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Acquired Immunodeficiency Syndrome (AIDS)
Zimmer, Lehr, Kornhuber, Breitag, Montagnier and Gietzen, Blut (1986),3099 exposed lymphocytes from twenty-four nor-mal controls and twenty-four patients treated with PHT (300-450 mg/day for a minimum of ten days) to125 I-labeled human immunodeficiency virus (HIV). After one hour, cell radioactivity was measured as an index of virus binding. Virus binding was significantly less in the lymphocytes from the PHT-treated patients. Mean counts per minute were 4,000 (range 2,000-7,000) in the PHT group, compared to 80,000 (range 64,000-92,000) in the control group. Similar differences were observed when an immunofluorescence assay was used.
To determine whether the inhibition of HIV binding was specific to PHT or shared by other drugs, the authors evaluated HIV binding to lymphocytes from twenty additional patients treated with ampicillin, haldoperidol, phenobarbital, flunarizine, or nimodipine. Only PHT inhibited HIV binding. In another series of experiments, the functional integrity of the lymphocytes from PHT-treated patients was evaluated by per-forming surface-marker determinations with monoclonal antibodies. The PHT-treated lymphocytes reacted with all of the antibodies tested (OKT3, OKT4, OKT8, OKTI I), and the T-cell subpopulations calculated by this means were the same as those of controls. The authors conclude that PHT inhibits HIV binding to T-lymphocytes and might therefore be useful in the prevention and treatment of AIDS. See also Ref. 2700.
Zimmer, J. P., Lehr, H. A., Kornhuber, M. E., Breitig, D., Montagnier,
L., Gietzeri, K., Diphenylhydantoin (DPH) blocks HIV-receptor on lymphocyte
surface, Blut, 53: 447-50, 1986.
2700. Lehr, H. A., Zimmer, J. P., Diphenylhydantoin in the prevention and treatment of AIDS?, Dtsch. Med. Wochenschr., 111(25): 1001-2, 1986.
Petrasch, Bechtold, Zou, Wacker and Brittinger, AIDS-Forschung (1988), 3712 in a study to learn more about the influence of PHT on monocytes and macrophages, injected 50 mg into each hind paw of Wistar rats. As control the authors applied phenobarbital, the excipients of commercial PHT tablets and NaCl solution. Seven days later 40 mg of alkaline phosphatase (AP) were administered at the same site for antigenic exposure. Ninety minutes and 24 hours after injection of the antigen, popliteal lymph nodes were removed, homogenized, washed, cells were counted and cytospin slides were prepared. Cells with membrane-bound or intracytoplasmatic antigen were detected by monoclonal anti-AP antibody. In animals pretreated with PHT the relative and absolute number of AP positive cells was significantly higher compared to controls. Nonspecific reactions were excluded by staining cells from PHT-, but not AP-exposed animals and by applying antibodies specific for other enzymes. By double-staining with two monoclonal antibodies, antigens of the mononuclear phagocytic system could be identified on cells with membrane-bound or intracytoplasmatic AP.
The authors state that several lines of evidence indicate that early in the course of AIDS relevant HIV infection may be limited to the mononuclear phagocyte lineage. Enhanced recruitment of the antigen-binding/presenting cells in the lymphatic tissue by PHT might reinforce cellular immunity, thus possibly adding to the favorable effect of this drug in HIV infection.
3712. Petrasch, S,, Bechtold, D., Zou, P., Wacker, H.H., and Brittinger, G, Diphenylhydantoin-induced increase of antigen-binding cells in the ymphatic tissue, Aids-Forschung, 6: 339-41, 1988.
