PubMed Health⌕ Search

Biomedical subjects

W Abraham

Publications and source records attributed to W Abraham.

At least 19 recordsLinked to original sources
PubMed2004

IPL576,092, a novel anti-inflammatory compound, inhibits leukocyte infiltration and changes in lung function in response to allergen challenge.

IPL576,092, a lead compound from a novel class of polyhydroxylated sterols, was tested in models of allergen-induced bronchoconstriction and airway inflammation. In a rat ovalbumin lung inflammation model, orally administered IPL576,092 significantly inhibited the challenge-mediated increase in total bronchoalveolar lavage leukocyte numbers, and macrophage and lymphocyte infiltration (1-10 mg/kg/day). There was a similar trend towards inhibition of eosinophil and neutrophil accumulation. Sheep were treated with IPL576,092 by inhalation (400 microg/kg/day), and lung resistance and airway hyper-responsiveness (AHR) were determined after Ascaris suum challenge. IPL576,092 significantly reduced the early and late phase bronchoconstrictor responses by 63+/-4.6 and 84+/-4.6%, respectively. IPL576,092 also blocked AHR (2.2+/-5.7% change from pre-challenge PC400), whereas control animals showed a 62.2+/-2.6% decrease in the PC400 (p<0.05). Oral IPL576,092 (5 mg/kg/day) also significantly decreased hyper-reactivity in mice. In a guinea pig model, IPL576,092 (5 mg/kg/day) significantly protected against allergen-induced increases in lung resistance (11.4+/-2.3 control versus 4.8+/-01.5 IPL576,092, area under the curve) and inhibited the increase in lung elastance (280+/-58 control versus 167+/-52 IPL576,092, p<0.05). IPL576,092, unlike dexamethasone, did not significantly decrease rat serum corticosterone levels or thymus and spleen weights, supporting a mechanism of action different from classic glucocorticoids. IPL576,092 significantly attenuates characteristics of an asthmatic response, indicating therapeutic potential for this drug class.

Airway Resistance↗
PubMed2001

Respiratory drive during carbachol challenge in allergic sheep.

Diaphragmatic activity is the standard assessment of respiratory neural output but is difficult to measure and cannot be used for long-term clinical monitoring. The tidal breathing minute ventilation (V') and mean inspiratory flow (VT/tI) reflect respiratory drive and can be monitored non-invasively using respiratory inductive plethysmography (RIP). Recent findings indicate that peak inspiratory acceleration (PIA) correlates to diaphragmatic activity during CO2 rebreathing in piglets. The aim of the present study was to assess whether tidal breathing peak inspiratory acceleration reflects respiratory drive during carbachol challenge. Aerosolized carbachol was administered to 15 allergic sheep until pulmonary resistance increased by at least 400%. After threshold dose, slight increases in V' and VT/tI were seen (8 and 5%, respectively; P=NS), while PIA increased by 30% (P<0.05). The change in PIA was closely correlated to changes in V'[bar over] and VT/tI (r=0.73, P<0.01 and r=0.88, P<0.001, respectively). In conclusion, peak inspiratory acceleration reflected respiratory drive during bronchoprovocation. Further, this new measure of drive has the potential to accurately estimate drive in chronic obstructive lung disease where intrinsic positive end expiratory pressure prevents accurate selection of beginning inspiration necessary for computation of, e.g. VT/tI.

Animals↗
PubMed1998

Characterization of the stratum corneum lipid matrix using fluorescence spectroscopy.

