Braz J Infect Dis. 1997 Mar;1(1):27-30.
Herpes Simplex Virus Shedding in Bone Marrow Transplant Recipients During Low-Dose Oral Acyclovir Prohylaxis.

Machado CM, Vilas Boas LS, Dulley FL, Canto CL, Freire WS, Macedo MC, Massumoto C, Ostronoff M, Pannuti CS.

Virology Laboratory, Instituto de Medicina Tropical de SP, Brazil.

A 400mg dose twice-a-day oral acyclovir prophylaxis regimen was evaluated in 50 allogeneic transplant recipients. Twenty (40%) patients experienced 24 episodes of herpes simplex virus (HSV) shedding; l7 (70.8%) occurring during prophylaxis. Thirteen of such episodes were asymptomatic and, in three, it was difficult to differentiate severe mucositis from viral lesions. In the remaining one, HSV pneumonia was suspected after a bronchoalveolar lavage (BAL) procedure performed in an attempt to early detection of cytomegalovirus (CMV). All cases responded to acyclovir therapy or dose adjustment suggesting that acyclovir resistance did not account for the occurrence of infection in our patients. These data demonstrated that oral acyclovir prophylaxis, 400mg dose twice-a-day, was inadequate to suppress viral shedding. The bronchoalveolar lavage procedure in a patient with HSV shedding could precipitate HSV spread to the lungs and the occurrence of pneumonia.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11107235&dopt=Abstract acyclovir Zovirax[PubMed - as supplied by publisher]




Antibiot Khimioter. 1995 Nov-Dec;40(11-12):29-33.
[Resistance of herpes simplex virus to acyclovir: laboratory and clinical aspects]

[Article in Russian]

Briazzhikova TS, Iurlova TI, Chizhov NP.

Clinical isolates of the Herpes simplex virus had different susceptibility to acyclovir. Along with highly susceptible variants there were often isolated resistant variants and variants with intermediate susceptibility to the drug. All the clinical isolates were from the patients previously not treated with acyclovir. Therefore, it is possible to consider the drug resistance of the Herpes simplex virus to be natural. Two cultures of the virus differing in their susceptibility to acyclovir were simultaneously isolated from the affections of various localization in one patient. The study of the time course of the resistance development in the cell cultures showed that it depended on the drug dose and the subculture level. It is advisable to test the isolates of the Herpes simplex virus for their susceptibility to drugs used in the patient treatment. This will provide individual therapy of the patients with Herpes simplex.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8830636&dopt=Abstract acyclovir Zovirax




Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5461-5.
A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant.

Hwang CB, Horsburgh B, Pelosi E, Roberts S, Digard P, Coen DM.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.

Clinical resistance to antiviral drugs requires that a virus evade drug therapy yet retain pathogenicity. Thymidine kinase (TK)-negative mutants of herpes simplex virus are resistant to the drug, acyclovir, but are attenuated for pathogenicity in animal models. However, numerous cases of clinical resistance to acyclovir have been associated with viruses that were reported to express no TK activity. We studied an acyclovir-resistant clinical mutant that contains a single-base insertion in its tk gene, predicting the synthesis of a truncated TK polypeptide with no TK activity. Nevertheless, the mutant retained some TK activity and the ability to reactivate from latent infections of mouse trigeminal ganglia. The mutant expressed both the predicted truncated polypeptide and a low level of a polypeptide that comigrated with full-length TK on polyacrylamide gels and reacted with anti-TK antiserum, providing evidence for a frameshifting mechanism. In vitro transcription and translation of mutant tk genes, including constructs in which reporter epitopes could be expressed only if frameshifting occurred, also gave rise to truncated and full-length polypeptides. Reverse transcriptase-polymerase chain reaction analysis coupled with open reading frame cloning failed to detect alterations in tk transcripts that could account for the synthesis of full-length polypeptide. Thus, synthesis of full-length TK was due to an unusual net +1 frameshift during translation, a phenomenon hitherto confined in eukaryotic cells to certain RNA viruses and retrotransposons. Utilization of cellular frameshifting mechanisms may permit an otherwise TK-negative virus to exhibit clinical acyclovir resistance.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8202508&dopt=Abstract acyclovir Zovirax




Enferm Infecc Microbiol Clin. 2002 Jan;20(1):25-7.
[In vitro susceptibility study of herpes simplex virus to acyclovir and foscarnet. Are routine susceptibility studies necessary?]

[Article in Spanish]

Losada I, Canizares A, Hellin T, Marti-Belda P, Guerrero A.

Servicio de Microbiologia, Complexo Hospitalario Juan Canalejo, A Coruna, Spain.

