bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of BOF-4272, a Xanthine Oxidase Inhibitor, after Single Intravenous or Oral Administration to Male Mice and Rats
Authors: Naito Shinsaku , Nishimura Masuhiro , Nogawa Hiroyuki 
Published: July 2003

Abstract
BOF-4272, (±)-8-(3-methoxy-4-phenylsulphinylphenyl) pyrazolo [1,5-a]-1,3,5-triazine-4 (1H)-one), is a new drug intended for the treatment of hyperuricaemia. This report describes the detailed pharmacokinetics of BOF-4272 in mice and rats after intravenous or oral administration.
Plasma concentrations of BOF-4272 at 2.8h after intravenous administration were significantly higher in mice than in rats. Plasma concentrations of BOF-4272 after oral administration were significantly higher in fed mice than in fasted mice, but were similar in fasted and fed rats. The elimination half-life of the distribution phase (t1/2(α)) was similar in mice (0.158 h) and rats (0.210 h). The elimination half-life of the terminal elimination phase (t1/2(α)) in mice was 1.936 h, while that in rats was 0.742 h. The volume of the central compartment (V1) was almost the same in mice (415mL kg-1) and rats (440mL kg-1). However, the volume of the peripheral compartment (V2) in mice was 1068 mL kg-1, while that in rats was 92mL kg-1. The steady-state volume of distribution (Vss) was 2.8 times larger in mice than in rats. The area under the plasma concentration-time curve (AUC) in mice was 5332ngh mL-1, while that in rats was 3806ngh mL-1. The AUC0-24h after oral administration was 2.5 times greater in fed mice than in fasted mice, and was 1.4 times greater in fasted rats than in fed rats. The correlation coefficients of Cmax and AUC0-24h in both mice and rats after oral administration were greater than 0.997 in the dose range 1–125 mg kg-1, indicating that the linear range of absorption or elimination (or both) of BOF-4272 is very wide.
The results of the present study demonstrate that the mouse is a suitable animal species for evaluating the clinical pharmacokinetics of BOF-4272.
Fate of the Flavonoid Quercetin in Human Cell Lines: Chemical Instability and Metabolism
Authors: Boulton David W , Walle U Kristina , Walle Thomas 
Published: July 2003

Abstract
Although cell cultures are increasingly being used as models for studying the biological actions of flavonoids, no information on the fate, such as uptake and metabolism, exists for these natural products in these models.
This study examined the elimination of quercetin, one of the most abundant flavonoids, from the cultured human hepatocarcinoma cell line Hep G2 using [14C]-labelled compound with HPLC and LC/MS for structure characterization. These cells showed a 9.6-fold accumulation of quercetin and the formation of an O-methylated metabolite, isorhamnetin. However, a rapid elimination of quercetin, with no unchanged compound present beyond 8 h, was mainly due to oxidative degradation. The initial intermediate reaction appears to involve peroxidation, leading to a dioxetan, as evidenced by a 32-amu increase in the molecular ion by LC/MS. Subsequently, opening of the C-ring leads to the formation of carboxylic acids, the major one identified in this study as protocatechuic acid. A separate reaction results in a polymeric quercetin product which is highly retained on a reversed-phase C18 HPLC column.
It is postulated that these degradative and metabolic changes contribute to the multiple biological actions reported for quercetin, using cell culture models. Interestingly, part of the degradative pathway could be inhibited by including nontoxic concentrations of EDTA in the cell culture medium.
Effect of Acute Renal Failure on the Disposition of Cefoperazone
Authors: Katayama Hirokazu , Yasuhara Masato , Hori Ryohei 
Published: July 2003

