Transformed erythrocytes, process for preparing the same, and th

Details Transformed erythrocytes, process for preparing the same, and th Transformed erythrocytes, process for preparing the same, and th

1993-11-03

1998-05-19

Stanton, Brian R.

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

424 9321, 424 9321, 4241791, 424450, 43524021, 514 43, 514 45, 514 47, 514 49, A01N 4304, C12N 506, G01N 3100, G01N 3348

Patent

active

057532214

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The invention relates to transformed erythrocytes, to a process for preparing the same and to their use in pharmaceutical compositions, more particularly in the field of the treatment of pathologies caused by the infections of a human or animal by RNA type viruses.
Among these pathologies, acquired immunodeficiency syndrome (AIDS) is a lethal multisystem disease that has become a major public health problem.
AIDS is caused by the human immunodeficiency virus (HIV), which replicate primarily within T cells and macrophages (monocytes) leading to a loss of CD4.sup.+ cells and culminating in severe immunosuppression.
It is now clear that AIDS is no longer confined to homosexual men and intravenous drug users but is spread in the heterosexual population as well. Furthermore, pediatric AIDS is a growing problem.
Treatment of AIDS is based on the assumption that continued viral replication is involved in both the development and progression of the disease. The ability to grow the virus have made possible the identification of a class of compounds known as dideoxynucleosides that inhibit in vitro HIV replication and which are not new agents since studies on these compounds were initiated in the 1960' and 1970', before human retroviruses were discovered. Furthermore, these nucleoside analogs are well known as reagents for the Sanger DNA-sequencing procedure (Sanger F. et al., (1977). DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. 74: 5463).
AZT (Zidovudine: 3'-azido-3'-deoxythymidine) was the first nucleoside analog to be tested clinically and found to reduce the morbidity and mortality associated with severe HIV infection. However, due to dose-limiting toxicity, particularly bone marrow suppression, other dideoxynucleosides were studied as potential therapeutic agents.
2',3'-Dideoxycytidine (ddCyd), unlike the naturally occurring 2'-deoxynucleoside, lacks the hydroxyl (--OH) group in the 3'-position of the sugar ring. ddCyd at concentrations equal to or higher than 0.5 .mu.M completely protects target helper/inducer T cells against HIV infections and enables them to survive and grow. Under conditions of low multiplicity of infection, concentration equal to or higher than 10 nM of ddCyd can suppress the virus.
Furthermore, ddCyd is the most active as inhibitor of HIV replication in vitro among all the dideoxynucleoside analogs tested. ddCyd is also resistant to cytidine deaminase (a major catabolic enzyme for cytidine analogs), has good bioavailability, straight forward pharmacokinetic clearance by the kidney, failure to reduce normal intracellular pyrimidine pools and when clinically tested produced immunologic and virologic improvement in AIDS patients and a toxicity profile that does not overlap with that of AZT.
ddCyd, as other nucleoside analogs, exerts its antiviral effect by inhibiting the action of reverse transcriptase in the HIV life cycle. To do this, ddCyd must be phosphorylated to the 5'-triphosphate and this phosphorylation occurs by cellular and not viral kinases through its 5'-monophosphate derivative and then by CMP/dCMP kinase and kinase to the 5'-diphosphate and 5'-triphosphate respectively.
It has been demonstrated that dideoxynucleosides concentration that inhibit HIV replication are 10- to 20-fold lower than those that inhibit the proliferation and survival of host cells. DNA polymerase alpha, in fact, is relatively resistant to the effect of dideoxynucleosides while DNA pol gamma (the mitochondrial DNA pol) and DNA pol beta are much more susceptible to inhibition and this fact may account for some of the observed clinical toxicities.
In clinical trials investigating ddCyd, plasma levels of the drug during the infusion in patients receiving 0.09 mg/Kg exceeded the in vitro concentrations (more than 0.5 .mu.M) that confer complete protection against a high multiplicity of viral infection in vitro. However, at four hours after intravenous administration of ddCyd at this level, the plasma level decreased to below 0.1 .mu.M. The plasma half li

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