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Biomedical subjects

D Fleisher

Publications and source records attributed to D Fleisher.

At least 37 records · Page 2Linked to original sources
PubMed1995

Topical delivery of growth hormone releasing peptide using liposomal systems: an in vitro study using hairless mouse skin.

The results of this study clearly demonstrates the utility of novel non-ionic liposomal systems in facilitating transfer of GHRP-6 into and across deeper strata of skin following topical application. These findings indicate that it may be possible to deliver therapeutic doses of a wide variety of peptides to local skin tissue via topical application. The results also suggest the possibility of controlled enhancement of skin penetration or metered polypeptide deposition through appropriate choice of liposomal lipid components. The pronounced enhancement of GHRP-6 and mannitol transport from emulsions containing the nonionic lipids suggests a promising delivery system for hydrophilic drugs in general.

Administration, Cutaneous↗
PubMed1994

Intestinal clearance of H2-antagonists.

Jejunal perfusion of cimetidine resulted in the appearance of lumenal cimetidine sulfoxide in both rats and humans. In the rat, ileal perfusion yielded negligible sulfoxide metabolite as compared with that of the jejunum. Jejunal co-perfusion of an anionic-exchange inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, blocked the appearance of drug sulfoxide, and methionine co-perfusion yielded concentration-dependent inhibition of lumenal cimetidine sulfoxide. Intravenous injection of high concentrations of cimetidine sulfoxide did not produce detectable lumenal metabolite levels during jejunal perfusion of drug-free buffer, providing in situ evidence that lumenal metabolite is generated by the small intestine. The extent of the appearance of lumenal sulfoxide was significantly greater for cimetidine than for the other three marketed H2-antagonists in rat jejunum. Variable intestinal clearance of this extensively prescribed class of therapeutic agents may contribute to their absorption variability.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Absorption of ACE inhibitors from small intestine and colon.

The intestinal absorption of two ACE inhibitors was studied to determine the potential for colonic delivery of small peptides. In addition, studies were also performed to assess intestinal tissue uptake and evaluate a canine intestinal-access-port model as techniques for screening absorption. To evaluate the impact of differences in the contributions of passive permeation and carrier-mediated peptide transport on in vitro uptake and in vivo absorption, an esterified prodrug, benazepril, and a free diacid non-prodrug, CGS 16617, were selected for study. Potential colonic absorption enhancement utilizing coadministration of Intralipid was also investigated. Studies in rat everted intestinal rings verified that jejunal benazepril uptake included a carrier-mediated component while that of the diacid did not. Uptake of both drugs was purely passive in colonic rings. Equilibrium uptake and uptake rate of the more lipophilic prodrug was 2-fold greater than the diacid. Benazepril and CGS 16617 jejunal uptake rate at 0.01 mM was 3.5 and 2.5 times higher, respectively, than from colonic rings. Following jejunal administration in dogs, maximum benazepril plasma levels (Cmax) and area under the plasma level versus time curve (AUC) were 5.5 and 3.0 times higher, respectively, than following colonic administration. Maximum benazepril plasma levels following colonic administration in dogs was 2-fold greater than for CGS 16617, consistent with in vitro results. Colonic coadministration of the poorly-absorbed CGS 16617 with 2 mL of Intralipid (within dietary range for fecal fat content) enhanced Cmax and AUC 2.5- and 3.5-fold, respectively, in the dog and AUC 1.5-fold in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

The intestinal uptake of "enzymatically-stable" peptide drugs in rats as influenced by D-glucose in situ.

In previous in situ and in vivo rat perfusion studies, the intestinal absorption of several low molecular weight drugs was increased by the presence of luminal D-glucose. The intent of this study was to determine the potential of this fed-state effect to improve the intestinal uptake of poorly permeable, small peptide and peptide-like drugs. Jejunal wall permeabilities (Pw*) of di-(D-kyotorphin), tri-(cephradine), hexa-(growth hormone releasing peptide, GHRP-6) and octa-(octreotide, a somatostatin analogue) peptides and corresponding net water fluxes were determined in rats using an in situ single-pass perfusion technique. Glucose was shown to enhance the uptake of the smaller (di- and tri-) peptides but not the larger peptides despite the fact that glucose elicited a significant net water absorption with each of the four peptide drugs. It is concluded that glucose enhances jejunal permeabilities of smaller peptides by solvent drag and the enhancement is limited in situ by peptide molecular size. The studies with nonmetabolizable 3-O-methylglucose suggest that the augmentation of the proton gradient across the transmucosal membrane by glucose contributes to the carrier-mediated transport observed with the smaller peptides.

