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PubMed2001

Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease.

The permeability of albumin, insulin, and human A beta 1--40 at the blood-brain barrier (BBB) was determined in the normal adult mouse (B6/SJL) and in the double transgenic Alzheimer mouse (APP, PS1) by using an I.V. bolus injection technique to quantify the permeability coefficient-surface area (PS) product for each protein after correction for the residual plasma volume (V(p)) occupied by the protein in the blood vessels of different brain regions using a second aliquot of the same protein radiolabeled with a different isotope of iodine ((125)I vs (131)I) as a vascular space marker. This technology for quantifying BBB permeability of proteins was adapted from the rat to the mouse and involved catheterizing the femoral artery and vein of the mouse instead of the brachial artery and vein as for the rat. Because of the smaller blood volume in the mouse, serial sampling (20 microl) of blood from the femoral artery of the mouse was performed and directly TCA precipitated to generate a whole blood washout curve for the intact protein. When similar blood sampling techniques were used in the rat, the PS values for albumin and insulin at the BBB were similar in these two species. In the double transgenic mouse, the V(p) values for albumin were significantly increased 1.4- to 1.6-fold in five of six brain regions compared to the normal adult mouse, which indicated increased adherence of albumin to vessel walls. As a result, the PS values were significantly decreased, from 1.4- to 3.2-fold, which likely reflected decreased transport of albumin by passive diffusion. In contrast, insulin, which is taken up into the brain by a receptor-mediated transport mechanism at the BBB, showed no significant difference in the V(p) values but a significant increase in the PS values in four of six brain regions. This suggests a compensatory mechanism in the Alzheimer's transgenic brain whereby there is an increased permeability to insulin at the BBB. Surprisingly, there was no significant difference in the V(p) or PS values for human A beta 1--40 at the BBB in the double transgenic Alzheimer mouse at 24, 32, or 52 weeks of age, when there is both significant A beta levels in the plasma and amyloid burden in the brains of these animals. These data suggest that there is not an alteration in permeability to human A beta 1--40 at the BBB with increasing amyloid burden in the double transgenic Alzheimer mouse. Although these observations suggest structural alterations at the BBB, they do not support the concept of extensive BBB damage with substantial increases in BBB permeability in Alzheimer's disease.

Age Factors↗
PubMed2000

Osmotic water permeability measurements using confocal laser scanning microscopy.

We have developed a method for measurement of plasma membrane water permeability (P(f)) in intact cells using laser scanning confocal microscopy. The method is based on confocal recording of the fluorescence intensity emitted by calcein-loaded adherent cells during osmotic shock. P(f) is calculated as a function of the time constant in the fluorescence intensity change, the cell surface-to-volume ratio and the fractional content of the osmotically active cell volume. The method has been applied to the measurement of water permeability in MDCK cells. The cells behaved as linear osmometers in the interval from 100 to 350 mosM. About 57% of the total cell volume was found to be osmotically inactive. Water movement across the plasma membrane in intact MDCK cells was highly temperature dependent. HgCl2 had no effect on water permeability, while amphotericin B and DMSO significantly increased P(f) values. The water permeability in MDCK cells transfected with aquaporin 2 was an order of magnitude higher than in the intact MDCK cell line. The water permeability of the nuclear membrane in both cell lines was found to be unlimited. Thus the intranuclear fluid belongs to the osmotically active portion of the cell. We conclude that the use of confocal microscopy provides a sensitive and reproducible method for measurement of water permeability in different types of adherent cells and potentially for coverslip-attached tissue preparations.

Amphotericin B↗
PubMed1988

Analysis of butylphenyl-guanine, butylphenyl-deoxyguanosine, and butylphenyl-deoxyguanosine triphosphate inhibition of DNA replication and ultraviolet-induced DNA repair synthesis using permeable human fibroblasts.

