RESUMEN
A questionnaire (Migraine Questionnaire; MQ) was developed to help pharmacists identify consumers with migraine suitable for non-prescription treatment with a triptan. Adults, who knew or thought that they had migraine, participated in three, sequential, community-based studies to validate the MQ. Overall, 1,353 subjects completed independent assessments with a pharmacist and a clinician (reference standard). The accuracy of the pharmacist assessment of suitability for a triptan was compared with the clinician assessment. Clinicians using their standard practice determined that triptan therapy was suitable in 76.8% of cases compared with 48.8% for pharmacists using the MQ. The lack of concordance between pharmacists and clinicians in the false-positive cases (n = 113 of 660 subjects considered suitable for triptan by the pharmacists) usually related to headache diagnosis (57.5%), not safety aspects. The MQ is an effective tool for pharmacists to guide appropriate recommendation of a non-prescription triptan for migraine.
Asunto(s)
Prescripciones de Medicamentos , Trastornos Migrañosos/tratamiento farmacológico , Encuestas y Cuestionarios/normas , Triptaminas/uso terapéutico , Adulto , Servicios Comunitarios de Farmacia , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Farmacéuticos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
Antiviral treatment of herpes simplex virus (HSV) infections with nucleoside analogues has been well established for >2 decades, but isolation of drug-resistant HSV from immunocompetent patients has remained infrequent (0.1%-0.7% of isolates) during this period. Even when drug-resistant HSV is isolated from an immunocompetent patient, this virus, with rare exceptions, is cleared normally without adverse clinical outcome. Although drug-resistant HSV is more commonly isolated from immunocompromised patients (4%-7% of isolates) and is more likely to be clinically significant, the prevalence of drug-resistant HSV even among these patients, has been stable over the past 2 decades. Despite this stable prevalence, disease due to drug-resistant HSV remains an important problem for many immunocompromised patients, including those with HIV infection. This article reviews the prevalence, pathogenesis, and implications of drug-resistant HSV infections in HIV-infected patients.
Asunto(s)
Antivirales/farmacología , Infecciones por VIH/complicaciones , Herpes Simple/tratamiento farmacológico , Nucleósidos/farmacología , Simplexvirus/efectos de los fármacos , Aciclovir/farmacología , Aciclovir/uso terapéutico , Animales , Antivirales/uso terapéutico , Farmacorresistencia Viral/genética , Farmacorresistencia Viral/inmunología , Infecciones por VIH/inmunología , Herpes Simple/complicaciones , Herpes Simple/inmunología , Humanos , Inmunidad Celular , Inmunocompetencia , Huésped Inmunocomprometido , Nucleósidos/uso terapéutico , Recurrencia , Simplexvirus/genética , Simplexvirus/patogenicidadRESUMEN
Subjects received topical penciclovir for 4 days during successive episodes of recurrent herpes labialis. Isolation of herpes simplex virus (HSV) was attempted from lesions obtained before initiation of treatment and on each day of therapy. Isolates remained sensitive to penciclovir when tested by a plaque reduction assay, and there was no significant change in sensitivity during any treatment course or between successive treatments. The proportion of nucleoside-resistant variants present within a subset of these isolates was further investigated using a more-sensitive plating efficiency assay. Although the proportion of antiviral-resistant HSV variants increased on successive days, it invariably remained a minor subpopulation. Moreover, isolates from successive episodes obtained before treatment showed no change in the proportion of resistant HSV variants. We conclude that antiviral-resistant variants, which are readily detected in HSV isolates from peripheral lesions, do not accumulate in the sensory ganglia of immunocompetent patients receiving multiple courses of nucleoside analogues.
