bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioavailability of pseudoephedrine from controlled release formulations in the presence of guaifenesin in human volunteers
Authors: Pade Vaishali , Aluri Jagadeesh , Manning Linda , Stavchansky Salomon 
Published: October 2006

AbstractA multiple‐dose bioequivalence study with six healthy human volunteers was conducted. The bioavailability of an experimental controlled release tablet containg pseudoephedrine was compared with a marketed controlled release pseudoephedrine capsule in a three‐way crossover study. Plasma samples, collected serially after oral drug administrtion, were analyzed for pseudoephedrine content using a specific HPLC method with UV detection. The bioavailability parameters, area under the concentration‐time curve (AUC), maximum plasma concentraton Cmax, and time to peak (Tmax) were obtained from the plasma concentraton—time data. Additionally, model independent pharmacokinetic parameters were estimated. Analysis of variance of the data revealed no statistically significant differences between the test and the reference formulation. The presence of guaifenesin in the sustained release tablet did not influence pseudoephedrine bioavailability. The relative bioavailability of the tablet dosage form with respect to the capsule was found to be 100.8%. Classical and Westlake 95% confidence limits as well as the two one‐sided t test, proposed by Schuirmann, and the Anderson—Hauck power analysis supported the inference that the two formulations demonstrated comparable bioavailability, even in the presence of guaifenesin.Using a non‐linear regression program, it was found that the parmacokinetics of pseudoephedrine followed a simple one‐compartment disposition model with no lag time. Additionally, an in vitro—in vivo correlation, based on the estimation of cumulative relative fraction absorbed, was developed between the absorption of pseudoephedrine in humans and the in vitro dissolution time.
Evaluation of the effects of ambroxol on the ofloxacin concentrations in bronchial tissues in COPD patients with infectious exacerbation
Authors: Paganin Fabrice , Bouvet Oliver , Chanez Pascal , Fabre David , Galtier Marc , Godard Philippe , Michel Francois B. , Bressolle Françoise 
Published: October 2006

AbstractInfectious excerbations of COPD are generally due to Streptococcus pneumoniae, Haemophilus speicies, and other Gram‐negative bacteria. Ofloxacin has potent activity against Gram‐negative species but is less effective against Gram‐positive species including Streptococcus pneumoniae. It has also been shown that the administration of ambroxol increases the concentration of some antibiotics in pulmonary tissues. The aim of the study was to determine whether ambroxol increases the bronchial tissue concentrations of ofloxacin to a level exceeding the MIC90 of the bacterial species less susceptible to ofloxacin. 24 patients with COPD were randomized in two groups. Drug regimens of ofloxacin alone (200 mg twice daily) or ofloxacin (200 mg twice daily) + ambroxol (30 mg thrice daily) were administered over 10d. A fibroscopy was performed on day 10 with bronchial biopsies and broncho‐alveolar lavage. At steady state, concentrations of drug in plasma and bronchial samples were assayed by HPLC with fluorometric detection. There was no significant difference in the bronchial levels of ofloxacin between the two groups; however, in alveolar cells, ofloxacin concentration was three times higher in the group with ambroxol. Ambroxol does not increase ofloxacin concentrations in bronchial tissue because high concentrations are already present in the lung.
Disposition and bioavailability of the β1‐adrenoceptor antagonist talinolol in man
Authors: Trausch Beate , Oertel R. , Richter K. , Gramatté T. 
Published: October 2006

AbstractIn an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β1‐adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC‐MS. At the end of infusion a peak serum concentration (Cmax) of 631 ± 95 ng mL−1 (mean ± SD) was observed. The area under the serum concentration‐time curve from zero to infinity (AUC0‐∞) was 1433 ± 153 ng h mL−1. The following parameters were estimated: terminal elimination half life (t1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg−1; and total body clearance, 4.9 ± 0.6 mL min−1 kg−1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a Cmax of 168 ± 67 ng mL−1 was reached after 3.2 ± 0.8h. The AUC0‐∞ was 1321 ± 382 ng h mL−1. The t1/2 was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first‐pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to be altered in poor metabolizers of debrisoquine type.
Pharmacokinetics of amphotericin B in rats as a function of dose following constant‐rate intravenous infusion
Authors: Chow Hsiao‐Hui , Wu Yuhong , Mayersohn Michael 
Published: October 2006

AbstractAmphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague‐Dawley rats were given diferent two‐step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 ± 0.33, 0.86 ± 0.24, and 0.37 ± 0.04mL min−1 kg−1 for the lowmedium and high‐dose groups, respectively; p < 0.05). Signs of renal impairment were observed in the high‐dose group, as documented by decreased creatinine clearance. Dose‐dependent renal clearance may have ben due either to nephrotoxicity associated with the high dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time‐averaged values (based on the estimation of area under the plasma concentration‐time profile). This suggests that clearance calculations from time‐averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation of systemic clearance.
The effect of caffeine on the pharmacokinetics of acetaminophen in man
Authors: Iqbal Nadeem , Ahmad Bashir , Janbaz Khalid Hussain , Gilani Anwar‐Ul Hassan , Niazi Sarfaraz Khan 
Published: October 2006

AbstractThe influence of caffeine (60 mg) was studied on the pharmacokinetic characteristics of acetaminophen (500 mg single dose) in ten healthy male human volunteers in a complete cross‐over design. A high‐performance liquid chromatography (HPLC) method was used to analyse serum drug concentrations. Caffeine caused a highly significant (p < 0.01) increase in AUC and AUMC, a significant (p < 0.05) increase in Cmax, and a significant (p < 0.05) decrease in clearance (Cl/F) of acetaminophen. We conclude that caffeine taken in doses commonly available commercially or in a cup of coffee can significantly potentiate the therapeutic potential of acetaminophen in man.
Influence of leucine on intestinal baclofen absorption as a model compound of neutral α‐aminoacids
Authors: Cercós‐Fortea T. , Polache A. , Nácher A. , Cejudo‐Ferragud E. , Casabó V. G. , Merino M. 
Published: October 2006

AbstractThe inhibitory effect of the essential α‐aminoacid L‐leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5–100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations, however, did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (±0.08)h−1, Ki = 0.25 (±0.09)mM, AIC= −97.02. In the light of some of the absorption features of the drug, however, the residual absorption of baclofen in the presence of high leucine concentrations should be attributed to another transport system not used by leucine.Apparent parameters characterizing absorption of leucine in the presence of baclofen (0.5mM) were Vm=61.02 (±5.46)mM h−1; Km=8.04 (±0.89)mM, and AIC=62.25. The results indicate that baclofen and leucine share some carriers in the intestinal absorption processes. Since leucine is an essential dietary aminoacid, and therefore a normal food component, this finding could be relevant in preventing interactions that would lead to a reduced oral bioavailability during baclofen therapy.
Effects of sensory (teasing) exposure to food on oral propranolol bioavailability
Authors: Power John M. , Morgan Denis J. , McLean Allan J. 
Published: October 2006

AbstractIn order to further examine the mechanism of the increase in the plasma propranolol concentration versus time curve (AUC) caused by ingestion of propranolol with food, we administered R, S‐propranolol tablets (0.5mg kg−1) orally to healthy human volunteers and dogs in the presence and absence of sensory exposure to food without ingestion (teasing). Six healthy human volunteers were fasted on one occasion and on the other they were presented with an appetising meal, without eating it (teasing protocol). There was a strong trend to a greater propranolol AUC in the teasing protocol (139.54 mg mL−1 h−1 fasting, 178.105 mg mL−1 h−1 teasing; p=0.1), and time of peak concentration (tmax) was significantly prolonged (80.22min and 120.32 min, respectively; p<0.03). Further studies were carried out in dogs who received R‐propranolol (2 mg kg−1) as an oral solution by gavage tube on four different occasions: fasting, following intragastric administration of a high‐value liquid meal, following teasing with food in the animal house at normal feeding time (high‐intensity teasing), and following teasing with food at a time and place not associated with feeding (low‐intensity teasing). There were no significant differences in pharmacokinetic parameters between the fasting and intragastric food protocols. Low‐intensity teasing resulted in significantly lower AUC and peak concentration (Cmax) compared with fasting (p<0.05), confirming food effect patterns known to occur in dogs. High‐intensity teasing resulted in significantly greater AUC and Cmax compared with fasting (p<0.05), reproducing in dogs the increase in propranolol AUC known to occur with food ingestion in humans. These findings suggest that the mechanism of the ‘food effect’ may involve physiological responses to the sight and smell of food additional to mechanisms activated by ingestion.
Factors influencing the protein binding of azosemide using an equilibrium dialysis technique
Authors: Lee Sun H. , Lee Myung G. 
Published: October 2006

