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PubMed1993

Platelet activating factor-induced microvascular permeability increases in the cat hindlimb.

Changes in microvascular permeability induced by platelet activating factor (PAF) were measured in the isolated, perfused cat hindlimb preparation, and compared to the effect produced by another inflammatory mediator, histamine. Permeability was assessed from changes in the protein reflection coefficient, as measured from changes in hematocrit and protein concentration resulting from microvascular fluid filtration. The findings were 1) PAF produces transient increases in permeability similar to histamine, but PAF is approximately 30 times as potent; 2) the permeability changes induced by 76 nM PAF can be totally inhibited by the specific PAF receptor blocker WEB-2086, but the blocker can only partially inhibit 380 nM PAF, a dose that produces a maximal increase in permeability; 3) Diphenhydramine (2 microM), an H1-receptor blocker, totally inhibits the transient permeability increase produced by 2 microM histamine; 4) Cimetidine (2 or 20 microM), an H2 blocker, could not inhibit this latter increase; 5) Isoproterenol (1 microM), a beta-agonist, totally inhibited the permeability increase produced by 1 microM histamine, but 10 microM isoproterenol only partially inhibited the maximal permeability increase produced by 10 microM histamine; 6) Isoproterenol could not inhibit PAF's permeability effect; and 7) PAF's effects were unchanged by depletion of white blood cells in the perfusate. These results suggest that PAF and histamine work through different pathways to increase permeability, but the final step of endothelial contraction, which opens large inter-endothelial gaps, occurs in response to both mediators. In addition, when concentrations of these inflammatory agents are sufficient to produce maximal permeability increases, as can occur in shock situations, then the permeability increases are more sustained and resistant to receptor inhibition.

Animals↗
PubMed1997

Size-dependent permeability of hydrophilic probes across rabbit colonic epithelium.

Colon-specific delivery of metabolically labile molecules, such as proteins and peptides, is of particular interest in pharmaceutical research. Among the factors that may influence the permeability of drug molecules across colonic mucosa are their molecular weight and geometry. The purpose of this study was to evaluate the influence of molecular geometry on in vitro permeability across rabbit distal colonic epithelia. Permeability of radiolabeled hydrophilic probes with different molecular weights and geometries across isolated rabbit distal colonic tissue was evaluated by means of the Ussing chamber technique. The hydrodynamic radii of the probes (an indicator of molecular geometry) were estimated by theoretical models as well as dynamic light scattering. We conducted the permeability studies in the presence and absence of the epithelial cells to evaluate the contribution of the underlying connective tissue to the overall in vitro permeability across the colonic mucosa. The rank order of the permeability of the markers was mannitol > lactulose > polyethylene glycol (PEG) 400 > PEG 900 > PEG 4000, which is consistent with their molecular weights and estimated hydrodynamic radii. The permeability of inulin, a polyfructose molecule with a molecular weight of about 5000, however, was approximately the same as that of PEG 900 (molecular weight about 900). When the epithelial cells were removed, for the homologous series of PEGs, the permeabilities were proportional to their free diffusion coefficients in water. It appears that for the PEG and lactulose probes, theoretical estimation of the hydrodynamic radii, which assumes the molecules to be spherical in shape, provides a good basis for the dependence of permeability on geometry. The relatively high permeability of inulin seems to be due to its compact structure. The PEG permeability values in the absence of epithelial cells, in combination with their diffusion coefficients, indicate that the underlying connective tissue does not contribute to the overall permeability of these molecules across colonic mucosa in vitro.

Animals↗
PubMed1999

Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives.

