Biomedical subjects

D T Lau

Publications and source records attributed to D T Lau.

At least 19 recordsLinked to original sources

PubMed1998

10-Year follow-up after interferon-alpha therapy for chronic hepatitis C.

Sustained responses to interferon-alpha occur in 10% to 25% of patients with chronic hepatitis C, but the long-term outcome is not well defined. We evaluated the long-term clinical, histological, and virological outcomes of 10 patients with chronic hepatitis C who were treated between 1984 and 1987 with interferon-alpha-2b for 52 +/- 6 weeks (total doses of 492 +/- 116 MU). Before therapy, all 10 had hepatitis C virus (HCV) RNA, elevations of serum aminotransferases, and chronic hepatitis with fibrosis on liver biopsy. Clinical follow up was 6 to 13 years, and liver biopsies were done 5 to 11 years after initiation of therapy. HCV RNA was assayed by qualitative and quantitative reverse transcriptase-polymerase chain reaction assays. Among 5 patients who had a 6-month sustained response after therapy, all remained HCV RNA negative, and at last follow-up, 4 had normal and 1 minimally elevated serum aminotransferase levels. Liver biopsy specimens were nonreactive for HCV RNA, and all the patients showed improvements in both inflammation and fibrosis and were either normal or had mild, nonspecific inflammatory changes. Among 5 patients without a sustained response, all continued to have HCV RNA in serum and persistent or intermittent aminotransferase elevations. Liver biopsy specimens showed little or no change in necrosis and inflammation; all except 1 patient had progression of fibrosis scores or cirrhosis. All 5 patients had symptoms of chronic hepatitis, 1 underwent liver transplantation, and another had progressive hepatic decompensation. In conclusion, patients with a 6-month posttreatment virological response have a favorable long-term clinical and histological outcome.

Adult↗

PubMed1998

Statistical models for predicting a beneficial response to interferon-alpha in patients with chronic hepatitis B.

Therapy with interferon-alpha has been reported to induce remissions in 35% of patients with chronic hepatitis B. The ability to identify patients likely to respond would be helpful in making recommendations for treatment. In this statistical analysis we included 82 patients with chronic hepatitis B who received interferon-alpha in clinical trials at the National Institutes of Health between 1984 and 1991. A response was defined as the loss of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) within 1 year of therapy. Multiple clinical parameters measured at pretreatment (month 0) and after the first month (month 1) of therapy were selected by stepwise regression to support the development of the prognostic models: the two-stage logistic regression model and a neural network that utilized higher-order non-linear interactions between variables. Among the 82 patients, 24 (29%) were responders. The two-stage logistic model using pretreatment variables: sex, hepatic fibrosis and alanine aminotransferase (ALT) levels correctly identified 61% of responders and 76% of non-responders. When HBV DNA at month 1 along with sex, initial ALT and fibrosis was included, the resultant model correctly identified 69% of responders and 77% of non-responders. The neural network, by incorporating interactions between variables, correctly identified 77% and 86% of responders, and 87% and 92% of non-responders, using pretreatment factors alone and the combination of pretreatment and month 1 factors respectively. Hence, the neural network was more accurate than the simple logistic regression model in predicting a response to interferon-alpha in chronic hepatitis B. The universality of these models needs to be further verified.

Antiviral Agents↗

PubMed1998

Combination therapy with famciclovir and interferon-alpha for the treatment of chronic hepatitis B.

Interferon-alpha (IFN-alpha) treatment results in long-term remissions in only 25%-40% of patients with chronic hepatitis B virus (HBV) infection. Famciclovir, the oral prodrug of penciclovir, inhibits HBV DNA replication. Five adults with chronic HBV infection in whom previous IFN-alpha therapy had failed were treated in a pilot study of overlapping IFN-alpha and famciclovir therapy totaling 20 weeks. HBV DNA levels decreased by 0.9 log units during the initial 4-week period of famciclovir alone, followed by a further decrease of 1.8 logs during the middle 12-week period of combination therapy. HBV DNA rose by 0.9 log during the final 4-week period of IFN-alpha alone. Two patients cleared HBV DNA, and their liver disease improved by clinical and histologic criteria. The combination of famciclovir and IFN-alpha appeared to be at least additive in suppressing HBV DNA. Efficacy trials of combination therapy with famciclovir and IFN-alpha are warranted.

2-Aminopurine↗

PubMed1997

Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.

