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Biomedical subjects

W C Shyu

Publications and source records attributed to W C Shyu.

At least 55 records · Page 3Linked to original sources
PubMed1996

The absolute bioavailability and pharmacokinetics of butorphanol nasal spray in patients with hepatic impairment.

OBJECTIVE: The objective of the study was to investigate the effects of hepatic impairment on the absolute transnasal bioavailability and pharmacokinetics of butorphanol. STUDY DESIGN: Twelve (eight men and four women) healthy subjects and 12 (eight men and four women) patients with hepatic impairment received a 1 mg dose of butorphanol by intravenous or transnasal administration on two separate occasions. Hepatic function was assessed by antipyrine and indocyanine green clearance tests. Serial blood and urine samples were collected after each dose. Plasma samples were analyzed for butorphanol, and urine samples were analyzed for butorphanol and its metabolites. RESULTS: No statistical difference in maximum plasma concentration (Cmax) for butorphanol was observed between the two groups of volunteers after transnasal administration. However, total plasma clearance (CL), steady-state volume of distribution, area under the concentration-time curve [AUC(0-infinity)], and elimination half-life of butorphanol in patients with hepatic impairment were significantly altered (approximately twofold to threefold). The absolute transnasal bioavailability of butorphanol was significantly higher (approximately 20%) in patients with hepatic impairment. A greater fraction of the administered dose was recovered from the urine in hepatically impaired patients compared to that in healthy subjects (23% to 31% versus 10% to 11%). There was a significant reduction in CL of indocyanine green and antipyrine in hepatically impaired patients. The percentage of reduction in butorphanol CL was highly correlated to the estimated degree of portosystemic shunts in the patients with hepatic impairment. CONCLUSION: Based on the comparable Cmax but the increased AUC in patients with liver dysfunction, the initial dose of butorphanol nasal spray may not need to be adjusted. However, the subsequent dosing intervals for butorphanol should be prolonged.

Administration, Intranasal↗
PubMed1996

Panencephalitic Creutzfeldt-Jakob disease in a Chinese family. Unusual presentation with PrP codon 210 mutation and identification by PCR-SSCP.

A point mutation at codon 210 (GTT to ATT) of the prion protein gene on chromosome 20 was found in a 48-year-old CJD-affected woman of a Chinese family. This affected woman had an early onset and long-duration form of CJD. Serial magnetic resonance image (MRI) analysis of this woman showed severe brain atrophy, prominent diffuse white matter degeneration, and subsequent mineralization of basal ganglia and thalamus. MR spectroscopy (1H) analysis elucidated the absence of peaks of choline, creatine and N-acetylaspartate. Using polymerase chain reaction and single-strand conformational polymorphism (PCR-SSCP) techniques, presymptomatic diagnosis of the second son of this woman showed that he has a similar codon mutation of prion gene as his mother.

China↗
PubMed1996

Pharmacokinetics and pharmacodynamics of CTLA4lg (BMS-188667), a novel immunosuppressive agent, in monkeys following multiple doses.

The dose proportionality and multiple dose pharmacokinetics of CTLA4Ig, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4Ig in suppressing the immunoresponses to sheep red blood cell (SRBC) was also assessed. Two monkeys per gender were randomly assigned to one of the three dose levels, 1.0, 2.9, and 8.7 mg/kg of CTLA4Ig. The monkeys in each dose level received the assigned intravenous dose of CTLA4Ig by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4Ig on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4Ig on day 18 (last dose). In addition, predose blood samples were obtained on days 1, 4, 8, 11, 15, and 18. Serum samples were analyzed for the concentrations of CTLA4Ig using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4Ig attained steady state by day 11 regardless of the dose levels. The mean AUC0-720 values of CTLA4Ig increased in a dose proportional manner. The mean values of Cmax increased in a ratio of 1:3:3:8:5 while the dose administered increased in a ratio of 1:3:9. Predose serum concentrations (Cmin) of CTLA4Ig increased in a dose proportional manner. The mean T1/2 values were not significantly different among the dose groups, suggesting that the elimination characteristics of CTLA4Ig were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4Ig (78-98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4Ig exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0-8.7 mg/kg in monkeys.

Abatacept↗
PubMed1996

A pharmacokinetic study of intravenous CTLA4Ig, a novel immunosuppressive agent, in mice.

