RESUMEN
Ritonavir-boosted lopinavir (LPV/r) is a protease inhibitor used for the treatment of human immunodeficiency virus (HIV) infection in both normal patients and in certain situations. In patients with renal failure, LPV/r does not require dosage adjustment because it is metabolized in the liver. Cohort studies have shown that the incidence of varying degrees of renal disease and/or crystalluria related to combination antiretroviral therapy with tenofovir and some protease inhibitors (PI) does not appear with LPV/r or that the incidence is much lower with this combination. Neurocognitive impairments are described in a high proportion of patients with HIV infection and viral replication or related inflammatory activity in the subarachnoid space. In these patients, LPV/r is one of the therapeutic options. A score has been published that rates antiretroviral drugs according to the concentration attained in the cerebrospinal fluid (CSF). LPV/r levels reached in CSF exceed the IC50 of wild-type HIV and has a valuable score (score 3) of the drugs currently used. The most important comorbid condition is chronic hepatitis, due to its frequency and because the biotransformation of LPV/r occurs in the liver. In these circumstances, it is important to evaluate the influence of liver failure on blood drug levels and how these values may cause liver toxicity. LPV/r dose modification has not been established in the presence of liver failure. LPV/r-induced liver toxicity has only been reported with a certain frequency when liver enzymes were elevated at baseline or in patients with chronic hepatitis C, although most cases of liver toxicity were mild.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico , Complejo SIDA Demencia/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Combinación de Medicamentos , Infecciones por VIH/complicaciones , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1 , VIH-2 , Hepatitis Viral Humana/complicaciones , Humanos , Lopinavir/administración & dosificación , Lopinavir/efectos adversos , Lopinavir/líquido cefalorraquídeo , Lopinavir/farmacocinética , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/complicaciones , Insuficiencia Renal/metabolismo , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Ritonavir/líquido cefalorraquídeo , Ritonavir/farmacocinética , Espacio Subaracnoideo/virologíaRESUMEN
The propensity of canine distemper virus (CDV) to spread to the central nervous system is one of the primary features of distemper. Therefore, we developed a reverse genetics system based on the neurovirulent Snyder Hill (SH) strain of CDV (CDV(SH)) and show that this virus rapidly circumvents the blood-brain and blood-cerebrospinal fluid (CSF) barriers to spread into the subarachnoid space to induce dramatic viral meningoencephalitis. The use of recombinant CDV(SH) (rCDV(SH)) expressing enhanced green fluorescent protein (EGFP) or red fluorescent protein (dTomato) facilitated the sensitive pathological assessment of routes of virus spread in vivo. Infection of ferrets with these viruses led to the full spectrum of clinical signs typically associated with distemper in dogs during a rapid, fatal disease course of approximately 2 weeks. Comparison with the ferret-adapted CDV(5804P) and the prototypic wild-type CDV(R252) showed that hematogenous infection of the choroid plexus is not a significant route of virus spread into the CSF. Instead, viral spread into the subarachnoid space in rCDV(SH)-infected animals was triggered by infection of vascular endothelial cells and the hematogenous spread of virus-infected leukocytes from meningeal blood vessels into the subarachnoid space. This resulted in widespread infection of cells of the pia and arachnoid mater of the leptomeninges over large areas of the cerebral hemispheres. The ability to sensitively assess the in vivo spread of a neurovirulent strain of CDV provides a novel model system to study the mechanisms of virus spread into the CSF and the pathogenesis of acute viral meningitis.
