Oxpentifylline is a licensed treatment for severe damaged circulation in the legs (intermittent claudication), where it works by making the blood less sticky, thus improving its flow. Oxpentifylline has been tested for its anti-HIV effects and as a possible treatment for a number of HIV-related conditions.

Oxpentifylline has been shown to have in vitro effects against HIV. It has been shown to prevent the secretion of tumour necrosis factor (TNF), a cytokine which is produced in excess in people with HIV infection.

At excessive levels, TNF makes people lose weight, can stop the bone marrow producing red cells, white cells and platelets and can damage the brain (it has been hypothesised that TNF is what causes HIV encephalopathy). High TNF levels are associated with increased HIV replication. It is theorized that blocking TNF production could have several beneficial effects for people with HIV infection.

However, at normal levels TNF also plays an important role in the immune system, especially in cellular responses to organisms such as MAI. Test-tube studies suggest that by suppressing TNF, oxpentifylline could lead to an increase in MAI growth in the body. There is also evidence that oxpentifylline stimulates cytomegalovirus (CMV) replication, and may cause latent CMV infection to become active in people with damaged immune systems.

There is some evidence that oxpentifylline is partially effective against itchy pimples (called pruritic papular eruption or pruritus) which commonly occur on the legs of people with severe immune damage.

Oxpentifylline is known as pentoxifylline in the USA, or as Trental, its British tradename. It is manufactured by Hoechst-Roussel Pharmaceuticals.

Current use

Early trials in people have suggested that oxpentifylline does reduce levels of TNF, but so far there is no evidence that this is accompanied by a decrease in levels of HIV, an increase in CD4 count or by clinical benefits such as reduced disease progression. New York researchers who treated people with high levels of TNF with either oxpentifylline or placebo found that although TNF levels fell in the treated group, they also fell in the placebo group. This is thought to be because TNF levels in any individual may fluctuate considerably over time and the trial recruited people with high levels that were likely to fall regardless of any treatment.

A placebo-controlled trial in Mexico found that oxpentifylline reduced TNF levels but did not prevent (and may have caused) weight loss among people with AIDS.

An uncontrolled pilot study of oxpentifylline in five people with AIDS-related wasting found no evidence of any effects on weight loss. Two participants who had low levels of TNF in their blood developed severe bacterial pneumonia within 3 weeks of taking oxpentifylline, leading the researchers to speculate that the drug might even be harmful.

When used for its approved indications, oxpentifylline can have side-effects of nausea, dizziness and flushing. As it can lower the blood pressure, it has to be used in caution with people who have autonomic neuropathy or adrenal gland disease (both of which can cause falls in the blood pressure), and should not be used by people with haemophilia. Trials in people with HIV have reported occasional side-effects of nausea, fevers and vomiting. There have also been recent reports that oxpentifylline may cause bleeding in the eye.

Use in combinations

Test-tube studies suggest that oxpentifylline increases the anti-HIV effect of ddI. Some test-tube research suggests that the combination of oxpentifylline and the discontinued tat inhibitor Ro 24-7429 could be very effective, although a small underground trial of the combination found no evidence of anti-HIV effects.

Taking it

Oxpentifylline comes as pink tablets which contain 400 mg of the drug in a sustained release formulation; the standard dose for people with circulation problems is three tablets per day. They need to be swallowed whole, not crushed or chewed. The tablets should be taken with food to reduce the risk of stomach irritation.

Getting it

Oxpentifylline is a licensed drug for treating circulation problems. Some doctors may be willing to write prescriptions for people who wish to try oxpentifylline as an immune modulator.

Key research

Zhang reported that in vitro pentoxifylline enhances the anti-HIV effect of ddI. Biswas reported that the in vitro effects of combined oxpentifylline and the tat inhibitor Ro 24-7429 were far more than additive, with maximal HIV inhibitory effects seen at concentrations low enough to avoid cytotoxicity.

Sathe showed that macrophages from people with MAI are already deficient in their ability to produce TNF. When macrophages were treated were a dose of oxpentifylline that reduced TNF production by 52.4%, MAI counts further increased 2.5 to 50-fold.

Staak reported that oxpentifylline is a powerful stimulator of human CMV replication in vitro and in vivo. The effects of oxpentifylline and TNF-alpha in promoting CMV replication were synergistic.

Dezube (1993) administered oxpentifylline to 25 people with AIDS and elevated TNF RNA levels, in ACTG 160. 17 completed treatment with 400 mg thrice daily. Median pre-treatment CD4 count was 32. Serum triglycerides (SG), a surrogate for cytokine activation, fell on average by 66 mg/dl. TNF mRNA levels fell in 10/16. HIV load decreased in 4 patients, remained stable in 10 and increased in 1. 5 and 7 patients have been on drug for longer than 6 months and longer than 1 year respectively. No patient in long-term follow-up has developed an OI despite very low CD4 counts. Drug was well tolerated, except for one oxpentifylline recipient who discontinued treatment due to recurrent fevers.

Dezube (1995) treated a further 30 people at a dose of 800 mg three times daily for eight weeks. A 34% reduction in TNF mRNA was observed during treatment. Treatment was well-tolerated.

Clerici treated 10 asymptomatic people with CD4 counst between 350 and 500 with oxpentifylline (1200 mg/day) for 4 months. Eight out of nine experienced a transient increase in CD4 count, and CD8 cells increased in 7 out of 9. Antigen-stimulated IL-2 production and proliferation was potentiated in 8 of 9 participants, and significant but transient decreases in virermia were observed in 7 of 9.