OBJECTIVE: Ankylosing spondylitis (AS) is reportedly associated with subclinical endoscopic gut inflammation in up to 57% of patients. Studies of bowel permeability, however, have not consistently revealed abnormalities in these patients. CD20+CD45RO+ expression is associated with increased antigen exposure, and previous work has shown increased expression in this B cell isoform in patients with Crohn's disease and their relatives, correlating with intestinal permeability abnormalities. We sought to re-examine intestinal permeability in patients with AS and their relatives, and relate any observed alterations in permeability with evidence of increased antigen presentation as assessed by the number of circulating B cells that were CD45RO positive. METHODS: We studied small intestinal and gastric permeability by measurement of excretion of lactulose, mannitol, and sucrose in 60 patients with AS and 24 of their first-degree relatives. We also studied expression of CD20+CD45RO+ by flow cytometry in these patients. RESULTS: Both patients and first-degree relatives had significantly increased small intestinal, but not gastric, permeability compared to controls. Among patients, current users of nonsteroidal anti-inflammatory drugs (NSAID) had significantly increased small intestinal permeability compared to nonusers, but relatives not using NSAID also had increased permeability. CD20+CD45RO+ expression was increased in one-third of patients but did not correlate with permeability abnormalities. CONCLUSION: Patients with AS have altered small intestinal, but not gastric, permeability. NSAID use cannot explain all the abnormality. Bowel permeability abnormalities, possibly genetically determined, may antedate development of bowel or joint symptoms. Increased CD20+CD45RO+ expression suggests increased antigen exposure, which may be related to previous or current intestinal permeability abnormalities.

Adult↗
PubMed2004

Vasopeptidase inhibition with omapatrilat increases fluid and protein microvascular permeability in cat skeletal muscle.

BACKGROUND: Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. OBJECTIVE: To analyse the effects of vasopeptidase inhibition on permeability. DESIGN: The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. METHODS: Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. RESULTS: After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. CONCLUSIONS: A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.

Animals↗
PubMed1997

Decrease in gastric permeability to sucrose following cure of Helicobacter pylori infection.

BACKGROUND: Gastric sucrose permeability is a noninvasive marker that reliably increases in association with gastrointestinal injury due to use of nonsteroidal antiinflammatory drugs. Despite the effect of Helicobacter pylori infection on the gastric mucosa, in a previous study we were unable to demonstrate that H. pylori infection was associated with abnormal gastric sucrose permeability. Our goal in this study was to explore further whether H. pylori infection changed gastric permeability; therefore, we evaluated the effect of treatment of H. pylori infection on gastric permeability to sucrose and the relation of sucrose permeability to density of polymorphonuclear leukocytes. MATERIALS AND METHODS: Five hundred milliliters of a solution containing 100 gm of sucrose was ingested by the subject at bedtime. Overnight urine was collected and assayed for sucrose by high-performance liquid chromatography. Sucrose permeability was assessed both before and approximately 4 weeks after anti-H. pylori therapy. RESULTS: Seventeen asymptomatic H. pylori-infected volunteers participated; 8 were cured. Sucrose permeability was in the range commonly found in normal controls both before and after anti-H. pylori therapy (mean excretion, 76.3 mg; range, 13-171 mg). Gastric sucrose permeability correlated with the density of polymorphonulcear cell infiltration of the mucosa. Cure of the H. pylori infection was associated with a small but significant decrease in sucrose permeability (98.8 +/- 18 mg to 51.7 +/- 9.8 mg (p = .01). Sucrose permeability was greater in those with a high density of mucosal polymorphonuclear cells compared to those with lower scores (119.5 +/- 4 vs 71.4 +/- 13 for those with scores > or = 5 compared to scores < or = 4; p = .023). Failed therapy resulted in an increase in the mucosal density of polymorphonuclear infiltration and sucrose permeability (56.4 +/- 13 mg-99.7 +/- 19 mg pretreatment vs posttreatment, respectively; p = .031). CONCLUSION: H. pylori gastritis causes a small but measurable increase in gastric permeability to sucrose that may reflect epithelial transmigration of neutrophils.

Anti-Bacterial Agents↗
PubMed1999

Rabbit corneal and conjunctival permeability of the novel aldose reductase inhibitors: N-[[4-(benzoylamino)phenyl] sulphonyl]glycines and N-benzoyl-N-phenylglycines.

