Suppression of infectious virus spread to the liver by foscarnet following lethal infection of Acyclovir / Aciclovir-resistant herpes simplex virus type 2 in mice.

Patients with the acquired immune deficiency syndrome (AIDS) occasionally develop hepatitis, pneumonia or esophagitis due to herpes simplex virus type 2 (HSV-2) infection. HSV hepatitis is a rare but serious complication in liver transplantation. Acyclovir / Aciclovir-resistant HSV strains may emerge in immunocompromised patients. Following intraperitoneal inoculation, HSV-2 induces necrotizing hepatitis in mice. We studied the virus spread and mortality following intraperitoneal inoculation of HSV-2 RK (an Acyclovir / Aciclovir-resistant recombinant virus with altered thymidine kinase activity) as compared to its parent virus 8620K. Neither the 50% lethal dose (LD50) nor the average survival time was significantly different between the two strains. Parenteral Acyclovir / Aciclovir treatment was found to be effective against 8620K but not RK infection. Parenteral foscarnet treatment was effective against both RK and 8620K, and also inhibited the spread of either virus to the liver, spinal cord and brain. Peroral foscarnet administration was found to prevent the virus growth in the liver.

In continuous ambulatory peritoneal dialysis (CAPD) patients, Acyclovir / Aciclovir-induced neurotoxicity is reported to be associated with high serum drug levels even when following the recommended reduced doses for this renal failure population. In view of the high oral bioavailability of valAcyclovir / Aciclovir (the L-valyl ester of Acyclovir / Aciclovir) the risk of neurotoxicity becomes more prominent. The present study was conducted in 12 CAPD patients who were administered a single oral dose of 500 mg valAcyclovir / Aciclovir. Acyclovir / Aciclovir was analyzed by high-performance liquid chromatography. Relative pharmacokinetic parameters were estimated based on Acyclovir / Aciclovir concentrations at 8, 12 and 24 h post-dose. High inter-patient variations were observed with Acyclovir / Aciclovir apparent total clearance 7.238 +/- 4 l/h and half-life (T1/2) 22.27 +/- 16.82 h. However, dosage simulations confirmed supratherapeutic Acyclovir / Aciclovir concentrations for all participants when following the recommended dose of 1,000 mg valAcyclovir / Aciclovir/24 h for varicella zoster infections.

Acyclovir / Aciclovir 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).

To examine the relationship between Acyclovir / Aciclovir 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 / Aciclovir were studied by stratified analysis of variance and Mantel-Haenzel chi 2 tests. The association between Acyclovir / Aciclovir and survival was studied with use of the proportional hazards regression model. Individuals reporting Acyclovir / Aciclovir 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 / Aciclovir use was not associated with prolonged survival.

Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance.

herpes simplex virus (HSV) infections in 75 allogeneic stem cell transplant recipients were analyzed. Sixteen patients developed HSV disease following transplantation. The risk factors were age, sex (females), unrelated donor graft, and graft-versus-host disease (GVHD) grade >/=2. Seven patients did not respond to Acyclovir / Aciclovir, and 3 patients failed to respond to foscarnet. Isolates from 4 patients developed resistance to Acyclovir / Aciclovir/Penciclovir ( Denavir ), and 3 patients had foscarnet-resistant isolates. The remaining 3 patients failed to respond to Acyclovir / Aciclovir, despite having sensitive isolates. All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for Acyclovir / Aciclovir (P=.01). The risk factors for clinical resistance to antiviral drugs were a GVHD grade >/=2 (P=.001) and the lack of ganciclovir prophylaxis (P=.01), with a higher nonrelapse mortality in the latter group (P<.0001). Clinical as well as in vitro resistance to antiviral drugs is common in patients with severe GVHD and is associated with a poor outcome.



Prophylactic Acyclovir / Aciclovir effectively reduces herpes simplex virus type 1 reactivation after exposure of latently infected mice to ultraviolet B.

