Biomedical subjects

H Y Pan

Publications and source records attributed to H Y Pan.

At least 19 recordsLinked to original sources

PubMed2006

Alteration of cell-cycle regulatory proteins in human oral epithelial cells immortalized by HPV16 E6 and E7.

E6 and E7 oncoproteins from high-risk human papillomavirus (HPV) can transform cells in tissue culture and induce tumors in vivo by abrogating the cell-cycle checkpoint. To investigate the impact of HPV16 E6 and E7 on the cell-cycle regulatory machinery in oral epithelial cells, normal human oral epithelial cells were transfected with HPV16 E6 and E7 open reading frames, and alterations in cell-cycle regulatory proteins in cells expressing HPV16 E6 and E7 were analyzed. E6 and E7 expression results in immortalization of oral epithelial cells. E7 inactivates retinoblastoma protein (Rb) by forming complexes with hypophosphorylated Rb in immortalized oral epithelial cells. P53 and P21 protein levels were increased in immortalized cells compared to normal primary oral epithelial cells. Cyclin D1-cell-cycle-dependent kinase 4 binary association is disrupted in immortalized oral epithelial cells. These results indicate that E7 plays an important role in abrogation of cell-cycle regulation in oral epithelial cells, with E6 having a smaller impact. This suggests that the pathogenesis of HPV in oral epithelial cells differs from that in cervical epithelial cells.

Blotting, Western↗

PubMed2001

Characterization of the promoter region of the viral interferon regulatory factor encoded by Kaposi's sarcoma-associated herpesvirus.

Viral interferon regulatory factor (vIRF) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) inhibits the expression of interferon-responsive genes, causes cellular transformation and transactivates KSHV genes. In the present study, we characterized the mRNA expression pattern of the vIRF gene and its promoter. A vIRF transcript of 1.7 kb in size was detected in low level in uninduced KSHV-infected cells and its expression was inducible by 12-O-tetradecanoylphorbol-13-acetate (TPA), sensitive to cycloheximide and resistant to phosphonoacetic acid. The transcription start site was mapped to 79 nt upstream of the ATG initiation site by 5'-RACE. Mutagenesis analysis identified a region between -56 and the transcription start site (+1) as the minimal promoter region that contains a functional TATA box at -27. A region between -337 and -125 contains a repressor domain negated by sequence from -991 to -499 in BCBL-1 cells, a region which was also identified to be responsive to TPA induction. These results demonstrate vIRF as a KSHV early gene, identify its promoter and define the promoter regions that contain regulatory elements controlling vIRF transcription.

Base Sequence↗

PubMed2001

Reverse transcription slippage over the mRNA secondary structure of the LIP1 gene.

The secondary structures in mRNA often cause early termination during the synthesis of cDNA. In an attempt to determine the 5'-untranslated region (UTR) of the gene LIP1 using the RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE), we found that reverse transcriptases skipped over the LIP1 RNA secondary structures and continued the DNA synthesis through RNA adapter sequences without early termination. A fragment of only three nucleotides upstream of the LIP1 translation initiation codon was obtained from the initial RACE-PCR, which was much shorter than the 57-nucleotide fragment obtained from the cDNA library screening. Analysis of the 5' end sequence indicates the presence of high G+C content and stem-loop secondary structures. Therefore, optimizations of the reaction with high temperature (70 degrees C) and a thermostable reverse transcriptase were performed to synthesize the first-strand cDNA, which was determined to have 73 nucleotides in the 5'-UTR. These results suggest that, under cDNA synthesis conditions at 42 degrees C and 60 degrees C, the reverse transcriptases skipped over the stem-loop structures of LIP1 mRNA and continued the cDNA synthesis until they reached the RNA adapter sequences. Thisfinding draws attention to adopting optimized conditions for cDNA synthesis on G+C-rich RNA templates.

5' Untranslated Regions↗

PubMed1997

Coping with systematic bias during bilateral movement.

