bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vitro Metabolic Interaction of Bunitrolol Enantiomers in Rabbit Liver Microsomes
Authors: Narimatsu Shizuo , Mizukami Takao , Huang Yong , Masubuchi Yasuhiro , Suzuki Tokuji 
Published: April 2011

Abstract
We have examined the 4-hydroxylation of bunitrolol in rabbit and rat liver microsomes.
Significant species differences (rabbit &lt; rat of both sexes) and sex (male &gt; female of both species) were observed in the formation of 4-hydroxybunitrolol from racemic bunitrolol (10 μM). The 4-hydroxylation of bunitrolol racemate and enantiomers showed biphasic kinetics, a low-Km system and a high-K.m system, in liver microsomes from rabbits of both sexes. There were significant differences in Km and Vmax values [(+) &gt; (-)] for 4-hydroxylations of (+)-bunitrolol and (-)-bunitrolol in the low-K.m system. Furthermore, the rate of clearance (Vmax/Km) was 20- to 200-fold for the low-Km system compared with the high-Km system, indicating that enzymes in the low-Km system play a major part in the rabbit liver microsomal bunitrolol metabolism. Inhibition studies using cytochrome P450 inhibitors such as quinidine, quinine, and α-naphthoflavone or polyclonal antibodies raised against rat P450-2D and −1A enzymes did not make clear which P450 enzymes are involved in bunitrolol 4-hydroxylation in rabbit liver microsomes. The 4-hydroxylase activity of (+)-bunitrolol was slightly higher than that of (-)-bunitrolol in separated incubations containing male rabbit liver microsomes and an enantiomer concentration of 10 μM. However, the 4-hydroxylation of (+)-bunitrolol (10 μM) was markedly suppressed in the presence of its antipode (10 μM), whereas (-)-bunitrolol 4-hydroxylation was not affected by the presence of its antipode, resulting in a change of the stereoselectivity from (+) &gt; (-) for enantiomer to (+) &lt; (-) for racemate.
The difference in the Michaelis constants in the low-Km system, where the Km value of (-)-bunitrolol is one-eighth that of (+)-bunitrolol, is thought to cause the change in the stereoselectivity in rabbit liver microsome-mediated bunitrolol 4-hydroxylation.
Physicochemical Properties of Calcium Polycarbophil, a Water-absorbing Polymer
Authors: Yamada Takehisa , Nagata Osamu , Tamai Ikumi , Tsuji Akira 
Published: April 2011

Abstract
The physicochemical properties of calcium polycarbophil were examined.
Calcium polycarbophil was decalcified rapidly under acidic conditions, affording polycarbophil. Polycarbophil absorbed about 10 times its own weight of water under acidic conditions, but the swelling ratio markedly increased at above pH 4.0 and reached 70 times the initial weight under neutral conditions. The swelling of polycarbophil was not affected by non-ionic osmolarity, but was affected by ionic strength, showing a decrease with increase of ionic strength. Monovalent metal ions such as sodium and potassium ions in gastrointestinal fluid did not reduce the equilibrium swelling of polycarbophil, but divalent ions such as calcium and magnesium ions did. However, calcium ion only slightly reduced the equilibrium swelling under sodium-rich conditions. The viscosity (as an indicator of fluidity) of polycarbophil was larger than that of CMC-Na at every shear rate and polymer content examined.
Biodegradable Injectable Implant Systems for Long Term Drug Delivery Using Poly (Lactic-co-glycolic) Acid Copolymers
Authors: Chandrashekar G , Udupa N 
Published: April 2011

Abstract
Poly (lactide-co-glycolide) (PLG), is one of the most widely employed biodegradable synthetic polymers for sustained-release preparations. In the present work, PLG (50:50) copolymer has been used to deliver diclofenac sodium in the form of microspheres and in situ gel-forming systems, both of which can be injected subcutaneously.
The pharmacodynamic and pharmacokinetic studies in the adjuvant-induced arthritic rats showed that the microspheres offered steady therapeutic levels of the drug in the plasma for about 16 days following a single subcutaneous injection. However, the in situ gel-forming system provided a significantly higher maximum plasma concentration and increased inhibition of inflammation, maintained for about 10 days.
Injectable microspheres and in situ gel-forming implant systems of PLG (50: 50) copolymer may therefore be considered as prospective implantable controlled-release dosage forms to deliver drugs in long-term therapy of chronic ailments.
Effectiveness and Mode of Action of Isopropyl Myristate as a Permeation Enhancer for Naproxen through Shed Snake Skin
Authors: Suh Hearan , Jun H W 
Published: April 2011