PURPOSE. To determine the potential efficacy and anatomic sites of action of prophylactic oral Acyclovir / Aciclovir using a murine model of ultraviolet-B-induced reactivation of herpes simplex 1 keratitis. METHODS. Latent infection with herpes simplex 1 (McKrae) was established in 80 National Institutes of Health inbred strain of mice. Forty of the mice were given Acyclovir / Aciclovir orally and the other 40 latently infected mice served as controls. Mice were exposed to 250 mJ/cm2 of ultraviolet-B radiation and killed on days 1, 2, 3, and 4 after ultraviolet-B radiation. Trigeminal ganglia and eyes from these mice were homogenized and incubated on Vero cell monolayers for recovery of reactivated virus. RESULTS. Based on the recovery of infectious virus after ultraviolet-B in treated versus control groups, Acyclovir / Aciclovir effectively reduced detectable viral reactivation at both the ocular level (P = 0.003) and the ganglionic level (P = 0.025). The numbers of viral culture-positive eye and trigeminal ganglia homogenates in the control group were 11 and 6 out of 40, respectively, compared to 1 and 0 out of 40 culture-positive eye and trigeminal ganglia homogenates in the Acyclovir / Aciclovir treated mice. Therapeutic serum levels of Acyclovir / Aciclovir were confirmed by high performance liquid chromatography. In the Acyclovir / Aciclovir-tested group, the single case of viral break-through at the ocular surface was not an Acyclovir / Aciclovir-resistant mutant. CONCLUSION. Prophylactic Acyclovir / Aciclovir effectively reduces the incidence of herpes simplex virus-1 reactivation after ultraviolet-B-induced reactivation in National Institutes of Health inbred strain of mice.

During childhood chickenpox, varicella-zoster virus becomes latent in neurons of the dorsal root or trigeminal ganglia. Shingles results years to decades later from a breakdown of viral latency within a ganglion and subsequent virus spread to the skin producing a unilateral dermatomal vesicular rash accompanied by segmental pain. Treatment with Famciclovir ( Famvir ), Valacyclovir ( Valtrex ), and high dose Acyclovir / Aciclovir is beneficial if started within the first 3 days of the rash. All three drugs can be given orally, are equally effective, shorten the duration of viral shedding and time to healing of the rash by 1 to 2 days, and lessen the intensity and duration of the acute neuritic pain. Famciclovir ( Famvir ) and Valacyclovir ( Valtrex ) have more convenient dosing schedules (three times daily) compared to Acyclovir / Aciclovir (five times daily). Mild cases of shingles in younger healthy individuals often do not require any antiviral treatment. Pain in shingles may have burning, lancinating, or allodynic qualities, ranges in intensity from mild to unbearable, and lasts 2 to 8 weeks. Pain treatment varies on the type and intensity of pain experienced. In a few patients, post-herpetic neuralgia develops and the dermatomal pain persists for months to years. Effective treatment of post-herpetic pain is often difficult.

Bioequivalence study of generic Acyclovir / Aciclovir compared with the brand name Acyclovir / Aciclovir.

The bioequivalence study of 200-mg generic Acyclovir / Aciclovir was conducted in healthy males. The reference Zovirax and the test Zevin were administered as a single oral dose after an overnight fast in a two-period, crossover design separated by 1 week. Serial blood samples were collected over a period of 24 hours. Plasma Acyclovir / Aciclovir concentrations were determined by HPLC and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The t 1/2 for the test (4.5 +/- 2.4 h) and Zoviraxl (3.9 +/- 2.6 h) were comparable. The analysis of variance was carried out and the median Tmax (1.50 h) for the test was not statistically difference from Zovirax. The mean (90% CI) of the AUC0-infinity and the Cmax ratios for (Test/reference) were 0.95 (0.83-1.09) and 0.95 (0.83-1.10), respectively. These values fell within the bioequivalence criteria of 0.80-1.25, thus it was concluded that Zevin and Zovirax were bioequivalence.

Long-term oral Acyclovir / Aciclovir therapy. Effect on recurrent infectious herpes simplex keratitis in patients with and without grafts.