The present studies examined the nature of kinematic interlimb interference during bilateral elbow movements of 1:1, 2:1 and 3:1 frequency ratios and the manner in which subjects cope with coordination bias. Analysis of movement trajectories in the first experiment indicated progressively greater angular velocity assimilation across 2:1 and 3:1 conditions. The desired temporal relationship was maintained by slowing or pausing the low-frequency movement at peak extension while the high-frequency arm produced intervening cycles. An increase in amplitude was also evident for concurrent, homologous cycles. Movement smoothness was emphasized and additional practice was provided in a second experiment. This resulted in dissociated peak angular velocity between limbs and eliminated hesitations and amplitude effects. Bias was still evident, however, as an intermittent approach toward a 1:1 ratio within each cycle. This systematic tendency was somewhat greater at the lower of two absolute frequency combinations but was not influenced by the role of each arm in producing the higher or lower frequency movement. The findings from the first experiment suggest that subjects initially accommodate interlimb kinematic assimilation, while producing the intended timing ratio, by intermittently slowing or pausing the lower-frequency movement. This attenuates the need for bilaterally-disparate movement parameters and provides additional time for organizing residual kinematic differences, perhaps reducing "transient coupling." Evidence from the second experiment indicates that subtle relative motion preferences are still evident following sufficient practice to perform the movements smoothly. The within-cycle locations of the points of greatest interlimb bias for the 2:1 rhythms were positively displaced from those previously observed for 1:1 oscillations. The persistent coordination tendencies noted in both experiments perhaps reflect an assimilation/compensation cycle and constitute one potential source of the systematic error that often emerges during the acquisition of complex skills.

Adult↗

PubMed1995

Gastrointestinal absorption of pravastatin in healthy subjects.

The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greatest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.

Adult↗

PubMed1993

Pravastatin experience in elderly and non-elderly patients.

Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering cholesterol concentrations to reduce morbidity and mortality from CHD. Pravastatin, a well tolerated HMG CoA reductase inhibitor with a convenient once-daily dosing regimen, has been shown to effectively lower total and low density lipoprotein (LDL) cholesterol. Individual data from more than 1800 hypercholesterolemic patients enrolled in six double-blind, randomized, multicenter studies were pooled and then analyzed to compare the safety and efficacy of pravastatin in the elderly (i.e., patients at least 65 years old) and the non-elderly. In short-term studies (8-16 weeks), response was dose-related and similar in elderly and non-elderly subjects. Pravastatin 20 or 40 mg daily lowered total cholesterol 19-25%, LDL-cholesterol 25-33%, and triglycerides 14-23%; high density lipoprotein (HDL) cholesterol increased 5-10%. During long-term studies, improvements were sustained for more than 24 months in both the non-elderly and elderly. The incidences of adverse drug events and laboratory abnormalities were similar in the elderly and non-elderly patients in all groups (active treatment control with resin, pravastatin alone, or combination therapy). In short-term studies, treatment was discontinued because of adverse events in < 1% of all patients treated with pravastatin (all doses) or placebo. The frequency and profile of adverse events were similar among patients treated with pravastatin or placebo. In long-term studies, treatment was discontinued in 0.4% of patients in the pravastatin group and in 0.3% of the patients in the bile-acid-binding resin group. If drug therapy is warranted, pravastatin appears to be safe and effective for long-term use in elderly patients with hypercholesterolemia.

Adult↗

PubMed1993

Steady state serum concentrations of pravastatin and digoxin when given in combination.

Pravastatin is an HMG CoA reductase inhibitor used in the treatment of hypercholesterolaemia. The steady state pharmacokinetics of pravastatin (20 mg) and digoxin (0.2 mg) were evaluated in 18 healthy male subjects following the administration of each drug alone or in combination for 9 days. Serum and urine were collected for up to 48 h after the ninth dose in this open, randomized 3-way crossover study. Digoxin concentrations were measured by radioimmunoassay, and pravastatin and its metabolites. SQ 31,906 and SQ 31,945 were measured by GC-MS. Digoxin and pravastatin pharmacokinetics were unchanged following combined administration. Combination therapy with pravastatin and digoxin is unlikely to expose patients to additional risk compared with pravastatin alone.

Adult↗

PubMed1993

Pharmacokinetics of pravastatin in elderly versus young men and women.

