bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of 5−Lipoxygenase Inhibitors on Interleukin Production by Human Synovial Tissues in Organ Culture: Comparison with Interleukin−1−synthesis Inhibitors
Authors: Rainsford K D , Ying C , Smith F 
Published: April 2011

Abstract
Prostaglandins and leukotrienes differentially regulate the production of interleukin−1 (IL−1) in monocytes. It was, therefore, decided to investigate the effects of some 5−lipoxygenase inhibitors compared with standard IL−1−synthesis inhibitors on the production of IL−1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1−5 days. Total bioactive IL−1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D−10 T-cell bioassay. Some assays of interleukins 1α, 1β, 6 or 8 were performed by ELISA. Of the 5−lipoxygenase inhibitors investigated, MK-886 (3−(1−(4−chlorobenzyl)−3-tert-butyl-thio−5−isopropylindol−2−yl)−2,2−dimethyl propanoic acid), L−656,224 ((7−chloro−2−[4−methoxypenyl]methyl)−3−methyl−5−propyl−4−benzofuranol), PF−5901 and tepoxalin were the most potent inhibitors of IL−1 production. While the PF−5901 was effective at 5–30 μM and tepoxalin was effective at 1−10 μM, the others were the most potent having minimal inhibitory activity in the range of 0.01−0.1 μM. The presumed IL−1−synthesis inhibitors, tenidap and IX−207,887, were inactive at concentrations of 30−50 μM. Leukotriene B4 (1−100 ng mL−1) added to MK−886 (5 μM)-treated cultures reversed the inhibitory effects of the latter on IL−1, confirming the role of 5−lipoxygenase products in the regulation of IL−1 production. Addition of polyethylene glycol 8000 to MK−886−treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL−1 inhibitors. MK−886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL−6 and IL−8. The results suggest that some 5−lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.
Pyridine Derivatives Stimulate Phosphatidylcholine Secretion in Primary Cultures of Rat Type II Pneumocytes
Authors: Kai Hirofumi , Murahara Koichiro , Isohama Yoichiro , Takahama Kazuo , Oda Yoshiaki , Hamamura Ichiro , Yoshitake Kazuhisa , Miyata Takeshi 
Published: April 2011

Abstract
We have examined the effects of pyridine derivatives on phosphatidylcholine secretion in primary cultures of rat type II pneumocytes.
Of 12 pyridine derivatives, 4−aminopyridine, 4−dimethylaminopyridine and 4−pyrolidinopyridine had a stimulatory effect on phosphatidylcholine secretion, whereas other derivatives had little effect. The stimulatory effect of 4−aminopyridine was concentration- and time-dependent, and was inhibited by the acetoxymethyl ester of 1,2−bis(2−aminophenoxy)ethane-N, N, N', N'-tetraacetic acid (3 μM), an intracellular Ca2+ chelator. In addition, the stimulatory effect of 4−aminopyridine was suppressed by W−7 (N-(6−aminohexyl)−5−chloro−1−napthalene-sulphonamide) (10 μM), a calmodulin inhibitor, and sphingosine (10 μM) and staurosporine (01μM), protein kinase C inhibitors.
These results indicate that several pyridine derivatives stimulate phosphatidylcholine secretion in type II pneumocytes.
Susceptibility of Mice to Bacterial and Fungal Infections after Intragastric Administration of Ebselen
Authors: Nozawa R , Arai M , Kuruto R , Motohashi T , Masayasu H 
Published: April 2011

Abstract
The seleno-organic compound ebselen (2−phenyl−1,2−benzisoselenazol−3(2H)-one) has anti-inflammatory activity and exhibits glutathione peroxidase-like activity in-vitro. Ebselen inhibited candidacidal activity over the same range of concentrations as it inhibited the production of microbicidal H2O2 by human neutrophils and macrophage-like cells. Therefore, the long-term administration of ebselen might be expected to induce an immunocompromised state in the host. To examine such a possibility, mice (5−weeks-old ddY, male) were given daily intragastric doses of 0, 10 or 100 mg kg−1 ebselen for 21 days and then infected intraperitoneally with Candida albicans (108 cells/mouse), Pseudomonas aeruginosa (1.5 times 107 cells/mouse) or methicillin-resistant Staphylococcus aureus (5 times 108 cells/mouse). Ebselen at none of the tested doses affected the increase in body weight of mice during administration of the drug. No evidence was obtained that mice became more susceptible to the various microorganisms after the administration of ebselen at any tested dose.
Serum Corticosterone Increases Reflect Enhanced Uptake Inhibitor-induced Elevation of Extracellular 5−Hydroxytryptamine in Rat Hypothalamus
Authors: Fuller Ray W , Perry Kenneth W , Hemrick-Luecke Susan K , Engleman Eric 
Published: April 2011