Three skin-intact mice in each group received a single 0.07-, 0.29-, or 0.57-mg dose of CTLA4Ig intravenously (i.v.). Three skin-grafted mice received a single 0.29-mg dose i.v. and another three skin-grafted mice received a 0.29-mg dose once daily for 7 days (the dose was administered via the tail vein). Serial blood samples (0.15 mL) were obtained by retro-orbital bleeds up to 240 h after all single doses and up to 360 h after the last multiple dose. Serum samples were analyzed for CTLA4Ig by a validated enzyme immunoassay method. The concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUCinf values increased in a dose-proportional manner in skin-intact mice. The CLT values were dose independent. The MRT, t1/2, and Vdss values at the 0.07-mg dose level were significantly lower than those obtained for both the 0.29- and 0.57-mg dose levels; however, the respective values between the 0.29- and 0.57-mg dose levels were not significantly different. No significant differences were found in the pharmacokinetic parameters between the skin-intact and skin-grafted mice.

Abatacept↗
PubMed1996

Bioequivalence of two tablet formulations of nadolol using single and multiple dose data: assessment using stereospecific and nonstereospecific assays.

Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.

Adult↗
PubMed1996

High-performance liquid chromatographic analysis of 2'-fluoro-2',3'-dideoxyadenosine and 2'-fluoro-2',3'-dideoxyinosine in dog plasma and urine.

A high-performance liquid chromatographic assay was developed and validated for a simulataneous determination of 2'-fluoro-2' 3'-dideoxyadenosine (FddA) and its metabolite, 2'-fluoro-2',3'-dideoxyinosine (Fddl) in dog plasma and urine. In vitro, FddA and Fddl exhibit activity against human immunodeficiency virus (HIV). A solid phase extraction was applied to extract FddA, Fddl, and the internal standard (IS; 3',5'-anhydrothymidine) from the biomatrices. The processed samples were chromatographed using a C8 column coupled with a mobile phase consisting of monobasic phosphate, dibasic phosphate, ethylene glycol monomethyl ether, and water. Detection was performed at 257 nm. The nominal retention times were 9, 14, and 26 min for Fddl, IS, and FddA, respectively. The lower limits of quantitation were 0.1 and 2.0 micrograms/mL in plasma and urine, respectively, for both analytes. The accuracy of the assay deviated < or = 10% from the nominal concentrations, and the precision was < or = 14% coefficient of variation. In either matrix, both analytes were stable for at least three freeze-thaw cycles and in the injection media for at least 54 h. The extraction recoveries of the analytes were greater than 80%. The application of this assay was demonstrated in a preliminary pharmacokinetic study of FddA and Fddl in dogs. Two male dogs per dose level received a 100, 250, or 500 mg/kg oral dose of FddA once daily for 14 days. The early appearance of Fddl in plasma (0.25 h; the first sampling time) and greater plasma levels of Fddl than FddA (> 50-fold of Cmax), suggested that the conversion of FddA to Fddl was rapid and extensive. Renal excretion appeared to be the major route of elimination of Fddl.

Administration, Oral↗
PubMed1996

Pharmacokinetics of butorphanol nasal spray in patients with renal impairment.

1. The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CLCR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were > or = 70 ml min-1, 30-60 ml min-1, and < or = 30 ml min-1, respectively. 2. Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy-butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection. 3. There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t1/2, MRT, and CLR with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters. 4. The elimination half-life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CLCR) significantly correlated with CLR (r = 0.563, P = 0.019), CLT/F (r = 0.505, P = 0.033), t1/2 (r = -0.554, P = 0.017) and lambda (r = 0.606, P = 0.008). 5. Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction. 6. Patients with less than 30 ml min-1 creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.

Administration, Intranasal↗
PubMed1996

Lack of pharmacokinetic interaction between butorphanol nasal spray and cimetidine.

The potential for a pharmacokinetic interaction between butorphanol nasal spray and cimetidine, under steady state conditions, was evaluated in 16 healthy male volunteers. Subjects received either a 1 mg butorphanol nasal spray every 6 h or a 300 mg cimetidine tablet every 6 h on days 1 4, the combination of two compounds every 6 h on days 5-8 and the original treatment as described in the first segment (days 1-4) on days 9-12. Serial blood and urine samples were collected on days 4, 8 and 12, and additional blood samples were taken immediately, prior to the morning dose on days 3, 7 and 11. Based on the analysis of the Cmin samples, the plasma concentrations of cimetidine and butorphanol achieved steady state by the third day of dosing. No statistically significant differences were found in the plasma concentrations of butorphanol or cimetidine (except for t1/2 and MRT) between any of the treatment phases. Butorphanol nasal spray and cimetidine can be co-administered without any adjustment of dosage for either drug.

Administration, Intranasal↗
PubMed1995

Lack of pharmacokinetic interaction between butorphanol tartrate nasal spray and sumatriptan succinate.

