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Biomedical subjects

S Y Chu

Publications and source records attributed to S Y Chu.

At least 19 recordsLinked to original sources

High-performance liquid chromatographic procedure for the determination of tiagabine concentrations in human plasma using electrochemical detection.

A sensitive and precise high-performance liquid chromatographic procedure has been developed for the measurement of tiagabine concentrations in human plasma. Isolation of tiagabine and the internal standard was achieved using solid-phase extraction on disposable C8 columns. Separation was performed on a C18 analytical column using a mobile phase containing sodium octanesulfonate. The effluent was monitored with coulometric electrochemical detection at ca. + 0.76 V. The workup procedure recovered more than 95% of tiagabine from plasma. Standard curves were linear over the concentration range 0-500 ng/ml. The precision of the method was good: coefficients of variation were typically less than 5% for concentrations as low as 8 ng/ml and although they were higher at concentrations less than 8 ng/ml, they remained within acceptable limits (less than 17%) for concentrations as low as the limit of quantitation (2 ng/ml using a l-ml plasma sample). The stability of tiagabine in plasma was excellent, with no evidence of degradation after 23 h at room temperature or 2 months at -20 degrees C.

Animals

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.

Administration, Oral

Erythromycin ototoxicity: prospective assessment with serum concentrations and audiograms in a study of patients with pneumonia.

BACKGROUND AND METHODS: The incidence and risk factors for erythromycin-induced ototoxicity are unknown. We conducted a prospective, nested case-control study of assessment of auditory function in patients receiving erythromycin versus other antibiotics (control group) for community-acquired pneumonia. Sequential audiograms were performed during antibiotic therapy for both cases and controls by an audiologist unaware of the identity of the therapy administered. Erythromycin serum concentrations were obtained for all patients receiving erythromycin. RESULTS: Symptomatic ototoxicity (tinnitus or hearing loss) confirmed by audiograms was documented in five of 30 patients receiving erythromycin and none of 15 receiving other antibiotics. Ototoxicity was significantly related to high peak concentration and high AUC 0-infinity as a function of decreased total systemic clearance. Ototoxicity occurred only in those patients who received 4 g/day versus 2 g/day or no erythromycin (p = 0.05). Ototoxicity resolved in all patients within 6 to 14 days after discontinuation of therapy. CONCLUSIONS: Erythromycin ototoxicity is dose- and serum concentration-dependent. Patients receiving erythromycin, especially at a total daily dose of 4 g, should be monitored regularly for subjective evidence of sensorineural hearing dysfunction. Ototoxicity is reversible if the diagnosis is made early in the course.

Adult

Biological actions of monoclonal luteinizing hormone/human chorionic gonadotropin receptor antibodies.

Several recent studies have elucidated the structure of the mammalian LH/hCG receptor; as reported in the present work, we have developed a series of monoclonal antibodies (mAbs) against the rat ovarian LH/hCG receptor using highly purified receptor as immunogen and by screening hybridomas with purified LH/hCG receptors. The mAbs were able to specifically immunoprecipitate LH/hCG receptors from solubilized preparations of rat ovarian membranes as well as from partially purified preparations. Western blotting with mAb P1B4 detected a probable receptor dimer and a receptor fragment in rat and porcine ovarian tissue but not in other tissues. This mAb also partially inhibited hCG binding to rat and porcine ovarian tissues. The receptor mAbs were able to inhibit hCG-induced progesterone synthesis in cultured human and porcine granulosa cells without affecting cAMP- and FSH-induced progesterone synthesis. The mAb P1B4 was used to demonstrate that the majority of ovarian receptors are internalized after hCG treatment and that in pseudopregnant rats receptors are present in the rough endoplasmic reticulum and in microvesicles. Bovine corpus luteal cells also contained P1B4 binding sites, as detected by immunohistochemical technique. Taken together, these results suggest that the mAbs are specific for the LH/hCG receptor, mAb P1B4 recognizes an epitope that is highly conserved among mammals, and this epitope is probably in the extracellular domain.

Animals

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.

Administration, Oral

Pharmacokinetics of a clarithromycin suspension in infants and children.

