PubMed Health⌕ Search

Biomedical subjects

N J Rogers

Publications and source records attributed to N J Rogers.

13 recordsLinked to original sources
PubMed1992

A phosphinic acid dipeptide analogue to stabilize peptide drugs during their intranasal absorption.

A major challenge in intranasal delivery of peptides is to overcome the enzymatic barrier that limits their absorption. Aminopeptidase inhibitors may be useful for improving systemic delivery of peptide drugs administered nasally. A phosphinic acid dipeptide analogue, a transition-state analogue aminopeptidase inhibitor in which the phosphinate moiety exists in a tetrahedral state mimicking peptides during their enzymatic hydrolysis, was synthesized and tested nasally in situ in rats. This inhibitor was found to inhibit greatly the degradation of the model peptide leucine-enkephalin in the nasal perfusate at less than or equal to 2 microM concentrations. The nasal peptidase hydrolytic activity was reversible after exposure to the inhibitor. This inhibitor has the advantage of efficacy at very low concentrations and reversibility of effects.

Absorption↗
PubMed1992

Atherogenic levels of low-density lipoprotein increase endocytotic activity in cultured human endothelial cells.

Cultured human umbilical vein endothelial cells (EC) exposed to atherogenic low-density lipoprotein (LDL) levels for protracted periods demonstrated heightened endocytosis. Confluent EC were incubated with LDL 90 to 240 mg/dl cholesterol for 1 to 4 days and endocytosis was measured by 14C-sucrose uptake. Control EC and cells incubated with 90 mg/dl LDL cholesterol showed similar uptakes of 14C-sucrose during all measured time periods. In contrast, EC exposed to 240 mg/dl LDL cholesterol showed an increase in endocytosis beginning at 2 days, whereas 160 mg/dl LDL cholesterol promoted increased uptake by 4 days. The endocytotic activity of LDL-perturbed EC is reduced to levels seen in control cells by cytochalasin B, an actin polymerization inhibitor. This finding suggests a modulatory role for the cytoskeleton in endocytosis changes. Examination of LDL-perturbed EC cytoskeleton reveals structural remodeling resulting in a marked increase in stress fibers. Cytochalasin B exposure causes a loss of stress fibers with the formation of globular filamental aggregates. Such LDL-induced cellular functional changes may contribute mechanistically to endothelial dysfunction, which is widely held to be a major contributing factor in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed1991

Problem drinkers.

Explore the source record for details and available documents.

Alcohol Drinking↗
PubMed1990

Bradykinin induces superoxide anion release from human endothelial cells.

The time-dependent release of superoxide anion (O2-) from bradykinin (Bk)-stimulated human umbilical vein endothelial cells (EC) was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome C employing a novel application of microspectrophotometry. In the absence of Bk, O2- release by EC was not detectable. EC exposure to Bk (10(-6) to 10(-5) M) resulted in a rapid release of O2-. The release of O2- occurred within 5 minutes of exposure. O2- release was partially inhibited by indomethacin (63 +/- 6%), thus suggesting that arachidonic acid metabolism, through cyclooxygenase, contributes to EC O2- production. EC O2- release may be an important component in the pathophysiologic actions of Bk on vascular function.

Bradykinin↗
PubMed1990

Transdermal oxymorphone formulation development and methods for evaluating flux and lag times for two skin permeation-enhancing vehicles.

Oxymorphone is a candidate for transdermal delivery since it is a very potent analgesic, is not very effective orally, and has a short duration of action. In developing a transdermal delivery system, two criteria that were considered important were achieving adequate flux and minimizing the lag time. Oxymorphone skin permeation rates in vitro were very low unless skin permeation enhancers were included in the vehicle. After an initial screen of 17 formulations, two skin permeation-enhancing formulations were selected for further study. These were myristic acid:propylene glycol:oxymorphone base (A), and decylmethylsulfoxide:ethanol:water:oxymorphone.HCl (B). With either formulation and either human or hairless guinea pig skin, there was little dependence of either in vitro flux or lag time on the section of skin used (stratum corneum, epidermis, epidermis/dermis). There were significant differences between human skin and hairless guinea pig skin when comparing in vitro fluxes with the two formulations. With formulation A, fluxes through hairless guinea pig skin were three-to fivefold greater than through human skin. With B, however, fluxes through human skin were up to fivefold greater than through hairless guinea pig skin. In vitro lag times with A were generally long (approximately 24 h), whereas those with B were much lower (approximately 1 to 10 h). The species dependence of permeation enhancement and the differences in lag time between formulations could be related to differences in the mechanisms of permeation enhancement. In vivo lag times with the fatty acid:propylene glycol vehicle were estimated in hairless guinea pigs based on plasma oxymorphone concentrations. These were much lower than in vitro lag times.

Administration, Cutaneous↗
PubMed1990

Effects of plasma protein binding displacement on the pharmacokinetics, tissue and tumor concentrations and efficacy of brequinar, a highly protein-bound antitumor agent.

