bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relative bioavailability of oral sustained‐release and regular‐release oxprenolol tablets at steady‐state
Authors: Gupta P. K. , Lim J. K. C. , Zoest A. R. , Lam F. C. , Hung C. T. 
Published: October 2006

AbstractThe relative bioavailability of a test sustained‐release (SR) oxprenolol tablet against an approved regular‐release (RR) tablet has been investigated at steady‐state. In a randomized two‐way crossover study, one tablet of 160mg SR oxprenolol once every 24 h and one tablet of 80 mg RR oxprenolol once every 12 h were given to 12 healthy volunteers for 5 days. Blood samples were collected from each subject just prior to each dose‐administration on days 1 through 4, and at scheduled time points on day 5 and analysed for oxprenolol concentration using HPLC. The SR tablet resulted in 42 per cent reduction in mean peak drug levels (p = 0·0341) and a statistically non‐significant 14 per cent increase in mean trough levels (p = 0·8357) than the RR tablet. However it required 160 per cent longer time to reach average steady‐state concentrations (CSS) on day 5 (1·38h for SR versus 0·53 h for RR; p =0·0205). The mean area under the plasma drug concentration—time curve at steady state (AUC96‐120) with the SR tablet was ∼ 18 per cent lower than that observed with the RR tablet, and the degree of fluctuation (DF) was reduced by 30 per cent (2·81 for SR versus 4·11 for RR;p = 0·0069). On average, a single dose of SR tablet and two doses of RR tablets maintained the drug levels above a constant CSS of 204·6 ngml−1 for 7·88 and 7·65 h, respectively (p = 0·3513).
Pharmacokinetics of diltiazem and propranolol when administered alone and in combination
Authors: Dimmitt Dan C. , Yu Dale K. , Elvin Alfred T. , Giesing Dennis H. , Lanman Robert C. 
Published: October 2006

AbstractMultiple oral doses of diltiazem (DTZ) and propranolol (PPL, 60 mg every 8 h daily for 13 doses) were administered to 14 healthy volunteers alone and in combination on three separate occasions. Serial blood samples were collected up to 24 h after dose 13 on day 5 to determine possible pharmacokinetic interactions between the two drugs. When administered alone, DTZ concentration peaked at 161·4 ng ml−1 3 h following the final dose with an elimination half‐life of 6·1 h. DTZ oral clearance was 65·11 h−1. PPL did not affect DTZ oral clearance and half‐life during the combination treatment. However, DTZ tmax was extended from 2·9 h to 3·5 h (p < 0·05) and Cmax was 144·7 ng ml−1. Unlike the parent drug DTZ, desacetyldiltiazem (DAD) plasma profile was elevated during the combination treatment. DAD Cmax and AUC both increased approximately 20 per cent (p < 0·05). PPL pharmacokinetics were altered as well. Oral clearance of PPL decreased from 80·4 1 h−1 to 61·0 1 h−1 while the half‐life increased from 5·9 h to 8·0 h (p < 0·05). PPL Cmax increased from 155·1 ng ml−1 to 167·5 ng ml−1.
Isomazole disposition in man as a function of dose and route of administration
Authors: Woodworth James R. , Delong A. F. , Fasola A. F. , Oldham S. 
Published: October 2006