The purine base and nucleoside analogues N2-(p-n-butylphenyl)-guanine (BuPh-Gua) and N2-(p-n-butylphenyl)-2'-deoxyguanosine (BuPh-dGuo) are strong inhibitors of isolated mammalian DNA polymerase alpha, but are less potent that expected as inhibitors of DNA replication in intact cultured cells [G. E. Wright, L. W. Dudycz, Z. Kazimierczuk, N. C. Brown and N. N. Khan, J. med. Chem. 30, 109 (1987)]. The mechanistic basis for these observations was explored using permeable human fibroblasts. DNA replication in the permeable cells was inhibited only slightly by BuPh-Gua and BuPh-dGuo at 100 microM, the highest concentration which could be attained. Similar results were obtained for ultraviolet-induced DNA repair synthesis, a process which is though to involve the same DNA polymerase as replication. More detailed studies were performed using the corresponding nucleotide analogue, N2-(p-n-butylphenyl)-2'-deoxyguanosine-5'-triphosphate (BuPh-dGTP), which is much more water-soluble than the base and nucleoside. The apparent Ki values for BuPh-dGTP inhibition of both replication and ultraviolet-induced repair synthesis in permeable cells were approximately 3 microM. These values are several hundred-fold greater than the apparent Ki for BuPh-dGTP inhibition of isolated human DNA polymerase alpha, which is approximately 10 nM. We conclude that BuPh-Gua and BuPh-dGuo are poor inhibitors of DNA replication in intact cells not because of permeability barriers, but because, unlike polymerase alpha, cellular DNA synthesis is relatively insensitive to this group of inhibitors. These results suggest that polymerase alpha may not be a good general model for predicting the potency of base, deoxyribonucleoside and deoxyribonucleotide analogues as inhibitors of mammalian cellular DNA replication. The fact that the permeable cell systems accurately reflect the relative insensitivity to butylphenyl-guanine derivatives of mammalian DNA replication suggests that permeable cells may be useful tools in future studies of base and nucleoside analogues.

Cells, Cultured↗
PubMed1995

Mucosal permeability after subclinical intestinal ischemia-reperfusion injury: an exploration of possible mechanisms.

Changes in mucosal permeability may be important in the etiology of necrotizing enterocolitis. The authors have previously shown that subclinical ischemia-reperfusion injury results in increased permeability in the rat intestine, and have partially characterized this phenomenon. In the present study the authors attempt to determine the mechanism by which these changes occur. Six-week-old rats underwent 10-minute superior mesenteric artery occlusion (SMAO) or sham, and mucosal permeability to 51CrEDTA was measured after 30 minutes. Rats were pretreated with saline, inhibitors of oxygen free radicals (superoxide dismutase+catalase, vitamin E, allopurinol, alpha-phenyl-N-tert butyl-nitrone), inhibitors of eicosanoids (indomethacin, quinacrine, diethylcarbamazine, 13-azaprostanoic acid), the putative cytoprotective agent prostaglandin E2, or the inhibitor of neutrophil free radical production fructose 1-6 diphosphate. None of the agents significantly attenuated the increase in mucosal permeability caused by SMAO, although indomethacin and prostaglandin E2 significantly exacerbated the permeability changes. To further explore the role of neutrophils, tissue myeloperoxidase was measured 30 minutes after SMAO. There was no significant difference in myeloperoxidase levels between sham and SMAO animals. These data suggest that the early increase in mucosal permeability after subclinical ischemia-reperfusion injury is not mediated by oxygen free radicals, eicosanoids, or neutrophils. The deleterious effect of indomethacin and prostaglandin E2 suggests a possible protective role for the cyclooxygenase system, but further studies are necessary to elucidate this possibility.

Animals↗
PubMed1991

The effect of endotoxin and turpentine administration on intestinal permeability in the rat.