Abstract
The effectiveness and mode of action of isopropyl myristate (IPM) as an enhancer for the permeation of naproxen through shed snake skin have been investigated.
The highest naproxen permeability was afforded by IPM (36.2 × 10−4 cm h−1), followed by menthol (25.0 × 10−4 cm h−1), oleic acid (11.1 × 10−4 cm h−1), azone (7.3 × 10−4 cm h−1)_and control (1.4 × 10−4 cm h−1). Whereas the permeability of un-ionized naproxen (47.4 × 10−5 cm h−1) was much greater than that of ionized naproxen (1.11 × 10−5 cm h−1), IPM-treatment of the intact skin increased the flux of ionized naproxen significantly more (50−fold) than that of un-ionized naproxen (15−fold). The large effect of pH on the permeation of naproxen through the intact stratum corneum became insignificant after extraction of lipids from the skin. Similar permeation of naproxen through intact and delipidized skin after IPM treatment indicated that the lipid barrier of the skin was largely impaired by IPM. Direct application of IPM to skin yielded a 2.6−fold higher naproxen permeability than the application of IPM as a gel. A greater amount of naproxen was absorbed from 1% test gel (pH 5) containing IPM than from 10% commercial gel (pH 7) containing no IPM.
These results show that use of IPM can significantly improve the bioavailability of naproxen in topical preparations.
Veratridine Augments and BDF 9148 Attenuates the Spontaneous Contractile Force of the Rat Portal Vein
Authors: Doggrell Sheila A , Bishop Brett E 
Published: April 2011

Abstract
Veratridine and BDF 9148 both increase the force of myocardial contraction but their effects on the contractility of vascular smooth muscle are largely unknown. We have examined the effects of the drugs on the contractile force of the rat portal vein.
The force responses of the rat portal vein were not altered by tetrodotoxin (≤ 30 μM) but were augmented by Bay K 8644 (10 nM-10 μM), and attenuated by nifedipine (10 nM-10 μM). Veratridine slightly reduced the force of spontaneous contractions at concentrations of 0.1−1 μM, then augmented the force at concentrations up to 100 μM. The reduction was prevented by 30 nM tetrodotoxin; a higher concentration of 3 μM prevented the effect of veratridine. Pretreatment with nifedipine at 30 nM reduced the maximum augmentation observed with veratridine. BDF 9148 (0.3−300 μM) attenuated the force and this attenuation was increased in the presence of tetrodotoxin at 3 μM but reversed to an augmentation in the presence of Bay K 8644 at 10 μM. The augmentation produced by BDF 9148 in the presence of Bay K 8644 was reduced by tetrodotoxin at 30 nM.
These results suggest that veratridine predominantly opens sodium channels which in turn open voltage-dependent calcium channels to augment the force responses of the rat portal vein, but attenuate force in the presence of sodium-channel blockade with tetrodotoxin. BDF 9148 predominantly closes calcium channels to attenuate the force of the rat portal vein but in the presence of maximum calcium-channel opening with Bay K 8644 augments force probably by opening sodium channels.
On the In-vivo Modulation of Neostriatal Dopamine Release by Fluoxetine and 5−Hydroxy-L-tryptophan in Conscious Rats
Authors: Li XI-Ming , Perry Kenneth W , Fuller Ray W 
Published: April 2011

Abstract
To help determine the nature of serotonergic regulation of dopamine activity in the brain an in-vivo microdialysis study has been performed in conscious rats to investigate the modulation of dopamine release in the neostriatum by 5−hydroxytryptamine (5−HT).
The 5−HT uptake inhibitor, fluoxetine, and the 5−HT precursor, 5−hydroxy-L-tryptophan (5−HTP), were used to produce an increase in extracellular 5−HT concentration. Systemic administration of fluoxetine (10 mg kg−1, s.c.) produced a 2−to 3−fold increase in extracellular 5−HT concentration but did not change extracellular dopamine concentration in the neostriatum. Co-administration of fluoxetine and 5−HTP (40 mg kg−1, s.c; 60−90 min after fluoxetine) caused a highly significant tenfold increase in extracellular 5−HT concentration in the neostriatum with a slight but non-significant decrease in extracellular dopamine concentration. Pergolide, a dopamine D2 agonist, given systemically caused a dramatic decrease in extracellular dopamine concentration demonstrating the responsiveness of the neurons.
These results demonstrate that high concentrations of extracellular 5−HT do not modulate dopamine release in the neostriatum. The possibility that different 5−HT receptor subtypes may mediate different regulation of dopamine release remains to be explored.
An Exploration of the Structure-activity Relationships of 4−Aminoquinolines: Novel Antimalarials with Activity In-vivo
Authors: Ismail F M D , DAscombe M J , CArr P , NOrth S E 
Published: April 2011

