Important note: Information in this article was accurate in August 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, August 23, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- A potent new drug may ultimately replace one of the mainstays of AIDS therapy.
The new drug is the racemic nucleoside-analog reverse transcriptase inhibitor (NARTI) 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC). It is structurally related to lamivudine (trade name, Epivir, Glaxo): (-) enantiomeric 2'-deoxy-3'-thiocytidine. Because it greatly enhances the potency of other NARTIs, lamivudine is one of the most frequently used antiretroviral agents.
New studies by researchers associated with BioChem Pharma show that the company's dOTC is more potent than 3TC and, at least in vitro, far slower to give rise to resistance mutations. It also retains its potency against HIV strains resistant to both 3TC and zidovudine (AZT).
"The data presented in this report support the advancement of dOTC into clinical trials," wrote Jean-Marc De Muys, Robert F. Rando, and colleagues.
De Muys et al. reported their findings in the journal Antimicrobial Agents and Chemotherapy ("Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2'-Deoxy-3'-Oxa-4'-Thiocytidine," Antimic Ag Chem, 1999;43(8):1835-44).
In vitro studies showed dOTC to have a high therapeutic index, with efficacy at much lower concentrations than those toxic to cells. In vivo studies showed no toxic effects on rats.
Other murine studies showed that the drug is well absorbed with good (77 percent) bioavailability. Perhaps even more importantly, high levels of the drug (16.5 percent of serum levels) were detected in animals' cerebrospinal fluid.
Attempts to raise HIV strains resistant to dOTC were unsuccessful through 12 passages in culture.
"This feature of dOTC may provide a significant advantage when the drug is administered to humans," De Muys et al. suggested.
NARTIs were the first class of antiretroviral drugs to be approved for human use. Interest in new NARTIs has waned in recent years with the success of HIV protease inhibitors and a focus on targets other than reverse transcriptase. De Muys et al. warned that it is too soon to give up on the search for better NARTIs.
"The effectiveness of dOTC against drug-resistant clinical isolates of HIV-1 suggests that the full potential of antiviral nucleoside analogs has not yet been realized and that further investigation into novel nucleoside analogs is warranted," they wrote.
The corresponding author for this study is Robert F. Rando, BioChem Pharma Inc., 275 Armand-Frappier Blvd., Laval, Quebec H7V 4A7, Canada. Phone: 450-978-7873. Fax: 450-978-7946. Email: <randor@biochempharma.com>.
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