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Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In vitro incubation of these cell lines with ANPs resulted in a concentration- and time-dependent inhibition of cell proliferation. This inhibitory effect was most striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various HPV-harboring cells were compared with those for primary human keratinocytes isolated from normal cervix, HPMPC emerged as the most selective ANP, with a selectivity index (SI) in the range of 15-42. When IC50 values as a function of time were determined for several tumor cell lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an antiproliferative effect as a function of time, although of a lower extent (5- to 25-fold decrease in the IC50 values between days 3 and 7) than for the HPV-positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs resulted in the inhibition of cell proliferation as a function of time, similar to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent antiproliferative agents. These results suggest that the antiproliferative activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be explained, at least in part, by a specific inhibitory effect on rapidly proliferating cells, and the presence of the HPV genome might enhance the sensitivity of cells to HPMPC due to interactions of the viral-transforming proteins with products of the tumor suppressor genes.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10338155&dopt=Abstract

Eur J Cardiothorac Surg. 1999 May;15(5):663-6.
Intermediate term results of total lymphoid irradiation for the treatment of non-specific graft dysfunction after heart transplantation.

Madden BP, Barros J, Backhouse L, Stamenkovic S, Tait D, Murday A.

Department of Cardiological Sciences, St. George's Hospital, London, UK.

BACKGROUND: A proportion of heart transplant recipients develop poor graft function in the absence of cellular infiltrate in endomyocardial biopsies or transplant associated coronary artery disease. The condition has a poor prognosis and its aetiology is poorly understood. We report encouraging intermediate term results with total lymphoid irradiation (TLI) in the management of this condition. METHODS: Eleven adult cardiac transplant recipients who developed severe allograft dysfunction (NYHA class-4) at a median period of 4 months after orthotopic heart transplantation were successfully treated with TLI. Endomyocardial biopsies and coronary angiography were normal in each patient and biventricular failure developed in spite of immunosuppression with Cyclosporin-A, Azathioprine, oral Prednisolone, Cyclophosphamide and intravenous Methylprednisolone therapy. Total lymphoid irradiation was given with standard Mantle and inverted Y-fields over ten treatments to achieve a cumulative dose of 8 Gy. RESULTS: Each patient had a significant improvement in clinical response and in ventricular performance within 2 months of commencing TLI. Nine patients are currently well (four NHYA class-1, five NHYA class-2) at 4-48 (median 26) months following TLI. Two patients died; one from bacterial septicaemia and one as a consequence of chronic renal failure. Three patients developed opportunistic infection which was successfully treated with appropriate antimicrobial agents. An Ebstein-Barr virus associated lymphoproliferative disorder occurred in one patient and was successfully treated by reduction in immunosuppression and high dose Acyclovir. Two patients developed transient bone marrow suppression. CONCLUSION: The intermediate term results of TLI in the management of poor graft function in cardiac transplant recipients with normal endomyocardial biopsies and coronary angiography are encouraging. Although complications of opportunistic infection, bone marrow suppression and lymphoproliferative disorder occurred, treatment was successful in each case.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10386414&dopt=Abstract

Clin Infect Dis. 1998 Jan;26(1):85-90.
Acyclovir use and survival among human immunodeficiency virus-infected patients with CD4 cell counts of < 500/mm3. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

Torres RA, Neaton JD, Wentworth DN, Barr MR, Abrams D, Sherer R, Ward T, Sampson J.

AIDS Center, St. Vincent's Hospital and Medical Center of New York, New York 10011, USA.

To examine the relationship between acyclovir use and survival in AIDS, we performed a retrospective analysis of data collected through an observational cohort of the 17-site Community Program for Clinical Research on AIDS (CPCRA), under the sponsorship of the National Institute of Allergy and Infectious Diseases. Data were analyzed regarding 2,368 patients with CD4+ lymphocyte counts of < 500/mm3, and 7,836 follow-up visits were conducted from September 1990 to July 1994. Factors associated with use of acyclovir were studied by stratified analysis of variance and Mantel-Haenzel chi 2 tests. The association between acyclovir and survival was studied with use of the proportional hazards regression model. Individuals reporting acyclovir use were more likely to be white, male, and homosexual; to have a history of herpes simplex and zoster; and to have lower CD4+ T cell counts than those who did not. After adjustments for differences in baseline factors, acyclovir use was not associated with prolonged survival.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9455514&dopt=Abstract

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