Using fluorescence techniques, we studied the dynamics of the lipid bilayer matrix of human stratum corneum (SC) and compared the results with that of distearoyl-phosphatidylcholine (DSPC). We employed a series of 9-anthroyloxy fatty acids (AF) that partitioned into the bilayer, enabling us to evaluate this structure as a function of depth within the lamellae. With AF probes, the re-orientation of the fluorophore is known to be affected by the polarity, hydrogen bonding, and rigidity of the surrounding medium, altering the emission maximum and lifetime in the excited state. In addition, we evaluated quenching, in which iodide collides with the fluorophore, revealing information on the accessibility of the fluorophore located in the bilayer. The emission and lifetime data showed that the reorientation of the fluorophore in SC was more hindered than in DSPC, indicating that SC bilayers were more rigid than DSPC bilayers. Quenching data of both SC and DSPC indicated that the deeper the fluorophore was positioned in the bilayer, the less accessible it was to iodide, pointing to a gradient in accessibility. In addition, the quenching results also showed that the SC is less accessible to iodide than in DSPC. The observed differences in bilayer rigidity and quencher accessibility between the two systems can be explained by differences in lipid composition and hydration. Whereas the DSPC bilayer consists of phospholipids, SC bilayers are composed of more anhydrous lipids like cholesterol and ceramides, which form a tight bilayer packing. In this way SC lipids exist in a relatively anhydrous and rigid environment, forming an effective diffusion barrier to water and ions.

Epidermis↗
PubMed1998

Fluorescence spectroscopic investigation of effect of excipients on epidermal barrier and transdermal systems.

Excipients are often used in transdermal formulations to overcome the formidable barrier offered by the epidermis in order to achieve the target flux. In this study we describe the use of frequency-domain fluorescence spectroscopy to characterize the effect of two commonly used excipients, propyleneglycol monolaurate (PGML) and oleic acid on stratum corneum and in a silicone-based transdermal delivery system. Fluorescence lifetime and limiting anisotropy for the probe 1,6-diphenyl-1,3,5-hexatriene in isolated human epidermis were measured as a function of formulation treatment. The drop in lifetime ranged from 0.5 to 2.3 ns, indicative of an increased dielectric constant of the lipophilic barrier exposed to all formulations. This increase is due to increased partitioning of the polar excipients from the delivery system into the stratum corneum. The limiting anisotropy showed a drop of 0.1 in the case of the epidermis exposed to oleic acid formulation and not the PGML formulations, indicative of the different modes of action for these two excipients. The fluorescence data suggested fluidization of the silicone matrix by both oleic acid and PGML. The dynamic fluorescence measurements described in this study are a powerful way to screen formulations while gaining valuable mechanistic insight into the mode of flux enhancement in transdermal formulations.

Administration, Cutaneous↗
PubMed1996

Activation of NMDA and muscarinic receptors induces nur-77 mRNA in hippocampal neurons.

Using in situ hybridization, we show that the expression of the immediately-early gene, nur-77, increases rapidly and transiently in hippocampal neurons following activation of muscarinic and N-methyl-D-aspartate receptors and after hippocampal long-term potentiation (LTP). On the basis of these results we hypothesize that nur-77 may coordinate with other transcription factors to initiate subsequent changes in hippocampal gene expression associated with plasticity-related activation of N-methyl-D-aspartate and muscarinic receptors.

Animals↗
PubMed1996

The influence of an electric field on ion and water accessibility to stratum corneum lipid lamellae.

PURPOSE: To study ion transport through stratum corneum (SC) lipid lamellae under passive and iontophoretic conditions. METHODS: Iodide ion transport was measured by fluorescence quenching. Since the process involves diffusion of an iodide ion to the fluorophore located within the SC lamellae, the accessibility of iodide ions was measured. Moreover, the use of anthroyloxy fatty acid probes, provided information as a function of depth within the lamellae. RESULTS: Fluorescence quenching by iodide ions increased with iontophoretic current density, suggesting increased ion accessibility within the SC lamellae. In addition, at constant current, quenching decreased as the fluorophore was located deeper within the lamellae. This gradient in ion accessibility suggests that more iodide is found near the head-group than near the core of the SC lipid lamellae. Results obtained in the absence of iodide also show increased water accessibility during iontophoresis. CONCLUSIONS: These results show that in the presence of an applied electric field the SC lipid lamellae interior becomes more accessible to water and ions. These results imply that during iontophoresis, ion and water transport through human skin is associated, at least in part, with the SC lipid lamellae.

Electricity↗
PubMed1995

Effect of PGML excipient mixture in a transdermal system on the in vitro transport of estradiol across skin.