BACKGROUND & AIMS: Therapy with interferon alfa (IFN-alpha) leads to remission of disease in one third of patients with chronic hepatitis B. The aim of this study was to better define the long-term prognosis of this outcome. METHODS: One hundred three patients with chronic hepatitis B who underwent IFN-alpha therapy in three clinical trials between 1984 and 1991 were followed up for serological status, biochemical evidence of liver disease, and liver complications or mortality through 1994. RESULTS: Among 103 patients, 31 (30%) responded to therapy with loss of hepatitis B e antigen and viral DNA from serum. Responders were more likely than nonresponders to be women, black, and to have more severe liver disease including cirrhosis (P < 0.05). Up to 11 years (mean, 6.2 years) after therapy, a higher percentage of responders than nonresponders were still negative for hepatitis B e antigen (94% vs. 40%; P < 0.001) and hepatitis B surface antigen (71% vs 8.3%; P < 0.001). Overall, the rate of liver-related complications and death did not differ by IFN-alpha response, but with adjustment for cirrhosis, nonresponders had higher rates of liver-related complications and mortality (hazard ratio, 13.7; 95% confidence interval, 3.0-63.5). CONCLUSIONS: The response to IFN-alpha therapy in chronic hepatitis B is usually a sustained improvement in disease markers and, when cirrhosis is considered, patient outcome.

Adult↗

PubMed1995

The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent, in the dog.

SDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross-over design, four dogs received a single 10 mg kg-1 dose of 14C-FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post-dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blood concentrations of 53-450, the active metabolite of FOX 988, were also determined. Serum concentrations of beta-hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low-fat meal at dosing and at 4 h post-dose exhibited similar extents of absorption, as shown by similar AUC values and urinary radioactivity recovery. Administration of the high-fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53-450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.

3-Hydroxybutyric Acid↗

PubMed1995

The effect of food on the absorption of 14C-SDZ FOX 988, an antidiabetic agent, in healthy human volunteers.

The objective of this study is to examine the effect of food on oral absorption of SDZ FOX 988 (FOX 988), an antidiabetic agent, and circulating levels of its active metabolite, SDZ 53-450 (53-450). Sixteen normal volunteers received a single 10 mg dose of 14C-FOX 988, either as gelatin capsules or in a suspension (0.5% CMC). For subjects receiving each formulation, four subjects received a meal, consisting of 50% fat by calories, immediately following dosing, while the other four received the same meal at 2 h post-dose. Serial blood, urine, and fecal samples were collected for 120 h and analyzed for total radioactivity. Blood concentrations of 53-450 were analyzed using an HPLC-UV method. Concomitant administration with food increased the extent of FOX 988 absorption from either suspension or capsule, as shown by an increase in AUC and in urinary recovery of radioactivity. Blood concentrations of 53-450 were only detected in subjects receiving food at dosing. No difference in absorption was observed between the capsule and the suspension. Results from this study showed that oral absorption of FOX 988 is enhanced by co-administration of food in normal volunteers.

Absorption↗

PubMed1995

Applying Bailer's method for AUC confidence intervals to sparse sampling.

Bailer developed a method for constructing confidence intervals for areas under the concentration-vs-time curve (AUC's) with only one sample per subject but with multiple subjects sampled at each of several time points post dose. We have modified this method to account for estimation of the variances. How the need to estimate variances affects study design is discussed. An extension of Bailer's method is proposed where variances are modeled as a function of the means, in order to get more precise estimates of variances. The modified and extended methods are applied to a rat toxicokinetic study with only two rats per time point per treatment group.

Animals↗

PubMed1994

Pharmacokinetics of SDZ 64-412, a novel antiasthmatic agent, following intravenous, oral, and inhalation dosing in the rat.

The pharmacokinetics of SDZ 64-412, an antiasthmatic agent, were investigated following intravenous, oral, and inhalation dosing in rats. 14C-SDZ 64-412 was administered intravenously (2.75 mg kg-1) and orally (5.5 mg kg-1, 110 mg kg-1), whereas non-radiolabeled drug (5.04 mg kg-1) was administered using nose-only inhalation chambers. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post-dose. SDZ 64-412 was rapidly and extensively (approximately 80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first-pass metabolism. The bioavailability of the parent drug, calculated by dose-normalized AUC and deconvolution methods, was only 10-15% from the low dose, but increased to approximately 40% following the high dose. Following inhalation dosing, SDZ 64-412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of approximately 40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64-412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of delivery of SDZ 64-412.

Administration, Inhalation↗

PubMed1994

Pharmacokinetics of intranasally-administered dihydroergotamine in the rat.

Intranasal dosing of dihydroergotamine (DHE) allows convenient self-administration and provides an alternate route of administration for the treatment of migraine in addition to the existing parenteral dosage forms. In this study, the pharmacokinetics of 3H-DHE were investigated following intravenous and intranasal dosing (0.343 mg DHE/animal) in the rat. Intranasal administration of DHE resulted in rapid absorption. The extent of absorption of the radiolabeled dose was approximately 45%-60%. Absolute bioavailability of the parent drug was 35%-40%, as determined by deconvolution and by the ratios of AUC0-infinity following intranasal and intravenous dosing. Due to the limited capacity of the nostrils, approximately half of the intranasal dose was swallowed into the gastrointestinal tract. Biliary excretion was found to be the predominant pathway of radioactivity excretion following both routes of administration. The results from this study suggest that intranasal administration provides a viable means of delivering DHE into the systemic circulation.

