Biomedical subjects

K C Yeh

Publications and source records attributed to K C Yeh.

At least 37 records · Page 2Linked to original sources

PubMed1998

Single-dose pharmacokinetics of indinavir and the effect of food.

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

Adult↗

PubMed1997

A cyanobacterial phytochrome two-component light sensory system.

The biliprotein phytochrome regulates plant growth and developmental responses to the ambient light environment through an unknown mechanism. Biochemical analyses demonstrate that phytochrome is an ancient molecule that evolved from a more compact light sensor in cyanobacteria. The cyanobacterial phytochrome Cph1 is a light-regulated histidine kinase that mediates red, far-red reversible phosphorylation of a small response regulator, Rcp1 (response regulator for cyanobacterial phytochrome), encoded by the adjacent gene, thus implicating protein phosphorylation-dephosphorylation in the initial step of light signal transduction by phytochrome.

Amino Acid Sequence↗

PubMed1997

Analysis of metabolite kinetics by deconvolution and in vivo-in vitro correlations of metabolite formation rates: studies of fibrinogen receptor antagonist ester prodrugs.

The pharmacokinetics of L-767,679, a potent fibrinogen receptor antagonist, were characterized following administration of its ethyl ester prodrug to dogs and monkeys. Deconvolution analysis was performed to determine the rate and extent of (1) the formation of L-767,679 from the prodrug in the systemic circulation, (2) the composite input (systemic and presystemic) of L-767,679 to the general circulation after oral administration of the prodrug, (3) the oral input of the prodrug, and (4) the input of the presystemically formed L-767,679 following oral administration of the prodrug. The results indicated that there were species differences in the kinetics of the disposition of L-767,679 and its prodrug. In dogs, the prodrug was absorbed faster than it was converted to the active drug, and the presystemic formation of L-767,679 contributed to about one-half of the total input of L-767,679 following oral administration of the prodrug. In monkeys, the low input of L-767,679 following oral administration of the prodrug was not due to an inefficient formation of L-767,679 in the systemic circulation but rather to the low oral bioavailability of the prodrug. Virtually all of the total oral input of L-767,679 following administration of its prodrug to monkeys resulted from the presystemic metabolism of the prodrug. These results were consistent with the finding in monkeys that the ester prodrug underwent extensive transformation to metabolites other than L-767,679. In addition, the present study also demonstrated a correlation between in vivo formation rates of L-767,679 determined using deconvolution analysis following its ethyl, methyl, and isopropyl esters in dogs and the ethyl ester in monkeys and in vitro formation rates of L-767,679 obtained following incubations of the corresponding esters with dog and monkey liver microsomes. The results suggested that deconvolution and/or convolution analysis together with in vitro metabolism results could potentially be used to predict in vivo formation rates of other ester prodrugs of L-767,679 and also plasma concentrations of L-767,679 as a function of time, following administration of its prodrugs.

Animals↗

PubMed1996

Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans.

Indinavir, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-tertiary- butylaminocarbonyl-4-(3-pyridylmethyl)piperazino]-4(S)- hydroxy-2(R)-phenylmethylpentanamide (L-735,524,MK-639, ayl-4- Crixivan), is a potent and specific inhibitor of the HIV-1(3 protease for the treatment of AIDS. Disposition of [14C]indinavir was investigated in six healthy subjects after single oral administration of 400 mg. AUC, Cmax, and Tmax values for indinavir were 492 microM x min, 4.7 microM, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times higher than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir were 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC-MS/MS analyses of urine showed the presence of indinavir and low levels of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyindanylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridine N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and indinavir (M6). M5 and M6 were the major metabolites in urine. The metabolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along with the urinary excretion of approximately 19%, suggested that the absorption of the drug was appreciable. In the feces, radioactivity was predominantly due to M3, M5, M6, and the parent compound. Thus, in urine and feces, the prominent metabolic pathways were oxidations and oxidative N-dealkylations. Excretion of the quaternary N-glucuronide metabolite in the urine, which is a minor metabolite in human, was specific to primates.

Adult↗

PubMed1995

Novel oral medication delivery system for famotidine.

A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)-antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40-mg famotidine wafer and the marketed 40-mg famotidine tablet were studied in a 2-period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post-dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20-mg and 40-mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40-mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage from for patients on H2-antagonist therapy.