AbstractThe disposition of a new cardiotonic agent (isomazole (ISO)) was evaluated in healthy volunteers after various single oral (p.o.), intravenous (i.v.), and multiple p.o. doses. Blood samples were collected after dosing in all studies, with urine collected in the single i.v. and multiple dose studies. All biological samples were measured for ISO. In the multiple dose study, samples were collected for analysis after the first and last doses administered. In addition to ISO, several known metabolites (hydroxyisomazole (OHISO), sulfone (SULF), and hydroxysulfone (OHSULF) analogs) were measured after the first and last doses given in the multiple dose study. Pharmacokinetic values compared between doses suggested no saturable processes existed over the entire dose range. The single i.v. dose data showed ISO experienced some extravascular distribution (mean Vβ = 1·82 1 kg−1), with a high clearance (mean (Cls = 18·8 ml min−1 kg−1) and a short half‐life (mean t1/2 = 1·1 h). Elimination was primarily nonrenal (Clr = 3·5 ml min−1 kg−1). Single p.o. data supported these findings and further suggested rapid absorption. ISO data from the first dose of the multiple dose study was in agreement with these data; however, the last dose showed a higher Cls (33·0 ml min−1 kg−1) (p = 0·055). Although not statistically significant, metabolite plasma data and urinary excretion patterns changed. An increase was observed in plasma AUC and metabolite excretion of SULF and OHSULF, while a decrease was observed in the same parameters for OHISO. These results suggest that multiple dosing of ISO produces autoinduction of ISO metabolism through selective metabolic routes.
Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep
Authors: Lanusse Carlos E. , Prichard Roger K. 
Published: October 2006

AbstractThe influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg−1by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1·5 mg kg−1. Blood samples were taken serially over a 120‐h period and plasma was analyzed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration—time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half‐life (t1/2β) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2t1/2β, AUC, and MRT.We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites.
A general method for calculating the mean transit times and distribution rate parameters of catenary metabolites
Authors: Cheng Haiyung 
Published: October 2006

AbstractA general method for calculating the mean transit times and distribution rate parameters is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration profiles of the metabolites and its precursor. The method is applicable to catenary metabolites with any precursor order and does not require separate administration of the metabolite. The approach is applied to published data for the primary and secondary metabolites of ketamine.
Methylxanthine levels in breast milk of lactating women of different ethnic and socioeconomic classes
Authors: Blanchard James , Webr Charles W. , Shearer Luz‐E. 
Published: October 2006

AbstractThe purpose of this study was to evaluate the dietary caffeine and dimethylxanthine concentrations in breast milk of 40 mothers from different ethnic and socioeconomic backgrounds. Their diets and drug intake were not restricted in any way. Each nursing mother provided a fasting and a combined breast‐milk sample each day for 3 consecutive days. No significant differences were found in intake levels of any of the methylxanthines among the groups tested. No significant differences were found among the four groups in breast‐milk levels of caffeine, theobromine, or paraxanthine. However, the mean theophylline milk levels were significantly higher on 2 of the 3 days examined in Anglo‐American woman compared to Hispanic‐American women. Socioeconomic and ethnic variables were also compared among the four groups. The daily amounts of methylxanthines found in the breast milk of this free‐living population of mothers do not appear to present clinically significant amounts to the infant.
Pharmacokinetics of ketoprofen in rats: Effect of age and dose
Authors: Satterwhite Julia H. , Boudinot F. Douglas 
Published: October 2006

AbstractThe effects of age and dose on the pharmacokinetics of ketoprofen were evaluated in young adult and senescent male Fischer 344 rats following intravenous administration of 2·5 and 10 mg kg−1. Plasma concentrations were measured by HPLC and free ketoprofen determined by equilibrium dialysis. The glucuronidation of ketoprofen was investigated in a preparation of rat liver microsomes and kinetic analysis of UDP‐glucuronyltransferase was carried out by determining the initial rate of metabolic activity as a function of ketoprofen concentration. Mean plasma clearance CLfree and steady‐state volume of distribution V calculated from unbound plasma ketoprofen concentrations were significantly lower in the aged rat, suggesting reduced metabolic activity and decreased ketoprofen binding to tissue components, respectively. Plasma protein binding demonstrated an age‐dependent decline due to decreases in both albumin concentration and binding affinity. Thus, plasma clearance CL and steady‐state volume of distribution Vss changes were insignificant when total plasma concentrations were examined, due to the greater free fraction of ketoprofen in the plasma of senescent rats. The maximal rate of ketoprofen glucuronidation by hepatic microsomes was reduced whereas the affinity of the metabolic enzymes for the compound was unaffected by age. Dose had a marked effect on the disposition of ketoprofen as well. Saturation of elimination pathways and tissue binding sites contributed to significant declines in CLfree and V with increasing dose. Likewise, concentration‐dependent plasma protein binding occurred, reflecting saturation of albumin binding. Thus, changes in the pharmacokinetic parameters based on total drug concentrations were offset by the increase in the unbound fraction of ketoprofen.
Distribution kinetics of FK‐506, a novel immunosuppressant, after intravenous administration to rats in comparison with cyclosporin A
Authors: Takada Kanji , Usuda Hisato , Oh‐Hashi Mamoru 
Published: October 2006

