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Biomedical subjects

G A Digenis

Publications and source records attributed to G A Digenis.

At least 19 recordsLinked to original sources
PubMed1995

Dynamic monitoring of total-body absorption by 19F NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats.

Six male and six female Sprague-Dawley rats were ventilated head-only for 1 h on a 15% atmosphere of 1,1,1,2-tetrafluoroethane (HFA-134a) in air in a magnetic resonance imaging spectrometer. Results from these dynamic 19F NMR studies suggest that a steady-state in vivo concentration of HFA-134a was approached at approximately 25 min into the exposure. Quantitative integration analysis using an external standard estimated this plateau to be 58.3 +/- 11.9 mg of absorbed HFA-134a per rat. The HFA-134a 19F NMR signal disappeared rapidly following removal of the test atmosphere, with an elimination half-life of 4.6 +/- 0.6 min in the male rats and 4.9 +/- 1.5 min in the female rats. The data suggest that there was no statistical difference between the sexes in amount absorbed or in elimination half-lives.

Absorption↗
PubMed1995

Synthesis and in vivo disposition studies of 18F-labeled HFA-134a.

A rapid synthesis of the chlorofluorocarbon replacement compound 1,1,1,2-tetrafluoroethane (HFA-134a) was identified and utilized to prepare 99+% radiochemically pure [18F]HFA-134a in 20-35% radiochemical yield. Four rats were then exposed to no-carrier-added (NCA) [18F]HFA-134a, and monitored via coincidence detection. Following withdrawal of the test atmosphere of [18F]HFA-134a, the mean half-life of [18F]HFA-134a in four rats was determined to be 7.8 +/- 1.5 min following a 10 s exposure and 8.1 +/- 1.7 minutes following a 10 min exposure.

Animals↗
PubMed1995

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor.

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

Alprazolam↗
PubMed1994

Synthetic macromolecular inhibitors of human leukocyte elastase. 1. Synthesis of peptidyl carbamates bound to water-soluble polymers: poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] and poly-alpha-[N5-(2-hydroxyethyl)-L-glutamine].

The design and synthesis of macromolecular peptidyl carbamate inhibitors of human leukocyte elastase (HLE), based on coupling of a low-molecular-weight peptidyl carbamate, succinylalanylalanylprolylmethyl isopropyl carbamate, with a linear hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] or poly-alpha-[N5-(2-hydroxyethyl)-L-glutamine], is described. The covalent linkage between a flexible linear polymer and a peptidyl carbamate inhibitor of HLE did not compromise in vitro inhibitory capacity. The macromolecular peptidyl carbamates reported here represent a novel class of elastase inhibitors with a Ki ranging from 35.5 to 2.0 nM.

Amino Acid Sequence↗
PubMed1994

Cross-linking of gelatin capsules and its relevance to their in vitro-in vivo performance.

The present review deals with the chemistry of gelatin cross-linking under conditions that are relevant to pharmaceutical situations. Mechanistic rationalizations are offered to explain gelatin cross-linking under "stress" conditions. These include elevated temperature and high humidity conditions. In addition, the chemical interactions between gelatin and aldehydes, such as formaldehyde and other formulation excipients, are discussed. The literature on the in vitro and in vivo dissolution and bioavailability of a drug from stressed gelatin capsules and gelatin-coated tablets is reviewed. Cross-linking phenomena, occurring in stressed hard gelatin capsules and gelatin-coated tablets, could cause considerable changes in the in vitro dissolution profiles of drugs. However, in a few cases, the bioavailability of the drug from the stressed capsules is not significantly altered when compared to that obtained from freshly packed capsules. It is concluded that, as with other drug-delivery systems, careful attention should be paid to the purity and chemical reactivity of all excipients that are to be encapsulated in a gelatin shell. It is suggested that in vitro dissolution tests of hard gelatin-containing dosage forms be conducted in two stages, one in a dissolution medium without enzymes and secondly in dissolution media containing enzymes (pepsin at pH 1.2 or pancreatin at pH 7.2, representing gastric and intestinal media, respectively) prior to in vivo evaluation. Such in vitro tests may constitute a better indication of the in vivo behavior of gelatin-encapsulated formulations. Furthermore, testing for contamination with formaldehyde as well as low molecular weight aldehydes should be a standard part of excipient evaluation procedures.

Amino Acid Sequence↗
PubMed1993

Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time.