Abstract
The effect of acute renal failure on the disposition of cefoperazone was investigated. Rats, 3 days after uranyl nitrate treatment, were used to model acute renal failure.
Although plasma-protein binding of cefoperazone decreased significantly in acute renal failure compared with control rats, the plasma clearance of total (bound plus unbound) drug after intravenous administration (50mg kg-1) did not differ significantly between the two groups (5.61 ± 2.37mL min-1 for control and 4.75 ± 2.82mL min-1 for acute renal failure). Consequently the plasma clearance of the unbound drug in acute renal failure (6.14 ± 1.16mL min-1) was significantly lower than in control rats (15.6 ± 3.7mL min-1, P &lt; 0.025). Plasma clearance of the drug (both total and unbound) was also dependent on bile flow, and clearance of the unbound drug in acute renal failure rats was lower than in control rats with identical bile flow rates. To examine the mechanism of reduced unbound cefoperazone clearance, an in-vitro experiment using a simultaneous perfusion system of rat liver and kidney was performed. By changing perfusate plasma protein from bovine serum albumin to human serum albumin, the plasma clearance of the total cefoperazone changed to one-sixth in proportion to the unbound cefoperazone in the perfusate plasma. On the other hand, the plasma clearance of the total and unbound drug in acute renal failure rats decreased significantly compared with controls.
These results demonstrate that the plasma clearance of unbound cefoperazone, which is mainly eliminated by the liver, decreased in acute renal failure in rats, probably due to changes in hepatic transport.
First-degree Atrioventricular Block in Alprazolam Overdose Reversed by Flumazenil
Authors: Mullins Michael E 
Published: July 2003

Abstract
This report describes a case of alprazolam overdose associated with marked first-degree atrioventricular block reversed by flumazenil.
Animal and human evidence suggests activity of certain benzodiazepines at peripheral benzodiazepine receptors in the myocardium and elsewhere. Myocardial benzodiazepine receptor ligands appear to affect calcium-channel activity, which may explain the clinical findings. Benzodiazepines may behave like weak calcium-channel blockers.
This case raises the possibility of a potential role for flumazenil as an adjunct in the management of calcium-channel blocker toxicity.
Clinical Consequences of the Biphasic Elimination Kinetics for the Diuretic Effect of Furosemide and its Acyl Glucuronide in Humans
Authors: Vree Tom B , Van Der Ven André J A M 
Published: July 2003

Abstract
This review discusses the possibility of whether furosemide acyl glucuronide, a metabolite of furosemide, contributes to the clinical effect of diuresis.
First an analytical method (e.g. HPLC) must be available to measure both parent drug and furosemide acyl glucuronide. Then, with correctly treated plasma and urine samples (light protected, pH 5) from volunteers and furosemide-treated patients, the kinetic curves of both furosemide as well as its acyl glucuronide can be measured. The acyl glucuronide is formed in part by the kidney tubules and it is possible that the compound is pharmacologically active through inhibition of the Na+/2Cl-/K+ co-transport system; up to now the mechanism of action has been solely attributed to furosemide.
The total body clearance of furosemide occurs by hepatic and renal glucuronidation (50%) and by renal excretion (50%). Enterohepatic cycling of furosemide acyl glucuronide, followed by hydrolysis, results in a second and slow elimination phase with a half-life of 20-30h. This slow elimination phase coincides with a pharmacodynamic rebound phase of urine retention. After each dosage of furosemide, there is first a short stimulation of urine flow (4h), which is followed by a 3-day recovery period of the body.
The following clinical implications arise from study of the elimination kinetics of furosemide. Repetitive dosing must result in accumulation of the recovery period. Accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure results from infinite hepatic cycling. Impaired kidney function may result in impaired glucuronidation and diuresis. While kidney impairment normally requires a dose reduction for those compounds which are mainly eliminated by renal excretion, for diuretics, a dose increment is required in order to maintain a required level of diuresis.
The full clinical impact of the accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure has to be determined.
Influence of pH and Temperature on Kinetics of Ceftiofur Degradation in Aqueous Solutions
Authors: Sunkara Gangadhar , Navarre Christine B , Kompella Uday B 
Published: July 2003