Abstract
The increase in extracellular 5−hydroxytryptamine (5−HT) in rat hypothalamus following administration of fluoxetine, a 5−HT-uptake inhibitor, was enhanced by the injection of LY206130 (1−[1−H-indol−4−yloxy]−3−[cyclohexylamino]−2−propanol maleate), a 5HT1A receptor antagonist, or by L−5−hydroxytryptophan (L−5−HTP), the 5−HT precursor. Elevation of serum corticosterone, measured as a functional output of hypothalamic 5−HT pathways, was greater in rats treated with fluoxetine plus LY206130 or with fluoxetine plus L−5−HTP than in rats treated with the agents alone.
Synergism between effects of fluoxetine and L−5HTP has often been reported, but this is the first report of an increased functional effect when a 5−HT1A receptor antagonist is combined with a 5−HT uptake inhibitor to augment the increase in extracellular 5−HT.
Acetylcholinesterase Inhibition and Protection by Dizocilpine (MK−801) Enantiomers
Authors: Galli Alessandro , Mori Francesca 
Published: April 2011

Abstract
The optical isomers of the N-methyl-d-aspartate (NMDA) receptor ion-channel blocker dizocilpine (MK−801) were shown to interact with electric eel and rat brain acetylcholinesterase (AChE) in a mixed competitive-noncompetitive way. The (-) form, pharmacologically less active, was the most potent of the two isomers as an AChE inhibitor (K1 for electric eel and rat brain AChE being 6&#x006d;̇2 and 17&#x006d;̇9μM, respectively, compared with 200 and 450 μM, respectively, of the (+) form). Both enantiomers premixed with AChE preparations, dose-dependently protected the enzyme from inactivation by diisopropylfluorophosphate (DFP). The maximal protective effects against 40 and 10 μM DFP were in the ranges 10&#x006d;̇7−23&#x006d;̇8 and 19&#x006d;̇5−31&#x006d;̇4% of control enzymic activity for the (+) and (-) forms of dizocilpine, respectively. The extent of the protective effect against DFP was increased up to 80&#x006d;̇1% of control enzymic activity for (-)-dizocilpine and to 38&#x006d;̇4% for (+)-dizocilpine by diluting the enzymic mixtures 1000 times after treatment with the organophosphate agent. The two enantiomers added to AChE 15 min after DFP, failed to reactivate the enzyme. Finally, it was shown that (+)- and (-)-dizocilpine dose-dependently and competitively decreased the DFP bimolecular reaction constant, Ki. We conclude that dizocilpine exerts a protective action towards AChE against irreversible DFP inhibition, but the molecular mechanism of such an action is at present unclear.
α-Trinositol: A Functional (Non-receptor) Neuropeptide Y Antagonist in Vasculature
Authors: Sun Xiangying , You Junping , Hedner Thomas , Erlinge David , Fellström Bengt , Yoo Heahyun , Wahlestedt Claes , Edvinsson Lars 
Published: April 2011

Abstract
Neuropeptide Y is a sympathetic co-neurotransmitter released with noradrenaline upon sympathetic nerve stimulation. This study describes the ability of a synthetic inositol phosphate, α-trinositol (d-myo-inositol 1,2,6−triphosphate; PP 56) to antagonize vasoconstrictor responses to neuropeptide Y in-vitro as well as in-vivo.
In human and guinea-pig isolated arteries α-trinositol potently (10 nM to 1 μM extracellular concentration) suppressed the constriction evoked by neuropeptide Y alone, the potentiation by neuropeptide Y of noradrenaline-evoked constriction, and the neuropeptide Y-induced inhibition of relaxation. Moreover, in the pithed (areflexive) rat, a non-adrenergic portion of the pressor response to preganglionic sympathetic nerve stimulation was sensitive to α-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of α-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found α-trinositol to inhibit the rise in intracellular Ca2+ as well as inositol triphosphate concentrations induced by neuropeptide Y.
It is, therefore, proposed that α-trinositol represents a non-receptor, but yet selective antagonist of neuropeptide Y in vasculature, opening up the possibility to investigate involvement of neuropeptide Y in sympathetic blood pressure control and in cardiovascular disorders.
3−Nitropropionic Acid Exacerbates [3H]GABA Release Evoked by Glucose Deprivation in Rat Striatal Slices
Authors: Boireau A , Meunier M , Doble A 
Published: April 2011

