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Biomedical subjects

D T Lau

Publications and source records attributed to D T Lau.

36 records · Page 2Linked to original sources
PubMed1992

Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement.

The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studied in vitro using hairless mouse skin. Storing the skin for 10 days at 4 degrees C did not alter barrier function to total nitrate flux [GTN + 1,2-glyceryl dinitrate (1,2-GDN) + 1,3-glyceryl dinitrate (1,3-GDN)]. However, metabolic function was significantly impaired and suggested at least fivefold loss of enzyme activity. Heating skin to 100 degrees C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still present, however, and remained constant over the 10-hr experimental period, in contrast to the "control," which showed progressively decreasing enzymatic function with time. Pretreatment of hairless mouse skin in vivo (prior to animal sacrifice, tissue excision, and in vitro transport/metabolism studies) with 1-dodecylazacycloheptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3-GDN) was increased from less than unity to slightly above 1 by the Azone treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-strips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1992

Glutathione S-transferase-mediated metabolism of glyceryl trinitrate in subcellular fractions of bovine coronary arteries.

The possible role of glutathione S-transferases (GTSs) in vascular glyceryl trinitrate (GTN) metabolism was investigated. GTN degradation to form its dinitrate metabolites (GDNs) in the 9000g (9k) supernatant fraction of bovine coronary arteries (BCA) was examined. BCAs were homogenized with a 3x volume of phosphate buffer, and the 9k fraction was obtained by centrifugation. GTN (40 ng/ml; 1.76 x 10(-7) M) was incubated for 2 hr in the 9k fraction of BCA in the presence of reduced glutathione (2 x 10(-3) M). Samples were taken at 10, 20, 40, 60, and 120 min. GTN was observed to degrade readily, exhibiting a half-life of 26 min in the incubate. While both 1,2- and 1,3-GDNs were generated from GTN, formation of 1,3-GDN was predominant (GDN ratio, as 1,2/1,3-GDN, = 0.7-0.8). Coincubation with 2 x 10(-5) M concentrations of two GST inhibitors, sulfobromophthalein (SBP) and ethacrynic acid (ECA), decreased the rate of GTN loss. The GTN half-lives in SBP- and ECA-treated incubations were 66 and 84 min, respectively. In addition, the pattern of GDN formation was also altered. The resultant GDN ratios exceeded unity in the presence of these inhibitors, indicating that 1,3-GDN formation was attenuated to a greater extent than that of 1,2-GDN. These data suggest that vascular GTN metabolism in BCA is carried out by cytosolic GST isozymes which possess a preference for C-2 denitration of GTN.

Animals↗
PubMed1992

Cutaneous metabolism of nitroglycerin in vitro. I. Homogenized versus intact skin.

The metabolism of nitroglycerin (GTN) to 1,2- and 1,3-glyceryl dinitrate (GDN) by hairless mouse skin in vitro has been measured. In the first set of experiments, GTN was incubated with the 9000g supernatant of fresh, homogenized tissue in the presence and absence of glutathione (GSH), a cofactor for glutathione-S-transferase. After 2 hr of incubation with GSH, 30% of the initially present GTN had been converted to 1,2- and 1,3-GDN; without GSH, less than 5% of the GTN was metabolized. The ratio of 1,2-GDN to 1,3-GDN produced by the homogenate was 1.8-2.1. In the second series of studies, GTN was administered topically to freshly excised, intact hairless mouse skin in conventional in vitro diffusion cells. The concurrent transport and metabolism of GTN was then monitored by sequential analysis of the receptor phase perfusing the dermal side of the tissue. Three topical formulations were used: a low concentration (1 mg/ml) aqueous solution, a 2% ointment, and a transdermal delivery system. Delivery of total nitrates (GTN + 1,2-GDN + 1,3-GDN) into the receptor phase was similar for ointment and patch formulations and much greater than that from the solution. The percentage metabolites formed, however, was greatest for the solution (61% and 2 hr, compared to 49% for the patch and 35% for the ointment). As has been noted before, therefore, the relative level of skin metabolism is likely to be greatest when the transepidermal flux is small. Distinct from the homogenate experiments, the 1,2/1,3-GDN ratios in the penetration studies were in the range 0.7-0.9.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1991

Pharmacokinetic studies of the nitroglycerin metabolites, 1,2- and 1,3- glyceryl dinitrates, in the rat.