AbstractVarious factors most likely to influence the plasma protein binding of azosemide to 4% human serum albumin (HSA) were evaluated using equilibrium dialysis at the initial azosemide concentration of 10 μg mL−1. It took approximately 8h of incubation to reach an equilibrium between 4% HSA and isotonic phosphate buffer of pH 7.4 containing 3% dextran (the ‘buffer’) using a Spectra/Por 2 membrane (molecular weight cut‐off 12000–14000) in a water bath shaker kept at 37°C and a rate of 50 oscillations min−1. Azosemide was fairly stable both in 4% HSA and in the ‘buffer’ for up to 24h. The binding of azosemide to 4% HSA was constant (95.5 ± 0.142%) at azosemide concentrations ranging from 5 to 100 μg mL−1. However, the extent of binding was dependent on HSA concentration: the values were 88.4, 91.0, 92.2, 94.2, 94.9, 94.9, and 94.9% at albumin concentrations of 0.5, 1, 2, 3, 4, 5, and 6% respectively. The binding was also dependent on incubation temperature; the binding values were 97.0, 94.9, and 94.9% when incubated at 6, 28, and 37°C, respectively. The binding of azosemide was also influenced by buffers containing various chloride ion concentrations and buffer pHs. The binding values were 95.3, 94.9, and 93.6% for the chloride ion concentrations of 0, 0.249, and 0.546%, respectively, and the unbound values were 6.8, 5.1, 3.8, 3.4, and 3.3% for buffer pHs of 5.8, 6.4, 7.0, 7.4, and 8.0, respectively. The binding of azosemide was independent of the quantity of heparin (up to 40 UmL−1), AAG (up to 0.16%), sodium azide (NaN3, up to 5%), its metabolite, Ml (up to 10 μg mL−1), and anticoagulants (EDTA and citrate).
A population pharmacokinetic study of alminoprofen penetration into synovial fluid
Authors: Tod M. , Pobel C. , Le Gros V. , Louchahi K. , Petitjean O. , Brion N. , Garcia‐Mace J. L. 
Published: October 2006

AbstractThe pharmacokinetics of alminoprofen in plasma and synovial fluid (SF) at steady state (300 mg t.i.d.) was studied in 45 patients with knee effusion. Plasma and SF samples, one each per patient, were obtained. Six groups were made according to the time of sampling after ingestion of the 13th dose: 1h (n = 7), 2h (n = 7), 4h (n = 7), 6h (n = 10), 8h (n = 6), 12h (n = 8). A three‐compartment model was used to describe alminoprofen kinetics in plasma and SF, with two parameterizations, a ‘classical’ and a ‘physiological’ one. The non‐linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean ±SE of the estimates (coefficient of variation of interindividual variability as a percentage) were volume of distribution, 11.0 ± 1.711 (12%); elimination rate constant, 0.236 ± 0.025 h−1 (18%); absorption rate constant 2.80 ± 0.31 h−1 (464%), clearance of influx into SF, 0.29 ± 0.14 mL min−1; clearance of efflux into plasma, 0.56 ± 0.25 mL min−1. These two clearances were not significantly different, which indicates that passive diffusion occurs in both directions. The mean ±SD alminoprofen concentration versus time curve in plasma and SF at steady state was simulated and showed that the mean ±SD maximal concentration in SF was 8.1 ± 6.3 mg L−1 and was obtained 4h after dose administration.
Pharmacokinetic parameters of antipyrine in dog after hepatectomy
Authors: Galtier Marc , Briand Dominique , Pinguet Frederic , Gomeni Roberto , Fabre David , Bressolle Francoise 
Published: October 2006

