bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers
Authors: Uematsu T , Kanamaru M , Nakashima M 
Published: April 2011

Abstract
The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QTc prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6·5 days, and single intravenous doses of 1·0 and 1·5 mg kg−1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7·9–9·7 h. The Cmax and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66–68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased biexponentially with a terminal half-life of 7·6–8·3 h and the urinary recovery as unchanged drug amounted to 84–88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QTc interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment. This analysis was shown to be effective to adjust the lag of effect behind a rapid change in plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)-sotalol.
Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats
Authors: Santa Tomofumi , Nishihara Kazuyo , Horie Shigeo , Kotaki Hajime , Sawada Yasufumi , Kawabe Kazuki , Iga Tatsuji 
Published: April 2011

Abstract
Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression.
Effect of Topical Preparation of Mycophenolic Acid on Experimental Allergic Contact Dermatitis of Guinea-pigs Induced by Dinitrofluorobenzene
Authors: Shoji Yoko , Fukumura Tadashi , Kudo Masataka , Yanagawa Akira , Shimada Jingoro , Mizushima Yutaka 
Published: April 2011

Abstract
The effects of a topical preparation of mycophenolic acid on the experimental allergic contact dermatitis induced by dinitrofluorobenzene was investigated. Visual assessment of skin reactions showed significant efficacy of a topical preparation of mycophenolic acid. This efficacy appeared from the early stage and endured up to 3 days. Morphological changes in the epidermis and dermis layers of animals treated with a mycophenolic acid cream were moderate compared with that in animals treated with vehicle only. In particular, hyperkeratosis was strongly suppressed. Since suppression of inflammatory cell infiltration was also observed, this efficacy might reach to the epidermis and dermis layer.
Anti-hypertensive Effect of Oral Controlled-release Microspheres Containing an ACE Inhibitor (Delapril Hydrochloride) in Rats
Authors: Akiyama Yohko , Yoshioka Minoru , Horibe Hidetoshi , Inada Yoshiyuki , Hirai Shinichiro , Kitamori Nobuyuki , Toguchi Hajime 
Published: April 2011

Abstract
An oral controlled-release drug delivery system based on microspheres of polyglycerol esters of fatty acids (PGEFs), was applied to an anti-hypertensive, delapril hydrochloride. The in-vitro release profile was controlled by selecting a PGEF with an appropriate hydrophilic-lipophilic balance value for the matrix. The microspheres from which 80% of the drug was released in 6 h were orally administered to rats. The plasma concentration of the active metabolite was sustained after administration of the microspheres in comparison with administration of a solution. The in-vivo release profile was in good agreement with the in-vitro release profile. When the microspheres were administered, the pharmacological effect of delapril hydrochloride on the angiotensin I-induced pressor response was also sustained showing consistency with the plasma concentration-time curve.
Cyclosporin Increases the CNS Sensitivity to the Hypnotic Effect of Phenobarbitone but not Ethanol in Rats
Authors: Hoffman Amnon , Habib Gustav , Gilhar Dalia , Zohar Hila 
Published: April 2011

Abstract
The purpose of this investigation was to determine whether repetitive administration of cyclosporin affects the pharmacodynamics of phenobarbitone- and ethanol-induced anaesthesia. Sabra male rats received either cyclosporin (50 mg kg−1 day−1, i.m.) for four days, or the same volume of the vehicle. Two hours after the last cyclosporin dose, phenobarbitone or ethanol solutions were infused intravenously at a constant rate until the onset of anaesthesia. Repetitive treatment with cyclosporin increased the CNS sensitivity to the hypnotic action of phenobarbitone. This was evidenced by the lower CSF phenobarbitone concentration, at the onset of the hypnotic effect, in the cyclosporin-treated group vs control values (115 ± 4 vs 93 ± 7 mg L−1, P = 0·01). However, the same pretreatment had no apparent effect on the pharmacodynamics of ethanol-induced sleep. It is suggested that anaesthesiologists must be alert to the possible increase in brain sensitivity when placing cyclosporin patients under anaesthesia with barbiturates.
Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs
Authors: Nomura M , Kubota M A , Kawamori R , Yamasaki Y , Kamada T , Abe H 
Published: April 2011

Abstract
Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL−1, pH7·4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg−1) at 3 h (8·3 ± 0·1 vs 15·6 ± 0·6 mmol, P &lt; 0·01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0·84 ± 0·11 vs 0·87 ± 0·05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 ± 383 vs 75 ± 24 m units min L−1, P &lt; 0·01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0·68 ± 0·14 vs 0·03 ± 0·01%, P &lt; 0·01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state.
Tissue- and subcellular-distribution of the binding site of [3H]9-methyl-7-bromoeudistomin D, a potent caffeine-like Ca2+ releaser, in rabbits
Authors: Adachi Masatoshi , Kakubari Masae , Ohizumi Yasushi 
Published: April 2011