PURPOSE: To measure the effect of a combination of excipients from a silicone based pressure sensitive adhesive (PSA) on drug transport across skin. METHODS: Partitioning of propylene glycol monolaurate (PG-ML) from silicone PSA and a solution formulation into the stratum corneum (SC) was measured using radiolabeled PG-ML. Transport of a model drug, estradiol, as well as PG-ML across skin were measured in vitro using heat separated epidermis from human cadaver skin. RESULTS: The PG-ML partitioning into SC showed a saturation and was independent of the formulation. The local dielectric of the lipid bilayers of the SC showed an increase as a result of PG-ML uptake, as determined by the decrease in fluorescence lifetime of a lipophilic probe incorporated into the SC. However, there was no alteration of lipid packing in SC. CONCLUSIONS: The PG-ML and estradiol transport showed a good correlation over 3 days, suggesting that the two species are co-transported across the epidermis.

Administration, Cutaneous↗
PubMed1994

Fluorescence spectroscopy of 9-anthroyloxy fatty acids in solvents.

A series of anthroyloxy fatty acid (AF) fluorescent probes, with the anthroyloxy group covalently linked at various positions along the alkyl chain, were studied in solvents exhibiting a wide range of polarity and hydrogen-bond donor (Hd) and acceptor (Ha) ability. These probes were sensitive to the solvent polarity as reflected by the Stokes' shift observed in steady state fluorescence. As determined by multi-linear regression analysis of the observed Stokes' shift and solvent parameters, such as orientation polarizability (delta f), Hd and Ha of the solvents, all the probes were sensitive to the Hd of solvents but were not affected by the Ha of solvents except the 2-AF. Due to the proximity of the polar headgroup to the fluorophore, it appears that some intramolecular hydrogen-bonding is present in 2-AF, an interaction that is sensitive to the pH of the solvent, but is less sensitive to the Hd and Ha of the solvents. Fluorescence lifetimes measured by the multi-frequency phase-modulation technique in mixtures of hexane and ethanol reflect a modified Stern-Volmer behavior suggesting the second solvent, ethanol, specifically interacts with the probe, in part through collisional quenching. Also, the lifetime data were sensitive to very low concentrations of the second solvent (0-0.1%, by vol.). The results from this study provide insight into the intrinsic differences between the different AF positions that must be taken into consideration while investigating the dynamics of lipid bilayer systems. Moreover, this study illustrates the utility and resolving power of lifetime based measurements needed for the interpretation of heterogeneous biophysical environments.

Anthracenes↗
PubMed1993

Brain-derived neurotrophic factor expression after long-term potentiation.

Long-term potentiation (LTP) of perforant-path dentate granule cell synapses, in awake rats, was followed by a time-dependent expression of brain-derived neurotrophic factor (BDNF) mRNA in dentate granule cells. This BDNF expression was blocked by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801), which also blocked LTP induction, and by sodium pentobarbital, which shortens LTP persistence. These results suggest that BDNF may participate in the NMDA-receptor mediated cascade of events that result in LTP stabilization.

Animals↗
PubMed1993

Fluorescence anisotropy studies on the interaction of the short chain n-alkanols with stratum corneum lipid liposomes (SCLL) and distearoylphosphatidylcholine (DSPC)/distearoylphosphatidic acid (DSPA) liposomes.

Previously, the action of the short chain n-alkanols (from C1 to C5) and isopropanol as possible enhancers on the transport of lipophilic and polar/ionic permeants across hairless mouse skin was investigated. In the present study, the steady-state fluorescence anisotropy was measured as a means of estimating the changes in fluidity caused by the n-alkanols at different depths in the stratum corneum lipid liposomes (SCLL). Some selected experiments with the distearoylphosphatidylcholine (DSPC)/distearoylphosphatidic acid (DSPA) liposomes were performed for relative comparisons. The effects of the n-alkanols on polarity sensitive parameters such as fluorescence lifetimes, fluorescence quantum yield ratios, and emission maxima were studied in the SCLL. The polarity of the bilayer decreased as the fluorescent probe was placed closer to the bilayer center and the n-alkanols did not alter this gradient. Assessment of the depth-dependent effects of the n-alkanols using SCLL showed that most of the significant changes in fluidity induced by the n-alkanols were observed at intermediate depths (C2-C9) and there was little or no increase in fluidity in the deep hydrophobic region close to the bilayer center. These results suggest that the short chain n-alkanols work as effective 'fluidizing' agents at the intermediate depths (C2-C9) in the bilayer.

