ABSTRACT Topical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study, we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249, and L'644, was performed using cellular and ex vivo genital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol-derivatized version of C34, relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids, and the compound was still active when tissue explants were treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multiactive antiretroviral (ARV) combination-based microbicide. These data support the further development of L'644 for microbicide application.

1994-01-01·Molecular and Chemical Neuropathology

Loop diuretic derivative L-644, 711 inhibits K+-stimulated cellular injury in neonatal guinea pig cortical astrocytes

Article

作者: Thakran, Purnima ; Leuschen, M. Patricia ; Nelson, Robert M. Jr.

An early pathological rise in extracellular K+ following acute hypoxia results in Cl- uptake into astrocytes through the Cl/HCO3- exchanger with an osmotic equivalent of water. This study addressed effects of the anion transport inhibitor, L-644,711, (5,6,-dichloro-2,3, 9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluroen-7-yl)oxyacetic acid. Confluent primary cultures from neonatal guinea pigs, characterized as > 95% astrocytes with antiserum to glial fibrillary acidic protein, were manipulated by incubation in either basal buffer (BB) with the ionic composition of Dulbecco's minimum essential media (DMEM) or one with high extracellular K+ (HiK). Incubation in 27 or 60 mM Hik significantly reduced cell viability and precipitated a time-dose dependent increase in lactate dehydrogenase (LDH) efflux (30 min to 4 h). L-644,711 was not cytotoxic, and significantly inhibited HiK-stimulated LDH efflux. The optimal effective dose of L-644,711 for preventing injury in guinea pig astrocytes was 10(-11)M when administered simultaneously with the HiK paradigm or in reversing injury when administered 30 min after exposing cells to HiK. These findings indicate the potential usefulness of agents which modify ion transport processes in hypoxic-ischemic cerebral injury.

1991-12-01·Journal of Neurosurgical Anesthesiology3区 · 医学

Effect of an Anion Transport Inhibitor, L-644,711, on Brain Injury and Edema After Temporary Middle Cerebral Artery Occlusion in Rats

3区 · 医学

Article

作者: Osborne, T N ; Cole, D J ; Ghazal, E A

The affect of L-644,711, an anion transport inhibitor, on ischemic brain injury and edema was investigated. Spontaneously hypertensive rats were given one of the following doses of intrathecal L-644,711 during 180 min of middle cerebral artery occlusion and 120 min of reperfusion: control, vehicle only; dose I, 100 microg/kg: dose II, 200 microg/kg; dose III, 250 mug/kg; or dose IV, 320 microg/kg. Immediately after the 5-h period of ischemia and reperfusion, the brains were analyzed for brain injury with 2,3,5-triphenyltetrazolium chloride, and for edema by microgravimetry (specific gravity). There were no between-group differences in specific gravity (brain water content). Brain injury (% of the hemisphere ipsilateral to middle cerebral artery occlusion) was less (p <0.05) in rats that received the 250 (35 +/- 5%, mean +/- SD) or 320 microg/kg (36 +/- 6%) doses of L-644,711 vs. the control group (47 +/- 5%). L-644,711 has been hypothesized to affect brain injury by improving the neuronal acid-base state, inhibiting astroglial swelling, decreasing neutrophil aggregation, or reducing glutamate release. The microgravimetric data do not support astroglial swelling as a primary mechanism of decreased brain injury.

100 项与 L-644 相关的药物交易

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