Abstract
Tissue and subcellular distribution of the binding site of 3H-labelled 9-methyl-7-bromoeudistomin D ([3H]MBED), a powerful caffeine-like Ca2+ releaser, were investigated in rabbits. The order of specific activities of total homogenates was liver &gt; brain &gt; other tissues. All binding was completely suppressed by 10 Mm caffeine, indicating that all [3H]MBED binding sites are modulated by caffeine. [3H]MBED binding sites distributed mainly in membrane fractions rather than soluble fractions in most tissues. In lung and liver, [3H]MBED binding was enriched in microsomes. [3H]MBED may be useful as a probe to investigate the actions of caffeine at the molecular level not only in muscles but also in a variety of tissues including liver, kidney and lung.
The Effect of TYB-2285 on Dual Phase Bronchoconstriction and Airway Hypersensitivity in Guinea-pigs Actively Sensitized with Ovalbumin
Authors: Muraki M , Tohda Y , Sugihara R , Nagasaka Y , Nakajima S 
Published: April 2011

Abstract
The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chloro-benzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg−l, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyper-responsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.
Endotoxin-induced Fever Increases the Clearance of Methohexitone in Rabbits
Authors: Redke Finn , Björkman Sven 
Published: April 2011

Abstract
We have previously observed that the clearance of methohexitone, given by continuous infusion for sedation in the intensive care unit, was influenced by body temperature in patients with post-operative fever. The aim of the present study was to reproduce this finding in an animal model that can then be used to predict similar influences for other anaesthetic agents. Sixteen rabbits were infused for 2·0 h with methohexitone (8·4 ± 0·5 mg kg−1 h−1 (mean ± s.d.)) and in eight of them fever was induced with intravenous Escherichia coli endotoxin. Arterial blood samples were taken over 6 h and plasma concentrations of methohexitone were assayed by gas chromatography. The mean body temperatures of the rabbits over the periods of measurement varied between 38·5 and 41·8°C, and the total clearance of methohexitone (mean 50·7 mL min−1 kg−1) was positively correlated with temperature (r = 0·545, P = 0029). No significant correlations with temperature were found for other pharmacokinetic parameters. We conclude that these observations correspond to the findings in the clinical pharmacokinetic study, showing the validity of the animal model.
In-vitro Smooth Muscle Relaxant Activity of a Series of Vecuronium Analogues in the Rat Aorta
Authors: Fiddes Shaun , Prior Chris 
Published: April 2011

Abstract
The ability of a series of 17-ester analogues of vecuronium to elicit a direct relaxant effect on vascular smooth muscle has been studied using rat isolated aortic rings contracted with 40 mm KCl. The IC50 for inhibition of KCl-induced contractions increased with increasing size of the 17-ester substituent, such that vecuronium (17β-acetate) was the least potent with an IC50 of around 500 μm and Org-9827 (17α-pivalate) was the most potent with an IC50 of around 5 μm. In addition, for the weaker-acting compounds, the 17α-esters were more potent than their corresponding 17β-esters, although this difference was lost as the size of the 17-ester substituent increased. From the results obtained here, it is concluded that the hypotensive activity of some of the newer neuromuscular blocking steroids seen in cats, pigs and dogs in-vivo is probably, at least in part, a consequence of a direct relaxant effect of the compound on vascular smooth muscle through inhibition of voltage-activated, L-type, calcium channels. This may have both advantageous and disadvantageous clinical consequences when using large doses of one of the newer vecuronium analogues with a low relative neuromuscular-blocking potency.
Mammary excretion of cannabidiol in rabbits after intravenous administration
Authors: Yoo S D , Fincher T K , Holladay J W 
Published: April 2011

Abstract
The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg−1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4–24-h period following the maternal injection. The mean milk to serum concentration ratio was 25·9, indicating a significant accumulation of the drug in milk.
Comparison of distribution of brush-border exo- and endopeptidases in rat and rabbit intestine
Authors: Bai Jane P F 
Published: April 2011

