Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates

Serabe, Baruti M.; Murry, Daryl J.; Dauser, Robert C.; Nuchtern, Jed G.; Durfee, John; McGuffey, Leticia; Berg, Stacey L.; Blaney, Susan M.

doi:10.1007/s002800050916

Cited by 21 publications

(14 citation statements)

References 8 publications

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“…The oral prodrug of ganciclovir, valganciclovir, is rapidly converted to ganciclovir and is approximately 60% bioavailable. Cerebrospinal fluid concentrations (calculated as ratio of AUCs in CSF to plasma) of ganciclovir in nonhuman primates were approximately 15.5% of plasma 74. In limited case reports, CSF penetration has been demonstrated following both intravenous ganciclovir and oral valganciclovir 75–77.…”

Section: Overview Of Antiviral Agentsmentioning

confidence: 99%

Management of Viral Central Nervous System Infections: A Primer for Clinicians

Bookstaver

Mohorn

Shah

et al. 2017

J Cent Nerv Syst Dis

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Viruses are a common cause of central nervous system (CNS) infections with many host, agent, and environmental factors influencing the expression of viral diseases. Viruses can be responsible for CNS disease through a variety of mechanisms including direct infection and replication within the CNS resulting in encephalitis, infection limited to the meninges, or immune-related processes such as acute disseminated encephalomyelitis. Common pathogens including herpes simplex virus, varicella zoster, and enterovirus are responsible for the greatest number of cases in immunocompetent hosts. Other herpes viruses (eg, cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses such as Japanese encephalitis virus and Zika virus are important pathogens globally, but the prevalence varies significantly by geographic region and often season. Early diagnosis from radiographic evidence and molecular (eg, rapid) diagnostics is important for targeted therapy. Antivirals may be used effectively against some pathogens, although several viruses have no effective treatment. This article provides a review of epidemiology, diagnostics, and management of common viral pathogens in CNS disease.

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Section: Overview Of Antiviral Agentsmentioning

confidence: 99%

Management of Viral Central Nervous System Infections: A Primer for Clinicians

Bookstaver

Mohorn

Shah

et al. 2017

J Cent Nerv Syst Dis

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“…Primary and long-term RhCMV infected RM are thus ideally suited to examine the impact of novel drugs as well as anti-CMV vaccines. For instance, the pharmacokinetics of Ganciclovir, a well-established anti-CMV drug, was tested in blood and CNS in RM and was found to be similar to humans [31]. Moreover, RhCMV was found to be equally susceptible to Ganciclovir as HCMV and the activity of the Ganciclovir-kinase, UL97, was found to be similar [32].…”

Section: Rhcmv As Model To Test CMV Anti-viral Drugsmentioning

confidence: 99%

Rhesus CMV: an emerging animal model for human CMV

Powers

Früh

2008

Med Microbiol Immunol

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Human CMV is the predominant infectious cause of congenital birth defects and an opportunistic pathogen in immunosuppressed individuals, including AIDS patients. Most individuals are infected early during their life followed by life-long latent infection. During this latent phase, frequent reactivation and antigen production continue to stimulate the immune system. While the immune response is able to control the virus, it is unable to eradicate it. Moreover, super-infection by diVerent CMV strains has been observed despite a strong immune response. Longterm immune stimulation by CMV has also been implicated in immune senescence and chronic conditions such as atherosclerosis. CMVs are highly species-speciWc and the relatedness of CMV genomes exactly mirrors the relatedness of their hosts. Thus, each CMV species is highly adapted to its respective host species, but is unable to infect other, even closely related hosts. While fascinating from an evolutionary perspective, this host restriction prevents studying HCMV in experimental animals. Exceptions are severely immunocompromised mice, e.g. SCID mice, or SCID/NOD mice, which might allow partial reconstitution of CMV infection in rodents. More practical however, is to study CMVs in their natural host, e.g. murine, rat or guinea pig CMVs. However, while these small animal models have many advantages, such as the availability of inbred animals as well as lower cost, the limited homology of the viral genomes with HCMV limits the functional analysis of homologous gene products. The closest relative to HCMV is chimpanzee CMV (CCMV), but this is not a practical animal model since chimps are a protected species, extremely expensive and of very limited availability. In contrast, rhesus macaques are a more widely used experimental animal species and, while more distant than CCMV, rhesus CMV (RhCMV) contains most of the HCMV gene families thus allowing the study of their role in acute and latent CMV infection. In this review we will discuss the current state of developing RhCMV as a model for HCMV.

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“…However, concentrations as high as 6 mM of ganciclovir (1.53 mg/mL) and 400 mM of foscarnet (120 mg/mL) may be required for the inhibition of drug-susceptible strains. These concentrations are difficult to achieve and sustain in CSF [12][13][14]. Therefore, inadequate drug penetration, as well as the severely immunocompromised state of the patient, may have contributed to treatment failure.…”

mentioning

confidence: 95%

Cytomegalovirus Ventriculoencephalitis in a Peripheral Blood Stem Cell Transplant Recipient

Miller¹,

Boivin²,

Dummer³

et al. 2006

Clinical Infectious Diseases

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Cytomegalovirus encephalitis occurs rarely in transplant recipients. We describe a patient with cytomegalovirus ventriculoencephalitis who had a very high CSF viral load but a low peripheral blood viral load. No resistance mutations were present in cerebrospinal fluid viral DNA, whereas DNA from blood showed a resistance mutation in the UL54 gene but not in the UL97 gene. Viral replication was intense in the brain ependyma and periventricular areas without evidence of peripheral cytomegalovirus disease. The data provide evidence for compartmentalization of cytomegalovirus infection. Levels of ganciclovir and foscarnet in the cerebrospinal fluid may be inadequate for treatment, even for some drug-susceptible strains, and, together with periventricular replication, may explain the disparity between cerebrospinal fluid viral load and peripheral blood viral load.

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Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates

Abstract: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors.

Cited by 21 publications

References 8 publications

Management of Viral Central Nervous System Infections: A Primer for Clinicians

Management of Viral Central Nervous System Infections: A Primer for Clinicians

Rhesus CMV: an emerging animal model for human CMV

Cytomegalovirus Ventriculoencephalitis in a Peripheral Blood Stem Cell Transplant Recipient

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