Administration, Oral↗

PubMed1995

Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease.

The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.

Adult↗

PubMed1994

Point mutations in the chloroplast 16s rRNA gene confer streptomycin resistance in Nicotiana plumbaginifolia.

In a previous paper we reported the isolation of streptomycin-resistant mutants from Nicotiana plumbaginifolia and presented evidence for chloroplast control of the resistance trait. To understand the molecular basis of the resistance in these mutants, we sequenced three regions in the chloroplast 16s rRNA gene, which correspond to the 5' terminus, the 530 loop, and the 900 stem/loop of Escherichia coli 16s rRNA, and compared them with the sequences of the wild-type. Our results show that: (1) nine mutants have a C to T change at position 912, (2) one mutant (SR1021) has a G to A change at position 885, (3) one mutant has a C to T change at position 526, based on E. coli numbering; and (4) three mutants do not have any change in the regions analyzed. The point mutation detected in SR1021 has not been reported previously. In E. coli 16s rRNA, position 885 is protected from chemical probing by ribosomal protein S12 and is closely juxtaposed with the streptomycin-binding region (positions 912-915) in the predicted secondary structure. It is likely that the G to A transition at this position is a novel mutation for streptomycin resistance.

Amino Acid Sequence↗

PubMed1994

Human pharmacokinetics and tolerability of L-697,639, a non-nucleoside HIV-1 reverse transcriptase inhibitor.

L-697,639, a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in vitro, was administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single and multiple oral doses. Single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, produced no clinically important adverse events. Dose proportionality with respect to AUC was seen over the range of 25-100 mg administered as a single dose. Single doses of 200 mg and 500 mg resulted in an increase in AUC and Cmax that was less than proportional to the increase in dose. The mean Cmax after single doses of 25 and 500 mg were 0.9 and 5.8 microM respectively. Mean Tmax values ranged from 1.7-3 h. Mean AUCs (0-48 h) were from 6.05 to 50.3 microM h after doses from 25 to 500 mg respectively. After the 500-mg dose less than 0.7% appeared unchanged in the urine over 48 hours. During multiple doses, steady-state was reached on day 3 and slight accumulation occurred (approximately 1.5-fold). L-697,639 was well tolerated for up to ten days at doses that resulted in mean steady-state trough concentrations that exceed their in-vitro susceptibilities.

Adult↗

PubMed1993

[Combined pregnancy: a case report and literature review].

Combined or heterotopic pregnancy has been regarded as extremely rare in the past three decades. If it continues without diagnosis, a life-threatening situation may occur. A case of eight-week gestation is presented in which there was threatened abortion. The patient underwent exploratory laparotomy for internal bleeding. Upon operation, combined pregnancy, with a ruptured ectopic pregnancy, was diagnosed. Left salpingectomy was performed uneventfully. Neither chronic salpingitis nor administration of ovulation-induction agents was part of past history. A viable ongoing intrauterine pregnancy continued after operation, and a normal male was delivered by cesarean section after a 39-week gestation where labor progressed too slowly for normal delivery.

Adult↗

PubMed1993

[Twin pregnancy complicated by single intrauterine death. Report of six cases and literature review].

From 1982 to 1991, six twin pregnancies, in which one of the fetuses died in utero, have been encountered. The causes of antepartum death in twin gestation could be identified in four cases; one with abruptio placenta, one with twin-to-twin transfusion syndrome, one with twisting of cord and one with velamentous insertion of cord. All six surviving infants had no abnormality in the follow-up of two to seven years. Although a conclusion about the prognosis could not be drawn from such a small series, these good results may have resulted from 1) 2 cases having been dichorionic twins, and 2) the other 4 monochorionic twins of 31-36 gestation weeks were delivered 1 to 5 days after the diagnosis. Conservative treatment was usually suggested until the fetal lung was mature enough for induction of labor. One case was treated after the death of its counterpart with tocolytic agent for a further 15 days because of prematurity. Cesarean section was performed finally for fetal distress resulting from chronic abruption placenta. The other five cases were delivered through vaginal route. According to experience as well as literature review, to improve the prognosis, obstetricians should be familiar with the management of one fetal death in twin pregnancy, especially in those with monchorionic twins.

Adult↗

PubMed1991

Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR).