OBJECTIVE: To assess the effect of age on the pharmacokinetics of pravastatin in men and women. A secondary objective was to evaluate the effect of oral contraceptive steroids on the pharmacokinetics of pravastatin in young women. DESIGN: Open, single-dose study. SETTING: Clinical Pharmacology Unit of Princeton Medical Center for study in men and Hill Top Pharmatest, Cincinnati, for study in women. PARTICIPANTS: Normal, healthy male (aged 19-75 y) and female (aged 18-78 y) volunteers. INTERVENTIONS: Subjects received a single 20-mg dose of pravastatin after an overnight fast. MAIN OUTCOME MEASURES: The maximum plasma pravastatin concentration (Cmax), time required for that concentration to develop (Tmax), and the elimination half-life (beta t1/2). Serum concentrations of pravastatin and its major metabolite, the 3-alpha isomer, SQ 31,906, were determined at 12 intervals from 0.33 to 48 hours after the dose. Urine was collected cumulatively during the same period to determine urinary excretion of pravastatin and SQ 31,906. Both measures were used to determine pharmacokinetic parameters. RESULTS: The pharmacokinetic profiles of pravastatin and SQ 31,906 in young and elderly subjects of men and women differed little. Although the mean area under the concentration time curve of pravastatin was higher in the elderly and significantly higher in the elderly women, Cmax and beta t1/2 values were similar in the young and the elderly volunteers. Concomitant administration of oral contraceptives in young women did not affect the pharmacokinetics of pravastatin or SQ 31,906. CONCLUSIONS: The pharmacokinetics of pravastatin do not necessitate dosage adjustments in elderly men or women. No differences were detected between the disposition of the parent drug or its metabolite in men and women.

Adolescent↗

PubMed1993

Effect of food on pravastatin pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of pravastatin 20 mg administered twice daily when taken with or one hour before meals were evaluated in 24 hypercholesterolemic men in an 8-week, open-label, randomized, two-way crossover study. The bioavailability of pravastatin was reduced significantly (p < or = 0.001) when it was taken with meals (AUC dropped 31% and Cmax dropped 49%), and mean Tmax increased 50% (p < or = 0.01). The mean elimination t1/2 was unaffected by taking pravastatin with food. However, reductions in mean total cholesterol and low density lipoprotein cholesterol were identical whether pravastatin was given with or before meals. In both treatment groups, total cholesterol and low-density lipoprotein cholesterol were significantly reduced from baseline (p < 0.001). These results indicate that although the bioavailability of pravastatin is reduced when taken with meals, the lipid-lowering efficacy of pravastatin is not altered. It can be concluded that pravastatin can be ingested without regard to meal time.

Cholesterol↗

PubMed1991

Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects.

The capability of pravastatin and lovastatin, HMG-CoA reductase inhibitors likely to be taken chronically for hypercholesterolemia, to cross the blood-brain barrier was investigated in normal male volunteers. Lovastatin, which is lipophilic, was detected in cerebrospinal fluid (CSF) at concentrations that may have a pharmacologic effect. Pravastatin, which is hydrophilic, was not detected in CSF. It is concluded that pravastatin may have less potential for causing CNS-related side effects than lovastatin.

Adult↗

PubMed1991

Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin.

1. Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.

Adult↗

PubMed1991

Clinical pharmacology of pravastatin, a selective inhibitor of HMG-CoA reductase.

