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Biomedical subjects

A Hsu

Publications and source records attributed to A Hsu.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.

Animals↗
PubMed1997

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.

Adult↗
PubMed1997

A laser microprobe mass analysis of brain aluminum and iron in dementia pugilistica: comparison with Alzheimer's disease.

We report a laser microprobe mass analysis of aluminum and iron content in the hippocampus and in the inferior temporal cortex in 2 cases of dementia pugilistica (DP), 4 cases of Alzheimer's disease (AD), and 3 controls. There was a predominant accumulation of Al and Fe within neurofibrillary tangles (NFT) in both DP and AD cases. High levels of Al and Fe were also detected in the nuclei of NFT-free and NFT-containing neurons, as well as in neuropil probe sites in these cases. In both regions, NFT contained substantially higher levels of Al and Fe in DP compared to AD cases. These findings suggest the existence of an association between the deposition of Al and Fe and NFT formation, and support the possibility of a global dysregulation of Al and Fe transport in DP and AD.

Aged↗
PubMed1997

Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir.

The effects of fluconazole on the pharmacokinetics of the HIV protease inhibitor ritonavir were investigated after multiple dosing in an open-label study. In this randomized, two-period crossover study, eight healthy subjects received ritonavir alone (200 mg every 6 hr for 4 days) and ritonavir with fluconazole (400 mg on day 1, 200 mg every day on days 2-5) with a 2-week washout period. Ritonavir plasma concentrations were measured during the final four ritonavir dosing intervals (24 hr) and a 12-hr washout period. There were statistically significant increases in ritonavir C(max) and AUC0-24 (p < 0.02), with concurrent administration of fluconazole compared with administration of ritonavir alone. The difference between regimens in C(min) was marginally statistically significant (p = 0.089), and t(max) and beta were not statistically significantly different. Although some ritonavir parameters were affected by fluconazole, mean increases in C(max) and AUC were < or = 15% for the 24-hr period, and only 7-19% for individual dose intervals. Thus, the pharmacokinetics of ritonavir may be influenced only to a small extent when administered with fluconazole. These changes are probably of limited clinical significance and do not necessitate dosage adjustment of ritonavir when fluconazole is added to the regimen.

Adult↗
PubMed1996

The application of laser microprobe mass analysis to the study of biological material.

Laser microprobe mass analysis (LAMMA) is an investigational method which is a powerful tool for the identification and quantitation of various elements present in small volumes of tissue. LAMMA is highly sensitive and capable of rapidly detecting concentrations of 1-3 p.p.m. of most metallic elements, in precisely localized cellular compartments. In order to further assess its value, cultured skin fibroblasts and biopsy tissues from human subjects and experimental animals were probed by LAMMA, and the results were correlated with ultrastructural findings. Biopsy samples were obtained from patients suffering from Gaucher disease, and from patients and animals with pathologic iron or copper metabolism. No significant abnormalities were detected in the cultured fibroblasts from patients with Gaucher disease, in contrast to the iron content of tissue biopsy Gaucher cells, which was markedly increased, apparently as a consequence of erythrophagocytosis. Particularly intense iron-related peaks were found in liver cytosiderosis due to neonatal or genetic haemochromatosis, thalassaemia major and in animal models of iron overload. An additional finding was the presence of aluminium accumulation in siderosomes of different cells. In liver biopsy samples from human Wilson's disease and from rats with an inherited disorder causing copper toxicosis, copper-containing compounds were identified and localized, and their relative concentration was estimated by LAMMA. The present study showed that LAMMA is a valuable technique for the localization and estimation of relative abundance of trace elements in various tissues containing excessive amounts of metals.

Animals↗
PubMed1996

A laser microprobe mass analysis of trace elements in brain mineralizations and capillaries in Fahr's disease.