Abstract
The distribution of brush-border endopeptidase-2, aminopeptidase W, carboxypeptidase P, and aminopeptidase P along the rat and rabbit intestine was examined. In both species, aminopeptidases P and W increased distally and reached the highest in the ileum; their activities in the ileo-caecal junction were the lowest. Endopeptidase-2 had a uniform intestinal distribution in both species with the highest activity in the ileum and little activity in the ileo-caecal junction or caecum. With a distribution similar to that of endopeptidase-2, carboxypeptidase P also had high activity in the ileum in rats and rabbits.
The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan O-demethylation in human and rat liver microsomes
Authors: Jaruratanasirikul Sutep , Hortiwakul Ratri 
Published: April 2011

Abstract
Amiodarone has been shown in-vitro to inhibit the activity of cytochrome P4502D6 (CYP2D6) in nonhuman primates. However, the influence of its major metabolite, desethylamiodarone, on this isozyme activity has not been studied. To determine the effect of these drugs on dextromethorphan O-demethylation, we carried out studies in 10 human and 10 rat liver microsomal preparations. In human microsomal studies, amiodarone and the metabolite competitively inhibited dextromethorphan metabolism with mean Ki values of 52·70 ± 5·27 and 34·40 ± 3·30 μm, respectively. Similar studies in rat microsomes showed a competitive inhibitory effect of amiodarone and its metabolite on dextromethorphan metabolism. These data suggest that amiodarone and desethylamiodarone have an inhibitory effect on CYP2D6 in man and CYP2D1 in rats. However, it cannot be concluded that both of them are substrates of this isozyme activity.
Scintigraphic Assessment of the Oropharyngeal and Nasal Depositions of Fusafungine from a Pressurized Inhaler and from a Novel Pump Spray Device
Authors: Newman S P , Steed K P , Hooper G , Brickwell J 
Published: April 2011

Abstract
The distributions of fusafungine (Locabiotal, Servier) radiolabelled with 99mTc, and delivered either orally or intranasally, have been assessed in healthy volunteers from a pressurized metered-dose aerosol inhaler (125 μg per dose) and from a novel mechanical pump spray device (500 μg per dose).
More than 90% of the dose was initially deposited in the oropharynx for oral dosing (n = 8), and more than 90% in the nose for nasal dosing (n = 9), with no significant penetration of aerosol into the lungs. Although not statistically significant, the mean area of deposition, measured in terms of gamma camera picture elements (pixels), was greater with the pump spray for both oral and nasal dosing. The area of deposition with the nasal pump spray extended into the turbinates in six of nine subjects, compared with only three of nine subjects for the pressurized aerosol.
The data suggest that the distribution patterns of pump sprays and pressurized aerosols of fusafungine in the oropharynx and in the nasal passages are similar, and that the former can be substituted for the latter with little change in drug delivery.
Bioavailability of Bropirimine 250 mg Tablet in Dogs: Effect of Food
Authors: Emori Hisatoshi , Yamamoto Ken , Yokohama Shigeharu , Nishihata Toshiaki 
Published: April 2011

Abstract
The postprandial effect on the bioavailability of bropirimine in dogs after oral administration of bropirimine tablets (Bropirimine 250 mg Tablet) was investigated.
At a dose of 500 mg bropirimine (two tablets of bropirimine 250 mg), the maximum plasma concentration under the postprandial condition was about twice that observed under the fasting condition, and the area under the plasma concentration vs time curve under the postprandial condition was also twice that under the fasting condition. The absolute oral bioavailabilities of bropirimine were 41.1% under the fasting condition and 83.5% under the postprandial condition.
It is considered that the longer gastric residence time and larger volume of the gastric fluid induced by food-intake caused the increase in dissolution of bropirimine which increased the bioavailability after oral dosing of bropirimine 250-mg tablets.
Metabolism of Beclamide after a Single Oral Dose in Man: Quantitative Studies
Authors: Ahmadi M , Nicholls P J , Smith H J , Spencer P S J , Preet-Ryatt M S , Spragg B P 
Published: April 2011

Abstract
A simple reverse phase HPLC assay is described for the determination of the anticonvulsant compound, beclamide and its 3- and 4-hydroxyphenyl metabolites in urine.
Following oral administration of 1 g beclamide to a panel of healthy volunteers, less than 0.4% of the dose was excreted unchanged in the 24-h urine and unconjugated 3- and 4-hydroxyphenyl metabolites were not detected. Based on examination of the urine after incubation with β-glucuronidase and aryl sulphatase, it was found that these hydroxyl metabolites were excreted as both glucuronide and sulphate conjugates. For each metabolite the glucuronide was the major excretory product (approximately 10: 1). The 24-h excretion of the combined conjugated metabolites was 7% (for the 3-hydroxy metabolite) and 24% (for the 4-hydroxy metabolite) of the dose. Approximately 22% of the administered dose of beclamide was excreted as hippuric acid.
In view of the simplicity of assay, beclamide may be a useful tool substance with which to examine factors influencing the xenobiotic metabolic pathways of benzene ring hydroxylation and glucuronide and sulphate conjugation in man.
Aggregation of Proteins and its Prevention by Carbohydrate Excipients: Albumins and γ-Globulin
Authors: Katakam Manohar , Banga Ajay K 
Published: April 2011