Administration, Intranasal↗

PubMed1994

Effect of current magnitude and drug concentration on iontophoretic delivery of octreotide acetate (Sandostatin) in the rabbit.

The effect of current magnitude and drug concentration on transdermal iontophoretic delivery of octreotide acetate (Sandostatin) was examined in the rabbit. Plasma samples were collected over 24 hours and octreotide concentrations were determined by a radioimmunoassay. Without an electrical current, negligible plasma concentrations of octreotide were obtained. Following initiation of iontophoresis, plasma concentrations of octreotide increased rapidly, although did not sustain at a plateau level during the dosing period. Octreotide concentrations declined rapidly after removal of the device. Increasing the electrical current from 50 microA/cm2 to 150 microA/cm2 yielded a proportional increase in the delivery. Increasing the drug concentration in the device from 2.5 mg/mL to 5 mg/mL resulted in approximately proportional increase in plasma octreotide concentrations; however, further increase in plasma concentrations was not observed for drug concentrations beyond 5 mg/mL. Iontophoretic delivery at the conditions which yielded the highest octreotide concentrations in this study (5 mg/mL solution at 150 microA/cm2 for 8 hours) yielded an apparent bioavailability (which represents an underestimate of the absolute bioavailability determined when the patches are run to exhaustion) of approximately 8%.

Amino Acid Sequence↗

PubMed1992

Improved gas chromatographic assay for the simultaneous determination of nitroglycerin and its mono- and dinitrate metabolites.

A sensitive, specific capillary gas chromatographic-electron-capture detection method for the simultaneous determination of nitroglycerin (GTN), 1,2- and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN, respectively) and 1- and 2-glyceryl mononitrate (1-GMN and 2-GMN, respectively) is reported. The minimum quantifiable concentration for GTN, GDNs and GMNs is 0.4 ng/ml in plasma, with extraction recoveries for GMNs greater than 76% and for GTN and the GDNs greater than 95%. Over the full range of quantifiable concentrations the inter-run assay precision and accuracy were less than 13 and 11%, respectively, for all five nitrates. Similar intra-run assay precision and accuracy values were found. The method was employed in the preliminary in vitro examination of GTN, GDN and GMN kinetics in human blood. Following addition of GTN to human blood, the ratio of 1,2-GDN to 1.3-GDN maximum concentrations (Cmax) was ca. 7:1, reflecting preferential denitration of the GTN molecule at the primary positions, while the Cmax ratio for 2-GMN to 1-GMN in this system was ca. 6:1, representing a highly selective if not specific primary denitration of the 1,2-GDN molecule. Following the intravenous administration of 1,2-GDN to five healthy male volunteers, 2-GMN/1-GMN Cmax ratios averaged 8.8:1, representing a highly selective but not specific formation of 2-GMN from the 1,2-GDN molecule. The assay will find utility in in vitro studies attempting to address the molecular pharmacology of GTN and its metabolites, and in in vivo clinical pharmacology studies attempting to address the relationship between pharmacokinetics and pharmacodynamics of GTN and its metabolites.

Chromatography, Gas↗

PubMed1992

Effects of sulfobromophthalein and ethacrynic acid on glyceryl trinitrate relaxation.

The effects of sulfobromophthalein (SBP) and ethacrynic acid (ECA), both inhibitors of glutathione S-transferase (GST), or glyceryl trinitrate (GTN)-induced vasorelaxation were investigated in rabbit aortic strips. The aortic strips were pre-contracted with phenylephrine, followed by relaxation with 0.5 microM GTN, with or without 0.1 mM SBP or ECA. ECA was observed to inhibit GTN relaxation approximately 32%, whereas SBP did not alter the GTN activity. The dinitrate metabolites (GDN) of GTN in the tissues were also measured. The amounts of both GDNs were decreased in the ECA-treated, but not the SBP-treated group. Moreover, in the ECA-treated group, a strong correlation was obtained between the loss of GTN activity and the decrease in GTN metabolism. Concentration-response studies also revealed that ECA attenuates GTN relaxation. The slope factor of the concentration-response curves was decreased by ECA, but not by SBP, although both inhibitors caused a mild decrease in Emax. In the 9000 g supernatant of rabbit aorta, ECA was also observed to inhibit GTN metabolism more significantly than SBP. The results suggest that the mechanism of GTN activation may involve a GST isozyme that possesses high activities towards ECA.

Animals↗

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↗