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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↗

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↗

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↗

PubMed2000

Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2.

Peptide transporters PEPT1 and PEPT2 transport numerous compounds including small peptides, peptide-like drugs and nonpeptidic compounds such as valacyclovir. PEPT1 and PEPT2 show low and high affinity for most substrates, respectively, but beta-lactam antibiotics without an alpha-amino group are the only known substrates that prefer PEPT1 to PEPT2. The aim of this study was to compare the recognition and affinity of various substrates between rat PEPT1 and rat PEPT2, and to determine the structural requirements influencing the substrate affinity. [14C]Glycylsarcosine uptake by PEPT1- or PEPT2-expressing transfectant was inhibited by di- and tripeptides, but not by amino acids, tetrapeptides or most cyclic dipeptides. All dipeptides and tripeptides examined showed more potent inhibition of [14C]glycylsarcosine uptake via PEPT2 than via PEPT1, irrespective of their charge and structure. Modification of the alpha-amino group of dipeptides reduced their substrate affinity to both transporters, as compared to unmodified dipeptides, but these dipeptides still showed potent inhibitory effects on PEPT2. Among the nonpeptidic substrates tested, only the eight-amino-octanoic acid displayed stronger inhibition of [14C]glycylsarcosine uptake in PEPT1 than in PEPT2. These findings suggest that alpha- or beta-amino carbonyl function is the key structure responsible for the higher affinity for PEPT2 than for PEPT1.

Animals↗

PubMed1998

Esophageal Infections.

Infectious esophagitis is a common problem in immunocompromised patients that can result in prolonged discomfort and malnutrition. Common infectious causes of esophagitis can be confirmed by laboratory testing, but esophagoscopy is often necessary not only to visualize the esophageal mucosa but also to obtain diagnostic biopsies. Empiric, systemic antifungal or antiherpetic therapies are often prescribed prior to confirming an etiologic diagnosis in esophagitis. In some cases, however, endoscopy is needed to guide therapy. Systemic antifungal therapy is usually superior to topical therapy for Candida esophagitis, and the first choice of agent is generally fluconazole. Valacyclovir or famciclovir are the preferred first treatments for herpetic esophagitis because of their clinical efficacy and convenient dosing schedules. Thalidomide may be useful in the management of aphthous ulcerations of the mouth and esophagus in patients with HIV.

Journal Article↗

PubMed2000

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Advances in the treatment of herpesvirus infection: the role of famciclovir.

Shingles (herpes zoster) is the result of reactivation of varicella-zoster virus after years of latency. The acute phase is self-limiting but is often associated with moderate-to-severe pain; postherpetic neuralgia is the most frequent and debilitating complication of shingles, occurring in 3.4 per 1000 individuals per year. In the case of genital herpes, herpes simplex virus can reactivate to cause recurrent episodes as often as several times a year, sometimes for the remainder of a person's life. Antiviral agents such as famciclovir, valacyclovir, and acyclovir can be used to shorten the course and decrease the severity of these diseases and may suppress the virus itself, thereby preventing future outbreaks of genital herpes. This article presents a brief synopsis of the etiology of herpes zoster and genital herpes and reviews 12 key studies that demonstrate the efficacy of famciclovir in the management of these two conditions.

2-Aminopurine↗

PubMed1999

New developments in the epidemiology, natural history and management of genital herpes.

The prevalence of genital herpes is increasing in several populations worldwide. Factors that may be contributing to this increase include greater numbers of sexual partners, the high frequency of asymptomatic infections, poor use of safe sexual practices, and possibly the decreased incidence of childhood oral herpes simplex virus infection. Transmission occurs via skin-to-skin or mucous membrane contact during periods of viral shedding when lesions are present but may also occur when the patient is unaware of the lesions or when lesions are not clinically apparent. This has important implications for strategies to prevent transmission of the disease. The introduction of the antiherpes agent, acyclovir, and more recently famciclovir and valacyclovir, facilitates the management of genital herpes. Treatment of first-episode genital herpes reduces the severity and duration of symptoms, time to lesion healing, and cessation of viral shedding. Episodic treatment of recurrences as they occur may be of benefit to some patients. Daily suppressive therapy significantly reduces the frequency of recurrences and asymptomatic viral shedding. Accordingly, patients who experience frequent or severe recurrences, those particularly troubled by their disease, and those who wish to reduce the frequency of asymptomatic infection generally prefer suppressive therapy. The possibility that suppressive therapy may have an impact on transmission of the disease is currently under investigation. Antiviral treatments have important implications for public health and may help reduce the psychological and psychosocial impact of genital herpes on individual patients.

Antiviral Agents↗

PubMed2000

Meeting future challenges in topical ocular drug delivery: development of an air-interfaced primary culture of rabbit conjunctival epithelial cells on a permeable support for drug transport studies.

The purpose of this study was to develop and characterize a functional air-interfaced primary culture of rabbit conjunctival epithelial cells grown on a permeable support for drug transport studies. Conjunctival epithelial cells from the pigmented rabbit were isolated, seeded at 1.2 x 10(6) cells cm(-2) on permeable Transwell filters, and cultured at the air interface using a modified PC-1 medium. Conjunctival epithelial cell layers showed a transepithelial resistance of 1.1+/-0.1 kOmega cm(2), a potential difference of 17.0+/-0.5 mV, and an equivalent short-circuit current (I(eq)) of 16.1+/-0.4 microA cm(-2). The I(eq) was reduced by 35% using 0.01 mM bumetanide, 66% using 0.1 mM ouabain, 46% using 2 mM barium chloride (all three in the basolateral fluid), and 63% using 0.3 mM NPAA in the apical fluid, consistent with active Cl(-)-secretion across the conjunctival epithelial barrier. Amiloride-sensitive Na(+) channels were absent. The permeability of the cell layers to polar solutes decreased with increased solute size, and the calculated equivalent pore size was about 8.0 nm. The Papp of beta-blockers varied with lipophilicity in a sigmoidal fashion. Uridine transport showed temperature sensitivity and directionality, favoring transport in the apical-to-basolateral direction. Apical L-carnosine uptake was reduced by 46% in the absence of an inwardly directed proton gradient, and lowering the temperature to 4 degrees C abolished direction-dependent L-carnosine uptake. Furthermore, uptake was inhibited by 73% using apical 10 mM glycyl sarcosine (a dipeptide transporter substrate) and by 60% using 1 mM L-valacyclovir (a dipeptide prodrug). In conclusion, a functional air-interfaced primary culture of rabbit conjunctival epithelial cell layers was established. This air-interfaced primary culture model may be useful for studying passive and active transport processes for ion and solute translocation in the mammalian conjunctival epithelial barrier in a defined experimental setting.

Adrenergic beta-Antagonists↗

PubMed1999

Acute varicella zoster with postherpetic hyperhidrosis as the initial presentation of HIV infection.

A 31-year-old man presented with acute pain in his left arm and hemorrhagic vesicles that followed his left 8th cervical nerve. A diagnosis of herpes zoster was made, and the patient was treated with valacyclovir. He refused testing for antibodies to HIV because he denied being at risk. Two months later he returned with postherpetic neuralgia and postherpetic hyperhidrosis in the distribution of the vesicles, which had since resolved. Serology for HIV at this visit was positive, and the patient admitted to having sexual relations with prostitutes. Six months later the patient was being treated with triple antiretroviral therapy, and all signs and symptoms of postherpetic zoster had resolved. This case report documents the need for HIV testing in patients with unusual presentations of herpes zoster even if they initially deny being at risk.

AIDS-Related Opportunistic Infections↗