1-Butanol↗
PubMed1993

Partition of sodium dodecyl sulfate into stratum corneum lipid liposomes.

Synthetic detergents produce deleterious effects on human skin as the result of being taken up by the stratum corneum (SC). The present study aimed to determine to what extent a typical detergent enters the SC lipid lamellae, and what effect this might have on the physical properties of the lipids. These effects were studied in large unilamellar liposomes prepared from SC lipids (50% by weight of epidermal ceramides, 28% cholesterol, 17% free fatty acids, and 5% cholesteryl sulfate) by extrusion through successive polycarbonate filters of decreasing pore size, finally 400 nm. Freeze-fracture electron microscopy and light-scattering particle size analysis indicated a uniform liposome diameter averaging 230 nm. Partitioning of sodium dodecyl sulfate (SDS) into the lipid phase from aqueous buffer solutions was measured using the SC lipid liposomes and [U-14C]SDS. The partition coefficient was 416, 450, and 588 at pH 8.5 and 524, 507, and 807 at pH 7 for three different concentrations (0.1%, 0.02%, and 0.004%) of SDS. This high degree of partitioning into the liposomes is consistent with the high level of SDS partitioning seen in full SC. At the maximum, the SDS represented 18% of the liposomal lipids. Preparation of stable liposomes from SC lipids to which 10% or 20% of SDS had been added confirmed the ability of the liposomes to survive these high concentrations of surfactant. The permeability of the liposomes was enhanced as a result of SDS partitioning into the bilayers, as measured by the increased release of trapped [U-14C]glucose from these vesicles, and by their increased permeability to water in osmotic shock experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Inhibition of antigen-induced airway and cutaneous responses by heparin: a pharmacodynamic study.

We have previously shown that heparin attenuates the acute bronchoconstrictor response and immediate cutaneous reaction (ICR) to antigen in allergic sheep. In the present investigation, we studied the pharmacodynamics of the antiallergic action of heparin. Specific lung resistance (sRL) was measured in eight sheep, allergic to Ascaris suum antigen, before and 5 min after inhalation challenge with the antigen. On different experiment days, antigen challenge was repeated after pretreatment with 1) aerosol heparin (1,000 U/kg) administered < or = 20 min, 6 h, 12 h, and 24 h and 2) intravenous heparin (1,000 U/kg) administered < or = 20 min, 1 h, 6 h, and 12 h before antigen challenge. sRL increased by 374 +/- 116% (SE) above baseline with antigen alone. Both aerosol and intravenous heparin attenuated the antigen effects on sRL in a time-dependent fashion. Prolonging the lag time between pretreatment and antigen challenge decreased the inhibitory effect of aerosol heparin; delta sRL was 31 +/- 29, 99 +/- 38, 142 +/- 40, and 306 +/- 60% for < or = 20-min, 6-h, 12-h, and 24-h pretreatment protocols, respectively. In contrast, prolonging the lag time increased the inhibitory effect of intravenous heparin: delta sRL was 246 +/- 64, 66 +/- 26, and 76 +/- 32% for < or = 20 min, 1 h, and 6 h, respectively. In seven additional sheep pretreatment with intravenous heparin (1,000 U/kg) attenuated the ICR also in a time-dependent manner; the inhibitory effect of heparin on ICR to antigen was enhanced 60% by increasing the heparin pretreatment interval from 20 to 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1993

Interaction between sphingosine and cholesteryl sulfate in epidermal lipids.