The gastrointestinal transit and systemic absorption of Sinemet CR (50-200) controlled-release tablets and standard Sinemet (25-100) immediate-release (IR) tablets have been studied in fasted and fed healthy human subjects. Both formulations were labelled with a gamma-emitting radionuclide and their gastric emptying, colon arrival and in vivo disintegration profiles monitored using gamma scintigraphy. The IR dosage forms were found to disperse soon after administration and to empty rapidly from both fasted and fed stomachs. Erosion of the CR system was independent of food or stomach pH. The CR tablet was observed to disintegrate fully in the gastrointestinal (GI) tract, resulting in complete release of levodopa over a 3-4 h time period. Considerable intersubject variation was found to exist for levodopa absorption. Absorption was more protracted with Sinemet CR than with standard Sinemet, due to the controlled release characteristics of the tablet matrix. There was no rapid initial absorption phase and instead, a gradual build-up in the absorption profile occurred.

Adult↗

PubMed1990

Simultaneous high-performance liquid chromatographic analysis of carbidopa, levodopa and 3-O-methyldopa in plasma and carbidopa, levodopa and dopamine in urine using electrochemical detection.

Two assay procedures are described for the analysis of levodopa, carbidopa and 3-O-methyldopa in plasma and levodopa, carbidopa and dopamine in urine. The methods are suitable for quantifying the analytes following therapeutic administration of levodopa and carbidopa. Both were based on reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and with methyldopa as the internal standard. Plasma samples were prepared by perchloric acid precipitation followed by the direct injection of the supernatant. Urine was prepared by alumina adsorption, and the analytes were desorbed with perchloric acid solution containing disodium EDTA and sodium metabisulfite prior to injection into the HPLC system. The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa.

Carbidopa↗

PubMed1990

Inhibition of human periodontal prostaglandin E2 synthesis with selected agents.

Considerable evidence has demonstrated the importance of PGE2 synthesis in the pathogenesis of periodontal disease. Although various cyclooxygenase inhibitors have been known to block periodontal PGE2 synthesis and prevent disease progression in animal models, there are few reports comparing relative efficacies of various inhibitors of arachidonic acid (ARA) metabolism. We have developed a sensitive in vitro assay to measure PGE2 synthesis in periodontal tissues. The apparent IC50 values (i.e. the concentration of drug which causes 50% inhibition of maximum PGE2 synthesis) have been determined for a series of arachidonic acid analogues as well as competitive and non-competitive cyclooxygenase inhibitors. Periodontal tissue homogenates were incubated in the presence of 3H-arachidonic acid for 45 min at 37 degrees C. Inhibitors were tested at 10(-10)-10(-4) M and at zero concentration to measure conversion of 3H-arachidonate to 3H-PGE2. Log or half log dilutions of inhibitors were tested in triplicate for each assay. Radiolabeled PGE2 was extracted from homogenates, purified by reverse phase chromatography and quantitated by double antibody capture. RIA was performed on each homogenate to determine the amount of endogenous unlabeled PGE2 present in the sample to correct for antibody capture recovery. The apparent IC50 values were determined for each drug by averaging two or more replicate assays. Specific total enzymatic activity of periodontal tissue homogenates was typically 5-11 pg PGE2/min/mg tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗

PubMed1989

Pharmacokinetic evaluation of stable piecewise cubic polynomials as numerical integration functions.

A numerical integration method based on piecewise cubic polynomial for computing the area under the curve in pharmacokinetics is presented. The method has been found to produce stable and monotone interpolations irrespective of experimental error. Spurious oscillations occasionally associated with cubic splines are eliminated. Comparisons with the previously available methods suggest that more reliable and less biased areas under the plasma concentration curve, AUC, or areas under the first moment of plasma curve, AUMC, can be generated by the present method.

Mathematical Computing↗

PubMed1989

Pharmaceutical design and development of a Sinemet controlled-release formulation.

Many different formulation techniques are available for designing controlled-release dosage forms. Five different erosion-controlled or diffusion-controlled delivery systems were evaluated to select the 1 most suitable for Sinemet CR. The system ultimately selected, containing carbidopa-levodopa 50-200 mg, is a monolithic matrix tablet designed to have both of its active components released by surface dissolution and erosion. This system was found to be the most effective following extensive in vitro testing, pharmacokinetic studies, and clinical trials. Sinemet CR releases both carbidopa and levodopa by a 1st-order release rate. Controlled-release dosage forms of levodopa with slower in vitro release rates have lower plasma levels.

