A Single-Dose Study to Assess the Penetration of Stavudine Into Human Cerebrospinal Fluid in Adults

Haworth, Stephen J.; Christofalo, Barbara; Anderson, Roger; Dunkle, Lisa M.

doi:10.1097/00042560-199803010-00008

Cited by 55 publications

(23 citation statements)

References 11 publications

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“…CART consisted of treatment with PMPA and RCV (75,76). PMPA is a nucleotide analog that does not penetrate the CNS, and RCV is a nucleoside analog of a class that has low-to-nondetectable CNS penetration (40,(77)(78)(79). PMPA and RCV were dissolved in water at 30 mg/ml and the PMPA pH adjusted to 7.0 with 3 N NaOH.…”

Section: Methodsmentioning

confidence: 99%

Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS

Williams¹,

Westmoreland²,

Greco³

et al. 2005

J. Clin. Invest.

122

163

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Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used 1 H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non-CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte-depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte-depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.

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Section: Methodsmentioning

confidence: 99%

Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS

Williams¹,

Westmoreland²,

Greco³

et al. 2005

J. Clin. Invest.

122

163

View full text Add to dashboard Cite

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“…This type of model is justified for two reasons. First, there is evidence that drug concentrations, and therefore efficacies, are reduced in certain physiologically distinct sites in the body such as the testes and the brain (Lewis et al, 1996;Haworth et al, 1998;Schlegel and Chang, 1998). Second, in vitro studies have demonstrated that there can be heterogeneities in intracellular drug concentrations.…”

Section: Compartmental Models With a Robust Low Steady State Viral Loadmentioning

confidence: 99%

HIV-1 Infection and Low Steady State Viral Loads

Callaway

Perelson

2002

Bulletin of Mathematical Biology

334

287

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Highly active antiretroviral therapy (HAART) reduces the viral burden in human immunodeficiency virus type 1 (HIV-1) infected patients below the threshold of detectability. However, substantial evidence indicates that viral replication persists in these individuals. In this paper we examine the ability of several biologically motivated models of HIV-1 dynamics to explain sustained low viral loads. At or near drug efficacies that result in steady state viral loads below detectability, most models are extremely sensitive to small changes in drug efficacy. We argue that if these models reflect reality many patients should have cleared the virus, contrary to observation. We find that a model in which the infected cell death rate is dependent on the infected cell density does not suffer this shortcoming. The shortcoming is also overcome in two more conventional models that include small populations of cells in which the drug is less effective than in the main population, suggesting that difficulties with drug penetrance and maintenance of effective intracellular drug concentrations in all cells susceptible to HIV infection may underlie ongoing viral replication.

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“…3 indicates that the concentration of virus in the main compartment is lower than that in the drug sanctuary due to the less efficacy in the latter. This may explain why there is less effect of treatment on some physiological sites such as the brain [6,12].…”

Section: Global Stability Of Equilibria E 0 and Ementioning

confidence: 99%

“…Examination of changes in drug efficacy after a treatment with antiretroviral drugs has shown that drug efficiencies are reduced in certain physiologically distinct sites such as the tests [2,18] and the brain [18,6,12]. Researches in vitro [2,16,17,10] have indicated that drug efficacy may vary in different types of cells.…”

Section: Introductionmentioning

confidence: 99%