AIDSWEEKLY Plus, 10 June 1996
Daniel J. DeNoon, Senior Editor

At the same time its anti-HIV properties were announced, a new drug entered clinical trials in Europe.

The drug, 1,1'-azobisformamide or ADA, is an azoic compound with a molecular weight of 116.08 and the structural formula H[2]N-OC-N=N-CO-NH[2].

M. Vandevelde of Hubriphar SPRL, Brussels, Belgium, and colleagues reported in a letter to the journal AIDS Research and Human Retroviruses that ADA dissolved in DMSO inhibited both HIV-1 and HIV-2 in cultures of human peripheral blood lymphocytes ("ADA, A Potential Anti-HIV Drug," AIDS Res H, 1996;12(7):567-8).

Vandevelde et al. then went on to announce that human testing of the compound has already begun.

"Healthy volunteers have taken ADA at oral doses of 500 mg tid for 1 month without any drug-related signs or symptoms," Vandevelde et al. reported.

These studies showed that the maximum tolerated oral dose of ADA is 120 mg/kg body weight. Single oral doses of 60 mg/kg were not toxic.

The Belgian research team also said that they had begun human clinical trials of ADA.

"Patients with advanced AIDS have been treated compassionately with daily doses of 500 mg tid up to 2 g tid for periods exceeding 12 months," they wrote. "No signs of intolerance, and no adverse events related to ADA have been reported. A formal Phase I/II study has started in Europe in advanced AIDS."

In laboratory studies, ADA's 50 percent cytotoxic concentration ranged from 23 to 180 mg/ml, while its 50 percent inhibitory concentration ranged from 5 mg/ml against the laboratory strain HIV-1[IIIB/LAI] to 10 mg/ml against patient isolates.

ADA had a median 90% inhibitory concentration of 19 mg/ml against patient strains, and it was equally effective against HIV strains resistant to zidovudine (AZT) and other HIV reverse-transcriptase inhibitors, Vandevelde et al. found.

ADA had additive, but not synergistic effects, when tested in combination with didanosine (ddI) or stavudine (d4T).

After 120 minutes of exposure to 80 mg/ml ADA, HIV was completely inactivated. When T lymphocyte cultures were pretreated for shorter durations and then exposed to HIV, the cells became infected (as shown by PCR) but did not express viral p24 antigen or form syncytia.

"This finding indicates that the virus remains partly infective, integrates in the host cell genome, but is not expressed," Vandevelde et al. suggested.

ADA did not inhibit reverse transcriptase, nor did it inhibit Tat transactivation of the HIV LTR gene element.

"ADA has multiple mechanisms of anti-HIV activity," Vandevelde et al. concluded. "In addition to its virucidal activity, ADA appears to inhibit HIV replication at a yet unidentified posttranscriptional stage."

Because the catabolite of ADA is biurea, nephrolithiasis would be expected to be the most likely drug-related toxicity.

The corresponding author for this study is J.-P. Tassignon, Tassignon & Partners S.A., 28A Avenue E. Van Becelaere, Bte 53, B-1170 Brussels, Belgium.

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