Intestinal permeability in 4-week-old rats has been assessed by the dual sugar (lactulose/mannitol) permeability test before and for two days after induction of systemic inflammation by various endotoxins and turpentine. Evidence of an inflammatory response to these agents was provided by marked reductions in food consumption and growth rate, hypoalbuminaemia, and a large increase in the plasma concentration of the acute-phase protein alpha-2-macroglobin. Abnormal values for intestinal permeability occurred only in animals which had been injected with E. coli 0111:B4 endotoxin. Neither turpentine nor the other endotoxins produced any detectable effect. Within 2-7h of the first exposure to a low dose, (3mg/kg) of either phenol or trichloroacetic extracts of E. coli 0111:B4 endotoxin, the lactulose:mannitol (L M ) ratio was elevated by 32% and 50% respectively (p < 0.05), but the rise was not sustained despite continued twice-daily injections of endotoxin. Administration of a higher dose, (10 mg/kg twice daily, phenol extract) resulted in diarrhoea, and a greater more persistent increase in the L M ratio; 115% (p < 0.05) 2-7h after the first injection, and 49% above control values, (p < 0.01) 24h later. The increase in L M ratio appeared to be due to a decrease in mannitol excretion. Total urinary lactulose also tended to fall, especially in rats given the high dose of endotoxin. It is concluded that a systemic inflammatory response does not necessarily lead to a change in intestinal permeability as measured by the dual sugar permeability test. The transient permeability changes observed following E. coli 0111:B4 administration may be a specific reaction to this material rather than to a more general systemic stimulus.

Journal Article↗
PubMed1992

Are Ca(2+)-permeable kainate/AMPA receptors more abundant in immature brain?

The permeability properties of kainate/AMPA receptors are determined by subunit composition. The GluR1 and GluR3 subunits form Ca(2+)-permeable channels and exhibit inward rectification; heteromeric receptors containing the GluR2 subunit are Ca(2+)-impermeable and electrically linear. These observations raise the possibility of a developmental 'switch' in which turning on or off of GluR2 expression regulates the level of Ca2+ permeable kainate/AMPA receptors. We examined the ratio of GluR1 and GluR3 to GluR2 gene expression in developing and adult rat brain by in situ hybridization. A larger value of this ratio is likely to be associated with greater Ca2+ permeability. Our data suggest that in neocortex, striatum and cerebellum the number of Ca(2+)-permeable kainate/AMPA receptors is high at P4 and declines monotonically with age. In hippocampus, the number increases from P7 to P21, after which it declines. These findings provide evidence for a developmental 'switch' in which Ca2+ permeable glutamate receptors are turned off following early developmental events.

Aging↗
PubMed1990

Superoxide dismutase as an inhibitor of postischemic microvascular permeability increase in the hamster.

The purpose was to elucidate the involvement of superoxide radical (O2-.) in the postischemic increase in the vascular permeability in the hamster cheek pouch. Cheek pouches of anesthetized hamsters were everted, prepared for intravital microscopy, and superfused with a bicarbonate buffered saline solution. Local ischemia for 30 min was obtained using a cuff placed around the proximal part of the cheek pouch. The vascular permeability in the postcapillary venules was quantified as leakage of intravenously injected fluorescein labeled dextran (FITC-dextran, Mw 150,000), using intravital microscopy and fluorimetry. There was a significant and reversible permeability increase after the reperfusion started. In the first series of experiments, combined intravenous infusion and topical application of human recombinant extracellular superoxide dismutase C (EC-SOD C) reduced the postischemic permeability response by 80%. Bovine CuZn-SOD given in exactly the same way reduced the response by 60%. In the second series of experiments, inactivated EC-SOD C was given to the control animals and active EC-SOD C was given to the treated animals. The topical treatment was excluded. Only active EC-SOD C reduced significantly the postischemic permeability increase when present during the ischemic period. Treatment with mannitol (i.v.) did not alter the postischemic response. Since active EC-SOD C and CuZn-SOD but not inactivated EC-SOD C effectively inhibited the response, we suggest that the superoxide anion is involved in the mediation of the postischemic permeability increase in the hamster.

Animals↗
PubMed1994

Effect of DNA polymerase inhibitors on repair of gamma ray-induced DNA damage in proliferating (intact versus permeable) human fibroblasts: evidence for differences in the modes of action of aphidicolin and 1-beta-D-arabinofuranosylcytosine.

