Vesnarinone is a drug that is approved in Japan as a treatment for mild to moderate heart failure. It is being studied in the United States as a treatment for HIV and Kaposi's sarcoma. Test tube studies have found that it has some direct anti-HIV effects and also reduces levels of tumour necrosis factor, a cytokine which may be implicated in HIV disease progression and wasting syndrome.

A phase I study in asymptomatic people found that it is well-tolerated. Further trials using higher doses are planned.

Vesnarinone was formerly known by the codename OPC-8212. It is manufactured by Otsuka Pharmaceuticals under the tradename Arkin-Z.

Key research

Marayuma reported that vesnarinone reduced the viral cytopathic effect of HIV-1 in acutely infected T cells in vitro (IC₅₀ = 8.55 - 15.8 µg/ml), and inhibited virus production in acutely and chronically infected macrophages. At concentrations greater than 3 µg/ml it inhibited the production of TNF-alpha from stimulated peripheral blood mononuclear cells in vitro.

Petit found that vesnarinone inhibited AIDS-KS cell proliferation in vitro at pharmacologically achievable concentrations, perhaps by inhibiting TNF and interleukin-6, which act as mitogens for AIDS-KS in culture.

Mitsuyasu enrolled 36 asymptomatic people in a Phase I study of vesnarinone (30, 60 or 90 mg/day for 12 weeks). Of 16 people who have completed the study at either the 30 or 60 mg/day dose levels, no significant changes in TNF levels and a modest increase in IL-6 levels were seen. No effect on viral titres (measured by HIV-RNA PCR), triglycerides, mean CD4 cell percentages or neutrophil counts were observed.

Gatell treated 24 asymptomatic HIV-positive people with CD4 counts between 200 and 500 with vesnarinone (60 or 90 mg/day orally) for 12 weeks. Among the first 16 participants to complete the study, four discontinued early, two due to transient reversible neutropenia. Tolerance was good in the remaining participants. In the 60 mg group, almost no effect on CD4 count, CDC8 count, plasma RNA, TNF, IL-6, beta-2 microglobulin or neopterin was seen. In the 90 mg group, a transient increase in viral load (less than or equal to 0.5 log) and CD4 counts was observed, which normalised by week 12, suggesting that this dose may have an immune-stimulating effect.

Ruxrungtham treated 20 HIV-positive people with CD4 counts above 200 with vesnarinone (60 mg/day) for 24 weeks. Mean CD4 count was increased by 100 above baseline at week 16, and 20 above baseline at week 24. Six out of nine participants with measurable viral load experienced reductions during therapy, while two participants with undetectable viraemia at baseline had become viraemic by week 24. No changes in cytokine levels were observed.

References

Gatell JM et al. Vesnarinone in asymptomatic HIV patients. Fifth European Conference on Clinical Aspects and Treatment of HIV Infection, Copenhagan, abstract 571, 1995.

Maruyama B et al. Vesnarinone inhibits production of HIV-1 in cultured cells. Biochem & Biophys Res Comm 195:1264-1271, 1993.

Mitsuyasu R et al. Preliminary results of a Phase I study of vesnarinone (OPC-8212) in HIV-infected persons with CD4 > 300 cells/mm³. Tenth International Conference on AIDS, Yokohama, abstract 005B, 1994.

Petit RG et al. Vesnarinone inhibits AIDS-KS cells in culture. Tenth International Conference on AIDS, Yokohama, abstract PB0104, 1994.

Ruxrungtham K et al. A phase I trial of vesnarinone in HIV-infected persons with CD4+ cells counts greater than 200 cells/µl. Third Conference on Retroviruses and Opportunistic Infections, Washington, abstract 138, 1996.