Sonnabend enrolled 34 participants with CD4 counts below 300 in a randomized double-blind placebo-controlled study of oxpentifylline (400 mg three times daily for 12 weeks). Oxpentifylline was well tolerated. TNF production was generally lower in both the treatment and the placebo group at evaluations compared with baseline. The TNF level in the treated group was significantly lower than the placebo group at 8 weeks. No differences in HIV levels between the groups were observed.

Kruse treated six HIV-positive individuals who had elevated plasma TNF-alpha in an open, controlled, randomized cross-over study of oxpentifylline (800 mg three times daily) for six weeks. Treatment did not affect TNF levels or blood counts, but was associated with gastrointestinal toxicities.

Hermida-Escobedo enrolled 40 adults with AIDS in a placebo-controlled study of oxpentifylline (400 mg three times daily for four weeks). There was a significant reduction in TNF levels in the treated arm. However, there was a significant weight loss in the treated group, but no weight reduction in the placebo arm.

Mole treated 11 mildly symptomatic individuals who had never received anti-retroviral therapy in an open-label study of pentoxifylline (800 mg three times daily). No changes in serum TNF RNA, plasma HIV RNA, or CD4 counts were observed after more than 3 weeks of treatment. 3/11 discontinued treatment due to nausea, fever or vomiting.

Landman treated five people with AIDS-related wasting with oxpentifylline. Three who had elevated baseline serum TNF levels did not have a significant weight gain after 4 to 8 weeks of treatment despite reductions in their serum TNF levels. Two participants with low baseline TNF continued to lose weight and developed extensive bacterial pneumonia within 3 weeks of starting therapy.

Berman treated 12 HIV-positive people with pruritic papular eruption with oxpentifylline for 8 weeks. The average degree of pruritis was reduced; only one of 11 had an increase in PPE. Changes in viral load were not statistically significant.

Navarro reported the resolution of recurrent oral aphthous ulcers in 3 of 4 people after 1-2 weeks of treatment with pentoxifylline 400 mg/day. Treatment was continued for 4 months, during which no relapses were observed.

References

Berman B et al. Efficacy of pentoxifylline in the treatment of pruritic papular eruption of HIV-infected persons. Journal of the American Academy of Dermatology 38(6):955-959, 1998.

Biswas DK et al. Cooperative inhibition of NF-kB and tat-induced superactivation of human immunodeficiency virus type-1 long terminal repeat. Proceedings of the National Academy of Sciences (USA) 90:11044-11048, 1993.

Clerici M et al. Pentoxifylline improves cell-mediated immunity and reduces human immunodeficiency virus (HIV) plasma viremia in asymptomatic HIV-seropositive persons. Journal of Infectious Diseases 175(5):1210-1205, 1997.

Dezube BJ et al. Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. J AIDS 6:787-794, 1993.

Dezube BJ et al. High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. Journal of Infectious Diseases 171(6):1628-1632, 1995.

Fox LM et al. Pentoxifylline inhibits HIV replication in acutely infected primary cells and chronically infected U1 cells through multiple mechanisms. First National Conference on Human Retroviruses and Related Infections, Washington, abstract 362, 1993.

Hermida-Escobedo EC et al. A double blinded clinical trial to assess the effect of pentoxifylline in the inhibition of tumor necrosis factor production in patients with AIDS. Eleventh International Conference on AIDS, Vancouver, abstract Mo.B.1394, 1996.

Kruse A et al. Pentoxifylline therapy in HIV seropositive subjects with elevated TNF. Immunopharmacology 31(1):85-91, 1995.

Landman D et al. Use of pentoxifylline therapy for patients with AIDS-related wasting: pilot study. Clinical Infectious Diseases 18(1):97-99, 1994.

Luke DR et al. Phase I/II study of pentoxifylline with zidovudine on HIV-1 growth in AIDS patients. International Journal of Clinical Pharmacology 31:343-350, 1993.

Matsuyama T et al. Editorial review: Cytokines and HIV infection: is AIDS a tumor necrosis factor disease? AIDS 5:1405-1417, 1991.

Mole L et al. A pilot study of pentoxifylline in HIV infected patients with CD4+ lymphocyte counts less than 400 cell/mm³. Ninth International Conference on AIDS, Berlin, abstract B26-2116, 1993.

Navarro A et al. Treatment of aphtous (sic) ulcers with pentoxifylline. Tenth International Conference on AIDS, Yokohama, abstract PB0158, 1994.

Sathe SS et al. Pentoxifylline aggravates impairment in tumor necrosis factor-alpha secretion and increases mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. Journal of Infectious Diseases 170(2):484-487, 1994.

Sonnabend J et al. Pentoxifylline (PTX) as a TNF inhibitor in HIV+ individuals. Tenth International Conference on AIDS, Yokohama, abstract PA0285, 1994.

Staak K et al. Pentoxifylline promotes replication of human cytomegalovirus in vivo and in vitro. Blood 89(10):3682-3690, 1997.

Zhang L et al. Pentoxifylline (Trental) enhances the antiretroviral activity of didanosine (dideoxyinosine, ddI). Eighth International Conference on AIDS, Amsterdam, abstract PoA 2326, 1992.