We report a detailed analysis of the content of aluminum, iron, zinc, copper, calcium, and magnesium in the non-vascular and pericapillary mineralizations and the normal capillaries of the globus pallidus and dentate nucleus of the cerebellum in two patients with clinically and neuropathologically confirmed Fahr's disease. The study employed laser microprobe mass analysis, a technique that enables highly sensitive detection of the levels of trace elements. In the globus pallidus, there was a significant increase in aluminum-, iron-, zinc-, and calcium-related peak intensity in the pericapillary and non-vascular mineralizations compared to the normal capillaries. The pericapillary and non-vascular mineralizations had comparable concentrations of these elements. No difference was found in copper levels between the different probe sites. Magnesium was almost absent in pericapillary mineralizations and normal capillaries, while it accumulated within non-vascular mineralizations. In the cerebellar dentate nucleus, non-vascular mineralizations displayed higher concentrations of all of these elements than normal capillaries, while pericapillary mineralizations had a higher aluminum and lower iron, copper, and calcium content than did non-vascular mineralizations. Zinc and magnesium were selectively deposited within the non-vascular mineralizations in this nucleus. Furthermore, the element composition of non-vascular mineralizations differed between the globus pallidus and dentate nucleus. These findings indicate that the formation of pericapillary and non-vascular mineralizations may be two independent phenomena which coexist in the course of Fahr's disease. The marked qualitative and quantitative differences in trace element content in non-vascular mineralizations between the globus pallidus and cerebellar dentate nucleus suggest that the involvement of trace elements in the pathogenesis of Fahr's disease is probably indirect.

Aged↗
PubMed1996

Ordered accumulation of mutations in HIV protease confers resistance to ritonavir.

Analysis of the HIV protease gene from the plasma of HIV-infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine-82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression.

Codon↗
PubMed1996

Evidence of neuronal oxidative damage in Alzheimer's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.

Adolescent↗
PubMed1995

A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.

BACKGROUND: Ritonavir is a potent inhibitor in vitro of human immunodeficiency virus type 1 (HIV-1) protease, which is needed for virions to mature and become infective. We assessed the safety and efficacy of ritonavir in patients with HIV-1 infection. METHODS: We administered ritonavir orally to 62 patients in one of four dosages during a 12-week trial containing a 4-week randomized, placebo-controlled, double-blinded phase followed by an 8-week dose-blinded phase. We assessed the response with serial measurements of plasma viremia and serial CD4 cell counts. RESULTS: Fifty-two patients completed the 12-week trial. Diarrhea and nausea were the most common side effects, and reversible elevations in serum triglyceride and gamma-glutamyltransferase levels were the most frequent laboratory abnormalities. Ritonavir had a rapid antiviral effect, with a mean maximal reduction in the number of copies of HIV-1 RNA per milliliter of plasma that ranged from 0.86 to 1.18 log in the four dosage groups. After 12 weeks of treatment, the antiviral effect was partially maintained, with a mean reduction in plasma viremia of 0.5 log. When we used a more sensitive assay for HIV-1 RNA in a subgroup of 20 patients, we found that plasma viremia decreased by a mean of 1.7 log. This antiviral effect was partly sustained at week 12, with a mean reduction of approximately 1.1 log. The patients' CD4 cell counts rose during treatment with ritonavir (median increase, 74 and 83 cells per cubic millimeter at weeks 4 and 12, respectively). CONCLUSIONS: The protease inhibitor ritonavir is well tolerated and has a potent antiviral effect, as shown by substantial decreases in plasma viremia and significant elevations in CD4 cell counts. Expanded clinical trials of ritonavir are warranted.

Adult↗
PubMed1995

Capillary zone electrophoretic resolution of recombinant human bone morphogenetic protein 2 glycoforms. An investigation into the separation mechanisms for an exquisite separation.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) is a disulfide-linked homodimeric glycoprotein (M(r) = 30,000) which induces bone formation in vivo in several animal model systems. In this paper, we report the separation of a homogeneous rhBMP-2 sample into nine peaks by capillary zone electrophoresis (CZE), using a simple, pH 2.5, phosphate buffer containing no additives. The nine peaks have been identified to be glycoforms of rhBMP-2 [designated as (rhBMP-2)2-(GlcNAc)4(ManZ), where Z varies from 10 to 18]. The difference between any adjacent pair of peaks is only one mannose residue (M(r) = 162). The ability of CZE to resolve rhBMP-2 glycoforms having the same charge and differing only 0.5% in molecular mass, without resorting to chemical complexation, is both unexpected and intriguing. Possible mechanisms explaining how the additional mannose can affect the mobility of rhBMP-2 glycoforms were explored. Zeta potentials of various glycoforms were calculated from their mobilities and interpreted in light of diffuse double layer parameters. Our results suggest that CZE employing a low-pH buffer, where proteins are highly charged, may be uniquely suitable for complex protein glycoform analysis.

Amino Acid Sequence↗
PubMed1995

The hypotransferrinaemic mouse: ultrastructural and laser microprobe analysis observations.

