Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-02-03
2000-03-21
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514 50, A01N 3312, A01N 4304
Patent
active
060403462
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel therapeutic use of L-carnitine, the derivatives thereof and their pharmacologically acceptable salts in combination with antiretroviral drugs for the therapeutic treatment of HIV-infection and AIDS. More particularly, the present invention relates to the use of L-carnitine, acyl L-carnitines wherein the acyl group, straight or branched, has 2-6 carbon atoms, and the pharmacologically acceptable salts thereof in combination with nucleoside-like inhibitors of reverse transcriptase, non-nucleoside inhibitors of reverse transcriptase and inhibitors of HIV protease, for reducing ceramide levels and enhance the activity of the aforesaid antiretroviral drugs in HIV-infected patients.
Most of the pathogenetic mechanisms that contribute to the progression of infection due to human immunodeficiency virus 1 or 2 (HIV-1, HIV-2) are directly or indirectly related to the state of general activation of the immune system.
Chronic activation of the immune system potentiates viral replication both via secretion of a number of cytokines favouring HIV expression and by maintaining a reserve of activated immune cells which act as targets for the HIV and facilitate its replication.
Moreover, the state of persistent activation of the immune system induces abnormalities of such a nature (e.g. an increased apoptosis) as to lead to a progressive weakening of the immune responses.
A vicious circle is thus set up: progressive loss of competence of the immune system.fwdarw.viral dissemination.fwdarw.reduced elimination of the virus.fwdarw.chronic activation of the immune system. The above process may last for years until such a marked deterioration of the immune system occurs as to lead to an uncontrolled viral replication and to the onset of opportunist infections, or to the development of acquired immuno-deficiency syndrome (AIDS).
On the basis of the pathogenetic mechanisms outlined above, it appears dear that any anti-HIV treatment must be aimed at reducing viral replication and at blocking the deterioration of the immune system.
As regards antiretroviral therapy, unfortunately HIV is characterized by a high degree of genetic variability originating above all in the very substantial lack of precision of reverse transcriptase. The retroviral enzyme lacks enzymatic systems for the control of possible transcription errors. The result is the emergence of variants of the virus--over a range which is a function of viral replication--which are responsible for the progressive eluding of the immune system and of resistance to antiretroviral drugs. In the case of zidovudine (AZT, ZDV) the loss of clinical efficacy in situations of monotherapy is an extensively acknowledged fact. Even the anti-retroviral agents discovered more recently, e.g. zalcitabine [ddc], didanosine [ddI] and lamivudine [3TC] suffer from the same drawback.
It has recently been demonstrated that ceramide stimulates HIV expression. What is more, ceramide is one of the factors capable of inducing cellular apoptosis, a phenomenon which is increased in subjects with HIV infection and which contributes to the depletion of TCD4 and TCD8 lymphocytes. It thus appears evident that changes in the concentration or metabolism of ceramide may affect the viral load and cellular apoptosis in HIV-infected subjects (Papp B. et al., AIDS, Res. Hum. Retrovirus, 10(7), 775-80).
Surprisingly, it has now been found that L-carnitine and derivatives thereof, i.e. the acyl L-carnitines wherein the acyl group, straight or branched has 2-6 carbon atoms and the pharmacologically acceptable salts thereof inhibit ceramide synthesis by at least 25% and when they are used in combination with antiretroviral drugs such as e.g. AZT, stavudine [d4T], fluorothymidine [FLT], azidouridine [Azdu], phosphonated acyclic nucleosides [PMEA], HIV-1 specific nucleosides ([TSAO], zalcitabine [ddC], didanosine [ddI] and lamivudine [3TC], dipyridodiazepinones, tetrahydroimidazobenzodiazepinones, pyridones or L drugs, bis-heteroarylpiperazines, derivatives of alpha-anilinophenyla
REFERENCES:
patent: 4194006 (1980-03-01), Cavazza
DeSimone et al, "High Dose L-Caritine Improves Immunologic and Metabolic Parameters in AIDS Patients", Immunopharmacology and Immunotixicology, 15(1), pp. 1-12, 1993.
Mendes s.r.l.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
Travers Russell
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