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PubMed1998

Synthesis and evaluation of 2-amino-6-fluoro-9-(2-hydroxyethoxymethyl)purine esters as potential prodrugs of acyclovir.

2-Amino-6-fluoro-9-(2-hydroxyethoxymethyl)purine (2) and its ester derivatives 4a-d were synthesized as potential prodrugs of acyclovir, and were evaluated for their oral acyclovir bioavailability in rats and in vivo antiviral efficacy in HSV-1-infected mice. Treatment of 2-amino-6-chloro-9-(2-hydroxyethoxymethyl)purine (3) with trimethylamine in THF/DMF (4:1) followed by a reaction of the resulting trimethylammonium chloride salt 5 with KF in DMF gave 2 in 78% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O) in DMF in the presence of a catalytic amount of DMAP at room temperature produced the esters 4a-d in 90-98% yields. Of the prodrugs tested in rats, the isobutyrate 4d achieved the highest mean urinary recovery of acyclovir (51%) that is 5.7-fold higher than that of acyclovir (9%) and comparable to that of valacyclovir (50%). The prodrug 4d protected dose-dependently the mortality of HSV-1-infected mice, and the group treated with 4d at a dose of 400 mg/kg showed the longest mean survival day (14.6+/-3.1 days) (mean+/-S.D.).

Acyclovir↗
PubMed2002

Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. METHOD: In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. RESULTS: Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. CONCLUSION: Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

Acyclovir↗
PubMed2002

Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease.

Cytomegalovirus (CMV) disease is a common complication of patients with advanced human immunodeficiency virus infection. The aim of the present study, based on a case-cohort design, was to determine the predictive value of follow-up and baseline qualitative plasma CMV polymerase chain reaction (PCR) values for CMV end-organ disease in 378 patients (158 who progressed to CMV end-organ disease and 220 who did not develop CMV disease). These patients are part of the full AIDS Clinical Trials Group 204 multinational study (1227 patients), a randomized, controlled trial that compared the effects of valacyclovir with those of acyclovir for CMV disease prevention. Baseline PCR positivity was a significant risk factor for CMV disease progression (relative risk [RR], 1.81; 95% confidence interval [CI], 1.09-3.00). In multivariate analyses, time-updated PCR positivity was strongly associated with progression to CMV end-organ disease (RR, 4.42; 95% CI, 2.87-6.81). Change in cumulative PCR status was informative for the risk of subsequent CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed2002

Challenges in genital herpes simplex virus management.

Development of serologic assays to detect antibodies to herpes simplex virus (HSV) glycoproteins (g)G1 and (g)G2 has allowed accurate definition of the seroprevalence of HSV-2 worldwide. Studies from all continents indicate epidemic proportions of HSV-2 infection. In the United States, 1 in 5 sexually active adults is infected. In Africa and the Caribbean, HSV prevalence is higher. Since the development of the acyclic nucleoside derivatives acyclovir, famciclovir, and valacyclovir, treatment of mucocutaneous HSV is a practice of everyday medical care. Yet, despite effective drugs, there is widespread discontent by clients and providers about care of patients with genital herpes. Much of this relates to transmission complexities and the varied natural history of the infection. However, over time, most patients adjust to their disease and the medical and psychosocial complications. Recent studies show condoms reduce transmission, providing an important tool for counseling the patient with newly diagnosed genital herpes.

2-Aminopurine↗
PubMed1998

Chronic vulvar ulceration in an immunocompetent woman due to acyclovir-resistant, thymidine kinase-deficient herpes simplex virus.

A 34-year-old healthy woman presented with a 15-month history of persistent, nonhealing vulvar ulcerations due to herpes simplex virus (HSV) type 2. Extensive dermatologic workup and serial skin biopsies failed to reveal an underlying vulvar dermatosis or autoimmune bullous disorder. Virologic studies revealed resistance to acyclovir in vitro due to deficiency in thymidine kinase activity. Serum antibody to human immunodeficiency virus was negative on two occasions, separated by 1 year. Immunologic evaluation showed normal HSV-specific proliferative and CD8 cytotoxic T lymphocyte responses as well as normal NK cell function. Vulvar lesions failed to heal in association with trials of topical trifluorothymidine and oral valacyclovir but resolved completely with the application of 1% foscarnet cream. No recurrence of HSV has been observed in 24 months of follow-up to date.

Acyclovir↗
PubMed2002

Noninvasive bioluminescence imaging of herpes simplex virus type 1 infection and therapy in living mice.