The single- and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (Cmax) for clarithromycin were reached within about 3 h under both conditions. The mean Cmax for the parent drug were 3.59 and 4.58 micrograms/ml in single-dose fasting and nonfasting patients, and the respective Cmax for the metabolite were 1.19 and 1.26 micrograms/ml. Data indicate good absorption and no significant effects by food. There was no unusual accumulation in the area under the concentration-time curve and Cmax in the multiple-dose group.

Administration, Oral

Absolute bioavailability of clarithromycin after oral administration in humans.

The absolute bioavailability of clarithromycin, a new macrolide antimicrobial agent, was assessed in a three-way, randomized, single-dose, crossover study conducted with 22 healthy volunteers, 19 of whom provided analyzable study data. The bioavailability parameters of two 250-mg oral tablet formulations were calculated with reference to an identical dose administered by intravenous infusion of the lactobionate salt. After adjustment for formulation potency, the mean absolute bioavailabilities of the two oral formulations were 52 and 55%, on the basis of the appearance of parent compound in the systemic circulation. Metabolite peak concentration and area under the plasma concentration-time curve data after oral dosing were generally greater than those after intravenous infusion, suggesting that marked first-pass metabolism of clarithromycin occurs after oral administration. Pharmacokinetic analysis of the parent drug and the active 14-hydroxy metabolite data suggests complete (or nearly complete) absorption of the drug after oral administration.

Administration, Oral

The reporting of HIV/AIDS deaths in women.

OBJECTIVE: This study was undertaken to assess the completeness of vital statistics and case reports of acquired immunodeficiency syndrome (AIDS) in measuring human immunodeficiency virus (HIV)-related mortality in women 15 through 44 years of age. METHODS: We used vital records to determine the number of deaths attributed to HIV infection and excess deaths due to causes that have increased in tandem with the HIV epidemic. RESULTS: In 1988, among women 15 through 44 years of age, there were 1365 deaths with HIV infection listed as the underlying cause, 202 deaths with HIV infection listed as an associated cause, and 149 excess deaths due to conditions highly associated with HIV infection (subtotal = 1716). In addition, there were 780 excess deaths due to causes that may be related to HIV infection or illicit drug use (maximum estimate of HIV-related deaths = 2496). Of the deaths that occurred in 1988, 1532 were reported through AIDS surveillance (1668 deaths when adjusted for reporting delays). CONCLUSIONS: Underlying-cause-of-death vital records and AIDS surveillance identified 55% to 80% and 67% to 97%, respectively, of HIV-related deaths in women 15 through 44 years of age in 1988. The wide ranges of these estimates reflect the potential role of both HIV infection and drug use in contributing to excess mortality.

AIDS-Related Opportunistic Infections

AIDS in bisexual men in the United States: epidemiology and transmission to women.

BACKGROUND: Homosexual and bisexual men with acquired immunodeficiency syndrome (AIDS) differ, and bisexual men play an important role in the sexual transmission of human immunodeficiency virus (HIV) to women. METHODS: To describe AIDS in these groups, we examined AIDS cases reported nationally through June 1990. RESULTS: Among 65 389 men who reported having had sex with men since 1977, 26% were bisexual. More Black (41%) and Hispanic men (31%) than White men (21%) reported bisexual behavior. Bisexual men were twice as likely to report intravenous drug use (20%) as were homosexual men (9%), regardless of race or ethnicity. Among 3555 women with heterosexually acquired AIDS, 11% reported sexual contact with a bisexual man and no other risk factor, although in some states approximately half reported such contact. In 1989, the AIDS rate due to sex with a bisexual man was three and five times higher among Hispanic and Black women, respectively, than among White women. CONCLUSIONS: Differences between bisexual and homosexual men with AIDS and the relative importance of AIDS in women due to sexual contact with bisexual men should be considered in the development of HIV prevention programs.

Acquired Immunodeficiency Syndrome

Simultaneous determination of clarithromycin and 14(R)-hydroxyclarithromycin in plasma and urine using high-performance liquid chromatography with electrochemical detection.