Abstract
The structure-activity relationships of bisquinolines, a potentially important group of novel antimalarial drugs, were studied.
The high-temperature (180−250°C) synthesis of 4−aminoquinolines, including bisquinolines, by nucleophilic displacement was both fast and efficient. Several bisquinolines including (±)-trans-N1,N2-bis(7−trifluoroquin-olin-4−yl)cyclohexane-1,2−diamine and 1R,2R-(-)-, 1S,2S-(+)-, (±)-trans- and cis-N1,N2-bis(7−chloroquin-olin-4−yl)cyclohexane-1,2−diamine exhibited potent activity against Plasmodium berghei in mice; (±)-trans-N1,N2-bis(7−chloroquinolin-4−yl)cyclohexane-1,2−diamine was orally active.
Our results indicate that these compounds conform to a putative receptor for quinoline antimalarials. In addition, a 7−haloquinoline linked by a heterocyclic bridge, at the 4−position, to another heterocycle (such as an acridine at the 9−position) maximally occupies the active site of our postulated target.
In-vivo Evaluation in Man of a Hydrophilic Matrix Containing Propylthiouracil
Authors: Kabanda Louis , Lefebvre Romain Adelin , Remon Jean Paul 
Published: April 2011

Abstract
To reduce the number of administrations of propylthiouracil required to treat hyperthyroidism, the bioavailability and sustained-release characteristics of 300 mg propylthiouracil formulated in hydrophilic matrix tablets were evaluated after single oral administration in healthy male volunteers. A conventional tablet was chosen as the reference formulation.
For tablets formulated from three different types of hydroxypropylmethylcellulose, K15M, K4M and K100LV, propylthiouracil dissolution in-vitro was 40%, 51% and 100%, respectively, in 8 h. The three matrix formulations showed sustained plasma concentration-time profiles. The relative bioavailability was 50, 51 and 87%, respectively, for K4M, K15M and K.100LV hydroxypropylmethylcellulose matrix tablets. When reverse triiodothyronine concentrations were plotted against the corresponding propylthiouracil concentrations, an antihysteresis loop was observed with the conventional tablets and the K100LV matrix tablet. A linear concentration-response curve was obtained for both the K4M and K15M formulations.
The results showed that the K100LV matrix tablet gave a sustained plasma concentration-time profile and a bioavailability and extrathyroidal effect similar to that of a conventional tablet.
Effect of YM934, a Novel Potassium-Channel Opener, in Various Experimental Asthma Models in Guinea-pigs
Authors: Ishikawa Jun , Saitoh Chikashi , Masaki Katsuhiro , Asano Masaharu 
Published: April 2011

Abstract
YM934 is a novel synthetic potassium-channel opener. We have investigated its anti-asthma effect after intravenous (i.v.) and oral (p.o.) administration in various experimental asthma models in the guinea-pig, and compared the results with those for lemakalim, theophylline and salbutamol.
In an ovalbumin-active sensitization anaphylaxis asthma model, YM934, lemakalim, theophylline and salbutamol dose-dependently prolonged the time before the occurrence of asthma attacks and reduced the mortality rate. The respective ED50 values (dose required to prolong by 50% the time before the occurrence of attacks) of the anti-asthma effects of YM934, lemakalim, theophylline and salbutamol were 6, 340, 30 000, and 45 μg kg−1 (i.v.); the efficacy ratios were YM934 (1) &gt; salbutamol (1/9) &gt; lemakalim (1/57) » theophylline (1/5000). YM934 also prolonged the period before the occurrence of attacks in the anti-BSA (bovine serum albumin) serum-passive sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values for these models of 15, 22 and 20 μg kg−1 (i.v.). Among these models a reduction in mortality rate was seen in the histamine- and methacholine-induced asthma models. After oral administration, YM934 showed an anti-asthma effect in the ovalbumin-active sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values of 38, 44 and 193 μg kg−1. YM934 was 5–6 times more potent than salbutamol. These results indicate that YM934 has potent anti-asthma activity, and that this activity is mainly attributable to bronchodilation, most likely mediated through its potassium-channel opening activity.
Pulmonary Catabolism of Interleukin 6 Evaluated by Lung Perfusion of Normal and Smoker Rats
Authors: Pessina G P , Paulesu L , Corradeschi F , Aldinucci C , Luzzi E , Bocci V 
Published: April 2011