PURPOSE: To evaluate the efficacy of long-term oral Acyclovir / Aciclovir therapy in reducing recurrences of dendritic or geographic herpes simplex keratitis (HSK). METHODS: Thirteen patients with a history of frequently recurring HSK were followed before (mean, 27 months) and during long-term systemic Acyclovir / Aciclovir, and eight were followed after the Acyclovir / Aciclovir was discontinued. RESULTS: Treatment ranged from 8.5 to 62 months (mean, 34 months). During treatment, the number of recurrences per month decreased from 0.15 to 0.03, and the average duration of relapses decreased from 12.6 to 7.8 days. Recurrences correlated with daily doses of oral Acyclovir / Aciclovir of 800 mg or less, intraocular surgery within 6 weeks of initiating treatment, and discontinuation of therapy against medical advice. CONCLUSION: The results of this small study appear to demonstrate the efficacy of long-term oral Acyclovir / Aciclovir in prophylaxis of recurrent epithelial herpes simplex infection: therapeutic doses of oral Acyclovir / Aciclovir reduce both the rate and duration of recurrences of infectious herpetic keratitis. A multicenter, double-masked, placebo-controlled study is indicated.

We have examined the susceptibility to Acyclovir / Aciclovir and frequency of Acyclovir / Aciclovir-resistant viruses in herpes simplex virus type (HSV) 2 clones isolated directly from genital lesions of 11 patients who had taken suppressive therapy (200 mg/day) for 1-9 years and 15 patients naive to Acyclovir / Aciclovir. Suppressive therapy significantly reduced the incidence of recurrence and the severity of the skin lesions. HSV samples from genital lesions were directly inoculated into Vero cells, and viral clones were isolated in the absence and presence of 10 microg/ml Acyclovir / Aciclovir. Five-hundred-and-ninety-two clones, isolated in the absence of Acyclovir / Aciclovir, were subjected to the Acyclovir / Aciclovir susceptibility test, and 155 clones isolated in the presence of Acyclovir / Aciclovir were analysed for the mechanisms of resistance to Acyclovir / Aciclovir. There were no significant differences in the susceptibility to Acyclovir / Aciclovir, the frequency of Acyclovir / Aciclovir-resistant virus and the ratio of thymidine kinase-deficient viruses in Acyclovir / Aciclovir-resistant viruses between the two groups. The frequency of Acyclovir / Aciclovir-resistant clones was about three per 10000 plaque forming units (PFU), and genital lesions contained up to 3x10(6) PFU of replicating virus in the specimens from the patients with genital herpes with or without Acyclovir / Aciclovir-suppressive therapy. Thus, the low dose of Acyclovir / Aciclovir suppressive therapy did not affect the susceptibility to Acyclovir / Aciclovir or increase the frequency of Acyclovir / Aciclovir-resistant viruses in the genital lesions.

Pregnancy outcomes following systemic prenatal Acyclovir / Aciclovir exposure--June 1, 1984-June 30, 1993.

Herpes infections are common among women of reproductive age (i.e., aged 15-44 years). Acyclovir / Aciclovir (Zovirax), an antiviral drug effective in the treatment of herpes simplex infection, was approved by the Food and Drug Administration (FDA) in 1984. Since its approval, the effects of Acyclovir / Aciclovir on human pregnancies have not been determined. However, inadvertent pregnancy exposures to Acyclovir / Aciclovir were expected to occur among women in whom treatment had been indicated for preexisting herpes simplex infections. Some physicians have reported intentional use of Acyclovir / Aciclovir during pregnancy for treatment of life-threatening herpes simplex infection. To assess the outcomes of pregnancies exposed to Acyclovir / Aciclovir, the Acyclovir / Aciclovir in Pregnancy Registry was established on June 1, 1984, by the manufacturer, in collaboration with CDC. This report summarizes data on pregnancies reported to the registry through June 30, 1993.

herpes simplex infection as possible etiology for febrile neutropenia and mucositis in patients treated for hematological malignancies.