Homozygote hypotransferrinaemic mice (hpx/hpx) have cytopathological features similar to those of human congenital atransferrinaemia, genetic haemochromatosis, and neonatal haemochromatosis. These conditions all have in common high levels of cytotoxic non-transferrin-bound serum iron. This study describes the ultrastructural features of iron overload in liver, pancreas, heart, and small intestine of 2- and 12-month-old hypotransferrinaemic mice. Electron microscopic studies of unstained sections showed early parenchymal cell siderosis, with accumulation of numerous ferritin particles and clusters in the cytosol, as well as ferritin and haemosiderin in lysosomes (siderosomes). In the 12-month-old animals, iron was also found in Kupffer cells and macrophages in other tissues. In addition, there were conspicuous iron-containing compounds in the bile canaliculi, and marked iron deposition in the pancreas and heart. Laser microprobe mass analysis (LAMMA) enabled localization and relative quantitation of iron deposition in subcellular compartments providing in situ documentation of iron accumulation in siderosomes and contributed in assessing total cytosolic iron in various cell types. Moreover, it demonstrated the importance and magnitude of the biliary route for iron excretion in these animals.

Animals↗
PubMed1995

Acute zinc administration prolongs hexobarbitone-induced sleeping time in C57/6J mice.

Two experiments were carried out in this study to demonstrate the effects of acute intraperitoneal (i.p.) administration of zinc chloride (ZnCl2) on hexobarbitone-induced sleeping time (HST) in female C57/6J mice. Serum and hepatic zinc content as well as hepatic cytochrome P450 content were also estimated in ZnCl2-treated and control mice. The ZnCl2 dose used was equal to the LD50 for chronic treatment (which was 28 micrograms g-1 body weight for mice given i.p. ZnCl2 five times a week for 3 weeks), determined in an earlier experiment. ZnCl2 injections at this dose were either given singly (in experiment I) or repeated on two mornings (in experiment II). Hexobarbitone, an ultra-short-acting experimental barbiturate, was given intraperitoneally 30 min after the single ZnCl2 injection in experiment I and 24 h after the second ZnCl2 injection in experiment II. Appropriate controls were given i.p. normal saline in each experiment. The HST was observed for all the animals, using the time-points at which the loss and regain of righting reflex occurred as the parameters. The animals were later killed; their blood and livers were obtained for estimation of zinc levels and cytochrome P450 content. The results of both experiments showed that ZnCl2 had caused a significant prolongation of the HST in C57/6J mice. Serum and hepatic zinc content were also elevated in both groups of ZnCl2-treated mice compared to their respective controls. The cytochrome P450 content in the single-dose ZnCl2-treated mice was unchanged while it was significantly reduced in the double-dose ZnCl2-treated mice when compared to the content in their respective controls. These findings suggest that acute zinc excess has an inhibitory effect on the function as well as the synthesis of hepatic cytochrome P450 enzymes.

Animals↗
PubMed1995

Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor.

A77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, was administered to asymptomatic HIV-1-infected patients in a phase I trial. The drug was given by continuous intravenous infusion at dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The drug was given first for 24 h and then for up to an additional 4 weeks in a second infusion period following at least a 6-day washout. Apart from reversible increases in hepatic transaminase levels in some patients, no systemic toxicities occurred during extended infusion of the drug. Dose-related local vein irritation, despite dilution of the infusate, however, caused severe infusion site phlebitis precluding dosage escalation beyond 0.28 mg/kg/h. Pharmacokinetic analysis demonstrated dose linear increases in mean steady-state concentrations. However, clearance of the drug from plasma was unexpectedly high, averaging 62 liters/h across all groups. The concentrations of A77003 in plasma achieved the in vitro 50% inhibitory concentration (0.16 microgram/ml) only in the 0.28-mg/kg/h dosage group, but it did not attain the 90% inhibitory concentration (0.48 micrograms/ml). No statistically significant effect on CD4 cell numbers occurred in any of the groups, and there was no evidence of antiviral activity, as determined by HIV-1 p24 antigen level, quantitative plasma and cell culture, and quantitation of viral RNA in plasma. In conclusion, A77003, as formulated in the present study, causes severe phlebitis, which prevents administration of the infusates necessary to achieve high concentrations of the drug in plasma. In conclusion, A77003, as formulated in the present study, causes severe phlebitis, which prevents administration of the infusates necessary to achieve high concentrations of the drug in plasma. The lack of antiviral activity observed in the study may be a consequence of the low concentrations in plasma in all groups.

Adolescent↗
PubMed1994

Cloning of a rat cDNA encoding dihydroxypolyprenylbenzoate methyltransferase by functional complementation of a Saccharomyces cerevisiae mutant deficient in ubiquinone biosynthesis.