Brequinar is a developmental antitumor agent which is highly bound to plasma proteins. The effects of plasma protein binding displacement on brequinar pharmacokinetics, tissue distribution, tumor distribution and antitumor efficacy were evaluated. Sodium salicylate and ibuprofen increased the percentage of free brequinar in serum in vitro, in proportion to their added concentrations. Sodium salicylate also altered the pharmacokinetics of i.v. brequinar in rats when adminstered i.v. or p.o. at 10- or 50-fold higher doses than brequinar. At the highest salicylate/brequinar dose ratio, significant increases were observed for terminal half-life, mean residence times in the body and tissues, systemic clearance, distribution clearance, the volume of the central compartment and volume of distribution at steady state. Neither salicylate nor ibuprofen increased brequinar concentrations in lung and muscle specimens from rats, 4 or 24 hr after dosing. Tumor, lung and muscle brequinar concentrations in mice were also unaffected by coadministered sodium salicylate, 4 or 24 hr after a single i.v. brequinar dose. In rats infused for 48 hr with brequinar or brequinar plus salicylate, salicylate increased the percentage of free brequinar in plasma and lungs, but total brequinar concentrations were reduced. Antitumor efficacy was evaluated by measuring the survival times of mice implanted with L1210 leukemia cells. Salicylate-treated mice had a similar brequinar dose/response profile as mice not coadministered salicylate. Ibuprofen also did not increase brequinar's antitumor potency.

Animals↗
PubMed1988

Low-density lipoprotein preparation by combined diafiltration and ultracentrifugation.

A method for isolating low-density lipoprotein by combining diafiltration and ultracentrifugation is described. Diafiltration separates plasma components by use of an ultrafiltration membrane that excludes particles of molecular weight greater than 300,000. The retentate is concentrated three- to fourfold by ultrafiltration, allowing large-scale preparation of low-density lipoprotein. Low-density lipoprotein prepared in this manner is similar in physical, chemical, and biologic properties to low-density lipoprotein isolated by sequential density ultracentrifugation alone. When low-density lipoprotein, prepared by either method, was added to human umbilical vein endothelial cell cultures, no cytotoxicity was observed. The techniques described reduce the demand on multiple rotors and ultracentrifuges for large-scale preparation of low-density lipoprotein suitable and often needed for tissue culture studies.

Arteriosclerosis↗
PubMed1988

Site dependence of absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery.

The site dependence of the absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin was studied in rats. Insulin absorption was estimated on the basis of the cumulative hypoglycemic response from 0 to 4 hr postdose, relative to that after intramuscular insulin. Insulin was administered with or without adjuvants to isolated rectal, nasal, and buccal absorption sites. Laureth-9, a nonionic surfactant which irreversibly removes membrane proteins or lipids, promoted insulin absorption from each site. The rectal, nasal, and buccal routes were 30% as effective as the i.m. route. The enhancing effects of Na salicylate and Na2EDTA, which have reversible mechanisms of permeability enhancement, were specific for rectal absorption. With these adjuvants, rectal insulin was 30-40% as effective as i.m. insulin, but nasal and buccal doses were less than 5% as effective as i.m. doses. This specificity can be at least partly explained by considering the site-to-site differences in membrane histology, although differences in pore size and membrane biochemistry might also contribute. The protease inhibitor aprotinin was ineffective in increasing insulin efficacy via each route, either alone or in combination with laureth-9.

Absorption↗
PubMed1988

Perturbation of cultured human endothelial cells by atherogenic levels of low density lipoprotein.

Cultured human umbilical vein endothelial cells (EC) exposed to atherogenic levels of low density lipoprotein (LDL) for protracted periods demonstrated no measurable evidence of overt cytotoxicity, but were perturbed as indicated by an increase in prostacyclin (PGI2) production. Confluent EC were incubated with high LDL concentrations (240 or 330 mg/dl cholesterol) for 1 to 12 days. LDL was added to culture media containing 25% human lipoprotein-deficient serum to determine the effects of LDL independent of other lipoproteins. LDL did not injure EC as assessed by cell count, vital dye exclusion, 51chromium release, and lactate dehydrogenase release. Although high concentrations of LDL did not cause EC cytotoxicity, such LDL concentrations did results in increased PGI2 generation. PGI2 accumulation in postincubation media was increased two-to-fivefold in otherwise unstimulated cells as measured by radioimmunoassay of the stable PGI2 breakdown product, 6-keto-PGF1-alpha. This elevation persisted for the entire 12-day exposure to high LDL concentrations. These results indicate that prolonged exposure to atherogenic concentrations of LDL does not effect EC viability, but does cause an endothelial perturbation as demonstrated by an increased PGI2 production.

Arteriosclerosis↗
PubMed1988

Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter.

The purpose of this investigation was to develop a method to quantitate insulin absorption, and to compare insulin absorption from various noninjection sites of administration. Log dose/effect curves were established for i.m. insulin in adult male rats. The effects measured were the maximum change in plasma glucose concentration and the cumulative percentage of change in plasma glucose concentrations from 0 to 4 hr. Both log dose/effect curves gave similar results when calculating the efficacy of other routes, relative to i.m. Nasal, buccal, sublingual and rectal absorption sites were isolated by ligation procedures or with physical barriers. Rectal insulin was more efficacious than nasal, buccal and sublingual insulin, when administered without an absorption-promoting adjuvant. However, the efficacy relative to i.m. insulin was low for each route, probably due to a combination of slow membrane permeation and metabolism at the absorption site. Administration in a solution containing 5% sodium glycocholate, an absorption-promoting adjuvant, increased insulin efficacy by each route. The rank order was nasal greater than rectal greater than buccal greater than sublingual, with nasal and rectal insulin being roughly half as efficacious as i.m. insulin. Orally administered insulin, at doses 5 times higher than administered by other routes, and with Na glycocholate, produced no hypoglycemic response.

Absorption↗