During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80-120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 microCi 111 InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.

Adult↗
PubMed1993

Peptidyl carbamates as novel elastase inhibitors: structure-activity relationship studies.

Twenty-six novel peptidyl carbamates and thiocarbamates were synthesized and evaluated as elastase inhibitors. Eighteen compounds inhibited porcine pancreatic elastase, whereas only eleven of the newly synthesized compounds inhibited human leukocyte elastase. Neither of the other serine dependent proteases, trypsin or chymotrypsin, were affected by any of the active inhibitors. Structure-activity relationship studies indicated that inhibition was dependent on P1 and P'1 substitution as well as on the presence of the carbamate functionality. Placement of an isostere of valine at P1 and a 1-(phenyl mercaptotetrazole at P'1 resulted in the most active human leukocyte elastase inhibitor within this series of compounds (Ki - 3.0 x 10(-7) M).

Amino Acid Sequence↗
PubMed1992

Effects of structural variations on the rates of enzymatic and nonenzymatic hydrolysis of carbonate and carbamate esters.

The effect of structural variations on the rates of elastase-catalyzed hydrolysis of model carbonate and carbamate esters was studied using HPLC. It is shown that branching in the immediate vicinity of the carbonate or carbamate functionally results in decreased hydrolysis rates. Whereas aryl carbonates act as substrates for elastase, p-nitrophenyl butyl carbamate inhibits the enzyme. A novel method was developed for the entrapment and quantitation of 14CO2 produced upon hydrolysis of carbonyl-14C-labeled carbonate esters. This technique could be useful in studying the mechanism of enzymatic hydrolysis of this type of compound and has the potential of being adapted as a convenient method in the assessment of estrolytic activity of tissue homogenates.

Carbamates↗
PubMed1992

Metabolism and distribution of 1-[14C]alprazolam in rats.

Using 14C-labeled alprazolam (1-[14C]APZ) as a model for 1-[11C]APZ, we evaluated the tissue distribution of total radioactivity and assessed the contribution of the polar metabolites of APZ (alpha-hydroxymethyl- and 4-hydroxy-APZ) to radioactivity levels in the plasma and brains of rats over the course of 1 h. The biodistribution data showed that the uptake of radioactivity by rat brain was 0.31% of the injected dose per gram of tissue weight at 10 min postinjection. Pretreating rats reduced the levels in brain to 0.21% of the injected dose at 10 min but had little effect on the distribution of radioactivity in plasma and other tissues studied. Analysis of the metabolites in plasma and brain homogenates by an extraction-thin-layer chromatography-liquid scintillation method revealed that greater than 94% of the radioactivity in the rat brain was due to 1-[14C]APZ over the course of 1 h. APZ, therefore, is stable to metabolic transformations in the rat brain, and the polar metabolites are readily conjugated and excreted so that their cerebral uptake is minimal.

Alprazolam↗
PubMed1992

Histochemical changes in the rabbit cornea and plasmin activity in the tear fluid during contact lens wear. Favourable influence of protease inhibitors (aprotinin, PC5, elastatinal).

Plasmin activity in the tear fluid of the rabbit eye was examined during the wearing of soft contact lenses (SCL) and compared with the occurrence of corneal disturbances assessed in cryostat sections. Plasmin activity was determined with a semiquantitative method using dry punches of filter paper previously soaked in 0.1 M Tris-HCl buffer solution containing mmol/l D-Val-Leu-Lys-FCA (trifluoromethylaminocoumarine), pH 7.2. Punches were applied to the corneal surface for 5 s (tear collection) and incubated in wet chamber. The time of appearance of the bright yellow fluorescence in UV light was recorded and taken as a measure of plasmin activity. For calibration punches soaked in solutions containing plasmin in various concentrations, and processed in the same manner were used. Changes in the cornea were examined histochemically using methods of choice for acid glycosidases, proteases, dehydrogenases, and Na(+)-K(+)-ATPase. SCL with high and low water content were worn in rabbits in 1, 2, 4, 7, 14, 21 and 28 days. Decreased activity of Na(+)-K(+)-ATPase, GGT, and SDH in the corneal endothelium and epithelium were not accompanied by detectable plasmin activity in the tear fluid. Pronounced damage of the corneal epithelium (increased activities of acid glycosidases, acid proteases, LDH, markedly decreased activity of SDH) was accompanied by low concentration of plasmin (0.4-1.0 micrograms/ml) in the tear fluid. Middle activity of plasmin (1.0-2.0 micrograms/ml) was detectable when PMNs were present in the corneal stroma. High plasmin activity (2.0-3.0 micrograms/ml) correlated with corneal ulceration and vascularization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Covalently linking a peptidyl carbamate elastase inhibitor to a hydrophilic polymer increases its effectiveness in preventing emphysema and secretory cell metaplasia in the hamster.