Abstract
Cytokines such as interleukin 6 are involved in the pulmonary inflammation arising as a result of smoking. By use of isolated and perfused lung preparations we have evaluated the role of the lungs in the catabolism of human recombinant interleukin 6 both in normal rats and in rats subjected to an acute cigarette smoking episode.
When interleukin 6 was incorporated into the lung perfusion medium, neither control nor smoke-exposed rat lungs cleared the cytokine and only 0.1 ± 0.2% of the total dose was recovered in the bronchoalveolar lavage fluid. When, on the other hand, the same amount of interleukin 6 was instilled into the bronchoalveolar tree, concentrations of the cytokine in the perfusate increased progressively so that after 3 h up to 70.1 ± 9.8% and 40.9 ± 22.5% of the administered dose, as measured by immunoenzymatic test, had been transferred from the bronchial lumen to the perfusion medium of either control or smoker rat lungs, respectively, indicating significantly (P &lt; 005) different behaviour of the cytokine in the two experimental groups. Total recoveries of the administered interleukin 6 evaluated in smoke-exposed rat lungs were 55.3 ± 23.2%, significantly lower than those for control rat lungs (83.9 ± 11%). Determination of biological activity gave values always lower than those measured by immunoenzymatic test, indicating loss of biological activity during the transalveolar transit.
It appears that the transfer of interleukin 6, especially in smokers, is almost exclusively unidirectional, from the alveolar space to the plasmatic pool with degradation during the transalveolar passage.
Oral Sustained-release Cisplatin Capsule
Authors: Houjou Takeshi , Nakano Kousuke , Ike Osamu , Wada Hiromi , Hitomi Sigeki , Shinmi Yuuko , Danno Noriyuki , Yoshikawa Yukako , Takada Kanji 
Published: April 2011

Abstract
An oral sustained-release cisplatin preparation was prepared by combining microporous water-insoluble pharmaceutical polymer, ethylcellulose, a membrane and a gel-forming polymer, poly(acrylic) acid (Carbopol). As cisplatin is an extremely hydrophilic and small compound, it was difficult to control the release rate solely by the micropores on the ethylcellulose capsule.
To retain cisplatin within the capsule, gel-forming polymer was formulated inside the capsule. The release rate of cisplatin was dependent both on the number of micropores of the capsule and the formulated amount of Carbopol. The number of micropores ranged from 20 and 30 to 60, and the formulated amount of Carbopol varied from 15 to 100 mg. In-vitro release experiments suggested that the release rate decreased as the formulated amount of Carbopol increased when the pore number was 60 and 30. However, when pore number was decreased to 20, the effect of the amount of Carbopol was not clearly observed.
In the in-vivo study using rabbits, the sustained-release cisplatin capsule was evaluated in comparison with solution after oral administration of 20 mg drug. With the pore number of 60, Cmax was 0.46 ± 0.02 μg mL−1 at 4 h and thereafter serum concentrations declined rapidly. When the pore number was 30, serum cisplatin level-time profiles showed long-acting patterns and AUC was reversely correlated with the formulated amount of Carbopol. Cmax and tmax were 0.41 ± 0.02 μg mL−1 and 3.33 ± 0.88 h, respectively and 0.23 ± 0.01 μg mL−1 was obtained at 24 h after oral administration of capsule having 30 pores and 15 mg of Carbopol.
We conclude that the possibility of developing an oral sustained-release cisplatin preparation is feasible.
Circadian Variation of α1-Adrenoceptor-mediated Pressor Response to Phenylephrine in Man
Authors: Tham Tony C K , Guy Suzanne , Riddell James G , Shanks Robin G , Harron Dean W G 
Published: April 2011

Abstract
The variability in the pressor effects of the α1-adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later.
The doses of phenylephrine required to increase systolic blood pressure by 20 mmHg after 8 and 12 h (5.30 and 9.30 pm, 81.4 ± 15.3 and 71.1 ± 16.0 μg min−1, respectively) were significantly (P &lt; 0.01) less than the baseline values (8.30 am, 108.0 ± 27.6 g min−1).
These results might indicate a circadian variation in the phenylephrine-induced α-adrenoceptor-mediated vascular response in healthy subjects. These observations lend further insight into circadian variations of vascular tone that might contribute to circadian rhythms in cardiovascular disease.
Synthesis and Anti-inflammatory Effects of Xanthone Derivatives
Authors: Lin Chun-Nan , Chung Mei-Ing , Liou Shiou-Jyh , Lee Tai-Hua , Wang Jip-Pyang 
Published: April 2011