Mouse models of herpes simplex virus type 1 (HSV-1) infection provide significant insights into viral and host genes that regulate disease pathogenesis, but conventional methods to determine the full extent of viral spread and replication typically require the sacrifice of infected animals. To develop a noninvasive method for detecting HSV-1 in living mice, we used a strain KOS HSV-1 recombinant that expresses firefly (Photinus pyralis) and Renilla (Renilla reniformis) luciferase reporter proteins and monitored infection with a cooled charge-coupled device camera. Viral infection in mouse footpads, peritoneal cavity, brain, and eyes could be detected by bioluminescence imaging of firefly luciferase. The activity of Renilla luciferase could be imaged after direct administration of substrate to infected eyes but not following the systemic delivery of substrate. The magnitude of bioluminescence from firefly luciferase measured in vivo correlated directly with input titers of recombinant virus used for infection. Treatment of infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced dose-dependent decreases in firefly luciferase activity that correlated with changes in viral titers. These data demonstrate that bioluminescence imaging can be used for noninvasive, real-time monitoring of HSV-1 infection and therapy in living mice.

Acyclovir↗
PubMed2001

Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein.

An hPepT1-GFP fusion construct was made to study drug inhibition of dipeptide uptake and apical, basolateral, or subcellular hPepT1 localization. The hPepT1 stop codon was mutated by polymerase chain reaction and was subsequently cloned into the pEGFP-N1 vector. The hPepT1-GFP fusion construct was then transfected into Caco-2 and HeLa cells, and drug inhibition was studied by inhibiting 3H-Gly-Sar uptake. Western blot analysis was used to determine hPepT1-GFP expression levels and confocal microscopy was used to examine the localization. Both anti-hPepT1 antibody and anti-GFP antibody recognized a 120-kd hPepT1-GFP fusion protein in the transfected cells. The 3H-Gly-Sar uptake in transfected HeLa cells was enhanced more than 20 times compared with the control. Valacyclovir (5 mmol/L) was able to completely inhibit 3H-Gly-Sar uptake in these transfected cells. Confocal microscopy showed that the hPepT1-GFP mainly localized in the Caco-2 cell apical membrane, but was present throughout the entire HeLa cell membranes. The hPepT1-GFP fusion protein was not found in either early endosome or lysosome of Caco-2 cells under normal conditions; however, it was detected in some subsets of lysosomes and early endosomes in phorbol 12-myristate 13-acetate (PMA)-treated Caco-2 cells.

Acyclovir↗
PubMed2001

Varicella in a pediatric heart transplant population on nonsteroid maintenance immunosuppression.

OBJECTIVE: Varicella-zoster virus has been reported to produce serious, often life-threatening, disease in immunosuppressed patients with a variety of diagnoses. The impact of this virus on the young child after heart transplantation has not been reported. METHODS: We reviewed the charts of 28 children who were <10 years of age at heart transplantation and had at least 1 year of follow-up. The median follow-up period was 7 years (1.4-13.0 years). All were seronegative for varicella-zoster virus before transplantation. Fourteen (50%) developed varicella at a median time posttransplantation of 3.3 years. The first 7 were admitted for intravenous acyclovir for 3 days followed by oral acyclovir for 7 days. The last 7 were treated as outpatients with oral valacyclovir for 7 days (n = 6) or with oral acyclovir for 10 days (n = 1). RESULTS: Intravenous and oral regimens both were well tolerated and were without complications. No patient was receiving steroids at the time that they developed their initial episode of varicella. One patient was receiving steroids for therapy of posttransplantation lymphoproliferative disease when she developed recurrent varicella or generalized zoster. No episodes of rejection were attributed to the varicella-zoster virus infection. There were no episodes of localized zoster. All patients experienced seroconversion from undetectable to detectable antibody titers early after varicella, and 12 of the 14 patients continued to have persistent detectable titers in late follow-up. Two of the 14 who received chemotherapy or enhanced immunosuppression after retransplantation transiently lost detectable varicella-zoster virus antibodies but currently have detectable titers. CONCLUSIONS: Primary varicella-zoster infection was well tolerated in our young pediatric heart transplant recipients, with no serious complications. We now reserve inpatient/intravenous therapy for those who are unable to tolerate oral medications or those who are receiving enhanced immunosuppression.

Acyclovir↗
PubMed2003

The role of antivirals in the management of neuropathic pain in the older patient with herpes zoster.