BACKGROUND: The objective of this study was to investigate the prevalence of resistance of herpes simplex virus to acyclovir and foscarnet. PATIENTS AND METHOD: An in vitro susceptibility study of HSV strains isolated from HIV-infected and non-infected (control group) patients was conducted by means of qualitative screening. When the screening results were positive, the method for reducing cytopathic effect was utilized for calculating ID50. An ID50 < 1 microgram/ml indicated susceptibility to acyclovir, ID50 1-2 microgram/ml was intermediate susceptibility to acyclovir and a value of ID50 >/= 2 microgram/ml denoted resistance. Resistance to foscarnet was considered at ID50 >/= 100 microgram/ml. RESULTS: The study involved investigating 84 HSV strains, 49 HIV-infected patients, and 19 control patients. In the control group, no strains resistant to acyclovir were present and infection recurred in only one patient. In patients with HIV infection, one acyclovir resistant strain was detected and one moderately resistant to acyclovir, with good response to acyclovir treatment. In this group, 24.4% of patients presented recurrent infection. No resistance to foscarnet was detected. CONCLUSION: Percentage of HSV strains resistant to acyclovir is very low and resistance to foscarnet was not detected. These data suggest that routine in vitro susceptibility testing of antiviral drugs against HSV does not seem to be necessary.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11820977&dopt=Abstract acyclovir Zovirax

ns.kumc.or.kr

OBJECTIVES: To determine the feasibility and efficacy of suicide-gene therapy using adenovirus (Ad)-mediated herpes simplex virus thymidine kinase (HSV-TK) and the prodrug acyclovir, and to evaluate changes in the biological phenotype for tumour cell proliferative activity after suicide-gene therapy in animal models of human prostate cancer. MATERIALS AND METHODS: Using a replication-defective adenoviral vector (cytomegalovirus, CMV) containing the beta-galactosidase gene (Ad-CMV-beta-gal) as a control and Ad-CMV-TK as the therapeutic vector under the transcriptional control of the CMV promoter, transduction efficiency was assessed in vitro by infecting LNCaP and PC-3 androgen-dependent and independent human prostate cancer cells with Ad-CMV-beta-gal, and using X-gal staining. The TK activity in prostate cancer cells infected with Ad-CMV-TK was determined by measuring TK-mediated [3H]-gancyclovir phosphorylation. The sensitivity of LNCaP and PC-3 cells to Ad-CMV-TK in vitro was determined after infection with the therapeutic vector with or without acyclovir. The inhibition of PC-3 tumour growth in vivo induced by the Ad-CMV-TK/acyclovir suicide-gene system was assessed in separate and controlled experiments using human prostate cancer mouse models. Ki-67 proliferative antigen and proliferating cell nuclear antigen (PCNA), both useful proliferative indices, were evaluated using immunohistochemical staining (MIB-1 monoclonal antibody and monoclonal anti-PCNA antibody) in formalin-fixed, paraffin-embedded tissues from gene therapy-treated and control animals. RESULTS: The mean TK activity was significantly higher in LNCaP and PC-3 cells infected with Ad-CMV-TK than in cells infected with Ad-CMV-beta-gal, used as a control (P < 0.05). The growth of human prostate cancer cells with Ad-CMV-TK was significantly inhibited by adding acyclovir in vitro (P < 0.05). In the in vivo experiments using the PC-3 human prostate cancer mouse model, tumour volume and growth was lower in mice treated with Ad-CMV-TK/acyclovir than in those treated with Ad-CMV-TK only, acyclovir only or untreated (controls) (P < 0.05). Histochemical staining of tumour tissues showed that Ad-CMV-TK/acyclovir destroyed PC-3 tumours through tumour cell death and apoptosis, with local lymphatic infiltration. The mean PCNA labelling index in prostate cancer cells of mice treated with Ad-CMV-TK/acyclovir was significantly lower than that in untreated controls (P < 0.05, Mann-Whitney U-test). The Ki-67 labelling index in prostate cancer cells of mice treated with Ad-CMV-TK/acyclovir was also lower than that in untreated controls (P < 0.05, Student's t-test). Adenovirus-mediated suicide-gene therapy using the HSV-TK gene decreased the proliferative activity of PC-3 human prostatic cancer cells in vivo. CONCLUSIONS: Adenovirus-mediated suicide-gene therapy using an HSV-TK/acyclovir system provided effective therapy in an experimental human prostate cancer mouse model, by significantly inhibiting tumour growth and decreasing the proliferative activity of human prostate cancer cells. Such therapy could be developed as a novel method for treating patients with androgen-independent prostate cancer.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10759680&dopt=Abstract acyclovir Zovirax