Abstract
Eighteen synthetic xanthone derivatives were tested for their inhibitory effects on the activation of mast cells and neutrophils.
1,3- and 3,5-Dihydroxyxanthone showed strong inhibitory effects on the release of β-glucuronidase and histamine from rat peritoneal mast cells stimulated with compound 48/80. 1,6-Dihydroxyxanthone and 1,3,8-trihydroxyxanthone showed strong inhibitory effects on the release of β-glucuronidase, and β-glucuronidase and lysozyme, respectively, from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP). 1,3- and 1,6-Dihydroxyxanthone, 1,3,7-trihydroxyxanthone, and 1,3,5,6-, 2,3,6,7-, and 3,4,5,6-tetrahydroxyxanthone showed potent inhibitory effects on superoxide formation of rat neutrophils stimulated with fMLP. 1,6- and 3,5-Dihydroxyxanthone showed remarkable inhibitory effects on hind-paw oedema induced by polymyxin B in normal as well as in adrenalectomized mice.
These data indicated that the anti-inflammatory effect of these compounds is mediated through the suppression of chemical mediators released from mast cell and neutrophil degranulation.
Neural Network Computer Simulation of Medical Aerosols
Authors: Richardson C J , Barlow D J 
Published: April 2011

Abstract
Preliminary investigations have been conducted to assess the potential for using artificial neural networks to simulate aerosol behaviour, with a view to employing this type of methodology in the evaluation and design of pulmonary drug-delivery systems.
Details are presented of the general purpose software developed for these tasks; it implements a feed-forward back-propagation algorithm with weight decay and connection pruning, the user having complete run-time control of the network architecture and mode of training. A series of exploratory investigations is then reported in which different network structures and training strategies are assessed in terms of their ability to simulate known patterns of fluid flow in simple model systems. The first of these involves simulations of cellular automata-generated data for fluid flow through a partially obstructed two-dimensional pipe. The artificial neural networks are shown to be highly successful in simulating the behaviour of this simple linear system, but with important provisos relating to the information content of the training data and the criteria used to judge when the network is properly trained. A second set of investigations is then reported in which similar networks are used to simulate patterns of fluid flow through aerosol generation devices, using training data furnished through rigorous computational fluid dynamics modelling. These more complex three-dimensional systems are modelled with equal success.
It is concluded that carefully tailored, well trained networks could provide valuable tools not just for predicting but also for analysing the spatial dynamics of pharmaceutical aerosols.
Effects of Doxazosin on Functional Alterations of Isolated Coronary Arteries from Cholesterol-fed Rabbits
Authors: Simonsen Ulf , Prieto Dolores , Nyborg Niels C B , Mulvany Michael J 
Published: April 2011

Abstract
Anti-hypertensive treatment is much less successful at reducing coronary artery disease than at reducing mortality from stroke and congestive heart failure. The effects of the α-adrenergic antagonist doxazosin on progression of atheromatous lesions and functional responses of isolated coronary arteries from cholesterol-fed rabbits have been investigated.
Normotensive rabbits were fed either a standard chow (control, n = 8) or a 1% cholesterol-rich diet (n = 16) for 20 weeks. After 3 weeks the cholesterol-fed animals were assigned randomly to two groups either given placebo capsules (n = 8) or treated with doxazosin (5 mg kg−1 day−1; n = 8). Doxazosin reduced the mean arterial blood pressure by 10% that of the control and placebo-treated cholesterol-fed rabbits, but did not affect the plasma cholesterol, triacylglycerol and phospholipid levels, which were, after 20 weeks, severalfold increased in the cholesterol-fed rabbits compared with controls. Histological examination showed atheromatous lesions in proximal (but not distal) coronary arteries from both groups of cholesterol-fed rabbits. Doxazosin either had no effect on reduced contractions to 125 mmol L−1 potassium saline solution or increased contractions to 5-hydroxytryptamine in proximal isolated coronary arteries from the cholesterol-fed rabbits. It did, however, abolish the hyper-responsiveness of the large atheromatous coronary arteries to noradrenaline. In both vehicle-and doxazosin-treated cholesterol-fed rabbits the maximum relaxation and sensitivity to acetylcholine were significantly reduced in proximal segments compared with the control group, whereas responses to acetylcholine in distal coronary segments were not significantly different. The relaxation to sodium nitroprusside, adenosine diphosphate and isoprenaline in proximal and distal coronary arteries were similar in the three experimental groups.
These results indicate that treatment of normotensive cholesterol-fed rabbits with doxazosin prevents the hyper-responsiveness to noradrenaline of proximal coronary arteries, although it does not prevent the progression of other functional alterations observed in the coronary circulation.