Asunto(s)
Aciclovir/análogos & derivados , Aciclovir/administración & dosificación , Aciclovir/uso terapéutico , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Farmacorresistencia Viral , Herpes Labial/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Aciclovir/farmacología , Adolescente , Adulto , Antivirales/farmacología , Femenino , Guanina , Humanos , Masculino , Factores de Tiempo , Ensayo de Placa ViralRESUMEN
Acyclovir, penciclovir, and their prodrugs have been widely used during the past two decades for the treatment of herpesvirus infections. In spite of the distribution of over 2.3 x 10(6) kg of these nucleoside analogues, the prevalence of acyclovir resistance in herpes simplex virus isolates from immunocompetent hosts has remained stable at approximately 0.3%. In immuncompromised patients, in whom the risk for developing resistance is much greater, the prevalence of resistant virus has also remained stable but at a higher level, typically 4 to 7%. These observations are examined in the light of characteristics of the virus, the drugs, and host factors.
Asunto(s)
Aciclovir/análogos & derivados , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Farmacorresistencia Viral , Herpes Simple/tratamiento farmacológico , Herpes Simple/epidemiología , Simplexvirus , Aciclovir/química , Antivirales/química , Guanina , Herpes Simple/fisiopatología , Humanos , Pruebas de Sensibilidad Microbiana , Simplexvirus/efectos de los fármacosRESUMEN
The antiherpesvirus agent penciclovir (PCV) shares an identical activation pathway and a similar mode of action with acyclovir (ACV). However, since PCV represents a relatively recent treatment option, the clinical resistance profile to PCV is less well known. A susceptibility program was established to assess the resistance profile for serial herpes simplex virus isolates from immunocompetent patients with recurrent herpes labialis obtained throughout a 4-day period of treatment with topical PCV (1% cream) or a placebo. Two isolates (2 of 1,035 [0.19%]), representing 0.34% of the patients (2 of 585), were confirmed to be PCV-resistant (Pcv(r)) herpes simplex virus type 1 by a plaque reduction assay in MRC-5 cells. These two viruses were highly resistant to PCV (50% inhibitory concentrations [IC(50)s], >55 micro g/ml) and were isolated less than 17 h after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from these patients were completely susceptible to PCV (IC(50)s, <2.0 micro g/ml). Thus, it is not clear whether the resistance to PCV for these two early-treatment isolates was directly associated with the 17 h of PCV treatment; several possible explanations are discussed. In an analysis of the distribution of IC(50) differences between the first and last isolates, there were three patients with minor IC(50) increases in the PCV-treated population and one in the placebo-treated group, although statistically, only the latter was an outlier. No patients were found to have Pcv(r) virus at the end of acute treatment, regardless of treatment group. Overall, the prevalence of Pcv(r) was found to be similar to the 0.3% Acv(r) reported for immunocompetent, untreated populations.
Asunto(s)
Aciclovir/análogos & derivados , Aciclovir/farmacología , Antivirales/farmacología , Herpes Labial/tratamiento farmacológico , Herpes Labial/virología , Herpesvirus Humano 1/efectos de los fármacos , Autorradiografía , Farmacorresistencia Viral , Mutación del Sistema de Lectura/genética , Guanina , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Proteínas Tirosina Quinasas/metabolismo , Recurrencia , Ensayo de Placa ViralRESUMEN
In a general population survey in the United States, the prevalence of antiviral-agent-resistant herpes simplex virus was very low among more than 1,000 isolates from individuals with an episode of recurrent herpes labialis not treated with topical antiviral agents. Two isolates had borderline resistance to acyclovir (0.2%), and all were susceptible to penciclovir.