Corneal and conjunctival permeability has been investigated for novel aldose reductase inhibitors (ARIs) of the N{[4-(benzoylamino)phenyl]sulphonyl}glycine (benzoylaminophenylsulphonylglycine) and N-benzoyl-N-phenylglycine (benzoylphenylglycine) series, compounds developed for prevention of cataract formation in diabetic subjects. Six benzoylaminophenylsulphonylglycines were synthesized with modifications either of the phenyl group or of the glycine structure and three benzoylphenylglycines were synthesized with modification in the phenyl group of the benzoyl moiety. Transport of ARIs in the mucosal to serosal direction was evaluated across rabbit cornea and conjunctiva bathed in glutathione-bicarbonate Ringer's solution maintained at pH 7.4 and 37 degrees C. The permeability coefficients of the novel ARIs across cornea and conjunctiva ranged from 1.87 to 8.95 x 10(-6) cm s(-1) and from 4.6 to 19.15 x 10(-6) cm s(-1), respectively. The ratio of corneal to conjunctival permeability ranged from 0.12 to 0.79. The calculated log partition coefficient (log P) values for the ARIs were in the range 0.84 to 2.78. The log distribution coefficients (log D) were in the range -2.87 to -0.89. There was no apparent relationship between log P or log D and the permeability coefficients of the ARIs for either tissue. Cornea was more resistant to ARI transport than was conjunctiva. Substitution of a phenyl group for hydrogen in the glycine methylene group reduced the permeability coefficient. Permeability coefficients were different for different stereoisomers. Compared with the permeability coefficient of benzoylaminophenylsulphonylglycine, that of 4-fluorobenzoylaminophenylsulphonylglycine was lower in the cornea but similar in the conjunctiva. In both tissues, the permeability coefficient of 2-nitrobenzoylaminophenylsulphonylglycine was less than that of 4-nitrobenzoylaminophenylsulphonylglycine. There was no significant difference between the permeability coefficients of 3-nitro- and 4-nitrobenzoylphenylglycines through either tissue and the permeability coefficients of these compounds were greater than that of the more lipophilic 4-methylbenzoylphenylglycine. The lack of dependence of the permeability coefficients on log P or log D and the different permeabilities of stereoisomers imply the existence of specialized transport processes for the ARIs tested in this study.

Animals↗
PubMed2004

PAMPA--a drug absorption in vitro model 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones.

Parallel artificial membrane permeability assay (PAMPA) was used to measure the effective permeability, P(e), as a function of pH from 4 to 10, of 17 fluoroquinolones, including three congeneric series with systematically varied alkyl chain length at the 4'N-position of the piperazine residue. The permeability values spanned over three orders of magnitude. The intrinsic permeability, P(o), and the membrane permeability, P(m), were determined from the pH dependence of the effective permeability. The pK(a) values were determined potentiometrically. The PAMPA method employed stirring, adjusted such that the unstirred water layer (UWL) thickness matched the 30-100 microm range estimated to be in the human small intestine. The intrinsic permeability coefficients (10(-6)cm/s), representing the permeability of the uncharged form of the drug, are for 4'N-R-norfloxacin: 0.7 (R=H), 49 (Me), 132 (n-Pr), 365 (n-Bu); 4'N-R-ciprofloxacin: 2.7 (H), 37 (Me), 137 (n-Pr), 302 (n-Bu); 4'N-R-3'-methylciprofloxacin: 3.8 (H), 20 (Me), 51 (Et), 160 (n-Pr), 418 (n-Bu). Increasing the alkyl chain length in the congeneric series resulted in increased permeability, averaging about 0.34 log units per methylene group, except that of the first (H-to-Me), which was about 1.2 log units. These results were compared to Caco-2 and rat in situ permeability measurements. The in situ closed loop technique used for obtaining permeability values in rat showed a water layer thickness effect quite consistent with in vivo expectations. The rat-PAMPA correlation (r2=0.87) was better than that of rat-Caco-2 (r2=0.63). Caco-2-PAMPA correlation indicated r2=0.66. The latter correlation improved significantly (r2=0.82) when the Caco-2 data were corrected for the UWL effect.