Abstract
3−Nitropropionic acid (3−NPA) is a metabolic poison that produces lesions of striatal intrinsic neurones such as γ-aminobutyric acid (GABA) neurones. This study was carried out to determine whether 3−NPA would impair the ability of striatal GABAergic neurones to withstand hypoglycaemic stress.
3−NPA (500 μM) did not affect [3H]GABA release from striatal slices under normal (11 mM) glucose concentrations. When the glucose concentration was lowered to 0&#x006d;̇3 mM, however, 3−NPA greatly potentiated the leakage of [3H]GABA from the slices. Blockade of N-methyl-d-aspartate (NMDA) or α-amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptors with 1 μM 5−methyl−10,11−dihydro−5H-dibenzo[a,d]cyclohepten−5,10−imine (MK−801) or 10 μM 2,3−dihydroxy−6−nitro−7−sulpha-moylbenzo[F]quinoxaline (NBQX), respectively, or a combination of both, had no effect. However, blockade of voltage-dependent sodium channels with tetrodotoxin totally antagonized the [3H]GABA overflow induced by the combination of 3−NPA and hypoglycaemia. Riluzole (10 to 100 μM), a neuroprotective agent that stabilizes the inactivated state of the voltage-dependent sodium channel, also dose-dependently antagonized the increase in [3H]GABA release induced by the combination of the two stresses.
Effects of Endothelin B Antagonist RES−701−1 on Endothelin-induced Contractile Responses In-vivo and In-vitro in Guinea-pigs
Authors: Ikemura Toshihide , Ohmori Kenji , Tanaka Takeo , Matsuda Yuzuru , Kitamura Shigeto 
Published: April 2011

Abstract
The effects of an endothelin (ET)-receptor B-specific antagonist, RES−701−1, on ET-induced contraction of guinea-pig trachea and on ET-induced bronchoconstriction in anaesthetized guinea-pigs were investigated.
In the epithelium-removed tracheal preparation, 1 times 10−5 M RES−701−1 inhibited contractions induced by the ETB-specific agonist sarafotoxin S6c (pKB = 6&#x006d;̇10). In the epithelium-intact tracheal preparation, RES−701−1 (1 times 10−5 M) inhibited the ET−3−induced contraction (pKB = 5&#x006d;̇27), but enhanced the ET−1−induced contraction significantly and shifted the concentration-response curve to the left. The maximal responses of ET−1- and ET−3−induced contraction were augmented by epithelium removal by 1&#x006d;̇5 and 1&#x006d;̇8−fold, respectively. Against ET−3−induced contraction in the tracheal preparation without epithelium, RES−701−1 (0&#x006d;̇3−10 times 10−6 M) antagonized the contraction in a concentration-dependent manner (pA2 = 5&#x006d;̇9). On the other hand, RES−701−1 (1 times 10−5 M) did not affect ET−1−evoked responses in the trachea without epithelium. The intravenous administration of ET−1 (1&#x006d;̇5nmol kg−1) or ET−3 (1&#x006d;̇5 nmol kg−1) evoked a biphasic, fast and sustained bronchoconstriction in anaesthetized guinea-pigs pretreated with propranolol (1&#x006d;̇0 mg kg−1). When administered intravenously, RES−701−1 (0&#x006d;̇3 or 1&#x006d;̇0 mg kg−1) showed significant reduction in both phases of bronchoconstriction induced by ET−3. As in the case of ET−1−induced bronchoconstriction, RES−701−1 augmented the sustained phase although a significant reduction of the fast phase was observed.
These results indicate that RES−701−1 can inhibit the ET−3−induced airway responses not only in-vitro but also in-vivo.
Antitussive Activity of Moguisteine Enantiomers in Guinea-pigs and Rats
Authors: Gallico L , Borghi A , Cavalletti E , Ceserani R , Tognella S 
Published: April 2011

