, especially zidovudine-resistant HIV infections, which comprises zidovudine or a physiologically functional derivative thereof, and a mutation-inducing HIV-RT inhibitor, whereby the antiviral sensitivity of a HIV population to zidovudine is enhanced or maintained by the said inhibitor;
(c) a method of enhancing or maintaining the antiviral sensitivity of an HIV population to zidovudine or a physiologically functional derivative thereof which comprises contacting said population with an effective amount of a mutation-inducing HIV-RT inhibitor;
(d) a method of treating a subject (e.g. a human) having an HIV infection resistant to zidovudine which comprises administering to the subject a combination of zidovudine or a physiologically functional derivative thereof and a mutation-inducing HIV-RT inhibitor;
(e) a mutation-inducing HIV-RT inhibitor for use in HIV therapy against HIV infections which are resistant to zidovudine;
(f) a method of increasing the sensitivity of a HIV population resistant to zidovudine or a physiologically functional derivative thereof comprising treating the virus with a mutation-inducing HIV-RT inhibitor.
It will be appreciated that the enhancement or maintenance of sensitivity to zidovudine of an HIV population in a patient can be readily determined in conventional manner, for example by observation of the relative clinical efficacy of the drug and/or by analytical determination of the levels of the virus or markers thereof in samples of appropriate biological materials (e.g. plasma) from the patient and/or by the determination of antiviral sensitivity in vitro in cell cultures of virus obtained from patients.
We have carried out in vitro experiments in which an HIV-1 population containing four mutations in the HIV-RT which confer zidovudine resistance was exposed in cell culture to increasing concentrations of a non-phosphorylated HIV-RT inhibitor represented by the compound known as “Chloro-TIBO”, i.e. 9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-S-imidazo[4,5,i-jk][1,4]benzodiazepine-2(1H)-thione. The virus became gradually more resistant to Chloro-TIBO and after five passages the 50% inhibitory concentration (IC
50
) for the compound against the virus had increased by more than fifty-fold, i.e. antiviral sensitivity to Chloro-TIBO had decreased. In contrast the sensitivity of the virus population to zidovudine had simultaneously increased about twenty fold, the IC
50
value for zidovudine decreasing from about 2 &mgr;M to less than 0.1 &mgr;M. It has been discovered through similar in vitro passage experiments that HIV can acquire rapid resistance to oxathialane nucleosides such as FTC and 3TC. Thus, the introduction of the M184 to V mutation into a zidovudine-resistant HIV strain (HIVRTMC), resulted in an increase in resistance to FTC (IC
50
values increased from 0.64 &mgr;M to >500 &mgr;M), whereas the virus became less resistant to zidovudine (IC
50
values fell from 1.26 &mgr;M to 0.17 &mgr;M). When the resistance mutation, Y181 to C, together with M184 to V, were introduced into this zidovudine-resistant virus, there was an even more pronounced effect on the enhancement of zidovudine sensitivity. The resulting mutant virus strain was now co-resistant to the oxathialane nucleosides and non-phosphorylated HIV-RT inhibitors, but had become completely sensitive to zidovudine (IC
50
values for zidovudine fell from 1.26 to 0.04).
In accordance with the present invention, a mutation-inducing HIV-RT inhibitor may be used to enhance the antiviral sensitivity of a zidovudine-resistant HIV population to zidovudine or alternatively to maintain the antiviral sensitivity of a HIV population in which zidovudine-resistance has not been induced.
Examples of non-phosphorylated HIV-RT inhibitors which may be employed in conjunction with the invention include:
a) tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-ones and -thiones (the so-called “TIBO” derivatives) for example as described by Pauwels et al (1990) Nature, 343, 470-474, and in European Patent Specification No. 384522.
A particularly preferred TIBO derivative for use in accordance with the invention is “Chloro-TIBO” (R-82913) referred to above.
b) dipyridodiazepinones for example as described by Merluzzi et al (1990) Science, 250, 1411-1413 and in European Patent Specification No. 429987.
A particular example of this class of compounds is the compound known as nevirapine (BI-RG-587), i.e. 11-cyclopr

Affiliated with

Also associated with

Rating

Therapeutic combinations does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Therapeutic combinations, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic combinations will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2548538