Animals↗
PubMed1996

Mechanisms of alpha-thrombin, histamine, and bradykinin induced endothelial permeability.

alpha-Thrombin, bradykinin, and histamine are endogenous mediators that increase endothelial permeability. We examined the mechanism by which these three vasoactive mediators could alter permeability to albumin of human umbilical vein endothelial cells (HUVEC). HUVEC were grown to confluence on Transwell membranes and we monitored the flux of fluorescein isothiocyanate-labeled human serum albumin across the membrane from the upper to lower chamber of the Transwell. Addition of alpha-thrombin, bradykinin, or histamine increased the permeability coefficient of the HUVEC monolayer. At 30 min the permeability coefficient for alpha-thrombin was 4.92 x 10(-6) cm/sec while histamine was 4.47 x 10(-6) cm/sec. Maximum changes in the permeability coefficient were about three-fold control baseline values (1.59 x 10(-6) cm/sec). There was also a temporal difference in the magnitude of the permeability coefficient. alpha-Thrombin and bradykinin induced HUVEC permeability was increased for the first 90 min after which it returned to control levels. In contrast, histamine increased the permeability of the HUVEC monolayer throughout the 2 h experiment. To determine a possible intracellular mechanism of the altered permeability coefficients, HUVEC were labeled with FURA-2 and intracellular calcium was monitored by digital fluorescence ratio imaging. Maximum intracellular calcium in HUVEC was increased by alpha-thrombin (245 +/- 20 nM) and histamine (210 +/- 22 nM), but not by bradykinin (70 +/- 7 nM) as compared to control (69 +/- 10). Fluorescent photomicrographs of HUVEC stimulated with the three agonists indicated that alpha-thrombin and histamine substantially altered HUVEC f-actin arrangement, while bradykinin had no effect on HUVEC f-actin distribution. These data support previous in vitro and in vivo studies demonstrating increased permeability by all three agonists. These data also show, for the first time, that histamine and alpha-thrombin increased permeability by calcium-dependent intracellular pathways, but bradykinin operates through a calcium-independent mechanism.

Actins↗
PubMed2001

Effect of common excipients on Caco-2 transport of low-permeability drugs.

The Biopharmaceutics Classification System (BCS) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. The objective of this work was to evaluate the effect of nine individual excipients on the Caco-2 permeability of seven low-permeable compounds that differ in their physiochemical properties. Generally, most excipients had no influence on drug permeability. With the exception of sodium lauryl sulfate, no excipient affected Caco-2 monolayer integrity. Sodium lauryl sulfate moderately increased the permeability of almost all the drugs. Tween 80 significantly increased the apical-to-basolateral direction permeability of furosemide, cimetidine, and hydrochlorothiazide, presumably by inhibiting their active efflux, without affecting mannitol permeability. Additionally, docusate sodium moderately increased cimetidine permeability. Other excipients did not have significant effect on the permeability of these three drugs. Further work is needed to interpret the in vivo consequences of these observations from cell culture.

Biological Transport↗
PubMed1995

Role of the endothelial cytoskeleton in blood-brain-barrier permeability to protein.

