scholarly journals Development and In Vitro Evaluation of a Mucoadhesive Oral Deliverv System for Antisense Oliaonucleotides

2003 ◽  
Vol 71 (3) ◽  
pp. 165-177 ◽  
Author(s):  
Andreas Bernkop-Schnürch ◽  
Julia Telsnig ◽  
Margit Hornof
Keyword(s):  
Delivery System ◽  
Permeability Coefficient ◽  
Enzymatic Degradation ◽  
Phosphorothioate Oligonucleotide ◽  
Apparent Permeability ◽  
Release Studies ◽  
Apparent Permeability Coefficient ◽  
Permeation Studies ◽  
Membrane Bound

It was the aim of this study to develop an oral phosphorothioate oligodeoxynucleotide (PS-ODN) drug delivery system and to evaluate its properties in vitro. Results demonstrated that the 16-mer phosphorothioate oligonucleotide used was completely stable towards enzymatic degradation by secreted and membrane bound intestinal enzymes. Permeation studies with freshly excised intestinal mucosa showed a comparatively high uptake of the PS-ODN with an apparent permeability coefficient (Papp) of 8.35 ± 1.24 x 10-6 cm/sec. The PS-ODN was incorporated in a poly(acrylic acid)-cysteine carrier matrix system exhibiting high cohesive and mucoadhesive properties. Release studies demonstrated that a controlled and sustained PS-ODN release out of this delivery system could be achieved. Because of these features, the dosage form developed within this study seems to represent a promising novel tool for oral PS-ODN delivery.

Hydrogen ion permeability of the rabbit proximal convoluted tubule

1984 ◽  
Vol 246 (1) ◽  
pp. F3-F11
Author(s):  
L. L. Hamm ◽  
L. R. Pucacco ◽  
J. P. Kokko ◽  
H. R. Jacobson
Keyword(s):  
Permeability Coefficient ◽  
Proximal Convoluted Tubule ◽  
Ion Permeability ◽  
Apparent Permeability ◽  
Ph Gradients ◽  
Apparent Permeability Coefficient ◽  
Convoluted Tubules ◽  
Leak Pathway

Acidification of luminal fluid in the proximal convoluted tubule has been modeled as a pump-leak system. Using isolated perfused rabbit proximal convoluted tubules in a HCO-3/CO2-free in vitro environment, we studied “H+ leak” by imposing pH gradients across the tubule and measuring the change in pH from perfusate to collected fluid. Active acidification was inhibited by acetazolamide with and without hypothermia. At 21 degrees C a symmetrical H+ leak with an apparent permeability coefficient of approximately 0.15 cm X s-1 was found with either a lumen-to-bath or bath-to-lumen [H+] gradient. At 37 degrees C a much higher apparent permeability coefficient was found that was dependent on luminal lactate. Phosphate movement did not affect H+ fluxes significantly. Without luminal lactate, the apparent permeability coefficient was 0.31 cm X s-1. Although this permeability coefficient is larger than other ionic permeability coefficients in this segment, it is not sufficient to account for a significant H+ leak compared with rates of acidification or bicarbonate reabsorption. To investigate the role of Na+-H+ exchange in mediating the observed H+ leak, we perfused tubules with low [Na+] solutions with and without amiloride (10(-3) M). Neither the lower [Na+] nor the presence of amiloride diminished the apparent [H+] permeability coefficient. We conclude that a H+ leak pathway independent of Na+-H+ exchange is present in the proximal convoluted tubule.

Permeability to albumin in isolated coronary venules

1993 ◽  
Vol 265 (2) ◽  
pp. H543-H552 ◽  
Author(s):  
Y. Yuan ◽  
W. M. Chilian ◽  
H. J. Granger ◽  
D. C. Zawieja
Keyword(s):  
Permeability Coefficient ◽  
Filtration Rate ◽  
Intraluminal Pressure ◽  
Apparent Permeability ◽  
Filtration Pressure ◽  
Diffusive Permeability ◽  
Apparent Permeability Coefficient ◽  
Chemical Conditions ◽  
Physical And Chemical ◽  
Intravascular Pressure

This study reports measurements of albumin permeability in isolated coronary venules. The isolated microvessel technique allows the quantification of transmural exchange of macromolecules under tightly controlled physical and chemical conditions. Transvenular exchange of albumin was studied in isolated coronary venules during alterations in filtration rate caused by changes in intravascular pressure. The apparent permeability coefficient of albumin (Pa) at an intraluminal pressure of 11 cmH2O was 3.92 +/- 0.43 x 10(-6) cm/s. Elevating intraluminal pressure to 16 and 21 cmH2O increased Pa to 5.13 +/- 0.57 x 10(-6) and 6.78 +/- 0.66 x 10(-6) cm/s, respectively. Calculation of the true diffusive permeability coefficient of albumin (Pd) at zero filtration rate was 1.54 x 10(-6) cm/s. The product of hydraulic conductance (Lp) and (1 - sigma), where sigma is the solute reflection coefficient, was 3.25 x 10(-7) cm.s-1 x cmH2O-1. At a net filtration pressure of 4-5 cmH2O, diffusion accounts for > 60% of total albumin transport across the venular wall. Transmural albumin flux is very sensitive to filtration rate, rising 6.7% for each cmH2O elevation of net filtration pressure. At 11 cmH2O net filtration pressure, convection accounts for nearly 70% of net albumin extravasation from the venular lumen. We suggest that the isolated coronary venule is a suitable preparation for the study of solute exchange in the heart.