Antiparkinson Agents↗

PubMed1989

Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies.

The pharmacokinetics of Sinemet CR, a controlled-release formulation containing carbidopa and levodopa, were investigated in healthy young and elderly volunteers and in patients with Parkinson's disease. Sinemet CR produced more sustained plasma levels of levodopa, carbidopa, and 3-O methyldopa than did conventional Sinemet. In elderly subjects, the corresponding steady-state plasma levels fluctuated in narrower ranges with Sinemet CR than those following the administration of Sinemet. Results indicate a levodopa bioavailability of 71% for Sinemet CR, in contrast to a bioavailability of 99% for Sinemet for these subjects. The carbidopa bioavailability of Sinemet CR was 58% relative to that of Sinemet. Systemic decarboxylase inhibition was comparable between the 2 regimens as indicated by the renal clearance of levodopa. The absorption of levodopa was slower and more protracted with Sinemet CR than with Sinemet. Food increased the levodopa bioavailability of Sinemet CR. This increase was attributed to an increased gastric retention time. No dose-dumping occurred with Sinemet CR in either the nonfasting or the fasting state. Levodopa bioavailability was lower in young volunteers than in elderly volunteers. This was attributed to an age-related decrease in gastric emptying and in 1st-pass metabolic decarboxylation in the gastrointestinal (GI) tract. In parkinsonian patients, as in healthy subjects, the Sinemet CR formulation produced more sustained levodopa plasma levels. These patients required a higher total daily dosage of Sinemet CR than of Sinemet for control of parkinsonian symptoms, but less frequent dosing was required during chronic therapy. Peak plasma levodopa levels increased proportionately with increasing Sinemet CR dosage. These observations were consistent with the pharmacokinetic characteristics of the formulation.

Adolescent↗

PubMed1988

Stereoselective disposition of the geometric isomers of a novel lipoxygenase cyclo-oxygenase inhibitor in dog and photochemical interconversion of its isomers.

A sensitive (10 ng/mL) and specific high-performance liquid chromatographic (HPLC) assay, with electrochemical (EC) detection, for the geometric isomers of 3-hydroxy-N-(2-phenyl-2-(2-thienyl)ethenyl-5-(trifluoromethyl)benzo(b) thiophene-2-carboxamide in dog and human plasma has been developed. Both isomers strongly absorb light, leading to an efficient E in equilibrium Z photoisomerization. After iv administration of a single isomer (Z) to a dog, only the Zisomer was detected in plasma; no in vivo conversion to the E isomer was observed. However, when a mixture of the E and Z isomers (58.6:41.4) was administered in the same manner to the same dog, the E:Z ratio decreased significantly to 47.5:52.5 six hours after drug administration, indicating stereoselective disposition of the isomers. The elimination of the E isomer was found to be faster than that of the Z isomer.

Animals↗

PubMed1988

Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man.

The plasma and urine concentrations of famotidine, a new, potent H2-receptor antagonist, have been measured in 16 healthy young adults, 8 healthy elderly people and 18 patients with varying degrees of renal dysfunction after intravenous administration. Both the plasma elimination and renal excretion of famotidine were decreased in the elderly volunteers and renal patients. The renal clearance of famotidine averaged 4.43 ml/min/kg (310 ml/min) in normal young volunteers, which exceeded the mean creatinine clearance 1.55 ml/min/kg (109 ml/min), suggesting net secretion is a significant mechanism for elimination of famotidine. The ratio of famotidine renal clearance to creatinine clearance decreased as creatinine clearance decreased; these results suggest that the deterioration in the secretion process was much faster than that in glomerular filtration and are incompatible with the "intact nephron hypothesis". Nevertheless, both total body clearance and renal clearance were significantly correlated with creatinine clearance. The apparent half-life was also significantly correlated with creatinine clearance. Since famotidine is essentially free of dose-related adverse effects, dose adjustment in patients with mild renal insufficiency and in elderly people is not required; however, either a prolonged dosing interval or a decrease in daily dose during long-term therapy may be adapted for the patients with severe renal insufficiency to avoid accumulation and the potential undesirable effects.

Adult↗