Abstract
The objective of this study was to evaluate the stability of ceftiofur (1mgmL-1)in aqueous solutions at various pH (1, 3, 5, 7.4 and 10) and temperature (0, 8, 25, 37 and 60°C) conditions. The ionic strength of all these solutions was maintained at 0.5 M. Ceftiofur solutions at pH 5 and 7.4 and in distilled water (pH = 6.8) were tested at all the above temperatures. All other solutions were tested at 60°C. Over a period of 84 h, the stability was evaluated by quantifying ceftiofur and its degradation product, desfuroylceftiofur, in the incubation solutions. HPLC was used to analyse these compounds.
At 60°C, the rate of degradation was significantly higher at pH 7.4 compared with pH 1, 3, 5 and distilled water. At both 60°C and 25°C, degradation in pH 10 buffer was rapid, with no detectable ceftiofur levels present at the end of 10 min incubation. Degradation rate constants of ceftiofur were 0.79 ± 0.21, 0.61 ± 0.03, 0.44 ± 0.05, 1.27 ± 0.04 and 0.39 ± 0.01 day-1 at pH 1, 3, 5, 7.4 and in distilled water, respectively. Formation of desfuroylceftiofur was the highest (65%) at pH 10. The rate of degradation increased in all aqueous solutions with an increase in the incubation temperature. At pH 7.4 the degradation rate constants were 0.06 ± 0.01, 0.06 ± 0.01, 0.65 ± 0.17, and 1.27 ± 0.05 day-1 at 0, 8, 25, 37 and 67°C, respectively. The energy of activation for ceftiofur degradation was 25, 42 and 28kcalmol-1 at pH 5, 7.4 and in distilled water, respectively.
Desfurylceftiofur formation was the greatest at alkaline pH compared with acidic pH. Ceftiofur degradation accelerated the most at pH 7.4 and was most rapid at pH 10. The results of this study are consistent with rapid clearance of ceftiofur at physiological pH.
Colon-specific Delivery of Budesonide with Azopolymer-coated Pellets: Therapeutic Effects of Budesonide with a Novel Dosage Form against 2,4,6-Trinitrobenzenesulphonic Acid-induced Colitis in Rats
Authors: Tozaki Hideyuki , Fujita Takuya , Komoike Junta , Kim Sooh-Ih , Terashima Hiroshi , Muranishi Shozo , Okabe Susumu , Yamamoto Akira 
Published: July 2003

Abstract
The objective of this study was to achieve colon-specific delivery of budesonide using azopolymer-coated pellets and to accelerate healing of 2,4,6-trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in rats.
After oral administration of azopolymer-coated pellets containing budesonide, a significant increase was observed in the therapeutic effects of the drug accompanied by a decrease in its systemic adverse effects when compared with oral administration in saline or rectal administration by enema. In addition, with the use of the colon-specific oral dosage form the dose of budesonide could be reduced.
These results suggested that azopolymer-coated pellets may be a useful dosage form for the colon-specific delivery of budesonide as an anti-inflammatory steroid drug to bring about the healing of TNBS-induced colitis in rats.
Adrenal Effects and Pharmacokinetics of CFC-free Beclomethasone Dipropionate: a 14-Day Dose-Response Study
Authors: Harrison Lester I , Colice Gene L , Donnell David , Soria Inmaculada , Dockhorn Robert 
Published: July 2003

Abstract
Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)-free propellant HFA-134a (HFA) than with the original CFC-beclomethasone dipropionate formulation, it is possible the HFA-beclomethasone dipropionate may have less safety concerns than the CFC formulation. Despite its chronic use, the steady-state pharmacokinetics of beclomethasone dipropionate has never been studied before. This double-blind study examined adrenal effects and pharmacokinetics after 14 days of dosing with HFA-beclomethasone dipropionate.
Forty-three steroid-naïve asthmatic patients were randomised into 5 parallel groups and dosed every 12 h for 14 days with: HFA-placebo; 200, 400 or 800 μg day-1 HFA-beclomethasone dipropionate; or 800 μg day-1 CFC-beclomethasone dipropionate. After two weeks of dosing, the 24-h urinary free cortisol of all but one patient remained within the normal range, showing that all doses were well tolerated from a systemic safety perspective. The active HFA-beclomethasone dipropionate treatment groups showed a dose-related fall in 24-h urinary free cortisol. Total-beclomethasone (beclomethasone dipropionate and metabolites) pharmacokinetics after either the first dose of HFA-beclomethasone dipropionate or CFC-beclomethasone dipropionate were not substantially affected by subsequent doses. The extent of drug absorption from 800 μg day-1 HFA-beclomethasone dipropionate and CFC-beclomethasone dipropionate was in the ratio of 1–7: 1. A non-linear correlation between 24-h urinary free cortisol and the pharmacokinetic parameters was observed, reflecting smaller changes in 24-h urinary free cortisol than in pharmacokinetics as the dose was increased.
No clinically meaningful change in the pharmacokinetics of beclomethasone dipropionate plus metabolites was seen on multiple dosing. The greater systemic availability of HFA-beclomethasone dipropionate was still associated with adrenal effects comparable with that of the CFC formulation at the same dose.
Drug Permeation through the Three Layers of the Human Nail Plate
Authors: Kobayashi Yoichi , Miyamoto Misao , Sugibayashi Kenji , Morimoto Yasunori 
Published: July 2003