Bicarbonate secretion in rat distal colon in vitro: a measurement technique

1988 ◽  
Vol 254 (3) ◽  
pp. C383-C390 ◽  
Author(s):  
G. M. Feldman ◽  
S. F. Berman ◽  
R. L. Stephenson
Keyword(s):  
Short Circuit ◽  
Distal Colon ◽  
Apparent Permeability ◽  
Chemical Gradients ◽  
Acid Generation ◽  
Rat Distal Colon ◽  
Tissue Surfaces ◽  
Apparent Permeability Coefficient ◽  
Transepithelial Voltage

To study HCO3- secretion in rat distal colon, we utilized a technique that permits control of electrical and chemical transepithelial gradients. With symmetrical solutions (pH 7.4, [HCO3-] 25 mM, and CO2 tension 40 mmHg) bathing both tissue surfaces and under short-circuit conditions, HCO3- secretion remained stable for greater than 4 h at 1 mueq. h-1.cm-2. As the mucosal solution was alkalinized, the serosal solution was acidified at 3.1 mueq.h-1.cm-2. Ninety-four percent of serosal acidification was accounted for by the rate of metabolic lactic acid generation and transepithelial HCO3- secretion. Clamping transepithelial voltage reversibly affected net HCO3- secretion, and a linear relationship existed between clamped mucosal voltage and net HCO3- flux (r = 0.99); mucosal voltage of -68 mV completely inhibited net secretion. The apparent permeability coefficient of the colon to HCO3- is 2.8 X 10(-6) cm/s. One millimolar ouabain completely inhibited net HCO3- secretion. Acetazolamide (10(-4) M) inhibited secretion by approximately 50%, whereas a 10(-3) M concentration inhibited secretion by 90%. These data demonstrate that net colonic HCO3- secretion can be measured without imposed electrical and chemical gradients and that this flux is voltage sensitive and depends on carbonic anhydrase and Na+-K+-ATPase activities.

Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade

1993 ◽  
Vol 264 (5) ◽  
pp. H1734-H1739 ◽  
Author(s):  
Y. Yuan ◽  
H. J. Granger ◽  
D. C. Zawieja ◽  
D. V. DeFily ◽  
W. M. Chilian
Keyword(s):  
Phospholipase C ◽  
Guanylate Cyclase ◽  
Permeability Coefficient ◽  
Direct Action ◽  
No Synthase ◽  
Constant Flow ◽  
Apparent Permeability ◽  
Apparent Permeability Coefficient ◽  
Synthase Inhibitor ◽  
Ly 83583

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (Pa) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 microM) transiently and progressively increased Pa. The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 microM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10 microM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 microM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. NG-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 microM) augmented Pa by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.

Active amino acid absorption by proximal convoluted and proximal straight tubules

1979 ◽  
Vol 236 (2) ◽  
pp. F149-F162 ◽  
Author(s):  
D. W. Barfuss ◽  
J. A. Schafer
Keyword(s):  
Permeability Coefficient ◽  
Rabbit Kidney ◽  
Apparent Permeability ◽  
Nonlinear Fitting ◽  
Luminal Membrane ◽  
Straight Tubules ◽  
Apparent Permeability Coefficient ◽  
Active Amino Acid ◽  
The Mean ◽  
The Relationship

Transport of glycine and alpha-aminoisobutyric acid (AIB) was studied in proximal convoluted (PCT) and proximal straight (PST) tubules isolated from rabbit kidney. In both segments, unidirectional lumen-to-bath fluxes (J1 leads to b) (pmol min-1mm-1) of glycine and AIB exceeded corresponding bath-to-lumen fluxes (Jb leads to 1), which demonstrated that both were actively absorbed. During J1 leads to b measurements, intracellular concentrations of both amino acids were greater than the luminal concentration, indicating that the site of active transport was the luminal membrane. Replacement of Na+ by choline in both perfusate and bath (PCT) or perfusate alone (PST) reduced J1 leads to b for glycine to equal Jb leads to 1. Nonlinear fitting of the relationship between J1 leads to b and the mean luminal glycine concentration according to Michaelis-Menten kinetics gave Jmax values of 28.5 (PCT) and 2.5 (PST) pmol min-1 mm-1, and Km values of 11.8 (PCT) and 0.7 (PST) mM. There was a parallel, Na+-independent, nonsaturable component of J1 leads to b characterized by an apparent permeability coefficient of 0.19 micron/s in the PCT and 0.04 micron/s in the PST.

scholarly journals Chitosan Nanoparticles as a Percutaneous Drug Delivery System for Hydrocortisone

