Rolipram: Antidepressant Used in Europe and Japan Might Have Promise Against TNF, HIV

An antidepressant drug known as rolipram has been found to be a potent inhibitor of tumor necrosis factor, which means it might be a useful treatment for HIV infection. Unfortunately, the drug may not reach clinical trials because the companies that control rights to it are not inclined to support further development.

This situation came about last year, when researchers supported by the U.S. National Institute of Allergy and Infectious Disease and led by Paul Skolnik, M.D., at Tufts University and the New England Medical Center, discovered that in laboratory tests rolipram strongly inhibited tumor necrosis factor (TNF), a naturally occurring chemical messenger that the immune system produces to excess in some diseases, including HIV infection. The work was published last October in the journal AIDS.(1)

Many of the symptoms of AIDS that are not caused by an opportunistic illness are at least partly the result of too much TNF: fatigue, fevers, dementia, aphthous ulcers, and, the most threatening, wasting. In fact, TNF is sometimes called cachectin, referring to its cachexia-related, or lean muscle destroying, effects. Many researchers now believe there is an HIV/TNF feedback loop in which TNF enhances HIV
replication while HIV progression increases TNF production.

TNF inhibitors would theoretically interrupt that cycle, and several of them have received attention recently in both laboratory research and community practice. NAC, pentoxifylline and thalidomide in particular have been widely discussed in medical reports, including AIDS TREATMENT NEWS. But only thalidomide has been reported to be clinically valuable. It effectively controls aphthous ulcers and may reverse the loss of lean muscle mass.

At best, however, thalidomide is a problematic drug. It causes sedation, which is why it was developed in the first place. But it can also provoke a serious sulfa-like reaction in many people with HIV, and it can cause neuropathy and neutropenia with extended use. And, of course, it leads to terrible birth defects if taken during pregnancy, which is why it was never licensed in the U.S.

A newer, ostensibly less toxic, generation of TNF inhibitors is under development by Celgene, one of the makers of thalidomide. But animal and human trials of those drugs could take years to complete. Rolipram is available and used now in Japan; it has also been used extensively in Europe.

In his research, Dr. Skolnik found that rolipram was at least 10 and perhaps 600 times more powerful then pentoxifylline at inhibiting tumor necrosis factor. Both drugs are phosphodiesterase inhibitors, although rolipram is more specific in that regard. Rolipram is also known to cross the blood-brain barrier, which is an important criterion for any HIV treatment. It is considered an essentially safe drug, the main side effect being mild gastrointestinal distress at doses approaching 15 mg a day. The dose prescribed for antidepressant use ranges between 0.5 to 1 mg taken three times daily.

Some of the data published by Dr. Skolnik's team seems to suggest that the amount of the drug necessary to inhibit TNF might not be tolerable in practice. The peak plasma concentration of rolipram from a single human dose -- 1 mg, when the drug is used as an antidepressant -- is 0.12 micromolar. But in the laboratory tests, the concentration required for 50% inhibition of HIV was 10 to 60 micromolar -- more than 80 times what is achieved in plasma by normal use of the drug.

In this case, however, the laboratory concentration needed to inhibit TNF may not predict what happens in people. In the body, if rolipram reduces excessive levels of TNF, as it is supposed to do, that reduction should prevent the excess TNF from stimulating HIV replication. Some residual TNF activity may be desirable for normal immune function.

In the laboratory, rolipram is acting on a largely static situation; but in the body, TNF and HIV interact in a constantly changing dynamic in specific locations. Local concentrations of TNF and rolipram may not be paralleled by plasma levels.

Even if the highest tolerated dose of rolipram does not inhibit HIV, inhibiting any amount of excess TNF could be useful for preventing wasting, fatigue, dementia and aphthous ulcers. So while the laboratory data may raise doubts, they do not reduce the need for clinical studies to see if this drug could have a role in the treatment of HIV disease. Only clinical trials with HIV-infected participants can determine if a dose that is tolerable will also produce clinical improvement.

Rolipram was first developed as an antidepressant and marketed in Europe by Schering AG. It is also being investigated as possible treatment for multiple sclerosis. The development rights to rolipram in the U.S. and Japan were licensed to Berlex Laboratories and Meiji Seika Kaisha, respectively. Since rolipram does not inhibit HIV directly, as do drugs which inhibit reverse transcriptase (AZT, ddI, ddC, d4T, 3TC) or protease (saquinavir, indinavir, ritonavir), it would probably not become an enormously profitable first-line treatment for primary HIV infection even if the research proceeds. That is why, after all, any number of potential treatments are not pursued.

But, for reasons discussed above, TNF inhibitors could easily become indispensable supportive therapies, much as acyclovir and testosterone are now. Rolipram or similar drugs could possibly improve the quality of life and even the survival of many people with AIDS.

Even before his research was published, Dr. Skolnik proposed a pilot trial of the drug in HIV-infected patients, and asked Schering for support. For months, the request passed back and forth between Schering, Meiji and Berlex, and responsibility for further development of the drug remained unclear. Finally, it became known that Schering had submitted an Investigational New Drug application to the FDA some years ago (presumably for a non-HIV related indication), and does not now want to pursue the research necessary to bring the IND up to date.

Admittedly, such research could be an expensive commitment. But for a promising agent to be withheld for non-scientific reasons from a legitimate research effort seems distastefully reminiscent of the 1980s. AIDS activists were successful in reversing some similar decisions, but only after unfortunate public confrontations.

An alternative may be for the drug to be imported and carried at HIV buyers' clubs, depending on how much community support rolipram gathers. Readers who have knowledge of, or experience with, rolipram, are encouraged to contact Denny Smith or John S. James at AIDS TREATMENT NEWS, fax 415/255-4659, phone 415/255-0588.

Rolipram in Medical Literature

Extensive computer searches failed to find any mention of rolipram in relation to HIV or AIDS, except for the paper by Dr. Skolnik's group. And that paper was omitted from AIDSLINE, apparently in error -- which may have reduced the attention this work received.

We found 475 citations mentioning rolipram in MEDLINE, the general medicine database of the U.S. National Library of Medicine -- and 739 references in EMBASE, a European database which often has more citations than MEDLINE on new or experimental treatments. Most of the recently published work consists of highly technical investigations into the drug's mechanism of action.

References

1. Angel JB, Saget BM, Walsh SP, and others. Rolipram, a specific type IV phosphodiesterase inhibitor, is a potent inhibitor of HIV-1 replication. AIDS. 1995; volume 9, pages 1137-1144.