A peptidyl carbamate, p-nitrophenyl N-(succinyl-L-alanyl-L-alanyl-L-prolyl-methyl)-N-isopropylcarbamate++ + (PCI) was tested for its ability to inhibit the elastolytic activity of human neutrophil elastase (HNE) and to prevent HNE-induced emphysema and secretory cell metaplasia in the hamster. In vitro, 50% of the elastolytic activity of 10 micrograms of HNE was inhibited by 0.9 micrograms of PCI, a molar ratio of PCI to HNE of 4.5. Bronchoalveolar lavage of hamsters receiving PCI intratracheally showed a rapid decrease in HNE inhibitory activity (4 min for 50% decrease), suggesting rapid clearance, binding, or inactivation of the PCI. Instillation of 300 micrograms of HNE combined with 100, 500, or 3,000 micrograms PCI, a 16-, 83-, and 503-fold molar excess of PCI, respectively (molar ratios of 17, 84, and 504), suppressed HNE-induced lung hemorrhage, but it did not moderate HNE-induced emphysema despite the large molar excess of inhibitor. When PCI was covalently bound to a linear hydrophilic polymer of alpha,beta-poly[N(2-hydroxyethyl)-D,L-aspartamide], producing a polymer-bound carbamate inhibitor (PPCI) of HNE, the time for a 50% decrease of PPCI functional activity from the hamster lung lavage was 421 min. Instillation of 100 micrograms of PPCI 1 h before instillation of 300 micrograms HNE resulted in significant amelioration of emphysema; 900 micrograms of PPCI was required to obtain amelioration of bronchial secretory cell metaplasia. The larger dose of PPCI also provided significant amelioration of emphysema when the interval between PPCI and HNE administration was 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Solubilization and in vitro spermicidal assessment of nonoxynol-9 and selected fractions using rabbit spermatozoa.

Selected oligomers representing the high, medium, and low molecular weight fractions of the spermicidal agent Nonoxynol-9 (N-9) were separated by HPLC. Nonoxynol-9 and the isolated fractions were formulated with polyvinylpyrrolidone (PVP) in order to increase their water solubility, particularly that of the insoluble low molecular weight fraction. The in vitro spermicidal activity of three molecular weight fractions were compared to that of N-9, using rabbit spermatozoa, at equimolar concentrations. Nonoxynol-9/PVP was far more effective in immobilizing the sperm than either N-9 alone or the separate fractions. The relative spermicidal activity of the oligomers was of the order middle molecular weight greater than high molecular weight greater than low molecular weight.

Animals↗
PubMed1991

High-performance liquid chromatographic (HPLC) analysis of oligomeric components of the spermicide nonoxynol-9.

The commercially available Nonoxynol-9 spermicide is a multicomponent mixture of oligomers. When Nonoxynol-9 was separated by normal phase gradient HPLC, 17 components were shown to exist in the commercial mixture. These oligomeric components follow a Poisson distribution around the most abundant oligomer, EO 8 (11.7%). Select oligomers were isolated by preparative HPLC (Rt = 19.6, 34.0, 45.6, 51.2, 61.6, and 79.2 min) and purified by HPLC. These were identified by FAB-MS and NMR to be the oligomers EO 3, EO 6, EO 8, EO 9, EO 11, and EO 16, respectively.

Chromatography, High Pressure Liquid↗
PubMed1991

Dual-isotope imaging of neutron-activated erbium-171 and samarium-153 and the in vivo evaluation of a dual-labeled bilayer tablet by gamma scintigraphy.

The feasibility of dual-label scintigraphic studies which use the neutron-activated isotopes erbium-171 and samarium-153 is described. Experimental details are provided to correct and minimize the compton scatter contribution of 171Er into the lower-energy 153Sm window. The results from this study demonstrate that this dual-label procedure is sensitive enough to monitor simultaneously the behavior of two discrete regions of the same unit dose in the gastrointestinal tract of man.

Digestive System↗