1,2- and 1,3-glyceryl dinitrates (1,2-GDN and 1,3-GDN) are the primary metabolites of glyceryl trinitrate, a commonly used anti-anginal agent. The goal of this study was to examine the pharmacokinetic properties of these metabolites in rats. Sprague-Dawley rats were infused intravenously with 0.25 or 2.0 micrograms min-1 of either 1,2- or 1,3-GDN for 70 min, during which steady state blood concentrations were achieved. Post-infusion blood samples were collected for 30 min. 1,2-GDN was found to possess slightly higher clearance (32.3 vs 20.8 ml min-1 kg-1) and volume of distribution (695 vs 454 ml kg-1) than 1,3-GDN; however, the two metabolites exhibited similar mean residence times (22.0 vs 21.8 min). Upon an 8-fold increase in the infusion rate, the pharmacokinetic parameters were not significantly altered for either 1,2- or 1,3-GDN. When each GDN was co-infused with an 8-fold higher dose of the other GDN, there were also no significant changes in the parameters.

Animals↗
PubMed1991

Immunogenetic influences on skin granuloma formation in mice.

Genetic influence on the development of granulomatous tissue reaction was investigated in C57BL/6 mice. Granulomas developed in the skin of euthymic C57BL/6 mice by transplantation of lyophilized hepatic granulomas were excised and lyophilized. The tissue mass free of parasite egg antigen and living cells was grafted into the skin of euthymic, athymic (nu/nu), and beige (bg/bg) C57BL/6 mice. Histological changes at the skin sites were studied weekly by light microscopy, and cells in newly developed granulomas at 6 weeks after grafting were examined by electron microscopy. Granulomatous inflammation occurred in all the variants but morphometric analysis showed that granulomatous inflammation was the most extensive in beige mice and least in athymic mice. The differences in the degree of tissue reaction were also quantified by measuring angiotensin converting enzyme and prolyl endopeptidase. Statistically significant differences among the animals with varying genetic background were confirmed by the marker enzyme activity. The findings confirm that initiation of a granulomatous response does not require T cells but T cell function is important for full expression of the reaction, while NK cell activity seems to suppress granuloma formation.

Animals↗
PubMed1991

Variable glyceryl dinitrate formation following infusions of glyceryl trinitrate at different vascular sites in the rat.

The availability of glyceryl trinitrate (GTN) and the differential formation of dinitrate metabolites (GDNs) in various organs as a function of routes of administration were investigated in the rat. GTN was infused at 2.0 micrograms/min via the left femoral vein (LFV), left external jugular vein (LJV), left femoral artery (LFA), and hepatic portal vein (HPV). Blood concentrations of GTN and GDNs were measured in femoral arterial samples. Different infusions yielded GTN steady-state concentrations in the following rank order: LJV greater than or equal to LFV greater than LFA greater than or equal to HPV. Furthermore, the GDN formation ratios (1,2-GDN/1,3-GDN) are different: LFV greater than LJV greater than LFA greater than HPV. The availabilities of GTN through the leg, vein, and liver were derived. GTN is significantly extracted and metabolized in these organs, and the leg and the vein prefer 1,2-GDN formation, while the liver forms 1,3-GDN predominantly.

Animals↗
PubMed1985

Synthesis and evaluation of a prototypal artificial red cell.

A new process allows microencapsulation of purified human hemoglobin and 2,3-diphosphoglycerate to form neohemocytes. The microcapsule membrane is composed of phospholipids and cholesterol. Neohemocytes are substantially smaller than erythrocytes, contain 15.1 grams per decaliter of hemoglobin, and have a P50 value (the partial pressure of oxygen at which the hemoglobin is half-saturated) of 24.0 torr. All rats given 50-percent exchange transfusions survived with only limited evidence of reversible toxicity. Normal serum glutamate-pyruvate-transaminase values at 1, 7, and 30 days after transfusion were consistent with minimal hepatotoxicity. The concentration of blood urea-nitrogen was elevated by 35 percent after 1 day but returned to normal by day 7. However, histopathology revealed normal kidneys on day 1 as well as on days 7 and 30. Neohemocytes cleared from the circulation of transfused rats with an apparent half-life of 5.8 hours.