AbstractThe distribution kinetics of a novel potent immunosuppressant, FK‐506 (FK) has been studied in comparison with cyclosporin A (CyA) both in vivo and in vitro using blood specimens. The infusion studies on FK, 5·0 mg kg−1 through the portal and femoral veins showed that the mean hepatic extraction ratio of FK was 27·9 per cent. The effect of clamping both the hepatic artery and the portal vein on the plasma disappearance profiles of FK, 5·0 mg kg−1, and CyA, 3·5 mg kg−1 was studied. The plasma disposition kinetics of CyA was almost the same as in the normal rats. However, the plasma FK levels were about 10 times higher than those obtained in the control group rats. This difference is attributed to the restricted initial distribution of FK to the liver, because the volume of the initial distribution space, V1, of FK was about 10 times smaller than that obtained in normal rats. In in vitro experiments, drug distribution was studied in blood samples (2·0 ml) spiked with FK or CyA, 1·0 μg ml−1. The plasma drug levels measured at 2 min after drug administration were 0·842±0·012 μg ml−1 and 0·769±0·047 μg ml−1 for FK and CyA, respectively. The distribution volume in the blood compartment, VB, was determined by dividing the spiked amount of drugs with these plasma concentrations. The VB was 2·38±0·04 ml for FK and 2·62±0·16 ml for CyA. There was no significant difference in VB between FK and CyA. The plasma free fraction, fp of the drugs was measured by the equilibrium dialysis method. For FK, the mean fp values (±SE) were 1·31±0·18 per cent (2·0 μg ml−1) and 1·93±0·18 per cent (5·0 μg ml−1). For CyA, the fp values were 4·85±0·36 per cent (1·0 μg ml−1) and 5·75±0·82 per cent (5·0 μg ml−1). The hydrophobicity parameter, logP′ determined through the HPLC method was 0·386 for FK and 0·545 for CyA. Although FK was less hydrophobic than CyA, its protein binding was higher than CyA.
Rapid toxicological model for use in assessing ocular drugs
Authors: Ellingson Cynthia M. , Schoenwald Ronald D. , Barfknecht Charles F. , Rao Chakradhara S. , Laban Saad L. 
Published: October 2006

AbstractNonsteroidal antiinflammatory drugs (NSAIDs) were applied to corneas either by in vitro or in vivo methods. The in vitro method involved excising and mounting corneas in a perfusion system at 37° and exposing drug for 2·5h. The in vivo methods represent either topical administration to the rabbit eye or topical in vivo infusion using a fixed well which permitted a constant concentration (0·05 per cent) to be applied to the eye of anesthetized rabbits for up to 120 min. An overlay grid procedure using scanning electron microscopy (SEM) showed less per cent endothelial damage with in vivo methods than with the in vitro method of administration, but per cent damage depended on which section was viewed. Damage to the epithelium and endothelium were also assessed by quantitative carboxyfluorescein and Janus green staining and uptake procedures, respectively, following drug exposure by the in vivo infusion method. Results for the epithelium indicated that the more lipophilic NSAIDs damaged the epithelial layer to a greater degree than newly synthesized hydrophilic NSAIDs. Damage to the epithelium correlated to the surface activity of the NSAIDs. Qualitative assessment of epithelial and endothelial toxicity can be performed with SEM and transmission electron microscopy (TEM) while vital staining procedures and the SEM grid procedure can be used to quantitatively assess corneal toxicity. The staining methods, however, possess advantages over SEM and TEM procedures in that they are rapid and do not require laborious preparation. As a result of these characteristics, the vital staining procedures could be used as part of a biopharmaceutical screening technique in evaluating new ophthalmic drugs.
Studies on the intravenous pharmacokinetics in rabbit and in vitro protein binding of two new salts of erythromycin: Erythromycin maltobionate and erythromycin fumarate
Authors: Basu S. K. , Manna P. K. , Goswami B. B. 
Published: October 2006