The mammalian DNA polymerase inhibitors aphidicolin and 1-beta-D-arabinofuranosylcytosine (araC), when used in combination, inhibit the repair of DNA damage induced by gamma rays or 4-nitroquinoline 1-oxide in normal human fibroblasts to an extent 2- to 4-fold greater than that seen with each inhibitor alone. Thus either aphidicolin modulates the rate of intracellular accumulation of araC 5'-triphosphate (araCTP), the presumed rate-limiting step in the genotoxic action of araC, or aphidicolin and araC inhibit repair by different mechanisms. To explore these possibilities, we compared the effects of aphidicolin, araC, araCTP, and 2',3'-dideoxythymidine triphosphate (ddTTP) on repair of DNA damage induced by 60Co gamma radiation in intact versus permeable human fibroblasts. Both aphidicolin and araC strongly inhibited repair in permeable cells, as indicated by the accumulation of DNA strand breaks in irradiated cultures that were subsequently treated with saponin (25 micrograms/ml; 10 min) and incubated for 2 h with either chemical. The extent of repair inhibition by each drug was comparable in intact and permeable cells, amounting to approximately 1.1 sites/10(8) daltons/2 h upon exposure to 150 Gy. The active metabolite of araC, araCTP, did not inhibit repair in intact cells, but did so in permeable cells to an extent within the range of that seen with araC or aphidicolin alone. The incidence of DNA strand breaks accumulating in gamma-irradiated permeable cultures as a result of incubation with araCTP plus aphidicolin, or araC plus aphidicolin, was approximately 2-fold greater than that arising in parallel cultures which had been incubated with optimal concentrations of each of the three drugs alone. Although the resolution of our assays compelled us to monitor repair events in moribund cell populations, we have reason to be confident that within the short post-irradiation period considered here, the observed drug-accumulated breaks truly represent functional repair inhibition and not merely abortive pathological responses. We thus conclude that (1) the accumulation of araCTP in intact cells is not limiting the ability of araC to inhibit DNA repair; and (2) the mode of the inhibitory action of araC/araCTP on gamma ray repair is different from that of aphidicolin. In contrast to the observations with these chemicals, ddTTP (20 microM), a potent inhibitor of DNA polymerase beta, did not produce any measurable effect on DNA repair in gamma-irradiated permeable fibroblasts, nor did it enhance the efficacy of araC, araCTP or aphidicolin to inhibit repair. These results strongly suggest that DNA polymerase beta plays no significant role in the repair of gamma radioproducts in human fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Aphidicolin↗
PubMed1996

Prevention of postoperative adhesions by an antibody to vascular permeability factor/vascular endothelial growth factor in a murine model.

OBJECTIVE: Our purpose was to test the ability of an antiserum to vascular permeability factor/vascular endothelial growth factor to inhibit postoperative adhesion formation in a murine model. STUDY DESIGN: After a standardized peritoneal injury, 28 Balb/c mice were randomized and treated intraperitoneally with either vascular permeability factor antiserum (n = 14) or preimmune serum (n = 14) at the time of abdominal closure. Mice were killed on postoperative day 14, and the development of intraabdominal adhesions was determined. Adhesion scoring was based on an overall assessment of the extent, location, and type of adhesions present. Statistical analyses were performed with the Mann-Whitney and Fisher's exact tests. RESULTS: The mice treated with the vascular permeability factor antiserum had significantly lower adhesion scores than did the control group (mean +/- SD 1.5 +/- 0.9, median 1.0, vs control 2.5 +/- 0.7, median 3.0). When the groups were analyzed for the presence of grade 2 or 3 adhesions, the group treated with vascular permeability factor antiserum had a significantly lower incidence of advanced adhesions (38%, vs control 92%). CONCLUSION: This study demonstrates that the intraperitoneal administration of a neutralizing antiserum to vascular permeability factor/vascular endothelial growth factor limits postoperative adhesion formation. These observations, to the best of our knowledge, are the first to suggest a role for vascular permeability factor in the pathogenesis of adhesion formation.

Abdomen↗
PubMed1996

Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier.