3-O-Methylglucose↗
PubMed1994

The role of rheological properties in mucociliary transport by frog palate ciliated model.

The effect of viscoelastic properties on mucociliary transport rate was investigated using the frog palate ciliated model. Mucociliary transportability of several hydrophilic polymeric gels with widely different viscoelastic characteristics were tested on the frog palate mucociliary model. An apparent negative relationship is observed between the relative transport rate (TR) and storage (G1) or loss (G2) modulus. However, a minimum in relative transport rate is observed at an apparent loss tangent (tan delta) value of between 0.7 and 0.9. A theoretical model for mucociliary transport is presented. The model predicted a minimum in transport rate at tan delta equal to 1.74 after adjustment for primary variation due to storage modulus (G1), which is in agreement with the observed frog palate transport rate. The model isolates the loss tangent (tan delta) and the magnitude of the complex modulus (magnitude of G*) as the important viscoelastic parameters for mucociliary transport. Optimum rheological characteristics with respect to slow transport rate can be achieved by using hydrophilic polymer gels with a large complex modulus and simultaneously with a loss tangent equal to 1.74.

Animals↗
PubMed1994

Noncompetitive inhibition of cephradine uptake by enalapril in rabbit intestinal brush-border membrane vesicles: an enalapril specific inhibitory binding site on the peptide carrier.

ACE inhibitors, as well as aminocephalosporins with peptide-like structures, are transported by the intestinal peptide carrier. We investigated the transport mechanism using intestinal brush-border membrane vesicles from rabbits and observed that enalapril, an angiotensin converting enzyme inhibitor and substrate of the peptide carrier, noncompetitively inhibited the uptake of cephradine, an aminocephalosporin and substrate of the peptide carrier, with an inhibition constant (Ki) of 2.6 mM when it was present on the cis side (outside) of the vesicles. By contrast, enalaprilat, cefadroxil and GlyPro competitively inhibited cephradine transport with Ki values of 5.4, 3.8 and 5.1, respectively. These results suggest the presence of an enalapril-specific inhibitory binding site on the peptide carrier. In addition, enalapril on the trans side (inside) of the vesicles inhibited the uptake of cephradine, suggesting an apparent reduction of carrier availability by a trapping mechanism. On the other hand, cefadroxil stimulated the uptake of cephradine in the trans experiment, consistent with the concept of countertransport. These findings reveal the uniqueness of enalapril regarding its mode of interaction with the peptide carrier(s) which has been of increasing interest regarding its role in the intestinal absorption of peptide-type drugs.

Animals↗
PubMed1993

Peptide carrier-mediated transport in intestinal brush border membrane vesicles of rats and rabbits: cephradine uptake and inhibition.

The uptake kinetics of cephradine, an amino-beta-lactam antibiotic, were studied in rat and rabbit intestinal brush border membrane vesicles preparations using both the Ca2+ and the Mg2+ methods of preparation, in the presence of an inward proton gradient. The Ca2+ method demonstrated greater uptake of cephradine in intestinal brush border vesicles prepared from both rat and rabbit and was used for these studies. The transport was observed to be of Michaelis-Menten carrier-mediated type with a passive transport component. The kinetic parameters obtained were as follows: for rat and rabbit, respectively, Km, 1.6 and 1.9 mM; Jmax', 1.7 and 20.7 nmol/mg/min; Pc' (= Jmax'/Km), 1.1 and 10.9 microL/mg/min; and Pm', 0.4 and 0.8 microL/mg/min. The kinetic parameters for the rat vesicles are consistent with those from our previous perfusion study using a conversion factor of 0.71 cm2/mg protein. The rabbit vesicles exhibited a similar Michaelis constant and a 10-fold larger maximal transport velocity, suggesting a quantitative advantage for the study of carrier-mediated transport in the rabbit compared to rat vesicles from the intestine. Cephradine uptake was inhibited by phenylpropionylproline, a proline derivative, and enalapril, an ACE inhibitor, which do not have an alpha-amino group, as well as dipeptides, tripeptides, and amino-beta-lactam antibiotics in both rat and rabbit vesicles. These results support the suggestion that they share the same peptide carrier pathway for oral absorption and that the vesicles may be a useful tool in developing orally effective peptide-type drugs.