Asunto(s)
Aciclovir/análogos & derivados , Antivirales/farmacología , Herpes Labial/tratamiento farmacológico , Aciclovir/administración & dosificación , Aciclovir/farmacología , Aciclovir/uso terapéutico , Administración Tópica , Adulto , Animales , Células Cultivadas , Farmacorresistencia Viral , Femenino , Guanina , Herpes Labial/epidemiología , Herpes Labial/virología , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Masculino , Población , Conejos , Recurrencia , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The thymidine kinase (tk) mutagenesis assay is often utilized to determine the frequency of herpes simplex virus (HSV) replication-mediated mutations. Using this assay, clinical and laboratory HSV-2 isolates were shown to have a 10- to 80-fold higher frequency of spontaneous mutations compared to HSV-1. METHODS: A panel of HSV-1 and HSV-2, along with polymerase-recombinant viruses expressing type 2 polymerase (Pol) within a type 1 genome, were evaluated using the tk and non-HSV DNA mutagenesis assays to measure HSV replication-dependent errors and determine whether the higher mutation frequency of HSV-2 is a distinct property of type 2 polymerases. RESULTS: Although HSV-2 have mutation frequencies higher than HSV-1 in the tk assay, these errors are assay-specific. In fact, wild type HSV-1 and the antimutator HSV-1 PAAr5 exhibited a 2-4 fold higher frequency than HSV-2 in the non-HSV DNA mutatagenesis assay. Furthermore, regardless of assay, HSV-1 recombinants expressing HSV-2 Pol had error rates similar to HSV-1, whereas the high mutator virus, HSV-2 6757, consistently showed significant errors. Additionally, plasmid DNA containing the HSV-2 tk gene, but not type 1 tk or LacZ DNA, was shown to form an anisomorphic DNA structure. CONCLUSIONS: This study suggests that the Pol is not solely responsible for the virus-type specific differences in mutation frequency. Accordingly, it is possible that (a) mutations may be modulated by other viral polypeptides cooperating with Pol, and (b) the localized secondary structure of the viral genome may partially account for the apparently enhanced error frequency of HSV-2.
Asunto(s)
ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Herpesvirus Humano 1/enzimología , Herpesvirus Humano 2/enzimología , Mutación/genética , Proteínas Virales/genética , Proteínas Virales/metabolismo , Animales , Bioensayo , Línea Celular , Chlorocebus aethiops , ADN Polimerasa II/biosíntesis , ADN Polimerasa II/genética , ADN Polimerasa II/metabolismo , Replicación del ADN/efectos de los fármacos , Replicación del ADN/genética , ADN Recombinante/genética , ADN Recombinante/metabolismo , ADN Viral/genética , ADN Viral/metabolismo , ADN Polimerasa Dirigida por ADN/biosíntesis , Exodesoxirribonucleasas/biosíntesis , Genoma Viral , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 2/genética , Humanos , Mutagénesis/efectos de los fármacos , Mutagénesis/genética , Mutación/efectos de los fármacos , Conformación de Ácido Nucleico/efectos de los fármacos , Plásmidos/biosíntesis , Plásmidos/genética , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , Transfección , Células Vero/química , Células Vero/metabolismo , Proteínas Virales/biosíntesisRESUMEN
BACKGROUND: A number of in vitro assays are used to determine susceptibility of HSV to antiviral agents, but results from these in vitro assays do not necessarily correlate with treatment outcome. OBJECTIVES: A method with improved capability for identifying an isolate as acyclovir (ACV) or penciclovir (PCV) resistant when resistance is borderline could greatly improve the management of HSV disease. STUDY DESIGN: A comparative evaluation of four in vitro assays, plaque reduction (PRA), DNA hybridization, plating efficiency (PEA) and plaque autoradiography (PAR) was performed to accurately identify and measure resistance of a TK-altered clinical HSV isolate (HSV-1 N4) from a patient who was non-responsive to ACV treatment. Two established criteria for the prediction of antiviral resistance, IC(50)> or =2.0 microg/ml or an IC(50) greater than 10x above a sensitive virus IC(50), as well as testing in human (MRC-5) and nonhuman (Vero and CV-1 monkey kidney) cell lines were evaluated. RESULTS: The PRA and DNA hybridization assays accurately identified HSV-1 N4 as ACV(r) in human cells when using the 10x above sensitive virus IC(50) resistance criterion. Moreover, the PEA and PAR assays failed to classify HSV-1 N4 as drug resistant and indicate that these technologies alone are inadequate for identifying resistant virus. CONCLUSIONS: The data presented herein indicate that the PRA and DNA hybridization assays most accurately identified an otherwise borderline-resistant isolate as drug resistant: (i) when a sensitive virus is used within each individual assay as a control, (ii) when ACV and PCV susceptibility is evaluated in human cells, and (iii) when the 10x above sensitive IC(50) criterion is used to classify a virus as drug-resistant. Testing of additional clinical samples is warranted to further confirm these findings.