Letter to Science on Memantine and AIDS Dementia
I discovered this letter to Science from last summer while doing a Medline search. It is interesting from a number of standpoints. First it points out how important NTII's memantine might become as not only a treatment but also maybe a prophylactic for AIDS Dementia. Second, it indicates that the drug cocktail treatment for HIV infection may not be able to prevent the development of AIDS dementia. Lastly, it suggests that memantine might be used in combination with the drug cocktails to prevent Dementia.
The market for memantine in the treatment of neuropathic pain is huge. This AIDS dementia market may also turn out to be a large market for memantine. If it is used chronicly for both treatment and prophylaxis, memantine could post major sales numbers.
John de C
I read with interest the elegant report by Ashley T.ÿHaase's group (W.ÿCavert et al., Reports, 9 May, p. 960) and the accompanying News article by Jon Cohen (9 May, p. 898) concerning the vulnerability of reservoirs of human immunodeficiency virus (HIV) stubborn to new treatments. The work by Haase and his colleagues, as well as related works (1), are crucial to the systemic treatment of AIDS. However, an important issue not dealt with is the reservoir of virus within macrophages and microglia in the brain. HIV-1 enters the brain very early after initial infection (2). The newer triple-drug combination therapies, which include protease inhibitors, are, in general, not capable of crossing the blood-brain barrier and eradicating infection in the central nervous system. Among these drugs, AZT alone may penetrate the brain to some degree, but its effects on the dramatic cognitive decline are manifest in about one-third of patients, who develop so-called AIDS dementia, level off, or fail after about 3ÿmonths of treatment (3).
For this reason, the Neurology Core Committee of the AIDS Clinical Trials Group (ACTG), of which I am a member, has designed adjunctive drug strategies to be piggybacked onto the best antiretroviral therapy in an effort to abort or even prevent AIDS dementia. Currently held models of HIV-induced neuronal damage are predominantly focused on neurotoxins that emanate from infected or immune-stimulated brain macrophages and astrocytes, which in turn overstimulate the N-methyl-D-glutamate (NMDA) subtype of glutamate receptor in the brain (2). This leads to excessive Ca2+ influx, free radical formation, and neuronal injury or apoptosis. One clinically tolerated NMDA antagonist, memantine, has recently entered a phase-II/III ACTG study, and it is hoped that this form of adjunctive therapy will prove useful to AIDS patients with cognitive decline. After all, who wants to live longer because of successful systemic treatment of the disease and yet be demented?
Stuart A. Lipton
Laboratory of Cellular and
Molecular Neuroscience,
Department of Neurology,
Harvard Medical School/Children's Hospital,
300 Longwood Avenue,
Boston, MA 02115,ÿUSA
E-mail: lipton_s@a1.tch.harvard.edu
REFERENCES
1.T.-W. Chun, et al., Nature 387, 183 (1997) ; A.ÿS.ÿPerelson et al., ibid., p. 188. 2.S. A. Lipton and H. E. Gendelman, N. Engl. J.ÿMed. 332, 934 (1995) . 3.S. A.ÿLipton and K.ÿD.ÿKieburtz, in The Neurology of AIDS, H.ÿE.ÿGendelman, S.ÿA.ÿLipton, L.ÿG.ÿEpstein, S.ÿSwindells, Eds. (Chapman Hall, New York, in press).
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Response: Lipton rightly points out that, quite aside from the question of whether an AIDS sanctuary such as the brain will thwart attempts to eradicate HIV-1, it would be tragic indeed for an individual to suffer neurological complications of infection while antiretroviral therapy successfully controls viral replication in the periphery. We agree that it is important and prudent to continue efforts to develop antiviral agents that cross the blood-brain barrier and to pursue other strategies that target neuropathological processes in AIDS patients. We also think it is worthwhile to commit coordinated efforts to supplement current tissue respositories with specimens from the nervous system and other potential viral refuges by collecting specimens at appropriate opportunities from persons with HIV infection who are on potent antiretroviral drug regimens. Assay of viral load in these samples would provide considerable insight into the scope of the sanctuary problem.
Winston Cavert Ashley T. Haase
Department of Microbiology,
University of Minnesota Medical School,
Minneapolis, MN 55455-0312, USA
REFERENCES
1.T.-W. Chun, et al., Nature 387, 183 (1997) ; A.ÿS.ÿPerelson et al., ibid., p. 188. 2.S. A. Lipton and H. E. Gendelman, N. Engl. J.ÿMed. 332, 934 (1995) . 3.S. A.ÿLipton and K.ÿD.ÿKieburtz, in The Neurology of AIDS, H.ÿE.ÿGendelman, S.ÿA.ÿLipton, L.ÿG.ÿEpstein, S.ÿSwindells, Eds. (Chapman Hall, New York, in press). |