Cloyd, Lynn, Ramsey and Baron, Virology (1989), 3713 report that phenytoin (PHT) inhibits de novo infection of various T-cell lines, as well as a monocytic cell line, consistent with the reports of Lehr and Zimmer and their colleagues (see Ref. 11981). However, in contrast to the hypothesis of these investigators, Cloyd et al, suggest that PHT does not inhibit binding per se, but another element in the development of cellular infection. Moderate inhibition of HIV-1 infection was observed with drug concentrations that are therapeutic in vivo for epilepsy (~20µg/ml), and no concentrations used induced deleterious effects on cell growth or viability. PHT demonstrated variable inhibitory effects on infection of normal phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) cultured in vitro. PHT was also synergistic to low-dose AZT (0.01 µg/ml) in inhibiting infection of cell lines.
In a second series of experiments, treatment of chronically infected H9 cells reduced HIV p24 expression within 1-6 weeks in a dose-dependent fashion. This apparent induction into latency was not inhibited by co-treatment of the chronically infected cells with 5-azacytidine, which indicated that PHT was not inducing latency by induction of methylation of the viral DNA.
Because the authors hoped to use the relevant effects of PHT to shed light on the mechanisms of HIV-1 infection, they carried out further studies. Flow cytometric analysis demonstrated that PHT did not significantly reduce cell-surface expression of the CD4 receptors responsible for initial viral recognition-binding. The possibility remained that the drug inhibited HIV infection by its effects on calcum-dependent cellular processes. Measurements of intracellular calcium demonstrated that an increase of [Ca2+]i occurred at least 24 hours after infection, prior to synthesis of the detectable viral structural protein p24 and that this virus-induced increase in [Ca2+]i was not due to binding of HIV to the cell. This HIV-induced rise in [Ca2+]i was significantly inhibited by PHT. These investigators conclude that calcium plays a role in HIV infection and maintenance and that PHT may be a candidate therapy for HIV infection.
3713. Cloyd, M.W., Lynn, W.S., Ramsey, K., and Baron, S., Inhibition of human immunodeficiency virus (HIV-1) infection by diphenylhydantoin (dilantin) implicates role of cellular calcium in virus life cycle, Virology, 173: 581-590, 1989.
Petrasch, Wacker, Zou, Bechtold and Brittinger, Clinical and Experimental Immunology (1989), 3714 present a monoclonal IgGl antibody, KiMylR, which is specific for macrophages and their derivatives in the lymphatic tissue of the rat, and evaluate the distribution of subsets of mononuclear cells in popliteal and para-aortic lymph nodes of Wistar rats after injection of 50 mg PHT into the hindpads. Compared with resting lymphatic tissue and lymph nodes of animals treated with phenobarbital, PHT induced a significant increase (p < 0.01) in the proportion of phagocytic cells. Furthermore, the soluble antigen alkaline phosphatase was traced after inoculation into the footpads of rats: in locoregional lymph nodes, the percentage (mean 12.8 / 10 3) and the total number (mean 476 X 10 3 cells/lymph node) of cells with membrane-bound or intracytoplasmic alkaline phosphatase, as detected by a monoclonal anti-alkaline phosphatase antibody, were significantly higher (p < 0.001) in animals pretreated with PHT than in rats pretreated with phenobarbital (mean 2.1/10 3; 31.2 X 10 3 cells/lymph node) and in untreated animals (mean 1.9/10 3; 4.1 X 10 3 cells/lymph node.) If verified in humans, the effect of PHT in enhancing the number and function of macrophages and other antigen-presenting cells may exert favorable effects in patients with impairment of the mononuclear phagocytic system.
3714. Petrasch, S., Wacker, H.H., Zou, P., Bechtold, D., and Brittinger, G., Enhancement in number and function of antigen-presenting cells in the lymphatic tissue of rats after in vivo administration of diphenylhydantoin (DPH), Clin. Exp. Immunol, 78: 133-37, 1989.
3715. Lehr, H.A., Zimmer, J.P., Hubner, C., Ballmann, M., Hachmann, W., Vogel, W., Baisch, H., Hartter, P., Albani, M., and Kohlschutter, A., Decreased binding of HIV-1 and vasoactive intestinal peptide following plasma membrane fluidization of CD4+ cells by phenytoin, Virology, 179(2): 609-17, 1990.
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