Alanine Transaminase↗
PubMed1984

Liposome disposition in vivo. VI: Delivery to the lung.

The effect of negatively charged liposome components and vesicle size on the time course and dose dependency of liposome disposition in mice was studied with a view to optimizing liposome delivery to the lung. The disposition of large multilamellar liposomes was followed using 125I-labeled p-hydroxybenzamidine phosphatidyl ethanolamine. Of the three negatively charged liposome compositions studied (phosphatidyl choline-X-cholesterol-alpha-tocopherol, molar ratio: 4:1:5:0.1; X = phosphatidyl serine, dipalmitoyl phosphatidic acid, or phosphatidyl glycerol), phosphatidyl serine liposomes resulted in the greatest accumulation in lungs. Lung levels decreased up to 95 h postdose, at which time 6% of the liposome dose present at 2 h still remained. The disposition of phosphatidyl serine-containing liposomes was independent of dose for the range 0.04-21 mumol/animal. When liposomes containing phosphatidyl choline were prepared using a variety of extrusion and dialysis conditions, a strong link between liposome size and lung accumulation was revealed. A maximum lung accumulation of 30.9% of the administered dose was achieved with no detectable gross pathological lung lesions up to 24 h postdose.

Animals↗
PubMed1982

De novo sterologenesis in intact primates.

Recent studies have demonstrated that in intact rodents, extrahepatic tissues are much more important sites of de novo sterologenesis than previously appreciated. The present investigation was undertaken to localize the sites of cholesterol and nonsaponifiable lipid synthesis in intact primates. Tritiated water was employed as the radiolabeled tracer for quantifying sterol synthesis. Our results indicate that in the intact primate, tissues other than the liver account for the majority of the newly synthesized cholesterol (74.5% to 84.4%) and nonsaponifiable lipids (77.3% of 86.5%). This extrahepatic sterologenesis is primarily localized to the intestine, skin, and carcass (all tissues not specifically analyzed). Sterologenesis in the other tissues made only a minor contribution to total animal cholesterol and nonsaponifiable lipid synthesis. Moreover, cholesterol feeding that inhibited hepatic and small intestinal sterol synthesis did not greatly affect skin or carcass sterologenesis. This indicates that transport of sterols from either the live or intestine to peripheral tissues does not contribute greatly to the newly synthesized sterols localized in extrahepatic, extraintestinal sites.

Animals↗
PubMedDate not supplied

Nitroglycerin metabolism in subcellular fractions of rabbit liver. Dose dependency of glyceryl dinitrate formation and possible involvement of multiple isozymes of glutathione S-transferases.

The hepatic transformation of glyceryl trinitrate (GTN), commonly known as nitroglycerin, was studied in subcellular fractions prepared from rabbit livers. Both the cytosolic and microsomal fractions show activity toward GTN metabolism. Moreover, the formation of glyceryl dinitrates (GDNs) seems to be governed by different enzymatic processes in the two fractions. 1,2-GDN was preferentially formed in cytosolic fractions, whereas in microsomal fractions, 1,3-GDN was the predominant product. In cytosolic fractions, increasing starting concentrations of GTN led to a decrease in both the GTN degradation rate and the GDN ratio (1,2-GDN/1,3-GDN), which was mainly accounted for by saturation of the 1,2-GDN formation pathway. Various glutathione S-transferase (GST) inhibitors affected the rate of GDN formation differentially. In cytosolic fractions, 1-chloro-2,4-dinitrobenzene and iodomethane caused no change in the GDN ratio, while sulfobromophthalein, ethacrynic acid, and p-nitrobenzyl chloride decreased the GDN ratio, suggesting that different GST isozymes are inhibited by these agents. In microsomal fractions, no dose-dependent GTN metabolism and related change in the GDN ratios could be observed. With the exception of ethacrynic acid, addition of GST inhibitors did not decrease GDN metabolite production, and even in this case, no change in the GDN ratio was observed. The results suggest that different GTN metabolic pathways are present in the liver, most likely involving different GST isozymes.

Animals↗