The role of the cytoskeletal elements, microfilaments and microtubules in cerebral endothelial permeability to protein during steady states was investigated by studies of cerebrovascular permeability to horseradish peroxidase (HRP) in rats pretreated with cytochalasin B or colchicine, agents known to disrupt microfilaments and microtubules, respectively. In addition, the effect of colchicine pretreatment on the alterations in cerebrovascular permeability that occur in acute hypertension were studied. Rats infused with cytochalasin B showed increased cerebrovascular permeability to HRP in multifocal areas of the ipsilateral hemisphere. Most of the permeable vessels were arterioles; however, capillaries and venules also showed increased permeability. Ultrastructural studies of permeable vessels showed HRP in all layers of vessel walls and in endothelial and smooth muscle cell pinocytotic vesicles, which were increased in number. Although segments of interendothelial spaces were labeled by tracer, continuous labeling of interendothelial spaces from the luminal to the abluminal end was not seen and tight junctions were not disrupted. Normotensive rats pretreated with colchicine showed no alteration in cerebrovascular permeability to HRP. Colchicine pretreatment attenuated the permeability alterations that were observed in acutely hypertensive rats. This study demonstrates that integrity of endothelial actin filaments is important for maintenance of the blood-brain barrier to protein during steady states since increased permeability occurred in the presence of an actin disrupting agent. The microtubular network had no demonstrable role during steady states; however, disruption of the microtubular network had a protective effect and prevented the development of alterations in permeability to protein in acute hypertension.

Animals↗
PubMed1995

We may not measure the correct intestinal wall permeability coefficient of drugs: alternative absorptive clearance concept.

It is shown that the conventional method (based on the thin-wall membrane theory) of studying the rate of disappearance or absorption from the lumen alone may not yield the correct intestinal wall (membrane) permeability coefficient of drugs. Potential reasons for causing this problem such as first-pass metabolism and accumulation of drugs in gut wall or tissue as well as back diffusion of drugs from the gut tissue to the lumen (i.e., a part of exsorption phenomenon) and potential major transport barriers across the protoplasm, basal membrane, and basement membrane are discussed. Contrary to the conventional concept, basal and basement membranes should also be considered major barriers for absorption into the blood for compounds with low intestinal permeability, and the protoplasm or cytoplasma should also be considered a major absorption barrier for compounds with high intestinal permeability. Strictly speaking, the conventional experimental method cannot be considered a bona fide method for studying drug permeability that deals with the movement of drug molecules from one side to the other side of a membrane, cell, medium, or device. The wall permeability coefficient thus obtained may therefore not represent the true wall permeability coefficient. "Intestinal absorptive clearance per unit gross surface area" is advocated as the best alternative term because it should more accurately reflect the true meaning of an experimental result for any compounds studied. In contrast to conventional cylindrical, unstirred tube models for the determination of wall permeability coefficients, the absorptive clearance calculation can be made based on a physiologically more realistic model-independent, "flat" or "distended," stirred (not well-stirred) intestinal model. Two model-independent terms, "effective intestinal permeability coefficient" and "effective absorptive permeability coefficient," are recommended as the second alternatives. These terms are theoretically valid for compounds that are not metabolized in the intestinal tissue; they represent the overall permeability across the intestinal tissue (from lumen to blood) under given experimental conditions. Potential shortcomings of using dimensionless wall permeability in the conventional absorption modeling are also discussed.

Animals↗
PubMed2005

Comparison of amniotic and intramembranous unidirectional permeabilities in late-gestation sheep.