Asunto(s)
Virus del Moquillo Canino/patogenicidad , Moquillo/virología , Meningoencefalitis/virología , Animales , Barrera Hematoencefálica/virología , Línea Celular , Líquido Cefalorraquídeo/virología , Chlorocebus aethiops , Plexo Coroideo/virología , Moquillo/patología , Virus del Moquillo Canino/genética , Virus del Moquillo Canino/fisiología , Células Endoteliales/virología , Hurones , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Leucocitos/virología , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Masculino , Meningoencefalitis/patología , Datos de Secuencia Molecular , Genética Inversa , Espacio Subaracnoideo/virología , Células Vero , Proteína Fluorescente RojaRESUMEN
El lopinavir potenciado con ritonavir (LPV/r) es un inhibidor de la proteasa indicado en el tratamiento de la infección por el virus de la inmunodeficiencia humana (VIH), tanto en el paciente normal como en determinadas situaciones. En pacientes con insuficiencia renal, LPV/r no requiere ajuste de dosis ya que se metaboliza por vía hepática. En estudios de cohortes se ha demostrado que la incidencia de afectación renal en grado variable y/o cristaluria, que se relaciona con el tratamiento antirretroviral combinado y fundamentalmente con tenofovir y algunos inhibidores de la proteasa, no aparece o su incidencia es mucho menor en el caso de LPV/r. De igual modo, en las alteraciones neurocognitivas descritas en una alta proporción de pacientes infectados por el VIH y relacionadas con replicación viral o actividad inflamatoria en el espacio subaracnoideo, LPV/r es una de las opciones terapéuticas indicadas. Se ha publicado un score que puntúa los fármacos antirretrovirales según la concentración que alcanzan en el líquido cefalorraquídeo (LCR). LPV/r alcanza valores en LCR superiores a la IC50 del virus y tiene una buena puntuación (score 3) entre los fármacos en uso actual. La comorbilidad más importante es la hepatitis crónica, tanto por su frecuencia como porque la biotransformación del LPV/r ocurre en el hígado. En estas circunstancias cabe valorar cómo influye el deterioro de la función hepática en los valores de fármaco en sangre y cómo estos valores pueden ser causa de toxicidad hepática. No se ha establecido modificación de dosis en caso de insuficiencia hepática y la toxicidad hepática causada por LPV/r solamente se ha descrito con cierta frecuencia en caso de aumento basal de transaminasas o de hepatitis C crónica, aunque en la mayoría de los casos se considera hepatotoxicidad leve (AU)
Ritonavir-boosted lopinavir (LPV/r) is a protease inhibitor used for the treatment of human immunodeficiency virus (HIV) infection in both normal patients and in certain situations. In patients with renal failure, LPV/r does not require dosage adjustment because it is metabolized in the liver. Cohort studies have shown that the incidence of varying degrees of renal disease and/or crystalluria related to combination antiretroviral therapy with tenofovir and some protease inhibitors (PI) does not appear with LPV/r or that the incidence is much lower with this combination. Neurocognitive impairments are described in a high proportion of patients with HIV infection and viral replication or related inflammatory activity in the subarachnoid space. In these patients, LPV/r is one of the therapeutic options. A score has been published that rates antiretroviral drugs according to the concentration attained in the cerebrospinal fluid (CSF). LPV/r levels reached in CSF exceed the IC50 of wild-type HIV and has a valuable score (score 3) of the drugs currently used. The most important comorbid condition is chronic hepatitis, due to its frequency and because the biotransformation of LPV/r occurs in the liver. In these circumstances, it is important to evaluate the influence of liver failure on blood drug levels and how these values may cause liver toxicity. LPV/r dose modification has not been established in the presence of liver failure. LPV/r-induced liver toxicity has only been reported with a certain frequency when liver enzymes were elevated at baseline or in patients with chronic hepatitis C, although most cases of liver toxicity were mild (AU)
Asunto(s)
Humanos , Ritonavir/uso terapéutico , Lopinavir/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Combinación de Medicamentos , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Espacio Subaracnoideo/virología , Hepatitis Viral Humana/complicacionesRESUMEN
Neurologic complications, including meningoencephalitis, transverse myelitis, and peripheral neuropathy, have been reported in patients with acute infectious mononucleosis. Chronic active Epstein-Barr virus and human immunodeficiency virus infections occasionally induce central nervous system lymphoma. On the other hand, central nervous system disease alone associated with Epstein-Barr virus rarely occurs in previously healthy individuals. A 15-year-old girl who developed acute disseminated encephalomyelitis-like disease presenting fever, anuresis, diplopia, and muscle weakness is described here. Clinical and neuroimaging studies led to the diagnosis of encephalomyelitis. Despite the absence of infectious mononucleosis-like symptoms, anti-Epstein-Barr virus antibody titers in serum and cerebrospinal fluid showed the virus reactivation. The copy number of Epstein-Barr virus DNA increased in cerebrospinal fluid but not in peripheral blood. Ganciclovir and repeated methyl-prednisolone pulse therapy resulted in complete resolution. Central nervous system disease on the limited intrathecal reactivation of Epstein-Barr virus in immunocompetent children should be differentiated from acute disseminated encephalomyelitis.