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Haliza Katas ◽  
Zahid Hussain ◽  
Tay Chai Ling
Keyword(s):  
Particle Size ◽  
Delivery System ◽  
Chitosan Nanoparticles ◽  
Entrapment Efficiency ◽  
Ionic Crosslinking ◽  
Low Molecular Weight Chitosan ◽  
Permeation Studies ◽  
Ft Ir ◽  
Inflammatory Drugs

Hydrocortisone (HC) has formed the mainstay for the management of atopic dermatitis. Hence, HC-loaded chitosan nanoparticles were prepared by ionic crosslinking of high, low molecular weight chitosan (HMwt, LMwt CS) and N-trimethyl chitosan (TMC) with tripolyphosphate. HC loading into CS nanoparticles was confirmed by FT-IR. The particle size of HC-loaded HMwt, LMwt, and TMC nanoparticles was increased from243±12,147±11,and124±9 nm to337±13,222±14,and195±7 nm, respectively, by increasing the pH of CS solution. Their respective zeta potential and entrapment efficiency (EE) were significantly decreased by increasing the pH of CS solution. The swelling ratios of HC loaded HMwt, LMwt, and TMC NPs were increased when the pH of incubating media (PBS) was increased. The same increasing trend was observed in particle size and EE of HC loaded as the CS concentration was increased. The HC loaded CS NPs were generally nonspherical.In-vitropermeation studies showed that HC was efficiently released from the CS NPs in QV cream while in aqueous cream CS NPs provided a sustained release for HC. Thus, it is anticipated that CS NPs are the promising delivery system for anti-inflammatory drugs.

scholarly journals Transport of Corilagin, Gallic Acid, and Ellagic Acid from Fructus Phyllanthi Tannin Fraction in Caco-2 Cell Monolayers

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Xin Mao ◽  
Ling-Fang Wu ◽  
Hai-juan Zhao ◽  
Wen-Yi Liang ◽  
Wen-Jing Chen ◽  
...  
Keyword(s):  
Tight Junction ◽  
Gallic Acid ◽  
Ellagic Acid ◽  
Organic Anion ◽  
Multidrug Resistance Proteins ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
Sodium Glucose Cotransporter ◽  
Apparent Permeability Coefficient

Objective. To investigate the absorption property of the representative hydrolyzable tannin, namely corilagin, and its hydrolysates gallic acid (GA) and ellagic acid (EA) from the Fructus Phyllanthi tannin fraction (PTF)in vitro.Methods. Caco-2 cells monolayer model was established. Influences of PTF on Caco-2 cells viability were detected with MTT assay. The transport across monolayers was examined for different time points, concentrations, and secretory directions. The inhibitors of P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), organic anion transporting polypeptide (OATP) and sodium/glucose cotransporter 1 (SGLT1), and tight junction modulators were used to study the transport mechanism. LC-MS method was employed to quantify the absorption concentration.Results. The apparent permeability coefficient(Papp)values of the three compounds were below 1.0 × 10−6 cm/s. The absorption of corilagin and GA were much lower than their efflux, and the uptake of both compounds was increased in the presence of inhibitors of P-gp and MRPs. The absorption of EA was decreased in the company of OATP and SGLT1 inhibitors. Moreover, the transport of corilagin, GA, and EA was enhanced by tight junction modulators.Conclusion. These observations indicated that the three compounds in PTF were transported via passive diffusion combined with protein mediated transport. P-gp and MRPs might get involved in the transport of corilagin and GA. The absorption of EA could be attributed to OATP and SGLT1 protein.

Base secretion in rat distal colon: ionic requirements

1990 ◽  
Vol 258 (6) ◽  
pp. G825-G832 ◽  
Author(s):  
G. M. Feldman ◽  
J. D. Koethe ◽  
R. L. Stephenson
Keyword(s):  
Permeability Coefficient ◽  
Distal Colon ◽  
Secretory Component ◽  
Bathing Solution ◽  
Apical Surface ◽  
Apparent Permeability ◽  
Rat Distal Colon ◽  
Apparent Permeability Coefficient ◽  
Diffusive Component ◽  
Active Base

To evaluate the ionic requirements of colonic base secretion, segments of rat distal colon were studied under short-circuited conditions. Net base flux was composed of an active secretory component and a diffusive component. Studied in the absence of a transepithelial HCO3- concentration gradient, active base secretion was dependent on the HCO3- concentration of the bathing solution but was not influenced by the CO2 tension or pH. Base secretion appeared to saturate with a Km of 33 +/- 9 mM and was inhibited by ouabain. The diffusive component was characterized by an apparent permeability coefficient to HCO3- of 8.9 +/- 0.9 x 10(-6) cm/s. In addition to requiring HCO3- on the serosal surface, net base secretion was inhibited by reducing the Na+ concentration in the serosal medium and the Cl- concentration in the mucosal medium. These data suggest that colonic base secretion involves HCO3- entry across the basolateral surface, energized by the Na+ gradient, and HCO3- exit across the apical surface in exchange for Cl-.

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