OBJECTIVE: Amniotic fluid volume is regulated by the intrinsic modulation of intramembranous absorption. However, neither the mechanisms nor the rate-limiting barriers of this transport are known. We tested the hypothesis that the amnion is the rate-limiting barrier of intramembranous absorption by comparing unidirectional permeabilities of the amnion in vitro and the intramembranous pathway in vivo. STUDY DESIGN: Unidirectional permeabilities to 99m technetium pertechnate or [14 C]inulin of fresh ovine amnion were measured in vitro in a Ussing chamber; the permeability-surface area products were calculated by the multiplication of the permeabilities by gestational age-specific amniotic surface areas. Unidirectional permeabilities of the intramembranous pathway of the 2 tracers were calculated from solute fluxes between amniotic fluid and fetal blood in chronically catheterized late-gestation fetal sheep. Statistical comparisons included t -tests, least squares regression, analysis of variance, and analysis of covariance. RESULTS: In the isolated amnion in vitro, the ratio of permeabilities in the amniotic fluid to chorionic direction and the reverse direction was not significantly different from unity for 99m technetium pertechnate (1.03+/-0.10 [SE]; n=7) or [14 C]inulin (1.10+/-0.17; n=7). In contrast, in the in vivo preparation, the ratio of intramembranous permeabilities outward from the amniotic fluid and the reverse direction was greater than unity for 99m technetium pertechnate (2.10+/-0.34; n=8; P=.014) and [14 C]inulin (4.68+/-1.24; n=7; P=.025). The permeability-surface area product of 99m technetium pertechnate (2.18+/-0.79 mL/min) of the isolated amnion was similar to the in vivo intramembranous permeability (n=8) in the amniotic fluid to fetal blood direction (1.42+/-0.34 mL/min) and greater than that in the reverse direction (0.84+/-0.25 mL/min; P=.046). The permeability-surface area product of [14 C]inulin of the amnion (0.53+/-0.20 mL/min) was similar to intramembranous permeability (n=7) in the amniotic fluid to fetal blood (0.68+/-0.15 mL/min) direction and greater than that in the reverse direction (0.22+/-0.06 mL/min; P=.0097). CONCLUSION: Solute transport across the ovine amnion depends on solute size and appears to be limited only by the amnion's passive diffusional properties. In vivo intramembranous transport similarly depends on solute size but is not exclusively a passive diffusional process because it is primarily unidirectional outward from the amniotic fluid. Although it is a major barrier, the amnion is not the only barrier and does not appear to be responsible for the unidirectional nature of intramembranous absorption. Thus, unidirectionality appears to be imparted by nonpassive mechanisms in non-amnion tissues, which most likely includes vesicular transport within the endothelial cells of the intramembranous microvessels.

Absorption↗
PubMed2006

Evaluation of cocktail approach to standardise Caco-2 permeability experiments.

The purpose of this study was to investigate the suitability and reliability of n-in-one approach using FDA suggested compounds for standardising Caco-2 permeability experiments. Special attention was paid to the evaluation of rank order correlation and mechanistic insights of compound permeability. Transport studies with antipyrine, metoprolol, ketoprofen, verapamil, hydrochlorothiazide, ranitidine, mannitol and fluorescein were performed in 12- and 24-well formats, as single compounds and in cocktails under iso-pH 7.4 and pH-gradient (pH 5.5 vs. 7.4) conditions. Compounds were quantified using n-in-one LC/MS/MS analysis. The cocktail-dosing proved to be a feasible method to determine the permeability of the Caco-2 cell line and to introduce external standards for permeability tests. Even though sink conditions were lost in cocktail experiments for highly permeable compounds, the rank order of compound permeability and the classification to low and high permeability compounds remained unchanged between single and cocktail studies and permeability values of 12- and 24-well formats were directly comparable. Under pH-gradient conditions the margin between high and low permeability compounds was narrower due to the lower permeability (higher fraction of ionisation) of basic molecules. Of the compounds studied, antipyrine, metoprolol, hydrochlorothiazide and mannitol are suitable for evaluation and standardisation purposes of passive permeability, while fluorescein would function as paracellular marker under iso-pH 7.4. As efflux activity may vary between cell batches, verapamil is a useful marker for P-glycoprotein.

Biological Transport, Active↗
PubMed2004

Experimental and theoretical investigation of directional permeability of human vertebral cancellous bone for cement infiltration.