Herpes zoster has been known since ancient times. It is a ubiquitous disease, occurring sporadically without any seasonal preference and is caused by the varicella-zoster virus. It may be defined as an endogenous relapse of the primary infection varicella. Herpes zoster is characterised by typical efflorescences in the innervation region of a cranial or spinal nerve and starts and ends with pain of varying intensity. Currently, several antiviral drugs are approved and many studies have shown that antiviral therapy, started early in the course of disease, can significantly reduce the risk and the duration of postherpetic neuralgia in elderly patients. The effects of all antivirals discussed in this article, given either orally or intravenously, are comparable with regards to the resolution of virus replication, prevention of dissemination of skin lesions and reduction of acute herpes zoster pain. Valaciclovir (valacyclovir), famciclovir and brivudine (brivudin) are comparably effective in the reduction of the incidence and/or prevention of zoster-associated pain and postherpetic neuralgia. Brivudine 125mg once daily is as effective as famciclovir 250mg three times daily in reducing the prevalence and the duration of zoster-associated pain and postherpetic neuralgia, especially if therapy is combined with a structured-pain therapy. The intensity of the therapy for pain should depend on the intensity of the pain that it is treating. Famciclovir and brivudine offer an advantage over other antivirals because they are administered less frequently; this is particularly relevant for elderly patients who may already be taking a number of medications for other diseases. Therefore, antiviral therapy in combination with adequate pain management should be given to all elderly patients as soon as herpes zoster is diagnosed.

2-Aminopurine↗
PubMed2002

Prognostic factors of postherpetic neuralgia.

The investigation was aimed to determine prognostic factors related to postherpetic neuralgia (PHN), and treatment options for preventing PHN. The data showed 34 (17.0%) out of 188 patients with herpes zoster had severe pain after 4 weeks, and 22 (11.7%) after 8 weeks, compared with 109 (58.0%) at presentation. The age (>/=50 yr), surface area involved (>/=9%), and duration of severe pain (>/=4 weeks) might be the main factors that lead to PHN. On the other hand, gender, dermatomal distribution, accompanied systemic conditions, and interval between initial pain and initiation of treatment might not be implicated in PHN. The subjects were orally received antiviral (valacyclovir), tricyclic antidepressant (amitriptyline), and analgesic (ibuprofen) as the standard treatment in the group 1. In addition to the standard medication, lidocaine solution was sub- and/or perilesionally injected in the group 2, while lidocaine plus prilocaine cream was topically applied to the skin lesions in the group 3. The rates of PHN in the 3 treatment groups were not significantly different, suggesting adjuvant anesthetics may not be helpful to reduce the severity of pain.

Acyclovir↗
PubMed1999

Antiviral agents for non-human immunodeficiency virus infections.

Several new agents for treating viral infections have been developed in recent years. All available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome and is effective in the treatment and prevention of cytomegalovirus infection in other immunocompromised patients. Famciclovir and valacyclovir are effective in the management of herpes simplex and varicella-zoster infection. Amantadine and rimantadine are useful therapeutically and prophylactically in the management of influenza A virus infection. Chronic hepatitis B infection can respond to lamivudine therapy, and the optimal treatment of hepatitis C is the combination of interferon alfa and ribavirin. Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral agents in specific settings.

2-Aminopurine↗
PubMed2000

Infectious complications of pentostatin therapy.

Managing the infectious complications associated with pentostatin (Nipent), used alone or in combination with other agents in patients with low-grade lymphomas, poses a significant problem for clinicians. Since there is limited experience with these therapies, definitive treatment recommendations concerning prophylaxis cannot be made. The panel members discussed the use of valacyclovir (Valtrex) to provide prophylaxis for herpes zoster, trimethoprim/sulfamethoxazole for Pneumocystis, and acyclovir (Zovirax) for varicella zoster. They also considered combinations of pentostatin with agents such as interferon, rituximab (Rituxan), and chlorambucil (Leukeran) and their effect on the immune system. The biology of B and T cells was discussed, with an emphasis on clinical application.

Acyclovir↗
PubMed2000

Recent advances in management of genital herpes.

OBJECTIVE: To provide an update on new diagnostic tests and antiviral strategies for managing genital herpes. QUALITY OF EVIDENCE: Treatment guidelines are based on randomized clinical trials and recommendations from the Expert Working Group on Canadian Guidelines for Sexually Transmitted Diseases. Recommendations concerning other aspects of managing genital herpes (e.g., indications for using type-specific serologic tests) are mainly based on expert opinion. MAIN MESSAGE: Genital herpes is one of the most common sexually transmitted diseases, affecting about 20% of sexually active people; up to 80% of cases are undiagnosed. Because of frequent atypical presentation and the emotional burden associated with genital herpes, clinical diagnosis should be confirmed by viral culture. Type-specific serologic assays are now available, but their use is often restricted to special situations and requires adequate counseling. New antivirals (valacyclovir and famciclovir) with improved pharmacokinetic profiles have now been approved for episodic treatment of recurrences and suppressive therapy. CONCLUSION: Wise use of new diagnostic assays for herpes simplex coupled with more convenient treatment regimens should provide better management of patients with genital herpes.