While previous studies have examined the effects of histamine on the permeability of the blood-brain barrier and reactivity of cerebral blood vessels, cellular mechanisms which account for histamine-induced affects on the cerebral microcirculation are not clear. The goals of this study were to determine the role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier and dilatation of pial arterioles. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier (clearance of fluorescent-labeled dextran; molecular weight 10,000 daltons; FITC-dextran-10K) and diameter of pial arterioles were measured in the absence and presence of histamine (10 and 100 microM). During superfusion with vehicle (saline), clearance of FITC-dextran-10K from pial vessels was minimal and diameter of pial arterioles remained constant. Topical application of histamine (10 and 100 microM) produced an increase in clearance of FITC-dextran-10K and diameter of pial arterioles. To determine a potential role for nitric oxide in histamine-induced increases in permeability of the blood-brain barrier and dilatation of pial arterioles, we examined the effects of NG-monomethyl-L-arginine (L-NMMA; 10 microM). L-NMMA inhibited histamine-induced increases in permeability of the blood-brain barrier and attenuated histamine-induced dilatation of cerebral arterioles. The findings of the present study suggest that histamine increases permeability of the blood-brain barrier and diameter of pial arterioles via the synthesis/release of nitric oxide or a nitric oxide containing compound.

Adenosine↗
PubMed2001

Glycosaminoglycan network geometry may contribute to anisotropic hydraulic permeability in cartilage under compression.

Resistance to fluid flow within cartilage extracellular matrix is provided primarily by a dense network of rod-like glycosaminoglycans (GAGs). If the geometrical organization of this network is random, the hydraulic permeability tensor of cartilage is expected to be isotropic. However, experimental data have suggested that hydraulic permeability may become anisotropic when the matrix is mechanically compressed, contributing to cartilage biomechanical functions such as lubrication. We hypothesized that this may be due to preferred GAG rod orientations and directionally-dependent reduction of inter-GAG spacings which reflect molecular responses to tissue deformations. To examine this hypothesis, we developed a model for effects of compression which allows the GAG rod network to deform consistently with tissue-scale deformations but while still respecting limitations imposed by molecular structure. This network deformation model was combined with a perturbation analysis of a classical analytical model for hydraulic permeability based on molecular structure. Finite element analyses were undertaken to ensure that this approach exhibited results similar to those emerging from more exact calculations. Model predictions for effects of uniaxial confined compression on the hydraulic permeability tensor were consistent with previous experimental results. Permeability decreased more rapidly in the direction perpendicular to compression than in the parallel direction, for matrix solid volume fractions associated with fluid transport in articular cartilage. GAG network deformations may therefore introduce anisotropy to the permeability (and other GAG-associated matrix properties) as physiological compression is applied, and play an important role in cartilage lubrication and other biomechanical functions.

Animals↗
PubMed2000

Permeability and disruption of the peritrophic matrix and caecal membrane from Aedes aegypti and Anopheles gambiae mosquito larvae.

In mosquito larvae, the peritrophic matrix (PM) separates the gut contents from the intestinal epithelium. This report describes a new in vivo assay for estimating PM permeability. The assay also allows for assessment of the permeability of the caecal membrane, a structure that separates each caecum from the gut lumen. Permeability was estimated by the appearance of fluorescently-labeled dextrans (size range 4,400 to 2 million Da) within the gastric caecae of mosquito larvae. While the intact peritrophic matrix was impermeable to 2 million Da dextran particles, it was permeable to dextran particles of 148 kDa and smaller. The caecal membrane appears to have considerably smaller pores, being permeable only to dextrans of 19.5 kDa and smaller. The assay was also used to devise a treatment that disrupts the PM sufficiently to allow the passage of virus-sized particles. Dithiothreitol and to a lesser extent, chitinase were effective in disrupting the PM. Cycloheximide had a small effect; Polyoxin D, Pronase and calcofluor did not alter the permeability to 2 million Da dextran particles. Disruption of the PM is discussed in the context of infecting mosquitoes with retroviral transformation vectors.

Journal Article↗
PubMed1999

Highly permeable polylactide-caprolactone nerve guides enhance peripheral nerve regeneration through long gaps.

