Synthesis and pharmacokinetics of a dihydropyridine chemical delivery system for the antiimmunodeficiency virus agent, dideoxycytidine (original) (raw)
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Antiviral Chemistry and Chemotherapy, 1994
Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 m...
Antiviral Chemistry and Chemotherapy, 1996
Lipophilic prodrugs of 2′,3′-dideoxycytidine (ddC), 4,5′-diacetyI-ddC (DAC), 4,5′-ditrimethylacetyl-ddC (DTMAC), 4,5′-dicyclopentylpropionyl-ddC (DCYPP) and 5′-cholesteryl-ddC (CHOL), were evaluated for their utility in improving brain delivery of the parent nucleoside. The lipophilicity of the prodrugs was greater, compared to ddC., with partition coefficient values increasing from 0.03 for ddC to 0.37,28, 63 and 483 for DAC., DTMAC., DCYPP and CHOL., respectively. Aqueous solubility was decreased proportionally to the increase in lipophilicity. Bioconversion studies were performed in phosphate buffer (pH 7.4), human serum, mouse serum, and mouse brain and liver homogenates. Whereas CHOL was stable in vitro in all media, DAC., DTMAC and DCYPP exhibited stability only in buffer, indicating that the hydrolytic reaction for these compounds was, predominately, enzymatically triggered. DCYPP was rapidly hydrolysed in mouse serum and liver and brain homogenates with degradation half-life...
Brain Research, 1989
Changes in striatal dopamine (DA) neurochemistry, tyrosine hydroxylase immunocytochemistry of DA fibers, and behavior following the combined administration of diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) to mice were assessed. The combined treatment of DDC and MPTP produced a dose-dependent decrease in striatal DA levels and a dose-related increase in the striatal DOPAC:DA ratio. Cumulative doses of MPTP equal to or exceeding 53.0 (26.5 mg/kg ×2, i.p.), given in combination with DDC, were effective in reducing striatal DA levels to less than 25% of control levels 2 weeks after treatment. Tyrosine hydroxylase immunocytochemistry revealed large deafferentation of DA terminal regions in striatum, moderate reductions in nucleus accumbens and dendritic regions of substantia nigra, and slight reductions in the number of DA cell bodies in substantia nigra. Mice treated with DDC and MPTP became hyperactive during the light phase of their diurnal cycle; psychopharmacological data suggest that postsynaptic DA receptors were supersensitized following this treatment. These data provide evidence that the combined treatment of DDC and MPTP produces severe and enduring depletion of mesostriatal DA, and also concomitant behavioral changes in mice.
Journal of Neuroscience Research, 2008
Dimethyl sulfoxide (DMSO) has long been used in studies as a vehicle to enhance the solubility and transport of ligands in biological systems. The effects of this drug on the outcomes of such studies are still unclear, with concentrations of DMSO reported as ''safe'' varying considerably. In the present work, we investigated the effects of very low concentrations of DMSO on the brain metabolism of [3-13 C]pyruvate and D-[1-13 C]glucose using 1 H/ 13 C NMR spectroscopy and a guinea pig cortical brain slice model. Our results show that DMSO is accumulated by brain slices. DMSO at all concentrations [0.000025%-0.25% (v/v)] increased the metabolic rate when [3-13 C]pyruvate was used as a substrate and also in the presence of D-[1-13 C]glucose (0.00025%-0.1% DMSO). These results are consistent with DMSO stimulating respiration, which it may do through altering the kinetics of ATP-requiring reactions. Our results also emphasize that there is no practical concentration of DMSO that can be used in metabolic experiments without effect. Therefore, care should be taken when evaluating the actions of drugs administered in combination with DMSO. V V C 2007 Wiley-Liss, Inc.
Effects of intracisternal dexmedetomidine on cerebral neuronal cells in rat: a preliminary study
Turkish Neurosurgery, 2012
The aim was to investigate whether dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route. mAterIAl and methOds: Eighteen rats were anesthetized and the right femoral artery was cannulated. Mean arterial pressures, heart rates, arterial carbon dioxide tension, arterial oxygen tension, and blood pH were recorded. When the free cerebrospinal fluid flow was seen, 0.1 ml normal saline (Group SIC, n=6) or 9 µg/kg diluted dexmedetomidine in 0.1 ml volume (Group DIC, n=6) was administered into the cisterna magna of rats. After 24 hours, the whole body blood was collected for measurement of plasma lipid peroxidation (LPO) levels. The hippocampal formations used for histopathological examination and measurement of tissue LPO levels.
Stable neurological function in subjects treated with 23-dideoxyinosine
Journal of Neurovirology, 1997
AIDS Dementia Complex (ADC) is a frequent and devastating complication of HIV infection. There is evidence that zidovudine (ZDV) has an effect in alleviating the symptoms of ADC, and may have a role in its prevention. It is therefore important that new antiretroviral therapies be evaluated not only for the risk of neurologic side effects, but also for their relative efficacy to ZDV in the prevention of ADC. The present study reports the effects of 2'3'dideoxyinosine (DDI, didanosine, Videx) therapy on neuropsychological performance in the context of several large clinical trials targeting advanced systemic HIV-1 infection. Subjects treated with DDI had stable neurologic performance in quantitative tests over a 1 year period and were similar to zidovudine treated subjects.
I lasma and Cerebrospinal Fluid Pharmacokinetics of 5-Aza-2'- deoxycytidine in Rabbits and Dogs 1
1983
Aza-2'-deoxycytidine (5-aza-dCyd) is an effective antileu- kemic agent. In view of the importance for an antileukemic agent to cross effectively the blood-brain-barrier, we studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of this drug in rabbits and dogs. The 5-aza-dCyd concentrations in biological fluids were determined by bioassay and high- performance liquid chromatography. 5-Aza-dCyd was admin- istered either as an