Abstract
The in-vitro permeation characteristics of a water soluble model drug, 5-fluorouracil, and a poorly water soluble model drug, flurbiprofen, were investigated through three layers of the human nail plate (namely, the dorsal, intermediate and ventral nail plates), using a modified side-by-side diffusion cell. The dorsal-filed nail plate, the ventral-filed nail plate and the dorsal-and-ventral-filed nail plate were prepared to known thicknesses and then used with the full-thickness nail plate to investigate the permeation characteristics of each single layer.
Most of the lipids in the human nail plate were found in the dorsal and ventral layers. The rank orders of the permeation fluxes for 5-fluorouracil and flurbiprofen were both: dorsal-and-ventral-filed nail plate &gt; dorsal-filed nail plate &gt; ventral-filed nail plate &gt; full-thickness nail plate. With respect to 5-fluorouracil permeation through each single layer, the permeability coefficient of the intermediate layer was higher than those of other single layers. However in the case of flurbiprofen, the permeability coefficient of the ventral layer was higher than other single layers. The diffusion coefficients of 5-fluorouracil and flurbiprofen in the dorsal layer were the lowest of any single layer. The drug concentration in each layer was estimated using each respective permeation parameter. The drug concentration in the nail plate was observed to be dependent on the solubility and the flux of the drug.
From these findings, we suggest that the human nail plate behaves like a hydrophilic gel membrane rather than a lipophilic partition membrane and that the upper layer functions as the main nail barrier to drug permeation through its low diffusivity against the drugs.
The Presence of an Na+/Spermine Antiporter in the Rat Renal Brush-border Membrane
Authors: Kobayashi Michiya , Fujisaki Hiroko , Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi 
Published: July 2003

Abstract
This study was aimed at determining the driving force for spermine transport in rat renal proximal tubular brush-border membrane.
The uptake of spermine and trientine, a spermine-like drug used for treating Wilson's disease, into rat renal brush-border membrane vesicles was significantly stimulated by an outwardly directed Na+ gradient. The Na+-dependent uptake was temperature dependent and saturable. A kinetic analysis of the initial uptake of spermine with an Na+ gradient gave a Km value of 1.44μM and a Vmax value of 6.31pmol (mg protein)-1 /30 s. The Na+- dependent uptake of [3H]spermine was inhibited by spermine, trientine and tetraethylenepentamine. Substrates of the H+/organic cation transporter (cimetidine and tetraethylammonium), physiological polyamines (putrescine and spermidine) with 2 or 3 amino groups and aminoglycosides (amikacin and tobramicin) with 4 or 5 cationic amines did not affect the uptake of spermine in the presence of an outwardly directed Na+ gradient.
These results suggest that the renal tubular secretion of spermine is mediated by an Na+/spermine antiport system which is specific for a straight-chain polyamine compound with more than 4 amino groups.
Inhibition by Magnolol of Formylmethionyl-leucyl-phenyl alanine-induced Respiratory Burst in Rat Neutrophils
Authors: Wang Jih P , Hsu Ei F , Raung Shue L , Chang Ling C , Tsao Lo T , Lin Pei L , Chen Chien C 
Published: July 2003

Abstract
The influence of the plant product magnolol on neutrophil superoxide anion (O2-.) generation has been investigated in the rat.
Intraperitoneal injection of magnolol (30mgkg-1) significantly inhibited the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat whole blood ex-vivo. Magnolol also inhibited the O2-. generation with an IC50 (concentration resulting in 50% inhibition) of 15.4 ± 1.6 μM and O2 consumption in rat neutrophils in-vitro. Magnolol weakly inhibited the O2-. generation in the xanthine-xanthine oxidase system, decreased cellular cyclic AMP level and had no effect on cyclic GMP levels. It weakly inhibited neutrophil cytosolic protein kinase C activity but did not alter porcine heart protein kinase A activity. Magnolol attenuated fMLP-induced protein tyrosine phosphorylation with an IC50 of 24.0 ± 1.9 μM and the phosphorylation of mitogen-activated protein kinase p42/44 with an IC50 of 28.5 ± 4.5 μM. However, magnolol alone activated neutrophil phospholipase D activity as determined by the formation of phosphatidic acid and phosphatidylethanol in the presence of ethanol. In the presence of NADPH, the arachidonate-activated NADPH oxidase activity in a cell-free system was weakly suppressed by magnolol.
These results suggest that the inhibition of respiratory burst in fMLP-activated neutrophils by magnolol is probably attributable mainly to the attenuation of protein tyrosine phosphorylation and p42/44 mitogen-activated protein kinase activation, and partly to the suppression of protein kinase C and NADPH oxidase activities.
Ca2+/Calmodulin-dependent Protein Kinase II Inhibitors Potentiate Superoxide Production in Polymorphonuclear Leukocytes
Authors: Watanabe Manabu , Kaihatsu Takayuki , Miwa Masao , Maeda Toshio 
Published: July 2003