Asunto(s)
Encefalitis Viral/virología , Herpesvirus Humano 4/fisiología , Mononucleosis Infecciosa/complicaciones , Mononucleosis Infecciosa/virología , Meningitis Viral/virología , Replicación Viral/fisiología , Adolescente , Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , Encéfalo/patología , Encéfalo/fisiopatología , Encéfalo/virología , ADN Viral/análisis , Encefalitis Viral/inmunología , Encefalitis Viral/fisiopatología , Femenino , Dosificación de Gen/genética , Humanos , Inmunocompetencia/inmunología , Imagen por Resonancia Magnética , Meninges/patología , Meninges/fisiopatología , Meninges/virología , Meningitis Viral/inmunología , Meningitis Viral/fisiopatología , Médula Espinal/patología , Médula Espinal/fisiopatología , Médula Espinal/virología , Espacio Subaracnoideo/patología , Espacio Subaracnoideo/fisiopatología , Espacio Subaracnoideo/virología , Resultado del Tratamiento , Carga ViralAsunto(s)
Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/líquido cefalorraquídeo , Líquido Cefalorraquídeo/virología , Herpes Zóster/líquido cefalorraquídeo , Herpes Zóster/diagnóstico , Herpesvirus Humano 3/inmunología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/líquido cefalorraquídeo , Anciano , Anticuerpos Antivirales/sangre , Exantema/diagnóstico , Exantema/virología , Femenino , Herpes Zóster/inmunología , Humanos , Inmunoglobulina G/sangre , Masculino , Valor Predictivo de las Pruebas , Espacio Subaracnoideo/virologíaRESUMEN
The exclusive detrimental role of proinflammatory cytokines in demyelinating diseases of the CNS, such as multiple sclerosis, is controversial. Here we show that the intrathecal delivery of an HSV-1-derived vector engineered with the mouse IFN-gamma gene leads to persistent (up to 4 wk) CNS production of IFN-gamma and inhibits the course of a chronic-progressive form of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein (MOG)(35-55). Mice treated with the IFN-gamma-containing vector before EAE onset showed an earlier onset but a milder course of the disease compared with control mice treated with the empty vector. In addition, 83% of IFN-gamma-treated mice completely recovered within 25 days post immunization, whereas control mice did not recover up to 60 days post immunization. Mice treated with the IFN-gamma-containing vector within 1 wk after EAE onset partially recovered from the disease within 25 days after vector injection, whereas control mice worsened. Recovery from EAE in mice treated with IFN-gamma was associated with a significant increase of CNS-infiltrating lymphocytes undergoing apoptosis. During the recovery phase, the mRNA level of TNFR1 was also significantly increased in CNS-infiltrating cells from IFN-gamma-treated mice compared with controls. Our results further challenge the exclusive detrimental role of IFN-gamma in the CNS during EAE/multiple sclerosis, and indicate that CNS-confined inflammation may induce protective immunological countermechanisms leading to a faster clearance of encephalitogenic T cells by apoptosis, thus restoring the immune privilege of the CNS.