Abstract
The antitussive effect of the R-(+)- and S-(-)-enantiomers of moguisteine were evaluated in comparison with the racemate in cough induced by 7&#x006d;̇5% citric acid and 30 μM capsaicin aerosol in conscious guinea-pigs.
No difference in potency was observed between moguisteine and the enantiomers. The oral ED50 values (with 95% confidence limits) for moguisteine, R-(+)- and S-(-)-enantiomers were respectively: 20&#x006d;̇4 (12&#x006d;̇9−26&#x006d;̇6), 20&#x006d;̇9 (14&#x006d;̇9−26) and 21&#x006d;̇6 (11&#x006d;̇8−30&#x006d;̇0) mg kg−1 in cough provoked by citric acid and 17&#x006d;̇7 (12&#x006d;̇5−29&#x006d;̇8), 18&#x006d;̇9 (14&#x006d;̇1−30&#x006d;̇1) and 20&#x006d;̇5 (15&#x006d;̇1−36&#x006d;̇6) mg kg−1 in cough induced by capsaicin. The acute oral and intraperitoneal toxicities of the enantiomers and moguisteine in the rat are very similar.
These findings suggest that the use of either enantiomer does not offer any advantage over the racemate.
hp, the Component of Log P Controlling Structure-activity Relationships Amongst Non-steroidal Anti-inflammatory Drugs
Authors: Dean Francis M 
Published: April 2011

Abstract
A range of 25 drugs and other compounds selected from published sources by strict criteria, has been used to confirm that their ability to inhibit the production of prostaglandin by mouse peritoneal macrophage does not correlate with log P but with hP, the parameter composed of only the hydrophobic contributions (atoms and groups composed of carbon, hydrogen and halogens). Other heteroatoms and physical properties can usually be ignored.
Anti-inflammatory activity does not depend upon pKa or partition phenomena unless extreme, nor does it depend primarily upon the structural types within the range phenols, salicylic acids, mefenamic acids, areneacetic and profenic acids.
Studies on Powder Plug Formation Using a Simulated Capsule Filling Machine
Authors: Britten Jeffrey R , Barnett Michael I , Armstrong N Anthony 
Published: April 2011

Abstract
Using an apparatus which simulates the action of a Macofar 13-2 dosating-type capsule-filling machine, the variation in plug weight and density with changing machine parameters has been studied.
The piston ejection speed has no effect on plug properties. However increase in compression speed leads to a less consolidated powder plug and hence reduced plug weight. Application of higher pressures reduces plug weight changes, but would be expected to affect release characteristics.
Comparison of axial and radial pressures generated by plugs of Starch 1500 and lubricated lactose show significant differences which can be explained by the different consolidation and elastic properties of the two solids.
Poly-(d,l-Lactic Acid) Microspheres Incorporating Histological Dyes for Intra-pulmonary Histopathological Investigations
Authors: Armstrong D J , Elliott P N C , Ford J L , Gadsdon D , Mccarthy G P , Rostron C , Worsley M D 
Published: April 2011

Abstract
Polylactic acid (PLA) microspheres incorporating fluorescein as a histological marker have been prepared and used as a model for the testing of inhaled PLA microspheres (2–5 μm) in the lung. PLA microspheres (20 mg) were delivered to rabbits in the form of a saline nebulization.
The distribution pattern within the pulmonary system showed that the fluorescein-labelled microspheres were distributed about the four lobes in discrete groups. The comparative numbers of these groups showed a trend towards a reduced concentration in the lower lobes. Subsequent histological examination revealed that the microsphere-treated lungs had been significantly damaged after 24 h.
Histological damage was assessed in terms of pulmonary haemorrhage, eosinophilia and neutrophil infiltration.
Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits
Authors: Jarho Pekka , Järvinen Kristhna , Urtti Arto , Stella Valentino J , Järvinen Tomi 
Published: April 2011

Abstract
The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various β-cyclodextrin (β-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether β-CyD (SBE7-β-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of β-CyD (SBE4-β-CyD and SBE7-β-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-β-CyD (HP-β-CyD) at pH 7:4. Coadministered SBE7-β-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-β-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-β-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-β-CyD solution decreases substantially eye irritation while ocular absorption is not affected.
Uptake and Transport Characteristics of Chloroquine in an In-vitro Cell Culture System of the Intestinal Mucosa, Caco-2
Authors: Augustijns P F 
Published: April 2011