Free sphingosine, a material with multiple and potent biological activities, is known to occur in high concentration in mammalian epidermis. In the present study, thin-layer chromatography showed that in lipid extracts of human and pig stratum corneum, sphingosine forms a relatively stable compound with endogenous cholesteryl sulfate. NMR spectrometry of sphingosine and its hydrochloride, sulfate, and mixtures with cholesteryl or dodecyl sulfate showed that interaction with the organic sulfates constituted simple salt formation. Under neutral or weakly acidic conditions, such salts were only slightly dissociated and migrated on thin-layer chromatograms as discrete compounds. Thin-layer chromatography revealed undissociated salt formation between several long-chain bases and organic sulfates, and showed that their interaction is stoichiometric. However, undissociated salts were not formed between long-chain bases and fatty acids or phosphatidic acid. Undissociated salt formation may therefore be specific for organic bases and sulfates. It was concluded that the free sphingosine in the stratum corneum may be present as its cholesteryl sulfate salt and in this form be unavailable for permeation into the viable epidermal cells.

Animals↗
PubMed1992

Lamellar structures formed by stratum corneum lipids in vitro: a deuterium nuclear magnetic resonance (NMR) study.

Hydrated lipid mixtures consisting of stratum corneum ceramides, cholesterol, specifically deuterated palmitic acid, and cholesteryl sulfate were investigated by solid-state 2H NMR spectroscopy at different temperatures. The mole ratio of cholesterol to ceramides was varied from 1 to 0. 2H NMR spectra from these mixtures showed powder patterns with quadrupolar splittings smaller than those obtained from control mixtures containing dipalmitoylphosphatidylcholine (DPPC) instead of the ceramides. This result is attributed to the rigid amide group of the ceramides, with a planar configuration, which could prevent close packing of the alpha-methylenes of the acyl chains. There was a gradual loss of symmetry in the powder pattern as the amount of cholesterol was decreased and the amount of ceramides (or DPPC) was increased concomitantly. The loss was more pronounced in the ceramide-containing samples. This phenomenon is interpreted as a decrease in the axial reorientation rate of the alpha-deuterated palmitic acid in the bilayers, presumably caused by the increased hydrogen bonding resulting from the high amount of hydroxyl-bearing ceramides. Spectra obtained at temperatures above 60 degrees C indicated the formation of a hexagonal phase (HII) by the ceramide-containing mixtures. Spectra of the omega-deuterated palmitic acid in the mixture containing 76 mol% ceramides and no cholesterol indicated phase separation into a more rigid phase and a more mobile phase in the temperature range of 25 to 60 degrees C. The bilayer configuration of lipids at 25 degrees C was confirmed by thin-section electron microscopy.

Animals↗
PubMed1992

Structures formed by epidermal lipids in vitro.

The extracellular membranous structures of stratum corneum constitute the major barrier to percutaneous penetration. These intercellular lipid lamellae are devoid of phospholipids and are unique in their lipid composition. In this article, some of the recent investigations of the structures formed by the stratum corneum lipids in vitro are discussed with relevance to the barrier function of epidermis. These studies have provided some insight into the dramatic physical changes that occur in the membranous structures of the epidermis during the formation of the stratum corneum.

Animals↗
PubMed1991

Deuterium NMR investigation of polymorphism in stratum corneum lipids.

The intercellular lipid lamellae of stratum corneum constitute the major barrier to percutaneous penetration. Deuterium magnetic resonance and freeze-fracture electron microscopic investigation of hydrated lipid mixtures consisting of ceramides, cholesterol, palmitic acid and cholesteryl sulfate and approximating the stratum corneum intercellular lipid composition, revealed thermally induced polymorphism. The transition temperature of bilayer to hexagonal transition decreased as the ratio of cholesterol to ceramides in these mixtures was lowered. Lipid mixtures in which the stratum corneum ceramides were replaced by synthetic dipalmitoylphosphatidylcholine did not show any polymorphism throughout the temperature range used in the present study. The ability of the ceramide-containing samples to form hexagonal structures establishes a plausible mechanism for the assembly of the stratum corneum intercellular lamellae during the final stages of epidermal differentiation. Also, the bilayer to hexagonal phase transition of these nonpolar lipid mixtures could be used to enhance the penetration of drugs through skin.

Animals↗