The use of acrylic polymers in infiltrating the porous bone structure is an emerging procedure for the augmentation of osteoporotic vertebrae. Although this procedure is employed frequently, it is performed based on empirical knowledge, and therefore, does not take into consideration the porosity-dependent permeability of human vertebral cancellous bone. The purpose of this study was to: (a). experimentally and theoretically investigate interdependence of the vertebral cancellous bone permeability and porosity, and (b). examine if the bone permeability of spinal cancellous bone can be predicted using bone mineral density measurements. If these relations can be established, they can be useful in optimizing the injection conditions for predicable cement infiltration. To determine the porosity-dependent and directional permeability, 34 bone cores-20 samples in the superior-inferior (SI) direction and 14 in the anterior-posterior (AP) direction-were cut from 20 lumbar vertebrae and infiltrated with silicone oil with a viscosity matching that of PMMA. The permeability of the cores was determined based on Darcy's law. The mean permeability of SI and AP cores was 4.45+/-1.72 x 10(-8) and 3.44+/-1.26 x 10(-8)m(2), respectively. An interesting finding of this study was that the permeability of the AP cores was approximately 78% of that of SI cores, though the porosity of the SI and AP cores taken from the same vertebra was approximately equal. In addition, we provided a theoretical model for the porosity-dependent permeability that accurately described non-linear dependency of the bone permeability and porosity in both directions. Although the relation of the bone permeability and porosity was established, bone mineral density was a weak predictor of the bone permeability. The experimental and theoretical results of this study can be used to understand polymer flow in cement infiltration procedures.

Adsorption↗
PubMed2002

Alterations in cytokine regulation in aged epidermis: implications for permeability barrier homeostasis and inflammation. I. IL-1 gene family.

Acute disruption of the cutaneous permeability barrier with either solvents or tape-stripping stimulates a homeostatic metabolic response in the subjacent nucleated layers of the epidermis that results in a rapid restoration of normal permeability barrier function. When the aged epidermal permeability barrier is stressed, it reveals a diminished capacity for recovery, in comparison to young epidermis, analogous to other organs in the aged when stressed. Although the signals that regulate this homeostatic response by the epidermis have not yet been resolved, acute permeability barrier disruption stimulates release of prestored IL-1alpha, and increased production of potentially regulatory cytokines, including IL-1alpha and TNFalpha in the epidermis. In these studies, we addressed the hypothesis that cytokine dysregulation explains the permeability barrier abnormality in aged epidermis, assessing the regulation of IL-1 and TNF signaling in aged vs young mice. To determine whether the IL-1 family of cytokines plays a key role in the permeability barrier abnormality of the aged, permeability barrier recovery rates were compared in transgenic mice lacking the functional IL-1 type 1 receptor vs wild-type mice at various ages. Knockout of the IL-1 type 1 receptor exacerbates the defect in permeability barrier homeostasis that is seen in age-matched, wild-type counterparts. Furthermore, the sluggish permeability barrier recovery in aged epidermis is associated with, and at least in part attributable to, altered expression of the IL-1 family of cytokines and receptors both under basal conditions and after acute barrier perturbations. Whereas modulations in cytokine expression with epidermal permeability barrier perturbation are qualitatively similar in aged epidermis, they greatly differ quantitatively. In contrast, examination of TNFalpha mRNA and protein basally, and following barrier perturbation revealed no alterations in aged epidermis. Together, these results show that selective alterations in the IL-1 family of cytokines occur with aging and that defects in IL-1 signaling may contribute to the epidermal permeability barrier abnormality of aged skin.

Animals↗
PubMed2001

In vivo and in vitro permeability in coeliac disease.