The pharmacokinetics of butorphanol tartrate given in a nasal spray with and without the co-administration of sumatriptan succinate were studied in 24 healthy men and women. In this crossover design study, all subjects received 2 treatments: a single 1-mg dose of butorphanol nasal spray and a 1-mg dose of butorphanol nasal spray plus a single 6-mg subcutaneous (SC) dose of sumatriptan. There was a two-week washout period between sessions. Serial blood samples were collected and plasma samples analyzed using validated radioimmunoassay and high-performance liquid chromatography/electrochemical procedures to determine the concentrations of unchanged butorphanol and sumatriptan, respectively. There were no statistically significant differences for butorphanol between the 2 treatments on any of the following pharmacokinetic parameters: Cmax, tmax, AUC, t1/2, CL/f, and Vz/f. Similarly, the pharmacokinetic parameters obtained for sumatriptan (given with butorphanol nasal spray) were comparable with the literature values obtained for a single 6-mg SC dose of sumatriptan. These data show a lack of pharmacokinetic interaction between butorphanol nasal spray and sumatriptan. Butorphanol nasal spray and sumatriptan were well tolerated. The adverse experience profiles of butorphanol nasal spray were comparable between the treatments, with and without sumatriptan. It can be concluded that regimens of butorphanol nasal spray and sumatriptan need not be changed for either pharmacokinetic or safety considerations when the two compounds are co-administered in treating acute migraine attacks.

Administration, Intranasal↗
PubMed1994

The effects of age and sex on the systemic availability and pharmacokinetics of transnasal butorphanol.

We have studied the effects of age and sex on the pharmacokinetics and the systemic availability of transnasal butorphanol in a randomized, two-way, cross-over study of 48 subjects: young men and women, and elderly men and women. Each subject took a single 1 mg dose of intravenous and transnasal butorphanol tartrate on separate occasions with a one-week washout period. Blood samples were collected over 16 hours. Plasma butorphanol concentrations were determined using radioimmunoassay. The AUC of plasma butorphanol concentrations after an intravenous injection were higher in the elderly women than in the other groups. However, there were no significant differences in Cmax and AUC between the groups after transnasal administration. The mean systemic availability of transnasal butorphanol was about 70%, except for the elderly women (48%). After intravenous and transnasal administration, the half-life and mean residence time were greater in the elderly than the young. Clearance was lower in women than men. Apparent volume of distribution was higher for elderly men than the others. The age- and sex-related changes in the pharmacokinetics of transnasal butorphanol are not large enough to necessitate dosage differences.

Administration, Intranasal↗
PubMed1994

Penetration of cefprozil into middle ear fluid of patients with otitis media.

Penetration of cefprozil into the middle ear fluid was investigated in patients with chronic otitis media. A total of 89 patients ranging from 7 months to 11 years old participated in the study. The middle ear fluid was removed by ventilation tubes inserted through the tympanic membrane at times ranging from 0.38 to 5.97 h after oral administration of a single dose of 15 or 20 mg/kg of body weight. A blood sample was also collected as soon as the middle ear fluid was removed. Plasma samples were analyzed for the concentration of cefprozil by a high-performance liquid chromatographic assay. Middle ear fluid samples were analyzed for the concentration of cefprozil by a microbiological assay. The concentrations of cefprozil in plasma ranged from 0.38 to 15.97 micrograms/ml at the 15-mg/kg dose level and from 1.28 to 21.47 micrograms/ml at the 20-mg/kg dose level. The corresponding middle ear fluid concentrations of cefprozil ranged from 0.06 to 4.44 micrograms/ml and from 0.17 to 8.67 micrograms/ml, respectively. Cefprozil penetrates well into middle ear fluid in patients with chronic otitis media.

Cephalosporins↗
PubMed1993

Recurrent ascending myelitis: an unusual presentation of herpes simplex virus type 1 infection.

We report on a healthy female with a unique relapsing transverse myelitis accompanied by herpes simplex virus type 1 (HSV-1) infection. Magnetic resonance imaging showed cord enlargement and increased signal intensity on T1-weighted image with gadolinium enhancement from T-4 to T-10 during the first attack and from C-1 to C-2 during the second episode. She was not diagnosed during the first attack. During the second episode, laboratory studies disclosed IgM and IgG antibodies to HSV at the outset with greater than fourfold increases in antibody levels in the serum and cerebrospinal fluid (CSF). Cells cultured from the CSF were positive for HSV-1 according to the immunofluorescence method. The presence of HVS-1 DNA in CSF was documented by polymerase chain reaction (PCR) technique. Acyclovir was given with a partial recovery. We anticipate that PCR assay of CSF will assist early diagnosis of herpetic central nervous system disorders.

Aged↗
PubMed1993

Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol.

A series of three-way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist-antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non-compartmental pharmacokinetic analysis. The elimination half-life of butorphanol was about 3-5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.

