Composition and methods used during Anti-hiv treatment

Abstract

This invention relates to a composition comprising an anti-HIV treatment and a treatment for side effects of said anti-HIV treatment in an HIV-infected patient. This invention is, for example, very useful in the treatment of side effects caused by certain anti-HIV treatments, for example premature aging and lipodystrophy, which can be caused by protease inhibitors or reverse transcriptase inhibitors. The composition of this invention includes at least one hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, at least one farnesyl-pyrophosphate synthase inhibitor, and at least one anti-HIV agent. One of the processes for treating an HIV-infected patient includes, in any order, the following steps: (i) administration of a mixture including at least one hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and at least one farnesyl-pyrophosphate synthase inhibitor and (ii) administration of an anti-HIV agent, in which the administrations are concomitant, successive or alternative.

Description

RELATED APPLICATIONS[0001]The present application relates to French Patent Application No. FR 08 / 50019 filed on Jan. 3, 2008. This application also relates to French Patent Application No. FR 06 / 06097 filed on Jul. 5, 2006 and its corresponding PCT Application filed on Jul. 5, 2007 entitled “Médicament destine au traitement des maladies avec persistence et / ou accumulation de proteins prénylées” [“Drug intended for the treatment of diseases with persistence and / or accumulation of prenylated proteins”]. The entire contents of each of the above-referenced patent applications are hereby incorporated by reference.TECHNICAL FIELD[0002]The invention relates to an anti-HIV composition and processes for treating an HIV-infected patient.[0003]This invention is, for example, very useful in the treatment of side effects caused by certain anti-HIV treatments, for example premature aging and lipodystrophy, which can be caused by protease inhibitors or reverse-transcriptase inhibitors.[0004]In the...

AI Technical Summary

Benefits of technology

[0106]After lengthy research, the inventors showed that the association of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin family) and a farnesyl-pyrophosphate synthase inhibitor (amino-biphosphonate family, NBP), or one of their physiologically acceptable salts, is an effective treatment in situations, pathological or not, associated with the accumulation and / or the persistence, in the cells, of prenylated proteins, in the sense that it acts on the entire protein prenylation pathway, at C15 and at C20, or in non-characterized forms. The inventors also observed that the association of a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and a farnesyl-pyrophosphate synthase inhibitor has an additive effect in the restoration of the normal phenotype in fibroblasts of patients with Progeria. The effect of the association is clearly superior to the effect of one or the other of the inhibitors used individually (Varela et al. 2008 (54 bis)). The use of the association on cells of patients with Progeria leads to an inhibition in the prenylation of proteins, and therefore the appearance of non-farnesylated prelamin A and the improvement of nuclear symptoms and the partial correction of anomalies of DNA repartition. The prenylation inhibition is also observed in mice model for restrictive dermopathy and partially restore the mice lifespan (Varela et al. 2008 (54 bis)). Antiretroviral treatments target a plurality of metabolic pathways and a plurality of cell compartments, the cytosol, the nucleoplasm and the mitochondria.

[0112]The present inventors deduced that the side effects described above of the antiretroviral treatments can be minimized owing to a composition including or a treatment combining:

[0126]The core of the biphosphonates (BP) is equivalent to a P—O—P bond as in ATP, for example, but in which the oxygen is replaced by a carbon. This confers a very specific stability on these molecules.

Problems solved by technology

Indeed, a lamin B1 deficiency causes perinatal lethality in mice.

A number of mutations of the LMNA gene notably modify the assembly of proteins in the nuclear envelope and disrupt its functioning.

These morphological abnormalities are followed by functional alterations, and end by causing cell death.

The skin is rigid and taut, and gives way in places, causing, for example, tears at the armpits or the neck.

The latter, including myocardial infarction or atherosclerosis, are often the cause of death.

Cell nuclei in patients aging “normally” can have bulges characteristic of a laminopathy caused by accidental splicing events, which lead to abnormal cell functions and probably at least partially responsible for their aging.

The results are promising in vitro, but this is “gene” therapy, and the development of a drug based on this approach is extremely long and complicated, with all of the inconveniences associated with OAS vectorization in order to obtain an in vivo effect.

Finally, FTIs are specific to only one of the protein prenylation pathways, and cannot be envisaged as general post-translational prenylation inhibitors.

Whether they are genetic or acquired, these abnormalities in the nuclear matrix result in genomic instability and cell aging (Mehta et al., 2007; Oberdoerffer and Sinclair, 2007).

Abnormalities in lamin A cause a reduction in telomerase activity, resulting in accelerated telomere shortening.

Images