Abstract
Moisture-induced (2–10 μL added to 10mg) aggregation of solid-state albumin and γ-globulin was investigated by incubation at 37°C for 24 h.
The insoluble aggregates were centrifuged from a reconstituted solution, dissolved in a solution containing denaturant and reducing agent, and analysed by a Bio-Rad protein assay kit. Of the three albumins used, maximum aggregation (8·2%) was observed with bovine serum albumin that was essentially fatty-acid free. The maximum aggregation observed with γ-globulin was 70%. A bell-shaped curve for percent aggregation was observed with increasing moisture content and was especially prominent for bovine serum albumin. When mixed with carbohydrate excipients in a 1:1 ratio, aggregation was reduced for both bovine serum albumin and γ-globulin by all four of the following excipients used: Emdex, dextrose, trehalose and hydroxypropyl β-cyclodextrin. For bovine serum albumin, the aggregation was reduced about sixfold, with Emdex being the most effective excipient.
The likely mechanism of the resulting aggregation was covalent linkages formed due to intermolecular thiol disulphide interchange.
Preparation and Characterization of 5-Fluorouracil-loaded Microparticles as Biodegradable Anticancer Drug Carriers
Authors: Boisdron-Celle M , Menei PH , Benoit J P 
Published: April 2011

Abstract
To provide a device releasing 5-fluorouracil in a controlled manner and injectable into the brain by stereotaxy, biodegradable poly ((±)-lactide-co-glycolide) (PLAGA) microparticles were prepared by an emulsion-extraction process.
Although the solubility profile of the drug was not suitable for its encapsulation by the aforementioned method, careful choice of process variables allowed significant drug loading, reaching 30%. Thus, the size of the 5-fluorouracil crystals, the organic phase/aqueous phase ratio, the theoretical drug loading and the microparticle size played a predominant role. The microsphere size was adjusted to 20–40 μm by selecting the appropriate PLAGA and polyvinylalcohol concentrations, and the stirring rate of the initial emulsion.
It was shown that the microparticle structure depended directly on the experimental conditions governing the precipitation rate of the coating material: two types of microparticles, I and II, were characterized. The morphology of the particles influenced the 5-fluorouracil-release patterns, as did other process parameters, such as the 5-fluorouracil crystal size and the PLAGA concentration.
It was possible to sustain the 5-fluorouracil release over 18 days.
Differential Effects of Modified β-Cyclodextrins on Pharmacological Activity and Bioavailability of 4-Biphenylacetic Acid in Rats after Oral Administration
Authors: Puglisi G , Ventura C A , Spadaro A , Campana G , Spampinato S 
Published: April 2011

Abstract
Gastric tolerability, absorption and pharmacological activity of the non-steroidal anti-inflammatory drug 4-biphenylacetic acid (BPAA), as an inclusion complex with β-cyclodextrin (β-CyD) or chemically modified β-CyDs: 2,6-di-O-methyl-β-CyD (DM-β-CyD), 2,3,6-tri-O-methyl-β-CyD (TM-β-CyD) and 2-hydroxypropyl-β-CyD (HP-β-CyD), were investigated in the rat after oral administration.
BPAA absorption, determined from area under the plasma concentration-time curve (AUC), was increased by complexation with all β-CyDs in the following order: DM-β-CyD &gt; TM-β-CyD &gt; HP-β-CyD &gt; β-CyD. The carrageenan paw oedema test demonstrated a significant increase in anti-inflammatory activity of BPAA and the ED50 values, compared with BPAA alone, were reduced to about a third for the BPAA-DM-βCyD complex and halved for the others. BPAAA complexed with DM-β-CyD, HP-β-CyD or β-CyD showed better gastric tolerability compared with uncomplexed drug, whereas the BPAA-TM-β-CyD complex produced marked gastric lesions similar in extent to BPAA alone. TM-β-CyD (500mg kg−1) and DM-β-CyD (1000mg kg−1) caused gastric erosions 21 h after oral administration.
The pharmacokinetic profiles of BPAA-β-CyD complexes have shown that DM-β-CyD is the most effective in enhancing the bioavailability of BPAA.