Biomaterial Database

The transport of the anti-HIV drug, 2',3'-didehydro-3'-deoxythymidine (D4T), across the blood-brain and blood-cerebrospinal fluid barriers. 1998

S A Thomas, and M B Segal

Sherrington School of Physiology, U.M.D.S., St. Thomas Hospital Campus, London.

1. The brain is a site of infection, viral replication and sanctuary for HIV-1. The treatment of HIV-1 infection therefore requires that an effective agent be delivered to the brain. 2',3'-Didehydro-3'-deoxythymidine (D4T) is a nucleoside analogue which has been shown to have beneficial clinical effects in the treatment of HIV infection. However, although D4T has been detected in human CSF, the ability of this drug to cross both the blood-brain and blood-cerebrospinal fluid (CSF) barriers and gain entrance into the brain tissue is not known. 2. This study examined the CNS entry of D4T by means of the bilateral vascular brain perfusion technique in the anaesthetized guinea-pig. 3. The results indicated that [3H]-D4T had a limited ability to cross the blood-brain barrier (BBB), which was not significantly greater than D-[14C]-mannitol (a slowly penetrating marker molecule). Although D4T was found to cross the blood-CSF barrier, the presence of D4T in the CSF did not reflect levels of the drug in the brain tissue. 4. These results can be related to the measured low lipophilicity of D4T, the higher paracellular permeability characteristics of the choroid plexus (blood-CSF barrier) compared to the BBB, and the sink action nature of the CSF to the brain tissue. 5. In conclusion, these animal studies suggest that D4T may only penetrate the brain tissue to a limited extent and consideration should be given to these findings in the clinical situation.

UI	MeSH Term	Description	Entries
D001812	Blood-Brain Barrier	Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue.	Brain-Blood Barrier,Hemato-Encephalic Barrier,Barrier, Blood-Brain,Barrier, Brain-Blood,Barrier, Hemato-Encephalic,Barriers, Blood-Brain,Barriers, Brain-Blood,Barriers, Hemato-Encephalic,Blood Brain Barrier,Blood-Brain Barriers,Brain Blood Barrier,Brain-Blood Barriers,Hemato Encephalic Barrier,Hemato-Encephalic Barriers
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D006168	Guinea Pigs	A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.	Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000704	Analysis of Variance	A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable.	ANOVA,Analysis, Variance,Variance Analysis,Analyses, Variance,Variance Analyses
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001692	Biological Transport	The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.	Transport, Biological,Biologic Transport,Transport, Biologic
D013936	Thymidine	A nucleoside in which THYMINE is linked to DEOXYRIBOSE.	2'-Deoxythymidine,Deoxythymidine,2' Deoxythymidine
D015215	Zidovudine	A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia.	AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D018119	Stavudine	A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV.	2',3'-Didehydro-3'-deoxythymidine,D4T,2',3'-Didehydro-2',3'-dideoxythmidine,BMY-27857,Stavudine, Monosodium Salt,Zerit,2',3' Didehydro 3' deoxythymidine,BMY 27857,BMY27857
D018894	Reverse Transcriptase Inhibitors	Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template.	Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse