Bioorg Khim. 1997 Nov;23(11):906-9.
[Synthesis and antiherpes activity of acyclovir phosphoesters]

[Article in Russian]

Galegov GA, Shobukhov VM, Leont'eva NA, Ias'ko MV.

Ivanovskii Institute of Virology, Russian Academy of Medical Sciences, Moscow, Russia.

9-(Hydroxyethyloxymethyl)guanine (acyclovir) phosphite and fluorophosphate were synthesized by the reactions of acyclovir with phosphorus trichloride in triethyl phosphate and with fluorophosphoric acid in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride, respectively, and characterized by the data of 1H and 31P NMR and mass spectra. These products selectively inhibit reproduction of the herpes simplex virus type 1 in the Vero cell culture, the phosphite being also substantially active against a herpes virus strain resistant to acyclovir.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9518431&dopt=Abstract acyclovir Zovirax

chmcc.org

It is generally assumed that reactivation of latent herpes simplex virus occurs through initiation of lytic viral gene transcription from the latent viral genome. Thus, antiviral compounds such as acyclovir, whose activation is dependent upon viral thymidine kinase, should be effective in preventing the initial production of infectious virus associated with reactivation. To test this concept, the ability of acyclovir to prevent the production of infectious virus was determined in the murine hyperthermic stress (HS) model of in vivo reactivation. Acyclovir treatment after HS blocked the production of infectious virus within the ganglia. Efficacy was dependent upon the timing of the first post-HS dose and the length of exposure to acyclovir. A single dose administered 6-9 h after HS resulted in >90% reduction in reactivation. Acyclovir administered 12 h after HS resulted in 75% reduction, but there was no effect if treatment was delayed for 18 h after HS.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10438371&dopt=Abstract acyclovir Zovirax




Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11835-9.
Acyclovir diphosphate dimyristoylglycerol: a phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus.

Hostetler KY, Parker S, Sridhar CN, Martin MJ, Li JL, Stuhmiller LM, van Wijk GM, van den Bosch H, Gardner MF, Aldern KA, et al.

Department of Medicine, University of California, San Diego.

Infection with herpes simplex viruses (HSVs) resistant to treatment with acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine, Zovirax) is a growing clinical problem in patients with AIDS and other immunosuppressed states. Most virus isolates resistant to acyclovir are deficient or defective in virally coded thymidine kinase (TK), which converts acyclovir to acyclovir monophosphate in virus-infected cells. To restore acyclovir efficacy, we synthesized acyclovir diphosphate dimyristoylglycerol, an analog of a naturally occurring phospholipid, CDP-diacylglycerol. Its biological activity was tested in WI38 human lung fibroblasts infected with the acyclovir-resistant DM21 strain of HSV, which is TK negative due to an 816-base-pair deletion in the TK coding region. Acyclovir diphosphate dimyristoylglycerol has substantial activity in DM21-infected cells (IC50 = 0.25 microM), whereas acyclovir and acyclovir monophosphate were ineffective (IC50 > 100 microM). Similar results were obtained in TK-altered and TK-deficient strains of HSV-1 and in acyclovir-resistant isolates of HSV-2 obtained from two AIDS patients. The phospholipid prodrug is active by means of TK-independent metabolic pathways that liberate acyclovir monophosphate inside the host cell. Acyclovir phosphates were 56 times greater in WI38 human lung fibroblasts incubated for 24 hr with [8-3H]acyclovir diphosphate dimyristoylglycerol relative to acyclovir. Acyclovir monophosphate added to the culture medium (outside the cell) did not circumvent the acyclovir resistance of the TK-negative DM21 mutant, presumably due to its conversion to acyclovir by phosphatases. Acyclovir diphosphate diacylglycerol prodrugs may be useful in treating TK-deficient mutant and wild-type strains of HSV.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8265634&dopt=Abstract acyclovir Zovirax




J Control Release. 1998 Jan 2;50(1-3):291-6.
In vitro acyclovir distribution in human skin layers after transdermal iontophoresis.

Volpato NM, Nicoli S, Laureri C, Colombo P, Santi P.

Pharmaceutical Department, University of Parma, Italy.

The purpose of the present work was to study the in vitro distribution of acyclovir in human skin layers after iontophoresis, applied in order to increase the amount of drug in the basal epidermis, site of Herpes simplex infections. Experiments were done with Franz diffusion cells applying, as donor, acyclovir solutions (pH values: 3.0 and 7.4) or a commercial cream. Quantification of drug at different skin depths was performed by horizontal slicing of frozen skin, and drug extraction and analysis by high-performance liquid chromatography. Seven h of transdermal iontophoresis (0.5 mA cm-2 induced an accumulation of acyclovir in epidermis and dermis ranging from 80 to 150 micrograms cm-3, characterized by homogeneous distribution of the drug in skin layers. After short current application time (30 min) however, the concentration profile of drug in skin was not significantly different from the obtained after seven h of passive diffusion, employing pH 3.0 donor solution. After 30 min of iontophoresis, the acyclovir reservoir on the skin was maintained for up to five h producing a dramatic increase of drug concentration in skin, evening out over 80 micrograms cm-3 until a depth of 300 micrograms. Acyclovir can be accumulated at target site more quickly and maintained at higher level through application of a iontophoretic pulse and by keeping the drug reservoir on skin.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9685896&dopt=Abstract acyclovir Zovirax




J Infect Dis. 1995 Oct;172(4):939-43.
Failure of high-dose acyclovir to prevent cytomegalovirus disease after autologous marrow transplantation.

Boeckh M, Gooley TA, Reusser P, Buckner CD, Bowden RA.

Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.

In a retrospective study, the strategy of giving high-dose acyclovir (500 mg/m2 every 8 h intravenously) from day 5 before transplantation to day 30 after transplantation was evaluated in 266 cytomegalovirus (CMV)-seropositive autograft recipients. the incidence of CMV pneumonia was compared with that in 85 control patients who did not receive high-dose acyclovir. There was no significant difference in the incidence of CMV pneumonia between groups at day 100 (Kaplan-Meier estimates, 6.3% [acyclovir] vs. 7.7% [controls], P = .63) and day 200 after transplantation (7.6% vs. 13.1%, P = .32). The overall rate of patients who presented with CMV disease without preceding excretion from blood, urine, or throat was 77%. CMV pneumonia was fatal in 9 (56%) of 16 acyclovir recipients compared with 5 (63%) of 8 controls (P = 1.0). Survival after transplantation was not different between groups (P = .68). Thus, high-dose acyclovir does not appear to be effective for prevention of CMV disease after autologous transplantation.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7561213&dopt=Abstract acyclovir Zovirax