BACKGROUND: An increased permeability to sugars is found in the intestine of untreated patients with coeliac disease after oral ingestion. AIM: To test whether in vitro permeability resembles in vivo permeability tests and whether an in vitro gliadin gluten challenge could be performed by an in vitro permeability test. METHODS: We measured in vivo (urinary excretion after sucrose-lactulose-mannitol ingestion) and in vitro permeability (by mini-Ussing chambers) in 25 healthy controls, 12 relatives of coeliac disease patients, 19 treated, eight partly treated and 16 untreated patients with coeliac disease. RESULTS: In vivo sugar permeability was increased in nearly all coeliac patients. Additionally, in vitro permeability to lactulose (P=0.0007), mannitol (P=0.004) and sucrose (P=0.042) was higher in untreated patients with coeliac disease. It correlated with in vivo permeability (sucrose tau=0.61, P=0.006; lactulose tau=0.41, P < 0.0001; mannitol tau=- 0.56, P=0.62) and was dependent on mucosal damage. An in vitro gliadin challenge over 24 h could not significantly change in vitro permeability in treated patients with coeliac disease. CONCLUSIONS: An in vitro permeability test capable of measuring elevated permeability in coeliac mucosa was described, but this test cannot replace oral gluten challenge by in vitro gliadin incubation.

Administration, Oral↗
PubMed1978

Animal cells reversibly permeable to small molecules.

A cell preparation, useful for studying the regulation of metabolism, was developed by making monolayer baby hamster kidney cells permeable. Hypertonically treated cells were permeable to nucleotides, but retained their gross cellular morphology, intact organelles, 100% of their DNA, and 91% of their total protein. The permeable cell synthesized DNA, RNA, and protein rapidly when supplied with the appropriate substrates and cofactors. They either could remain permeable or were able to "reseal" when replaced in complete medium under appropriate conditions. Optimal conditions for DNA synthesis were established for permeable cells, giving rates equal to those of intact cells. Replication rather than repair was shown by the cell-cycle dependence of DNA synthesis and its discontinuous nature. Ribonucleotide reductase was active in permeable cells, permitting equal rates of DNA synthesis when ribonucleotide diphosphates or deoxyribonucleotide triphosphates were provided. Hydroxyurea did not inhibit DNA synthesis in permeable cells supplied with deoxyribonucleotide di- or triphosphates, but drastically inhibited DNA synthesis when ribonucleotide diphosphates were supplied. Hydroxyurea is therefore primarily an inhibitor of ribonucleotide reductase. Permeability was reversed, exposing permeable cells to [(3)H]thymidine triphosphate, which was incorporated, which labeled nuclei of cells that went on to mitosis. The reversible permeability procedure should prove especially useful in studying the functions of poorly penetrating compounds, such as drugs. Intact cells were unaffected by cytosine arabinoside triphosphate, while cells that had been made permeable and resealed were killed.

Cell Cycle↗
PubMed1995

The relationship between membrane fluidity and permeabilities to water, solutes, ammonia, and protons.

Several barrier epithelia such as renal collecting duct, urinary bladder, and gastric mucosa maintain high osmotic pH and solute gradients between body compartments and the blood by means of apical membranes of exceptionally low permeabilities. Although the mechanisms underlying these low permeabilities have been only poorly defined, low fluidity of the apical membrane has been postulated. The solubility diffusion model predicts that lower membrane fluidity will reduce permeability by reducing the ability of permeant molecules to diffuse through the lipid bilayer. However, little data compare membrane fluidity with permeability properties, and it is unclear whether fluidity determines permeability to all, or only some substances. We therefore studied the permeabilities of a series of artificial large unilamellar vesicles (LUV) of eight different compositions, exhibiting a range of fluidities encountered in biological membranes. Cholesterol and sphingomyelin content and acyl chain saturation were varied to create a range of fluidities. LUV anisotropy was measured as steady state fluorescence polarization of the lipophilic probe DPH. LUV permeabilities were determined by monitoring concentration-dependent or pH-sensitive quenching of entrapped carboxyfluorescein on a stopped-flow fluorimeter. The relation between DPH anisotropy and permeability to water, urea, acetamide, and NH3 was well fit in each instance by single exponential functions (r > 0.96), with lower fluidity corresponding to lower permeability. By contrast, proton permeability correlated only weakly with fluidity. We conclude that membrane fluidity determines permeability to most nonionic substances and that transmembrane proton flux occurs in a manner distinct from flux of other substances.

Acetamides↗