Mucositis is a common complication following chemotherapy. Clinical findings similar to herpetic infection are observed in some patients. Acyclovir / Aciclovir administered in addition to empirical, antibiotic treatment improves the course of mucositis, and can also bring down the temperature. The aim of our study was to define the etiological influence of herpetic infection on the course of febrile neutropenia in patients with mucositis. A total of 34 patients with febrile neutropenia were divided into 2 groups: 15 with typical herpetic eruption, and 19 with non-specific mucositis. Both groups received 5-10 mg/kg Acyclovir / Aciclovir every eight hours together with empiric antibiotic treatment. The effect of Acyclovir / Aciclovir was studied, and results compared in the two patient groups. Body temperatures decreased in both groups, clinical symptoms, however, disappeared more slowly in the group with non-specific mucositis. The beneficial effect of Acyclovir / Aciclovir treatment was particularly well expressed in seropositive patients. In this group of patients, herpetic infections may recur under further chemotherapy. Thus, it would be useful to administer Acyclovir / Aciclovir to them prophylactically during risk periods.

A novel strategy was developed for the synthesis of N(7)-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p-methoxyphenyloxy)ethoxy]methyl chloride and N(9)-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N(7)-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than Acyclovir / Aciclovir (2). N(7)-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows for a greater expression of antiviral activity of antiviral agents, such as N(9)-adenine acyclic nucleoside 1 and ara-A (3). Compound 14 was phosphorylated neither by herpes simplex virus (HSV) thymidine kinase nor by Vero cell thymidine kinase, yet it enhanced the rate constant for the monophosphorylation of Acyclovir / Aciclovir (2) by HSV thymidine kinase. Consequently, the combination of Acyclovir / Aciclovir (2) and 14 exhibited greater antiviral activity than Acyclovir / Aciclovir alone. 7-[2-(Phosphonomethoxy)ethyl]adenine (20) was also synthesized. The key step involved the reaction of 9-(2-cyanoethyl)adenine (15) with methyl iodoacetate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. Unlike 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, 4), the N(7)-isomer 20 was not phosphorylated effectively by 5-phosphoribosyl 1-pyrophosphate synthetase (PRPP synthetase). Thus, it did not exhibit pronounced antiviral activity. Dinucleotide 5'-monophosphate 24 and its butenolide ester 25 were also synthesized. Compound 24 showed substrate activity toward PRPP synthetase and exhibited notable activity against DNA viruses. The antiviral activity of the ester derivative 25 was found to be higher than that of the parent molecule 24. Dinucleotide 5'-monophosphate 24 is susceptible to degradation by snake venom and spleen phosphodiesterases. However, its respective butenolide ester derivative 25 was completely resistant to snake venom and spleen enzymes. Butenolide ester derivatives 28 and 29 were also synthesized and exhibited notable anti-DNA virus and anti-retrovirus activity in vitro. Compounds 2, 4, 9, 14, 20, 24, 25, and 28 were also evaluated for their inhibitory effect on HSV-1-induced mortality in NMRI mice. N(7)-adenine acyclic nucleoside 14 [LD(50) (intraperitoneal, ip) 950 mg/kg], nucleotide-containing butenolide 25 [LD(50) (ip) 675 mg/kg], and butenolide 28 [LD(50) (ip) 710 mg/kg] were found to be potent anti-HSV-1 agents in vivo. In addition, butenolide 28 efficiently decreased tumor formation induced by Moloney murine sarcoma virus (MSV) in NMRI mice while significantly increasing the survival time of MSV-infected mice.

herpes simplex Virus Shedding in Bone Marrow Transplant Recipients During Low-Dose Oral Acyclovir / Aciclovir Prohylaxis.

A 400mg dose twice-a-day oral Acyclovir / Aciclovir 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 / Aciclovir therapy or dose adjustment suggesting that Acyclovir / Aciclovir resistance did not account for the occurrence of infection in our patients. These data demonstrated that oral Acyclovir / Aciclovir 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.