Alkaline Phosphatase↗
PubMed1993

Natural history and clinical evaluation of the lumpectomy scar.

After lumpectomy with axillary dissection and radiation therapy, there are numerous changes that occur to the breast that, if unrecognized as routine, post-treatment changes, can lead to inappropriate intervention by the physician. The purpose of this study is to evaluate the time required to achieve stable post-treatment mammographic and physical findings. One hundred twenty-three patients age 56.6 years with a mean tumor size of 15.9 +/- 8.2 mm were observed every 6 months with a mean change in scar size of 16.7 +/- 10.6 mm. A scar never developed in 27 per cent and completely resolved or decreased in 90 per cent. Calcifications developed in 16 per cent of the patients; 40 per cent in the scar, 60 per cent outside the scar. Recurrence developed in 2 per cent of the patients at a mean time of 53 months and was believed to be favorably influenced by cytologic evaluation of the resection margins at the time of tumor excision. Stabilization or resolution of the post-treatment changes occurred within 24 to 36 months. The conclusion is for careful surgical and radiologic follow-up with examinations, fine-needle aspirations, and meticulous mammograms guiding the need for biopsy.

Biopsy, Needle↗
PubMed1992

Influence of D-glucose-induced water absorption on rat jejunal uptake of two passively absorbed drugs.

The intestinal absorption of D-glucose is coupled to transepithelial sodium transport and this process generates intestinal water absorption. In situ jejunal perfusions were performed in rats to determine the extent of water transport as a function of perfusion flow rate, perfusate osmolality, and D-glucose concentration. Jejunal perfusions of iso-osmolar D-glucose, at flow rates and concentrations representative of the fed state, increased the dimensionless membrane permeabilities of the analgesic acetaminophen from 0.6 to 1.4, and that of the corticosteroid prednisolone from 1.6 to 2.2. This increase is less important for the more hydrophobic prednisolone since its baseline permeability (1.6) is indicative of complete uptake from solution, while the lower baseline permeability (0.6) of the more hydrophilic acetaminophen represents incomplete membrane uptake. The results suggest that nutrient-induced water transport can enhance jejunal uptake of small hydrophilic solutes. This phenomenon may contribute to variability in the absorption of drugs in this physicochemical class during the fed state.

Acetaminophen↗
PubMed1992

Intestinal water and solute absorption studies: comparison of in situ perfusion with chronic isolated loops in rats.

The effects of lumenal glucose on jejunal water transport and the influence of glucose-induced water absorption on solute uptake from single-pass perfusions are compared in anesthetized rats in situ and isolated chronic loops in unanesthetized rats in vivo. While the magnitudes of solute membrane permeabilities are consistently higher in the chronic loop system, the effects on water transport and its promotion of jejunal solute uptake are comparable between the two experimental systems. The effect of glucose-induced water absorption on the enhanced/baseline jejunal uptake ratio of the hydrophilic drug, acetaminophen, is greater than that for the lipophilic drug, phenytoin, in both experimental systems. The fact that chronic loop effective solute permeabilities were equivalent to solute membrane permeabilities in situ is consistent with greater lumenal fluid mixing in vivo. In addition, in situ body temperature affects the uptake of phenytoin but not acetaminophen, water, or glucose. This suggests that active and paracellular solute transport is not compromised in situ, while membrane partitioning and diffusion of lipophilic species are more sensitive to experimental conditions.

Acetaminophen↗
PubMed1991

Calculation of the aqueous diffusion layer resistance for absorption in a tube: application to intestinal membrane permeability determination.

