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More About Drugs

Spring 1998

Inexpensive AIDS Drug

At the Fifth Conference on Retroviruses and Opportunistic Infections, Jeffrey E. Galpin of the Sherman Oaks Hospital Research Institute in Los Angles reported that a combination of an older leukemia treatment drug, hydroxyurea, with the drug ddI and d4T, reduced the level of HIV in the blood of 42 patients below detectable levels. The new drug is inexpensive-it costs $30 a month-compared to the $1,300 monthly price tag of combination therapies that use protease inhibitors and reverse transcriptase inhibitors. Researchers also reported that three HIV-positive patients who received hydroxyurea treatment over a year ago may have permanent remission of the virus. The drug targets host cells in the patient, rather than the virus itself, preventing HIV from developing a resistance to the drug. The drug also appears to reduce the chance of HIV resistance to other AIDS treatments. While some researchers are skeptical about the remission claims, many have begun incorporating hydroxyurea into existing combination treatments.


Zerit

ZERIT (stavudine, also known as d4T) has overtaken AZT as the most commonly prescribed nucleoside reverse transcriptase inhibitor (NRTI) in HIV therapy.

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In its recently issued "Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents," the U.S. Department of Health and Human Services recommends using a nucleoside analog as the foundation of combination therapy.

Effectiveness, low side effects, low chance of resistance, and convenient dosing are among the benefits of using Zerit in your combination therapy. It also appears to demonstrate a sustainable antiviral effect.

While rapid development of resistance has been observed with AZT, long-term use of d4T has rarely been associated with the development of resistance.

Bristol-Myers Squibb is developing two protease inhibitors for the treatment of HIV as well as integrase inhibitors and chemokine receptors.

In the U.S., d4T is indicated for the treatment of HIV-infected patients who have received prolonged prior AZT therapy. The most notable clinical toxicity of d4T is peripheral neuropathy, which usually resolves if treatment is withdrawn. Resumption of treatment may be considered at a reduced dose.


The Problem with AZT

Adapted from JAMA

Newsline A team of German researchers have discovered a glitch in the processing of AZT which may explain the drug's limitations and eventually lead to the development of improved HIV medications.

In order to infect a cell, HIV must convert its genetic material, or RNA, to take over the DNA of the cell it is targeting. To do so, the virus requires the help of its enzyme, reverse transcriptase (RT). AZT works by preventing this enzyme from doing its job properly.

However, researchers have known for some time that AZT is only partially able to block the action of RT, a fact which explains the drug's limited effect when used as monotherapy. In an issue of Nature Medicine, German investigators report the discovery of a "bottleneck" in the processing of AZT which may explain why the drug has never lived up to its initial promise.

AZT is a pro drug; that is, a substance which must be converted to its active form once inside the body. To become active, AZT must pass through three distinct metabolic stages. At each of these stages, a chemical reaction occurs during which a cluster of atoms called a phosphate group is attached to the AZT molecule. Once each of these steps has been completed, AZT, now in its triphosphate form, is inserted into a growing viral DNA molecule by RT. Once there, the drug interferes with the growth of the DNA chain, thereby preventing the virus from completing its replication.

However, according to the study in question, the second stage necessary to AZT's conversion to its active form takes place very slowly. As a result, an accumulation of AZT in its powerless monophosphate form occurs, a fact that researchers claim may explain not only the drug's sluggishness, but also many of its worst side effects.

In explanation of the slow conversion of AZT to its diphosphate form (second stage), the researchers offer the following: The structural modification of AZT that equips it to block RT is bulky and therefore disrupts the ability of an enzyme called TmpK to attach the phosphate group to the AZT molecule. This results in what the researcher's describe as a "bottleneck". As the conversion of AZT slows, the production of functional HIV DNA progresses with little interruption. Hence the need to combine AZT with other antiretrovirals to control viral replication.

Although this discovery may seem discouraging, the information it provides may help guide the design of future HIV medications that will not share the disadvantage described above. As well, researchers speculate that given the accumulation of AZT in its monophosphate form, it may be possible to prescribe lower doses of the drug in the future without compromising its effect. In the meantime, AZT must still be viewed as an important part of the anti-HIV arsenal, especially given its ability to penetrate the central nervous system and its effectiveness when used in combination therapies tested in clinical trials.




  
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This article was provided by Women Alive. It is a part of the publication Women Alive Newsletter.
 

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