Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system

Sawchuk, Ronald J.; Yang, Zheng

doi:10.1016/s0169-409x(99)00017-4

Cited by 54 publications

(40 citation statements)

References 119 publications

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“…Just like endogenous nucleic acids, NRTIs have to undergo phosphorylation by a number of kinases to give the active triphosphorylated form (Kakuda 2000). It is known that the concentrations of NRTIs decrease progressively as they move from the plasma to the CSF (Sawchuk and Yang 1999;Kandanearatchi et al 2003). The penetration of NRTIs into the CNS has been an issue to date (Enting et al 1998;Sawchuk and Yang 1999).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that the concentrations of NRTIs decrease progressively as they move from the plasma to the CSF (Sawchuk and Yang 1999;Kandanearatchi et al 2003). The penetration of NRTIs into the CNS has been an issue to date (Enting et al 1998;Sawchuk and Yang 1999). An increase in the incidence of HIV dementia has been thought to be due to the prolonged survival of the HIV virus in the brain resulting from the poor penetration of the antiretroviral used in the therapy (Deutsch et al 2001), but studies now suggest that some of these drugs do effectively penetrate the CNS (Enting et al 1998;Arendt et al 2001;Gibbs et al 2003a).…”

Section: Discussionmentioning

confidence: 99%

“…As noted above, despite the reduction of late stage HIV complications with the use of antiretroviral treatment, neurological complications are still being reported, questioning the efficacy of these drugs in the brain (Bouwman et al 1998). It is therefore our view that in addition to the prolonged survival of the HIV virus in the brain (Deutsch et al 2001) and increased penetration of the antiretrovirals to the CNS (Enting et al 1998;Sawchuk and Yang 1999), these NRTIs could by themselves contribute to this neurological complication through increased oxidative stress as shown by the increase in oxidative stress biomarkers measured here. It is also possible that ddC could potentiate and act synergistically with other compounds such as Tat, gp120 and gp41 in inducing mechanisms implicated in HIVD (Pocernich et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The rise in the prevalence of HIVD despite the use of HAART is consistent with the poor penetration of some of these antiretrovirals into the CNS, hence increasing the longevity of the virus in the CNS (Deutsch et al 2001). It has recently been reported that these drugs can effectively cross into the CNS, therefore, raising the question of their efficacy in the CNS and their possible role in HIVD (Enting et al 1998;Sawchuk and Yang 1999;Gibbs et al 2003a;Gibbs et al 2003b). For example, one treatment study showed variable results on the efficacy of NRTIs in the brain: one group of patients on HAART and having HIVD remained stable from cognitive impairment, while the other group showed signs of progressive neurological impairment even with treatment (Kandanearatchi et al 2003).…”

Section: Introductionmentioning

confidence: 95%

“…Synaptosomal and mitochondrial concentrations of 4mg/ml were then treated with the ddC to a final concentration based on the CSF-achievable concentration range of 6-11ng/ml (Sawchuk and Yang 1999). These samples were then incubated for 6 h at 37°C with frequent vortexing.…”

Section: Incubation Of Synaptosomes and Mitochondria With Ddcmentioning

confidence: 99%

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Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

Opii

Sultana

Abdul

et al. 2007

Experimental Neurology

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Human immunodeficiency virus dementia (HIVD) is the most common form of dementia occurring among young adults. In HIVD, neuronal cell loss occurs in the absence of neuronal infection. With the advent of highly active anti-retroviral therapy (HAART), the incidence of HIVD has drastically reduced, though prevalence of milder forms of HIVD continues to rise. Though these agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. Here we examine the possible role of NRTIs, in particular 2′, 3′-dideoxycytidine (ddC), in the neuropathology of HIVD. Synaptosomes and isolated mitochondria treated and incubated for 6 h with CSF-achievable concentrations of ddC, i.e., 6-11ng/ml, were found to show a significant increase in oxidative stress with 40 nM ddC as measured by protein carbonyls and 3-nitrotyrosine (3NT), effects that were not observed in the more tolerable NRTI; 3TC. Protection against protein oxidation induced by ddC was observed when brain mitochondria were isolated from gerbils 1 h after injection i.p with the brain accessible antioxidant and glutathione mimetic, tricyclodecan-9-yl-xanthogenate (D609). In addition, there is a significant reduction in the levels of anti-apoptotic protein Bcl-2 and a significant increase in cytochrome-c release and also a significant increase in the expression of pro-apoptotic protein caspase-3 after mitochondria were treated with 40 nM ddC. The results reported here show that ddC at 40 nM can induce oxidative stress, cause the release of cytochrome c, and in addition, reduce the levels of anti-apoptotic proteins, increase the levels of pro-apoptotic proteins, thereby increasing the possibility for induction of apoptosis. These findings are consistent with the notion of a possible role of the NRTIs, and in particular, ddC, in the mechanisms involved in HIVD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Incubation Of Synaptosomes and Mitochondria With Ddcmentioning

confidence: 99%

See 3 more Smart Citations

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

Opii

Sultana

Abdul

et al. 2007

Experimental Neurology

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High‐Technology Therapy Using Biomolecules or Synthetic Compounds for HIV Inhibition

Fosso‐Kankeu

Fonteh

Mishra

2013

Nanomedicine for Drug Delivery and Therapeutics

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2012

Methods and Principles in Medicinal Chemistry

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Abbreviations 3TC2 0 ,3 0 -dideoxy-3 0 -thiacytidine or lamivudine ABC ATP binding cassette ABCG2A member of the ABC transporter family ATP Adenosine triphosphate AZT Azidothymidine BCRP Breast cancer resistance protein CNS Central nervous system CSF Cerebrospinal fluid d4T 2 0 -3 0 -didehydro-2 0 -3 0 -dideoxythymidine or stavudine ddC 2 0 -3 0 -dideoxycytidine or zalcitabine ddI 2 0 ,3 0 -dideoxyinosine or didanosine ECF Extracellular fluid HIV Human immunodeficiency virus i.v. Intravenous Mwt Molecular weight MRP Multidrug resistance-associated protein

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Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system

Cited by 54 publications

References 119 publications

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

High‐Technology Therapy Using Biomolecules or Synthetic Compounds for HIV Inhibition

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