The synthesis and in vitro anti-hepatitis B virus (HBV) activity of two mononucleoside phosphotriester derivatives of Acyclovir / Aciclovir incorporating S-acyl-2-thioethyl (SATE) groups are reported. In contrast to the parent nucleoside, the described phosphotriesters emerged as potent and selective inhibitors of HBV replication in HepG2.2.15 cells. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the delivery to Acyclovir / Aciclovir 5'-monophosphate inside the infected cells. Moreover, the in vitro anti-HBV activities of one of these bis(SATE)phosphotriesters and of (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC) were compared alone and in combination. Analysis of the combination data indicates that 3TC and the studied SATE pronucleotide of Acyclovir / Aciclovir exhibited strong synergistic interactions. The present study provides an example where the use of a pronucleotide approach extends the antiviral spectrum of a nucleoside analogue. Given the potency of SATE pronucleotides of Acyclovir / Aciclovir against HBV in HepG2.2.15 cells, further studies including animal experiments seem warranted to evaluate the potential of these compounds as anti-HBV agents.

Purification and characterization of a rat liver enzyme that hydrolyzes valAcyclovir / Aciclovir, the L-valyl ester prodrug of Acyclovir / Aciclovir.

ValAcyclovir / Aciclovir is an oral prodrug of the antiherpetic agent Acyclovir / Aciclovir. An enzyme that hydrolyzes valAcyclovir / Aciclovir to Acyclovir / Aciclovir, valAcyclovir / Aciclovir hydrolase (VACVase), was purified from rat liver and characterized. VACVase was a basic (pI 9.4) protein associated with mitochondria. It was monomeric and had a molecular mass of 29 kDa. Amino acid sequences of six VACVase peptides, including its NH2 terminus (13 amino acids) and accounting for approximately 20% of its complete sequence, were not found in the SwissProt protein data base. VACVase hydrolyzed other amino acid esters of Acyclovir / Aciclovir in addition to valAcyclovir / Aciclovir (kcat/Km = 58 mM-1 s-1), with a preference for the L-alanyl (kcat/Km = 226 mM-1 s-1) and L-methionyl (kcat/Km = 200 mM-1 s-1) esters. It did not hydrolyze other types of esters or numerous di- and tripeptides and aminoacyl-beta-naphthylamides. Hydrolysis of valAcyclovir / Aciclovir by VACVase was not inhibited by amastatin, antipain, aprotinin, bestatin, chymostatin, E-64, EDTA, ebelactone A, ebelactone B, elastatinal, leupeptin, pepstatin, or phosphoramidon. It was neither inhibited nor activated by Ca2+, Co2+, Mg2+, Mn2+, or Zn2+. Therefore, this enzyme is not a typical esterase or peptidase and, to our knowledge, it has not been described previously. Its physiological function is not known; however, it may play a significant role in the biotransformation of valAcyclovir / Aciclovir to Acyclovir / Aciclovir.

In vitro cytostatic activity of 8-substituted and tricyclic analogues of Acyclovir / Aciclovir.

Out of a series of twenty 8-substituted or/and 1,N-2-bridged (tricyclic) derivatives of Acyclovir / Aciclovir (a selective antiherpetic drug), known to be nontoxic to normal cells, seven compounds were found to exhibit moderate cytostatic activity in KB human tumor tissue culture system with ED50 activity values ranging from 0.052-0.094 x 10(-3) mole/l. The structure-activity relationship analysis indicated that the primary factors determining their cytotoxicity were: 1) bromine atom at the C-8 position of the bicyclic derivatives and 2) unsubstituted appended ring in the tricyclic derivatives. Combination of two structural elements carrying the cytotoxicity gave diverse effects, enhancement or decrease in activity depending on particular cases. Two compounds (of four selected), 8-bromoAcyclovir / Aciclovir and 1,N-2-etheno-Acyclovir / Aciclovir, having unsubstituted 9-[(2-hydroxyethoxy)methyl] chain, showed approximately 2-fold increase in their cytotoxicity against HeLa tumor cells in the presence of the induced microsomal generating system suggesting that their cytotoxicity depends on the drug metabolic transformation into their active metabolites (intermediates) via MFO-system, and that structural unit of this chain is essential for abovementioned activation. Presently found remarkable cytotoxic selectivity of Acyclovir / Aciclovir analogues against KB and HeLa tumor cells together with previously reported in the literature specific cytotoxic activity of Acyclovir / Aciclovir against murine leukemia L 1210 cells seem to be encouraging.