Pravastatin, lovastatin and simvastatin are HMG-CoA reductase inhibitors with very similar structures. However, minor substitutions in the decalin ring have resulted in major differences in physiocochemical, pharmacological, and pharmacokinetic properties. Both in vitro and in vivo studies have demonstrated that lovastatin and simvastatin are non-selective lipophilic inhibitors, while pravastatin is a selective hydrophilic inhibitor. An extensive clinical pharmacology program has been conducted for pravastatin. Radiolabelled studies demonstrated oral absorption and bioavailability values of 34% and 17%, respectively. The parent drug is cleared equally by renal and non-renal routes. Peak blood level after oral administration is reached at approximately 1 h and the mean plasma elimination half-life is 1.8 h. Binding of total radioactivity to plasma proteins averages 45%. Non-radiolabelled studies showed that mean areas under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) are proportional to the doses administered, whereas times to reach Cmax (Tmax) and plasma elimination half-life values are independent of dose. Measurement of trough plasma concentrations of pravastatin at steady state showed no evidence of drug accumulation. Pharmacodynamic studies demonstrated an average LDL-C decrease of 30-35% at a daily dose of 40 mg. HDL-C increases are between 10% and 25% and triglyceride decreases, between 10% and 25%. These results indicate that pravastatin is very effective in lowering LDL-C. With its consistent decrease in triglycerides and increase in HDL-C, pravastatin offers a well-balanced lipid-modulating response.

Anticholesteremic Agents↗

PubMed1991

[Determination of D-catechin plasma concentration and pharmacokinetic parameters using HPLC method].

d-Catechin (alpha-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol) is an important hepatotropic drug. It has been extensively used in 1980's. A few methods for quantitative analysis of d-catechin in biological fluids have been reported, but they are not so sensitive or specific for pharmacokinetic interest. In this study, a specific, sensitive and reproducible RPHPLC-DAD method for quantifying d-catechin in plasma is established. Sep-Pak C18 cartridge is used for sample preparation. HPLC separation is performed on Waters HPLC system consisting of a Model 990 diode array detector. A 150 x 5 mm ID column containing YWG C18, held at 25 +/- 0.5 degrees C, and a mobile phase of methanol-0.03 mol/L citric buffer solution containing 0.04% TEMED,pH 4.7 (16:84, v/v) at a flow rate of 2 ml/min is used. Under the studied conditions, the tR for d-catechin is 7.74 min, that of the internal standard (cefetaxime, CTX) is 9.32 min. The peak of d-catechin is identified with the DAD and MS techniques. The limit of detection of the method is 9 ng, and the minimal detectable concentration in plasma is 17.4 ng/ml. There is a linear relationship between the peak area ratio over the range of 69.6-1160 ng/ml with r = 0.9993. The method has been applied to determine the d-catechin concentration in rabbit plasma. The pharmacokinetic characteristics and parameters are studied.

Animals↗

PubMed1990

Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin.

The oral bioavailability of two HMG-CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two-way crossover study. Twenty healthy men were randomly assigned to treatment with a 40-mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean +/- SEM AUC0-24 values of 285 +/- 25 and 189 +/- 13 ng-equiv x hr/mL, respectively, P less than .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open-acid active metabolites (62%) and closed-ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low-density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1990

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing.

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.

Adult↗

PubMed1990

Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia.

The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p less than 0.001 versus baseline) and low-density lipoprotein cholesterol by 23% to 35% (p less than 0.001). High-density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration-time curve and maximum serum concentration of pravastatin showed dose-proportionality; time to maximum serum concentration and serum elimination half-life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid-lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p less than 0.001 versus baseline), and low-density lipoprotein cholesterol was reduced by 47% to 56% (p less than 0.001). High-density lipoprotein cholesterol increased by 11% to 18% (p less than 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.

Adult↗

PubMed1990

Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects.

Pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]-pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first-pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min-1 kg-1, respectively, and the steady-state volume of distribution averaged 0.51 kg-1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.

Administration, Oral↗

PubMed1990

Wilson's disease: 35 years' experience.

Thirty-seven Chinese patients fulfilling the criteria for Wilson's disease seen during a 35-year period were reviewed. Males and females were equally affected. Twenty-two patients were symptomatic and 15 asymptomatic; most of them presented before the third decade. Thirty-one per cent of the relatives screened showed evidence of disease, and parents were rarely affected (13 per cent). Half of the adult symptomatic females presented with primary amenorrhoea. Liver laboratory tests were abnormal in only 50 per cent of patients, with gamma-glutamyltranspeptidase being the most sensitive index. Renal disease was infrequent. Serum caeruloplasmin level was the single biochemical parameter of prognostic significance (p = 0.0001). Seventy per cent of the symptomatic patients showed an improvement after treatment with penicillamine.

Adolescent↗