2-Aminopurine↗
PubMedDate not supplied

[Effect of the Epstein-Barr virus on the nervous system].

On the basis of a comprehensive examination of 12 patients with verified Epstein-Barr virus (EBV) infection it has been shown that this infection can be accompanied by acute and chronic affections of the central and peripheral nervous system. The pathogenesis of chronic EBV-infection involves autoimmune disorders, neurosensitization, a hazard of an injury to the muscular tissue. Chronic EBV-infection calls for differential diagnosis with other slow virus infections, systemic tumor afflictions, systemic diseases of the connective tissue. Acyclovir or valacyclovir can be recommended as treatment of acute and chronic EBV-infection.

Acyclovir↗
PubMed2002

Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management.

OBJECTIVE: To present to general dentists the typical signs and symptoms associated with adult acute (primary) herpetic gingivostomatitis. The pertinent laboratory tests, management options and current pharmacotherapy are also reviewed. REVIEW DESIGN: The clinical files of 13 adult patients were reviewed. All had no history of herpes simplex virus infection and presented with oral lesions suggestive of primary herpetic infection. The subjects were all patients of one of the investigators, and their workup included Tzanck testing and viral culture. RESULTS: The patients ranged in age from 18 to 79 (mean 37.2, standard deviation 19.6) years. Nine (69%) were men. Viral culture was confirmed as the gold standard for diagnosis. The sensitivity of Tzanck testing was 77% (10/13), slightly higher than that reported previously (40% to 50%). In this patient group the febrile lymphadenopathic profile was typical of younger patients (18 to 42 years of age), whereas older patients presented with predominantly oral symptoms. CONCLUSIONS: Primary herpetic gingivostomatitis is not limited to children but can affect people of any age. Proper diagnosis and treatment are essential, particularly in elderly and immunocompromised patients. Tzanck testing may serve as a useful adjunct in diagnosis. Antiviral agents such as valacyclovir and famciclovir should be considered part of early management. Dentists are often the first health care professionals to be consulted by patients with this condition, and recognition of the infection is paramount.

2-Aminopurine↗
PubMed2003

Recurrent herpes simplex labialis: selected therapeutic options.

Recurrent infection with herpes simplex virus 1 (HSV1), called herpes simplex labialis (HSL), is a global problem for patients with normal immune systems. An effective management program is needed for those with frequent HSL recurrences, particularly if associated morbidity and life-threatening factors are present and the patient's immune status is altered. Over the past 20 years, a variety of antiviral compounds (acyclovir, penciclovir, famciclovir, valacyclovir) have been introduced that may reduce healing time, lesion size and associated pain. Classical lesions are preceded by a prodrome, but others appear without warning, which makes them more difficult to treat. Various methods of application (intravenous, oral, topical) are used, depending on whether the patient is experiencing recurrent HSL infection or erythema multiforme or is scheduled to undergo a dental procedure, a surgical procedure or a dermatological face peel (the latter being known triggers for recurrence). This article outlines preferred treatment (including drugs and their modes of application) for adults and children in each situation, which should assist practitioners wishing to use antiviral therapy.

2-Aminopurine↗
PubMedDate not supplied

Antiviral therapy for genital herpes in nonpregnant and pregnant women.

There have been major developments in basic and clinical research in the field of antiviral therapy. The health care provider needs to know the availability of numerous antiviral compounds and begin to view them as we do antibiotics. They need to be used selectively to modify infections and prevent the morbidity and mortality associated with viral infections, such as herpes simplex virus (HSV, genital herpes). Therapy of these infections is required to treat not only the patient but also to prevent infection of sexual partners and the newborn. Numerous and varied antiviral compounds have been approved by the FDA to treat genital HSV infections. They all have the same mechanism of action. Acyclovir, valacyclovir, and famciclovir have been approved for the treatment of primary and recurrent disease. All three agents can be used for daily administration for the suppression of recurrent disease. Use of these antiviral compounds in the nonpregnant and pregnant woman can significantly alter the disease and influence transmission rates along with decreasing the morbidity and mortality associated with HSV infections.

2-Aminopurine↗
PubMed2003

Phase II study of alemtuzumab in chronic lymphoproliferative disorders.

BACKGROUND: Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders. METHODS: Seventy-eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T-cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4-12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir. RESULTS: The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty-six patients (46%) experienced at least one episode of fever or infection. CONCLUSIONS: Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders.

Adult↗