A sensitive method for the simultaneous high-performance liquid chromatographic determination of clarithromycin and its active metabolite in plasma and urine is described. Alkalinized samples were coextracted with an internal standard and analyzed on a C8 column using electrochemical detection. Recoveries were greater than or equal to 85% and consistent. Standard curves for plasma were linear in the range 0-2 micrograms/ml for both compounds (r greater than 0.99), with limits of quantification of approximately 10.03 micrograms/ml (0.5-ml sample). Within-day and day-to-day precision were good, with coefficients of variation mostly within +/- 5%; accuracy for both compounds were routinely within 90-110% of theoretical values. Standard curves for urine were linear in the range 0-100 micrograms/ml with limits of quantification of 0.5 micrograms/ml (0.2-ml sample). Urine assays also had similar within-day and day-to-day precisions and accuracy.

Chromatography, High Pressure Liquid

The relationship between body mass and breast cancer among women enrolled in the Cancer and Steroid Hormone Study.

We examined the relationship between body mass [weight (kg)/height (m)2] and breast cancer using data from the Cancer and Steroid Hormone Study. The study compared 4323 women aged 20-54 years with newly diagnosed breast cancer identified through population-based tumor registries with 4358 women randomly selected from the general population of the same geographic areas. Among naturally menopausal women, risk of breast cancer increased with increasing body mass index (BMI); those severely overweight (BMI greater than or equal to 32.30) had nearly 3-fold higher risk of breast cancer compared with women in the leanest category (BMI less than 20.00). This positive association appeared stronger with increasing years since menopause and in women who had ever used estrogen replacement therapy. A positive association between body mass and breast cancer risk also was observed among premenopausal women; however, risk estimates were substantially lower. Substantial weight gain from adolescence to adulthood was a more important risk factor than lifelong obesity. Prevalence of obesity increases with age; our results suggest that interventions that prevent this trend could have an important effect on breast cancer risk, especially during the menopausal years.

Adult

Risk factors for regret after tubal sterilization: 5 years of follow-up in a prospective study.

The Collaborative Review of Sterilization is a prospective, multicenter study that interviewed 7,590 women before they underwent tubal sterilization and then conducted yearly follow-up interviews that included questions on sterilization regret. These women contributed 26,641 observations (for up to 5 years after the procedure, 1978 to 1988) to an analysis of the presterilization characteristics most consistently associated with poststerilization regret. Young age at the time of sterilization was the strongest predictor of regret, regardless of parity or marital status; among women 20 to 24 years of age at sterilization, an average of 4.3% reported regret over the follow-up period. The rate of regret was significantly lower for women 30 to 34 years of age (2.4%).

Adult

Impact of the human immunodeficiency virus epidemic on mortality in children, United States.

To assess the effect of the human immunodeficiency virus (HIV) epidemic on mortality in US children younger than 15 years of age and to identify associated causes of death, the authors examined final national mortality statistics for 1988, the most recent year for which such data are available. In 1988, there were 249 deaths attributed to HIV/acquired immunodeficiency syndrome (AIDS) in children younger than 15 years of age. Associated causes of death listed most frequently on 270 death certificates with any mention of HIV/AIDS included conditions within the AIDS surveillance case definition (30%), pneumonia (excluding Pneumocystis carinii pneumonia) (17%), septicemia (10%), and noninfectious respiratory diseases (8%). The impact of HIV/AIDS as a cause of death was most striking in the 1-through 4-year-old age group and in black and Hispanic children, particularly in the Northeast. By 1988 in New York State, HIV/AIDS was the first and second leading cause of death in Hispanic and black children 1 through 4 years of age, accounting for 15% and 16%, respectively, of all deaths in these age-race groups. With an estimated 1500 to 2000 HIV-infected children born in 1989, the impact of HIV on mortality in children will become more severe.

Acquired Immunodeficiency Syndrome

Surveillance for AIDS and HIV infection among black and Hispanic children and women of childbearing age, 1981-1989.

Surveillance systems indicate that the most documented human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome (AIDS) cases among children and women of childbearing age in the United States occur among black and Hispanic populations. Intravenous-drug use (IVDU) is the presumptive origin of HIV infection for most of these cases, through direct IVDU, sexual contact with an intravenous (IV)-drug user, or birth to women with either mode of exposure. These data confirm the need for HIV-prevention programs directed to the racial, ethnic, age, and reproductive concerns of black and Hispanic women of childbearing age and their children. Services should be available for those who are HIV infected, as well as for those who are not infected with HIV, to prevent the further spread of HIV. Services for prevention and treatment of drug abuse are an integral part of HIV prevention and treatment for these groups.

Acquired Immunodeficiency Syndrome