AbstractPharmacokinetics in rabbits following intravenous administration and in vitro protein binding were studied for two new salts of erythromycin (erythromycin maltobionate and erythromycin fumarate). Serum erythromycin levels following intravenous injection were described by two compartment model kinetics, and values for the distribution volume of the central compartment, the peripheral compartment and overall distribution volume were calculated. The elimination half‐lives of erythromycins in serum were 83 min, 168 min, and 103 min for erythromycin maltobionate, erythromycin fumarate, and erythromycin lactobionate (reference standard), respectively. The erythromycin salts were highly (c. 90 per cent) protein bound, but the binding was found to be reversible. Differences in the pharmacokinetic parameters after administration of equivalent doses of the salts, indicate possible variation in efficacies of different salts.
Simultaneous modelling of mexiletine and hydroxy‐methyl‐mexiletine data after single‐ and multiple‐dose administration of a sustained‐release mexiletine formulation
Authors: Bruno R. , Santoni Y. , Iliadis A. , Djiane P. , Serradimigni A. , Cano J. P. 
Published: October 2006

AbstractThe pharmacokinetics of mexiletine and its metabolite hydroxy‐methyl‐mexiletine have been investigated following single‐dose and during multiple‐dose administration of a sustained‐release form of mexiletine to six post‐myocardial infarct patients. Comparison of single‐dose and washout pharmacokinetics, after short‐term multiple‐dose administration, showed significant (p<0·005), but not systematic, modifications in mexiletine apparent clearance for three patients. Furthermore, for these patients, simulation with both sets of parameters indicated that the steady‐state was achieved before washout experiment in two cases. The fraction of mexiletine metabolized to hydroxymethyl‐mexiletine was lower for multiple‐dose administration (about 18 per cent) than for the single dose (about 42 per cent). The hydroxy‐methyl‐mexiletine elimination rate constant was about four times that of mexiletine. Mexiletine clearance could be accounted for by other metabolic pathways. In one patient, hydroxy‐methyl‐mexiletine was undetectable even during multiple‐dose administration, despite a significant increase in mexiletine clearance. However, the observed changes in mexiletine disposition had no therapeutic implications and active plasma levels were achieved by the third day of administration and maintained in the therapeutic range (0·75 to 2 μg ml−1) in all patients after a twice daily dosage regimen.
Pharmacokinetics of oxatomide given percutaneously to healthy volunteers
Authors: Benvenuti C. , Broggini M. , Botta V. , Valenti M. , Broccali G. , Bo L. Dal 
Published: October 2006

AbstractThe percutaneous absorption of oxatomide gei at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25·7 ± 0·8 years (mean ± SEM) weighing 64·4 ± 4·5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0·2 ng ml−1 in plasma and 1·0 ng ml−1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5·03 ± 0·79 ng ml−1 following application of the gel for 7 days and 10·08 ± 1·29 ng ml−1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1·42 ± 0·39 μg and 3·93 ± 0·92 μg.
In vivo evaluation of the effect of the size and opsonization on the hepatic extraction of liposomes in rats: An application of Oldendorf method
Authors: Harashima Hideyoshi , Ohnishi Yuriko , Kiwada Hiroshi 
Published: October 2006