Abstract
The possible role of Ca2+/calmodulin-dependent protein kinase II (CaMK II) in superoxide anion (O2-) production induced by formyl-methionyl-leucyl-phenylalanine (FMLP) was investigated in mouse polymorphonuclear leukocytes (PMNs).
KN-93 and KN-62, specific CaMK II inhibitors, augmented FMLP-induced O2-production. KN-92, an analogue which did not inhibit CaMK II, did not affect O2-production. W-7, a calmodulin inhibitor, augmented O2- production when administered at 30 mM for 5 min. KN-93 and recombinant mouse tumour necrosis factor-α (rmTNF-α) each augmented the maximal production of O2- induced by FMLP, and an additive effect of a combination of KN-93 and rmTNF-α was observed. CaMK II activity in the PMNs was increased by FMLP, and the increase was inhibited by KN-93 but not by rmTNF-α.
These results suggest that the inhibition of CaMK II resulted in the augmentation of FMLP-induced O2- production in PMNs by a mechanism different from that of the augmentation shown by TNF-α.
Synthesis, Physicochemical Properties and Biological Evaluation of Aromatic Ester Prodrugs of 1-(2‘-Hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): Orally Active Iron Chelators with Clinical Potential
Authors: Liu Zu Dong , Liu Ding Yong , Li Lu Shu , Hider Robert C 
Published: July 2003

Abstract
The synthesis of seven aromatic ester derivatives of 1-(2′-hydroxyethyl)-2-ethyl-3-hydro-xypyridin-4-one is described. These ester prodrugs have been designed to target iron chelators to the liver, the major iron storage organ. In principle this should improve chelation efficacy and minimize toxicity.
The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7·4 were measured together with their rates of hydrolysis at pH 2 and pH 7·4, in rat blood and liver homogenate. Esters with heteroaromatic acid moieties were found to be less stable than benzoyl analogues. The in-vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion. However, not all prodrugs provided increased efficacy, demonstrating that lipophilicity is not the only factor which influences drug efficacy. Furthermore, no clear correlation between efficacy and susceptibility to hydrolysis was detected.
The picolinic and nicotinic ester derivatives appear to offer the best potential as prodrugs as they have a relatively low LogP value and yet lead to enhanced efficacy over the parent hydroxypyridinone.
Characterization and In-vivo Ocular Absorption of Liposome-encapsulated Acyclovir
Authors: Fresta Massimo , Panico Anna Maria , Bucolo Claudio , Giannavola Claudia , Puglisi Giovanni 
Published: July 2003

Abstract
The potential of liposomes as an in-vivo ophthalmic drug delivery system for acyclovir was investigated.
The drug-membrane interaction was evaluated by means of differential scanning calorimetry analysis. These experiments showed that acyclovir is able to interact with both positively and negatively charged membranes via electrostatic or hydrogen bonds. No interaction was observed with neutral membranes made up of dipalmitoylphosphatidyl-choline.
Different liposome preparation procedures were carried out to encapsulate acyclovir. The drug encapsulation mainly depends on the amount of water which the liposome system is able to entrap. In the case of multilamellar vesicles, charged systems showed the highest encapsulation efficiency. No particular difference in the encapsulation efficiency was observed for oligolamellar vesicles prepared with the reverse-phase evaporation technique. Oligolamellar liposomes showed the highest acyclovir encapsulation parameters and had release profiles similar to those of multilamellar liposomes. In-vivo experiments using male New Zealand albino rabbits were carried out to evaluate the aqueous humour concentration of acyclovir bioavailability.
The most suitable ophthalmic drug delivery system was oligolamellar systems made up of dipalmitoylphosphatidylcholine—cholesterol—dimethyldioctadecyl glycerole bromide (7:4:1 molar ratio), which presented the highest encapsulation capacity and were able to deliver greater amounts of the drug into the aqueous humour than a saline acyclovir solution or a physical liposome/drug blend.