Potent combinations of zidovudine and drugs that select for the K65R mutation in the HIV polymerase

A medicament and dosage technology, applied in the direction of pharmaceutical formulations, antiviral agents, carbohydrate active ingredients, etc., can solve the problems of high toxicity compliance, non-elimination of HIV-1, decline, etc.

Inactive Publication Date: 2010-11-03
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these multiagent therapies do not eliminate HIV-1, and long-term treatment often leads to multiagent resistance
Also, many of these agents are highly toxic and / or require complex dosing regimens that can reduce compliance and limit efficacy

Method used

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  • Potent combinations of zidovudine and drugs that select for the K65R mutation in the HIV polymerase
  • Potent combinations of zidovudine and drugs that select for the K65R mutation in the HIV polymerase
  • Potent combinations of zidovudine and drugs that select for the K65R mutation in the HIV polymerase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: Computer Simulation Study to Determine Optimal AZT Dose Range

[0135] The current first-line highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV-1) infection combines two nucleoside reverse transcriptase inhibitors (NRTIs) together with protease inhibitors (PIs) or non- - Nucleoside reverse transcriptase inhibitors (NNRTI) (12, 13, 40) in combination. These drug combinations significantly reduced mortality and morbidity due to HIV-1 infection in developed countries (7). The failure of existing therapies to eradicate HIV-1 infection is due to compartmentalization of the virus and its underlying properties (58, 59). Thus, chronic therapy maintains the standard of care for the foreseeable future. Although the choice of HAART regimen was able to partially minimize cross-resistance and thereby delay the emergence of resistant virus, all regimens ultimately failed, mainly due to lack of adherence to rigorous regime...

Embodiment 2

[0172] Example 2: Synergy between amdosovir and zidovudine in a randomized double-blind placebo-controlled study in HIV-infected subjects

[0173] background

[0174] Amdosovir (AMDX; DAPD) has been well studied in 6 trials in nearly 200 subjects. In human lymphocytes, zidovudine (AZT) synergizes with DAPD and prevents selection for K65R mutations and thymidine analog mutations (TAMs). In computer simulations, the toxicity of lower doses of AZT could be reduced by reducing AZT monophosphate (AZT-MP) accumulation while maintaining the antiviral effect. The objective of the study was to examine the virological response to DAPD in HIV-infected subjects with and without reduced doses of AZT (ie, 200 mg twice daily, and the approved dose, 300 mg twice daily).

[0175] method

[0176] Subjects with HIV RNA viral load (VL) ≥ 5,000 copies / mL participated in the experiment and were randomly given 1:1:1 DAPD 500mg twice a day: DAPD 500mg+AZT 300mg twice a day: DAPD 500mg within 10 da...

Embodiment 3

[0183] Example 3: Dose Study on Effect of DAPD / AZT Combination Therapy and Mean Viable Cell Volume (MCV)

[0184] 24 subjects participated in the experiment [placebo (n=2), AZT 200mg (n=2), AZT 300mg (n=2), DAPD 500mg (n=6), DAPD / AZT 200mg (n=6), and DAPD / AZT 300mg (n=6)] and treated for 10 days. Blood indices including hemoglobin (g / dl) and mean corpuscular volume (MCV, femtoliter (fL)) were measured at screening 1 day before treatment and on days 5, 10, and 20 of treatment . One subject receiving DAPD / AZT 200 had a Grade 1 decrease in hemoglobin observed on Days 10 and 20, and microcytosis was observed at baseline and at all other sampling points. An increase in MCV (97 femtoliters (fL), normal 86±6) was observed at Day 20 in one subject receiving DAPD / AZT 300. At day 20, the trend in hemoglobin reduction from baseline was DAPD / AZT 300 ≥ AZT 300 ≥ DAPD / AZT 200 > AZT 200 > DAPD > placebo (results as Image 6 shown), while the rising trend of MCV from baseline was DAPD / AZT...

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Abstract

Combinations of antiretroviral nucleoside reverse transcriptase inhibitors, and methods for their use in treating retroviral infections, are provided. In one embodiment, the combinations include non-thymidine nucleoside antiretroviral agents, such as tenofovir-DF, abacavir, APD and DAPD, that select for the K65R mutation and relatively low doses of zidovudine (AZT) or other thymidine nucleoside antiretroviral agents. The thymidine nucleoside antiretroviral agents retard development of the K65R mutation, and at the low doses, are less likely to produce side effects. In another embodiment, the combinations include DAPD and AZT. DAPD retards the development of TAMs, and AZT retards the development of the K65R mutation. In a third embodiment, the combinations include adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, in further combination with at least one additional antiviral agent that works via a different mechanism than a nucleoside analog. This combination has the potential to eliminate the presence of HIV in an infected patient.

Description

Background technique [0001] In 1983, the cause of AIDS was identified as human immunodeficiency virus (HIV). In 1985, the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) was reported to inhibit the replication of human immunodeficiency virus. Since then, many other synthetic nucleosides have been shown to be effective against HIV, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), 2′ , 3′-Dideoxy-2′, 3′-Didehydrothymidine (D4T), ((1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9 -yl]-2-cyclopentene-1-methanol sulfate (salt) (ABC), cis-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxo Thiolane (FTC), (-)-cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC). In the use of cells Following cellular phosphorylation of 5′-triphosphate by kinases, these synthetic nucleosides are incorporated into the growing strand of viral DNA, causing chain termination due to the lack of a 3′-hydroxyl group. They are also capable of inhibiting the viral enzyme reve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70A61K31/7072A61K31/505A61P31/18
CPCA61K31/505A61K31/7072A61K31/70A61P31/14A61P31/18A61K2300/00
Inventor 雷蒙德·F·斯基纳齐
Owner EMORY UNIVERSITY
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