AbstractIn the hepatic uptake of large particles such as liposomes, a serum component called opsonin plays an important role. In this study, the ‘Oldendorf method’ is introduced to evaluate the hepatic extraction under the condition of single passage, which enabled examination of the effect of opsonization on liposome uptake by the intact liver. 14C‐labelled liposomes and, an internal reference, 3HH2O were injected as a bolus into portal vein. Liver uptake index (LUI) was calculated from the ratio of the extraction of 14C to that of 3H. The effect of liposome size (mean diameter of 0·8, 0·4, 0·2, and 0·05 μm) and opsonization (preincubation with fresh blood for 5 min) on liposomal hepatic uptake were investigated using this method. LUI increased with size significantly (p<0·001), and opsonization enhanced LUI only for the large liposomes (0·8 μm). This result suggests that the critical diameter of opsonization for these liposomes lies between 0·4 and 0·8 μm.
Comparative bioavailability and steady state fluctuations of tegretol commercial and carbamazepine oros tablets in adult and pediatric epileptic patients
Authors: Thakker Kamlesh M. , Mangat Surinder , Garnett William R. , Levy René H. , Kochak Gregory M. 
Published: October 2006

AbstractThe comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24‐h treatment interval.
The metabolism of CGS—15873 in man using stable isotope pattern recognition techniques
Authors: Leal M. , Hayes M. J. , Powell M. L. 
Published: October 2006

AbstractCGS 15873 is a relatively specific dopamine agonist with preferential activity at the presynaptic autoreceptor and therefore may represent a novel agent for the treatment of schizophrenia and/or Parkinson's disease. Several metabolites have been identified in the rat and monkey using an isotopically enriched dosing solution and pattern recognition techniques coupled with GC/MS and LC/MS. In this study, the metabolism of CGS 15873 was investigated in man using these same techniques. In urine, specific isotope clusters were found that matched the dosing solution pattern. Three metabolites were identified: an O‐glucuronide conjugate of the parent drug, N‐despropyl CGS 15873, and a keto metabolite of CGS 15873. Thermospray LC/MS allowed for the direct confirmation of the conjugated metabolite. GC/MS required derivatization but afforded greater sensitivity compared to LC/MS.
Human dolasetron pharmacokinetics: I. Disposition following single‐dose intravenous administration to normal male subjects
Authors: Boxenbaum Harold , Gillespie Todd , Heck Kathleen , Hahne William 
Published: October 2006

AbstractDolasetron is a 5‐hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy‐induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0·6 to 5 mg kg−1 dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2‐4 h. Less than 1 per cent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0·625h. (median). Its median terminal disposition half‐life was 7·56 h; median values for fraction of dose excreted in urine and renal clearance were 31·0 per cent and 2·68 ml min−1 kg−1, respectively. Over the dose‐range covered, pharmacokinetics of both dolasetron and reduced metabolite appeared to be independent of dose. The median ratio of the areas under the plasma concentration‐time curves for metabolite relative to dolasetron was 11·9. As a result of its activity and significant plasma concentrations, reduced dolasetron may play a significant role in pharmacodynamic activity.
Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization
Authors: Curry Stephen H. , Lopez Larry M. , Lambert Charles R. , Kwon Hae‐Ryun , Stack Robert K. 
Published: October 2006

AbstractIntravenous, sublingual, or aerosolized nitroglycerin was administered to 19 patients with coronary artery disease during clinically indicated cardiac catheterization. Eight blood samples were collected over 15 min from each patient, and analyzed for content of nitroglycerin, 1,2‐glycerol dinitrate, and 1,3‐glycerol dinitrate. Simultaneously, heart rate (HR), systolic blood pressure (SBP), and left ventricular end‐diastolic pressure (LVEDP) were recorded. Plasma concentrations of nitroglycerin were highest after intravenous injection and lowest after sublingual tablets. Metabolite concentrations were highest after intravenous injection at early time‐points; at later time‐points, no betweengroup differences could be detected. SBP was minimally affected by intravenous nitroglycerin but was significantly reduced by sublingual and aerosolized formulations. Minor fluctuations in HR were observed in association with all three formulations. LVEDP was reduced by all three formulations of nitroglycerin but most rapidly by the intravenous form. Overall, no differences were detected in hemodynamic responses caused by sublingual and aerosolized nitroglycerin. Efficacy of sublingual and aerosolized nitroglycerin in patients undergoing cardiac catheterization is equivalent.