We compared regeneration and functional reinnervation after sciatic nerve resection and tubulization repair with bioresorbable guides of poly(L-lactide-co-epsilon-caprolactone) (PLC) and permanent guides of polysulfone (POS) with different degrees of permeability, leaving a 6 mm gap in different groups of mice. Functional reinnervation was assessed to determine recovery of motor, sensory and sweating functions in the hindpaw during four months postoperation. Highly permeable PLC guides allowed for faster and higher levels of reinnervation for the four functions tested than impermeable or low-permeable PLC guides, while semipermeable 30 and 100 kDa POS tubes yielded very low levels of reinnervation. The regeneration success rate was higher with PLC than with POS tubes. Morphometrical analysis of cross-sectional nerves under light microscopy showed the highest number of regenerated myelinated fibers at mid tube and distal nerve in high-permeable PLC guides. Impermeable PLC guides allowed slightly worse levels of regeneration, while low-permeable PLC guides promoted neuroma and limited distal regeneration. The lowest number of regenerated fibers were found in POS tubes. In summary, highly permeable bioresorbable PLC guides offer a suitable alternative for repairing long gaps in injured nerves, approaching the success of autologous nerve grafts.

Absorbable Implants↗
PubMed1997

Blocking effect of 1-naphthyl acetyl spermine on Ca(2+)-permeable AMPA receptors in cultured rat hippocampal neurons.

Effects of 1-naphthyl acetyl spermine (NASPM), a synthetic analogue of Joro spider toxin (JSTX), on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors were studied in cultured rat hippocampal neurons using the whole-cell patch clamp technique. A population of cultured neurons had AMPA receptors with a strong inward rectification and a high permeability to Ca2+ (type II neurons). Whereas most neurons (type I neurons) had AMPA receptors with a slight outward rectification and little Ca2+ permeability. NASPM selectively suppressed the inwardly rectifying and Ca(2+)-permeable AMPA receptors expressed in type II neurons. It had no effect on AMPA receptors in type I neurons. The blocking effect of NASPM on the Ca(2+)-permeable AMPA receptors was use and voltage-dependent. When the effect of NASPM reached a steady state, current responses induced by ionophoretic applications of kainate, a non-desensitizing agonist of AMPA receptors, in type II neurons were suppressed by NASPM in a dose-dependent manner at -60 mV (IC50 0.33 microM, and Hill coefficient 0.94). The response to kainate recovered partially after washing out NASPM. NASPM did not affect the Ca(2+)-permeable AMPA receptors when the neuronal membrane was held at potentials more positive than +40 mV. Furthermore, the blockade by NASPM which was attained at negative potentials was transiently removed by shifting membrane potential to +60 mV for 5 s together with a single ionophoretic application of kainate. NASPM would be useful as a pharmacological tool for elucidating both physiological and pathological significances of Ca(2+)-permeable AMPA receptors in the CNS.

Animals↗
PubMed1999

Analysis of structure-permeability correlation of nitrophenol analogues in newborn rat abdominal skin using semiempirical molecular orbital calculation.

Theoretical analysis of the permeation process in percutaneous absorption is important for the molecular design of bioavailable transdermal drugs. In the present study, we examined the difference in permeability of nitrophenols across newborn rat abdominal skin and analyzed the structure-permeability correlation by molecular orbital calculation. The permeable rate of o-, n-, p-nitrophenol and 2,4-, 2,5-, 2,6-dinitrophenols was 0.291, 0.212, 0.085 and 0.042, 0.109, 0.027 micromol/cm2/h, respectively. The permeability of the nitrophenols correlated with their pKa values, indicating the ionizing process related to the permeation through the skin. The pKa values better correlated with the ionization potential (IP) energies than lowest unoccupied molecular orbital (LUMO) energies. Solvation free energies (dGW) of molecular form nitrophenols correlated better with permeabilities (pA) than partition coefficients (log P). In analyzing the dGW values with the permeability at pH 7.4, o-nitrophenol outlay from the theoretical line by ortho-effect. We conclude solvation free energy is a practical parameter and very useful for the molecular design of transdermal drugs.

Abdomen↗
PubMed1996

Effect of the enantiomers of flurbiprofen, ibuprofen, and ketoprofen on intestinal permeability.