The single-pass intestinal perfusion technique has been used extensively to estimate the wall permeability in rats. The unbiased membrane parameters can be obtained only when the aqueous resistance is properly accounted for. This aqueous resistance was calculated numerically from a convective diffusive mass transfer model, including both passive and carrier-mediated transport at the intestinal wall. The aqueous diffusion layer resistance was shown to be best described by a function of the form, [formula: see text] where G zeta, P*m, P*c, Km, and Co are, respectively, Graetz number, passive permeability, carrier-mediated permeability, Michaelis constant, and the drug concentration entering the tube. Asterisked are dimensionless quantities obtained by multiplying the permeability constants with R/D, where R and D being radius and drug diffusivity, respectively. A, B, C, D and E were obtained by a least-squares nonlinear regression method, giving values of 1.05, 1.74, 1.27, 0.0659, and 0.377, respectively, over the range of 0.001 less than or equal to G zeta less than or equal to 0.5, 0.01 less than or equal to P*m less than or equal to 10, 0.01 less than or equal to P*c less than or equal to 10, and 0.01 less than or equal to Km/Co less than or equal to 100. This aqueous resistance was found to converge to those calculated from Levich's boundary layer solution in low Graetz range, indicating the correct theoretical limit. Using an iteration method, the equation was shown to be useful in extracting the intrinsic membrane permeability from the experimental data.

Absorption↗
PubMed1989

Nutrient influences on rat intestinal phenytoin uptake.

The intestinal uptake of phenytoin was studied as a function of concentration, intestinal region, coperfused glucose, and calcium chloride in rat intestinal perfusions and everted intestinal rings. Steady-state intestinal membrane permeabilities were obtained in an in situ perfusion system and initial rates of intestinal tissue uptake were obtained in an in vitro everted ring system as rate of absorption parameters. Steady-state membrane permeabilities were independent of phenytoin perfusion concentration and decreased from duodenum to ileum. Coperfusion of glucose increased, and high calcium chloride concentrations decreased phenytoin permeabilities. While phenytoin uptake in the in vitro ring system was also concentration-independent and depressed by high calcium concentrations, regional variations and glucose enhancement were not observed. Thus, drug-nutrient interactions involved in intestinal absorption from phenytoin solutions are a function of the isolation procedure.

Animals↗
PubMed1988

Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds.

Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P*eff, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P*aq is not rate controlling give the following equation for fraction dose absorbed: F = 1 - e-2P*w. The correlation between fraction dose absorbed in humans and P*w determined from steadystate perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P*w is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.

Animals↗
PubMed1986

Mixing-tank model for predicting dissolution rate control or oral absorption.

A mixing-tank model is used to simulate GI absorption of nonionized drugs. The model is useful for predicting circumstances under which dissolution rate dominates membrane transport and transit rate, thus limiting the extent of absorption. The model is developed from mass balance considerations in which the nonsink dissolution term is a function of the remaining surface area and the concentration gradient across the boundary layer. Other dissolution parameters include initial particle radius, dose, diffusivity, density, and boundary-layer thickness. Readily calculable estimators for the general solution of the model are derived and their ranges of usefulness are discussed. Drug examples chosen for simulation are griseofulvin and digoxin. The model correctly predicts bioavailability as a function of particle size for both of these poorly soluble drugs.

Administration, Oral↗
PubMed1986

Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans.

Gastrointestinal pH as a function of time was recorded for 4 beagle dogs and 10 human subjects using radiotelemetric pH measuring equipment. Results indicated that in the quiescent phase, gastric pH in the dogs (mean = 1.8 +/- 0.07 SEM) was significantly (p less than 0.05) higher than in humans (1.1 +/- 0.15). No significant difference in the time for the pH monitoring device to empty from the stomach was noted for the two species (99.8 +/- 27.2 min for dogs, 59.7 +/- 14.8 min for humans, p greater than 0.05). The fasting intestinal pH in dogs was consistently higher than in humans, with an average canine intestinal pH of 7.3 +/- 0.09 versus 6.0 +/- 0.14 for humans. The implication of these observations for extrapolation of drug absorption data from dogs to humans are discussed.

Animals↗
PubMed1986

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets.

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.

Animals↗
PubMed1986

Oral absorption of 21-corticosteroid esters: a function of aqueous stability and intestinal enzyme activity and distribution.

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.

Adrenal Cortex Hormones↗