Administration, Buccal↗
PubMed1993

The absolute bioavailability of transnasal butorphanol in patients experiencing rhinitis.

The absolute bioavailability (f) and pharmacokinetics of transnasal butorphanol were evaluated in patients experiencing rhinitis. In an open three-way crossover study, a single 2-mg dose of butorphanol tartrate was administered by intravenous bolus injection (Treatment A), by the transnasal route (Treatment B), or by the transnasal route with pretreatment of the vasoconstrictor, oxymetazoline (Treatment C). Plasma concentrations of butorphanol were determined using a drug specific radioimmunoassay. The pharmacokinetic parameters were derived using the noncompartmental methods. Butorphanol was rapidly absorbed after transnasal administration. The mean maximum concentrations (Cmax) for the transnasal treatment with and without pretreatment of oxymetazoline were 1.61 and 3.01 ng.ml-1, respectively. The corresponding mean absorption times (MAT) were 1.34 and 0.23 h. The mean half-life values were 5.95, 6.28, and 5.77 h, for treatments A, B, and C, respectively. The resulting mean area under the plasma concentration curve (AUC) values were 11.9, 8.6, and 8.07 ng.h.ml-1 for treatments A, B, and C, respectively. The estimates for absolute bioavailability (f) of transnasal butorphanol were 69% and 72% when administered with and without oxymetazoline, respectively. The mean CLT and Vss were 121 l.h-1 and 791 l, respectively, for the intravenous treatment. The pretreatment of oxymetazoline significantly lowered the Cmax and prolonged the absorption time of butorphanol. Although the rate of absorption of transnasal butorphanol was affected by oxymetazoline, the absolute bioavailability in rhinitis patients (72%) was similar to that found with the pretreatment of oxymetazoline (69%) and those reported in healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1993

Biopharmaceutics of didanosine in humans and in a model for acid-labile drugs, the pentagastrin-pretreated dog.

Didanosine is a purine nucleoside analogue approved for the treatment of human immunodeficiency virus infection. It is extremely unstable at pH values less than 3 and requires protection against gastric acid-induced hydrolysis. Beagle dogs pretreated with pentagastrin, an analogue of gastrin that reproducibly stimulates gastric acid secretion, have been used to screen different didanosine formulations. The absolute bioavailability of didanosine from a saline solution decreased from approximately 43% in untreated dogs to 8% after pretreatment with pentagastrin. Administration of buffered solution of didanosine to untreated and pretreated dogs yielded bioavailability estimates of 37 and 30%, respectively. In humans, the bioavailability from a similar buffered solution was approximately 40%. Pentagastrin-pretreated dogs were used to evaluate four new products relative to a citrate-phosphate buffer sachet, the formulation selected for large-scale clinical trials in humans. Two of these new formulations, a chewable tablet and an antacid suspension, were more bioavailable then the reference sachet. This also proved to be true in man, necessitating an adjustment in the dose of didanosine when administered as the chewable tablet. Dogs pretreated with pentagastrin accurately predicted the improved bioavailability of new didanosine formulations prior to clinical use. This animal model may be helpful in evaluating the biopharmaceutics of other acid-labile drugs.

Adult↗
PubMed1993

Multiple-dose phase I study of transnasal butorphanol.

The safety, tolerance, and pharmacokinetics of transnasal butorphanol were evaluated in a double-blind, multiple-dose phase I study. A total of 18 subjects received either placebo (n = 6) or a single transnasal dose of 2 mg butorphanol tartrate on the first day and 1, 2, and 4 mg doses of butorphanol tartrate every 6 hours on days 2 through 6, 7 through 11, and 12 through 16, respectively. Safety assessment was performed on days 7, 12, and 17. Serial blood samples were collected on days 1, 6, 11, and 16, and the plasma was analyzed for unchanged butorphanol by a validated and specific radioimmunoassay. Butorphanol was rapidly absorbed and peak levels in plasma were generally attained within 1 hour after the nasal administration. The values of maximum concentration, minimum concentration, and area under the concentration versus time curve from time zero to the dosing interval [AUC(0-tau)] increased as the administered dose increased in a dose-proportional manner. The values of AUC from time zero to infinity after a single dose of 2 mg butorphanol tartrate, 10.9 ng.hr/ml, were identical to the values of AUC(0-tau) after a multiple administration of 2 mg dose, 10.4 ng.hr/ml. Mean elimination half-life value was 5.45 hours. Steady state was reached in fewer than eight doses when given every 6 hours. Transnasal butorphanol was well tolerated by all subjects. After repeated administration of transnasal butorphanol, no significant changes were observed in the nasal examination, which included evaluation of color, wetness, and thickness of nostril membrane, air flow, airway patency, and general nasal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