Numerous studies have demonstrated that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) increases small intestinal permeability, and this has been suggested to be a prerequisite to enteropathy. It is believed that the inhibitory effect of chiral NSAIDs on the synthesis of prostaglandins and hence their efficacy and toxicity are mainly due to the S enantiomer. Using the urinary excretion of [51Cr]-EDTA, we have investigated the effects of three nonsteroidal anti-inflammatory drugs (flurbiprofen, ibuprofen, and ketoprofen) on small intestinal permeability in rats. Single doses of each NSAID were administered orally as either the racemate or the R or S enantiomer, the enantiomer dose being half that of the racemate. Each treatment caused a significant increase in intestinal permeability above that seen in untreated animals. The R enantiomers of all three NSAIDs increased small intestinal permeability significantly above base line, which was expected for (R)-ketoprofen and (R)-ibuprofen due to substantial chiral R to S inversion. The intestinal permeability for (R)-flurbiprofen, although minimal and likely due to 10% inversion, may also suggest prostaglandin-independent involvement. Furthermore, (S)-flurbiprofen, used at one-half the dose of the racemate, increased permeability to a similar magnitude as the racemate. This observation was similar to that previously reported for etodolac. A stereochemically pure enantiomer does not necessarily offer a safer alternative than its racemic form.

Animals↗
PubMed1998

In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents.

To combat infection and inhibit viral replication of HIV in the brain, antiretroviral agents must cross the blood-brain barrier (BBB). An in vitro BBB model consisting of bovine brain microvessel endothelial cells grown on porous filters was used to study and compare the transport of nevirapine, a potent and selective nonnucleoside reverse transcriptase inhibitor, with other HIV antiretroviral agents currently in use for the treatment of HIV infection. These included nucleoside reverse transcriptase inhibitors (didanosine, stavudine, zalcitabine, zidovudine), a nonnucleoside reverse transcriptase (delaviridine), and protease inhibitors (indinavir, saquinavir, VX-478). Nevirapine was the most permeable antiretroviral agent studied in the BBB model. The order of in vitro BBB permeability was nevirapine >> VX-478 > didanosine, stavudine, zalcitabine, zidovudine > indinavir > saquinavir. There was an apparent bell-shaped relationship between in vitro BBB permeability and octanol/phosphate-buffered saline distribution coefficient (D) where all lipophilic (log D > 2.5) as well as hydrophilic (log D < -0.5) antiretrovirals were less permeable than nevirapine (log D = 1.8). There were no significant effects on the in vitro BBB permeability of nevirapine in combination with other antiretroviral agents. Saquinavir was the only drug shown to have an affinity for the P-glycoprotein efflux pump, which may have contributed to its very low permeability. The apparent ability of nevirapine to readily permeate the BBB and enter the brain, where it may inhibit replication of HIV, potentially increases its therapeutic value.

Animals↗
PubMed2006

Electrochemically modulated permeability of poly(aniline) and composite poly(aniline)-poly(styrenesulfonate) membranes.

The influence of oxidation state on the permeability of several probe molecules through conducting polymer membranes comprising composites of poly(aniline) and poly(styrenesulfonate) was examined in aqueous solution. Pure poly(aniline) membranes displayed a characteristic increase in permeability between reduced and half-oxidized states for neutrally charged phenol and negatively charged 4-hydroxybenzenesulfonate. In contrast, positively charged pyridine experienced decreased permeability through the membrane when poly(aniline) was switched from the reduced to the half-oxidized state. This behavior can be explained by a combination of oxidation-induced film swelling and the anion-exchange character of the positively charged membrane. The membrane composition was modified to include a fixed negative charge by the addition of poly(styrenesulfonate) during synthesis. The incorporation of this negatively charged component introduced cation-exchange character to the film and substantially reduced membrane permeability to 4-hydroxybenzenesulfonate in both oxidation states. In addition, increasing the fraction of poly(styrenesulfonate) in the membrane served to decrease film permeability for all species because of a densification of the membrane. This work demonstrates how both film composition and oxidation state can be used to tune the permeability of conducting polymer membranes.

Journal Article↗