Abstract
The transepithelial transport and uptake of chloroquine were studied in cultured human intestinal Caco-2 cell layers, to investigate whether a specific mechanism facilitates the flux of chloroquine. Due to ionization of chloroquine at the pH of the intestinal lumen, the fraction of the neutral form, which is required for partitioning into biological membranes, is very low, while oral bioavailability has been reported to be nearly complete. Several observations, such as concentration-dependent uptake and temperature-dependent transepithelial flux, suggest the presence of carrier mediated transport. However, alternative mechanisms may be invoked to explain these observations. It is suggested that concentration dependence can originate from ion-trapping in acidic compartments of the cell or non-specific binding to cell components, while temperature-dependent transport can, at least partly, be explained by the temperature dependence of the acid dissociation constants of chloroquine. No differences were observed in the transepithelial flux of the enantiomers of chloroquine. pH-dependent uptake as well as pH-dependent transepithelial transport suggest that the translocation of chloroquine occurs according to the fraction of neutral molecules.
From the data obtained in this study, it is concluded that chloroquine crosses the gastrointestinal barrier by passive diffusion. The extensive area of the gastrointestinal tract probably compensates for the low fraction of the neutral molecule. An interesting finding of this study was the concentration-dependent increase in transepithelial electrical resistance across monolayers incubated with chloroquine at the apical side.
Influence of Plasma-protein Binding on Analgesic Effect of Methadone in Rats with Spontaneous Withdrawal
Authors: Garrido M J , Jiminez R , Gomez E , Calvo R 
Published: April 2011

Abstract
The effect of spontaneous withdrawal on α1-acid glycoprotein (AAG) levels and methadone protein binding has been studied in the rat.
Animals were made physically dependent on morphine by providing morphine HCl in drinking water for three weeks. The natural opiate withdrawal was induced in rats by substituting the morphine solution with drinking water. The severity of the abstinence syndrome was assessed at various time intervals. After 12 h of withdrawal, the animals showing abstinence signs and low morphine levels were injected with intravenous methadone (0.35 mg kg−1) and the analgesic effect was measured by the tail-flick method and compared with animals receiving water.
The oral administration of morphine produced an increase in AAG levels from 0.64 ± 005 g L−1 in control animals to 1.47 ± 0.92 g L−1 in experimental animals at the point of withdrawal and 1.21 ± 009 g L−1 24 h after withdrawal. The percentage of methadone unbound was significantly lower in morphine-treated than in control animals. A significant correlation between AAG levels and percentage of methadone bound was observed. A parallel analgesic effect after intravenous methadone, as measured by AUC in the tail-flick test, was less in abstinence animals than in control (287.6 ± 24.8 compared with 401.0 ± 37.06 s min). We suggest that in the withdrawal syndrome an adjustment of methadone dose may be necessary because of changes in protein binding.
Changes in the Subcellular Distribution of the Rat Uterus Oestrogen Receptor as Induced by Oestradiol, Tamoxifen and ZD 182,780
Authors: Mendes A Ferreira , Caramona M M , Lopes M Celeste 
Published: April 2011

Abstract
The aim of this work was to compare the subcellular distribution of the oestrogen receptor from the uteri of rats treated with vehicle alone (control group), oestradiol or one of the antio-estrogenic drugs tamoxifen and ZD 182,780. The nuclear, microsomal and cytosolic oestrogen receptor contents were evaluated by an immunoenzymatic method (“ER-EIA” kit from Abbott Laboratories) and the results in each fraction were expressed as a percentage of the total number of receptors. Parallel studies were performed to assess the uterotrophic effect of these drugs and to assess that they had reached the uterus.
In the control group, we found that the oestrogen receptor was distributed mainly between the microsomal (29.1 ± 1.3%) and cytosolic (68.1 ±0.9%) fractions, with only a small amount located in the nucleus (2.8 ± 0.5%). When oestradiol was administered, the oestrogen receptor distribution was: nuclear 11.7 ± 2.0, microsomal 15.5 ± 1.3 and cytosolic 72.8 ± 3.3% and, in the tamoxifen group, the results were: nuclear 18.5 ± 1.5, microsomal 26.0 ± 31 and cytosolic 55.5 ± 3.4%, which shows a relative shift both to the control and the oestradiol-treated groups. In the uteri of rats treated with ZD 182,780 the results were very similar to those obtained in the control group.
Our results indicate that the subcellular distribution of the oestrogen receptor varies according to the drug administered and that this receptor may not be located in a single subcellular compartment. Moreover, the nuclear uptake of the ZD 182,780-oestrogen receptor complex seems to be blocked, possibly due to impaired receptor dimerization. In the case of tamoxifen, the intracellular transport of the receptor also seems to be blocked, probably due to the nuclear retention of the receptor, thus suggesting that tamoxifen must impair the oestrogen receptor function on a step subsequent to the receptor dimerization.