3,4-Dihydroxy-5-hexaprenylbenzoate methyltransferase (DHHB-MTase) is the product of the COQ3 gene in Saccharomyces cerevisiae and catalyses the fourth step in the biosynthesis of ubiquinone (coenzyme Q) from p-hydroxybenzoic acid. A full-length cDNA encoding a mammalian homologue of DHHB-MTase was isolated from a newly constructed rat testis cDNA library by functional complementation of a coq3 deletion mutant of S. cerevisiae. The complementing clone contained a 1.1-kb poly(A)(+)-tailed insert with a 858-bp open reading frame and presumably encodes 3,4-dihydroxy-5-polyprenylbenzoate-MTase. The deduced rat amino acid (aa) sequence has a 39% identity over 138 aa with the yeast DHHB-MTase and a 37% identity over this same region with an Escherichia coli protein encoded by the ubiG gene, a MTase that catalyses the terminal step of ubiquinone biosynthesis. The rescue of the yeast coq3 mutant by the rat homologue suggests that yeast and rat synthesize ubiquinone via the same early steps in this pathway.

Amino Acid Sequence↗
PubMed1994

Microbial transformation of immunosuppressive compounds. III. Glucosylation of immunomycin (FR 900520) and FK 506 by Bacillus subtilis ATCC 55060.

The regiospecific glucosylation of FK 506 and immunomycin (FR 900520) at the 24-hydroxy position was performed using resting cells of Bacillus subtilis ATCC 55060. 24-Glucopyranosyl FK 506 and 24-glucopyranosyl immunomycin were isolated by methylene chloride extraction and purification using reverse phase HPLC. The metabolite structures were established using spectroscopic techniques including MS and NMR. The glucose conjugate was further confirmed by chemical degradation. Enzymatic glucosylation was demonstrated using cell-free extracts derived from Bacillus subtilis ATCC 55060. The 24-glucosyltransferase, which appears UDP-glucose dependent, was solubilized from cell membranes by treatment with 0.1% Nonidet P-40 detergent. The optimal conditions for assay of the enzyme have been determined.

Bacillus subtilis↗
PubMed1993

A comparison of a new polypropylene suture with Prolene.

The purpose of this paper is to examine the performance of the newly available monofilament polypropylene suture (Surgipro) manufactured by U.S. Surgical and compare it with commercial Prolene sutures for determining the merit of this new suture. Two different sizes of Surgipro sutures were used. They were 4/0 and 0 sizes and were tested in terms of their fundamental properties: level of crystallinity, melting temperature, fiber morphology, and mechanical properties including knot strength and knot security. The effect of three different sterilization methods on the mechanical and fundamental properties of the new polypropylene (PP) sutures was also examined. In general, the new Surgipro sutures performed as good as Prolene sutures in terms of mechanical properties; but there were some differences in fundamental properties between these two types of PP sutures, particularly in finer size PP sutures. The major differences were in interior fiber morphology, level of crystallinity, and melting temperature. Surgipro suture fibers showed homogeneous interior morphology, while Prolene fibers exhibited two distinctive fiber morphologies. These two types of PP suture fibers also responded differently to the three sterilization methods tested. Surgipro sutures are less affected by different sterilization methods than the same size Prolene control. Except for the Co 60 gamma sterilization, Surgipro suture fibers did not exhibit statistically significant differences in tensile breaking strength between sterilized and control. Ethylene oxide and autoclave sterilized Prolene suture fibers, however, showed statistically (p less than 0.05) consistently lower tensile breaking strength than their unsterilized controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystallization↗
PubMed1993

Microbial transformation of L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease.

The microbiological transformation of L-696,474 [1], a novel cytochalasin that is an inhibitor of HIV-1 protease, was investigated using Actinoplanes sp. ATCC 53771. Six hydroxylated metabolites 2-7 of 1 were isolated and purified using reversed-phase hplc. All six metabolites were found to have undergone hydroxylation at the C-16 methyl group (C-22) of 1. Three of the compounds, 3, 4, and 5, were further hydroxylated at the para (C-29), the meta (C-28), and both the para and the meta, positions of the phenyl ring, respectively. Metabolites 6 and 7 were shown to result from vicinal dihydroxylation on both C-16 and its attached Me (C-22). The metabolite 7 was further hydroxylated on the meta position of the phenyl ring. The structures of the metabolites were established using spectroscopic techniques including ms, 1H nmr, 13C nmr, and various 2D nmr spectroscopy experiments.

Actinomycetales↗