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Treatment of drug-resistant human immunodeficiency virus infection

A technology for human immunodeficiency and viral infection, applied in antiviral agents, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as adverse therapeutic effects, drug insensitivity, and limited treatment options

Inactive Publication Date: 2003-04-30
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although advances have been made in AIDS treatment through the use of antiretroviral agents, an unfortunate consequence of this treatment is that the same antiretroviral agents put HIV-I under selective pressure to produce mutations that lead to drug insensitivity Sex and adverse treatment effects (Richman, Scientific American, 1988 279:88)
Viral resistance to antiretroviral drugs used to treat HIV infection is a major cause of treatment failure, limiting options for alternative antiretroviral treatments

Method used

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  • Treatment of drug-resistant human immunodeficiency virus infection

Examples

Experimental program
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preparation example Construction

[0035] Tablets are prepared by mixing the active ingredient (ie, one or more compounds described herein) with pharmaceutically inert, inorganic or organic carriers, diluents and / or excipients. Examples of such excipients which may be used in the manufacture of tablets include lactose, corn starch or derivatives thereof, talc, stearic acid or stearates. Examples of suitable excipients for gelatin capsules are vegetable oils, waxes, fats, semi-solids, liquid polyols. Lipid analogs can be prepared in microencapsulated form.

[0036] For nasal administration, formulations may contain a compound of the invention dissolved or suspended in a liquid carrier, especially an aqueous carrier for aerosol application. The carrier may contain solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives.

[0037] The present invention includes the use of a pharmacodynamic composition comprising a pharmaceutically acceptable ster...

Embodiment 1

[0063] Cultures of MT-2 cells infected with wild-type (xxLAI) or drug-resistant HIV-1 strains listed above were treated with lipid analogs of PFA (B-PFA, MB-PFA, or EB-PFA) . The concentrations (EC50) at the μM level required for 50% inhibition of the replication of drug-resistant HIV strains were determined and listed in Table 1. Drug effects were determined by measuring p24, a viral protein, in the culture medium.

[0064] Table 1 B-PFA, MB-PFA and EB-PFA against a group of drug-resistant HIV-1 strains

[0065] antiviral activity

[0066] EC 50 , μM

[0067] Virus PFA B-PFA MB-PFA EB-PFA

[0068] HIV-1 LAI (Control) 18.3 1.9 0.35 0.22

[0069] K65R 57.3 17.7 1.24 3.22

[0070] L74V 37.4 4.25 0.52 1.34

[0071] M184V 15.7 2.29 0.48 0.58

[0072] T215Y nd 0.84 0.27 0.14

[0073] M14L / T215Y 16.2 1.25 0.13 0.41

[0074] M184V / T215Y nd 1.49 0.54 0.48

[0075] 4xAZT 8.82 1.25 0.46 0.33

[0076] AZT...

Embodiment 2

[0082] The multidrug-resistant virus strains were tested at a multiplicity of infection increased by 5 times, that is, the MOI was 0.05, and the results are shown in Table 2.

[0083] Table 2 B-PFA, MB-PFA and EB-PFA against HIV-1 with multidrug resistance

[0084] Antiviral activity of virus strains

[0085] EC 50 , μM

[0086] Virus PFA B-PFA MB-PFA EB-PFA HIV-1 LAI (Control) 20.1 3.01 1.04 0.76

[0087] 11163pl 24.4 3.48 1.95 1.23

[0088] 11588pl 23.5 9.31 1.16 0.73

[0089] The p24 reduction assay was performed in MT-2 cells infected with 0.01 MOI. Abbreviated as in Table 1, RT mutants present in multi-drug resistant HIV-1: 11163p1=

[0090] M41L, A62V, V75I, F77L, K103N, F116Y, Q151M, Y181C, M184V; 11588p1 = A62V, K65R, K70R, V75I, F77L, F16Y, Q151M, M184V, K219Q.

[0091] As shown above, MB-PFA and EB-PFA showed high activity even in multi-drug resistant HIV-1 strains, such as clinical isolates 11163pI...

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PUM

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Abstract

The invention provides methods for treating HIV infection in a subject in need thereof comprising lipid analogs of phosphonoformate-containing pharmaceutically active compounds. Lipid analogs contemplated for use in the practice of the present invention comprise phosphonoformates covalently linked (directly or indirectly through a linker molecule) to a substituted or unsubstituted alkylglycerol, alkylpropanediol, alkylethanediol, or related moiety. In particular, the invention provides methods for treating viral infections caused by viruses which have developed resistance to currently available antiviral agents, as well as methods comprising the use of invention compounds in combination with azidodeoxythymidine to minimize the selection of drug-resistant HIV variants during therapy.

Description

technical field [0001] The present invention relates to methods of treating human immunodeficiency virus (HIV) infection. In particular, the invention relates to methods of treatment of viral infections caused by HIV variants which have developed resistance to antiviral agents which inhibit the replication of said virus. Background technique [0002] Antiviral agents have been successfully used to treat various diseases caused by viral infections. These agents are effective in treating viral infections by inhibiting the replication of the virus, for example, by interfering with the action of the viral polymerase, ie, replicase. In particular, infections caused by HIV have been effectively treated with agents that interfere with the normal function of the viral reverse transcriptase (RT), a replicase common to all retroviruses. [0003] Phosphoformate (PFA or phosphonate) is an effective antiviral agent because of its ability to inhibit the action of viral polymerases such ...

Claims

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Application Information

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IPC IPC(8): A61K31/66A61K31/661A61K31/662A61K31/7072A61K45/06A61P31/18
CPCA61K31/7064A61K31/662A61K31/661A61K31/66A61K31/7072A61K45/06A61P31/12A61P31/18A61K31/70A61K2300/00
Inventor K·Y·霍斯泰特勒J·W·梅勒斯
Owner RGT UNIV OF CALIFORNIA