AbstractPharmacokinetic studies with antipyrine were carried out on beagle dogs to determine the consequence of hepatectomy on hepatic drug metabolizing capacity, the rate of hepatic regeneration, and the possible beneficial effect of hepatocellular transplantation. The drug (250 mg) was administered by short IV infusion in three groups of dogs (first group, 65% hepatectomy; second group, 65% hepatectomy with hepatocyte transplantation; third group 80% hepatectomy). Pharmacokinetic parameters of antipyrine were evaluated before surgery and within 10 d after surgery. Blood samples were taken at frequent intervals after drug administration and antipyrine was assayed in plasma by a specific HPLC method with UV detection. Before surgery, the mean elimination half‐life was about 1.1 h and total clearance averaged 6 L h−1. In dogs with 65% hepatectomy, no statistical differences in pharmacokinetic parameters of antipyrine appeared before or after surgery. When 65% hepatectomy was associated with hepatocyte transplantation, a significant increase in elimination half‐life and a significant decrease in total clearance were observed. The same statistical differences in the pharmacokinetic parameters were observed in the group with 80% hepatectomy. Transplantation of isolated hepatocytes into the spleen did not correct hepatocellular insufficiency. In this study, numerous laboratory tests were performed. A significant correlation was found between serum albumin, cholesterol, factor V, ALAT, total bilirubin, and ratio of aminoacids and the pharmacokinetic parameters of antipyrine.
Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration
Authors: Carr Robert A. , Pasutto Franco M. , Lewanczuk Richard Z. , Foster Robert T. 
Published: October 2006

AbstractThe protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32±2 years, n=5) and elderly (73±6 years, n=5) male and female humans, and young (8 weeks, n=4) and elderly (60 weeks, n=3) male Sprague—Dawley rats. Serum samples were collected and immediately frozen at −20°C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL−1 and 500 ng mL−1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut‐off), capped, equilibrated to 37°C, and centrifuged at 1850g for 1.5h at 37°C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non‐stereoselective.
Enantioselective pharmacokinetics in animals of pazinaclone, a new isoindoline anxiolytic, and its active metabolite
Authors: Kondo Takahiro , Yoshida Kiyoshi , Yoshimura Yoshinobu , Tanayama Shigeharu 
Published: October 2006

AbstractThe enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN‐2327), and its active metabolite, M‐II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)‐pazinaclone were lower than those of (R)‐pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)‐pazinaclone than that for the (S)‐enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)‐pazinaclone in rats and dogs, and for the (R)‐enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M‐II. The unbound clearance (CLu) of (S)‐pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)‐ and (R)‐pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first‐pass metabolism of (S)‐ and (R)‐pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.
The ratio of first to zeroth moments of the plasma profile of an oral drug undergoing first‐pass and linear reversible metabolism
Authors: Cheng Haiyung 
Published: October 2006

AbstractBased on the convolution integral, equations have been drived for the ratio of the first to the zeroth moments of the plasma concentration—time curve (AUMC/AUC) parameters for a drug (p) undergoing first‐pass and reversible metabolism and its reversible metabolite (m). According to these equations, the AUMC/AUC of a drug administered orally and of its reversible metabolite can be related to the mean absorption times, the ratios of the fraction of the dose entering the systemic circulation to the bioavailability, the first‐time fractional conversion of each compound, and the AUMC/AUC ratios after intravenous administration of each compound. The proposed approach allows a more generalized derivation method for AUMC/AUC of a drug administered orally and undergoing first‐pass and reversible metabolism. It is also applicable to any other extravascular route.
Ars loquendi et ars tacendi
Authors: Schmidt Paul Gerhard 
Published: October 2006

AbstractThe monastic rule of Saint Benedict imposes silence in the chapel, dormitory and refectory. A monk who wishes to communicate in these places is permitted to use signs (signa loquendi) which are made with the hands. Ever since the 11 th century these signs have been assembled in lists for the use of novices. The size, composition and arrangement of the lists reflect the requirements and the spirituality of the individual monastic orders (Cluny, Order of St. Victor and Cistercians) and they are adapted to local conditions. The excessive use the Cistercians made of sign language was rejected and condemned by the other orders.