bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leukotriene Receptor Antagonism and Augmentation of β-Receptor-mediated Events by LY171883
Authors: Rinkema Lynn E , Roman Carlos R , Russell Weihua L , Spaethe Stephen M , Bemis Kerry G , Henry David P , Marshall Winston S , Fleisch Jerome H 
Published: April 2011

Abstract
LY171883, (1-[2-hydroxy-3-propyl-4-((4(1H-tetrazol-5-yl)butoxy)phenyl]ethanone), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment β-receptormediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.5 μM IBMX, 28 μM LY171883, or 140 μM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4-induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10-fold lower concentrations. Antigen-induced release of histamine and LTC4 from guinea-pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine-induced bronchospasm in anaesthetized guinea-pigs. LY171883, 30 mg kg−1, or IBMX, 1 mg kg−1, did not affect the isoprenaline-induced decrease in the histamine response. IBMX, 3 mg kg−1, and theophylline, 30 mg kg−1, augmented the isoprenaline-induced bronchodilation. LTE4-induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg−1. Therefore, in both in-vitro and in-vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.
Effect of zinc sulphate on acetic acid-induced gastric ulceration in rats
Authors: Li Kong M 
Published: April 2011

Abstract
The effects of zinc sulphate on gastric ulcer healing rate and mucosal mucus content of acetic acid-induced ulceration in rats have been assessed. Daily treatment with zinc sulphate progressively accelerated ulcer healing in a dose-dependent manner with a significant increase observed on day 15 after ulcer induction in rats treated with 44 and 88 mg kg−1 zinc sulphate. A significant increase in gastric mucosal adherent mucus was also observed in those animals treated with 88 mg kg−1 zinc sulphate. The results suggest that a minimum treatment period of 15 days is needed for the zinc sulphate to be effective, and that zinc ions may promote gastric ulcer healing by enhancing mucus formation to prevent acid back-diffusion into the gastric mucosa.
The effect of Fluosol-DA and Hespan haemodilution on S-warfarin elimination in the rat
Authors: Shrewsbury Robert P , Hong Donald D 
Published: April 2011

Abstract
Fluosol and Hespan haemodilution in rats did not change 5-warfarin elimination within 72 h although previous studies had indicated that Fluosol haemodilution caused an increased cytochrome P450b and P450c activity at 48 h. This study showed that the increased activity at that time was specific for those isoenzymes.
Improved method for morphine determination in biological fluids and tissues: rapid, sensitive and selective
Authors: McLean Colin F , Mather Laurence E , Odontiadis John , Sloan Paul A 
Published: April 2011

Abstract
Morphine was assayed using a simple two step solvent extraction—acid back extraction sample preparation method, coupled with normal phase high-performance liquid chromatography (HPLC) and dual electrode coulometric detection. HPLC is performed with a 1.0 M Tris-methanol (5:95) mobile phase with subtle pH adjustments to separate morphine and internal standard from any interfering compounds. The use of normal phase HPLC (silica column) substantially reduces problems from interfering lipophilic substances sometimes encountered with reverse phase HPLC following solvent extraction and which would otherwise require more time-consuming sample preparation. Dual electrode detection further improves the selectivity for morphine and gives excellent sensitivity (0.5 ng mL−1), reproducibility and stability for automated sample injection. This method has proven suitable for pharmacokinetic studies of morphine.
Effects of Fedotozine on Gastrointestinal Motility in Dogs: Mechanism of Action and Related Pharmacokinetics
Authors: Pascaud X , Honde C , Gallou B LE , CHanoine F , Roman F , Bueno L , Junien J L 
Published: April 2011

Abstract
The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg−1 stimulated and at 5 mg kg−1 inhibited antral motility. Between 1 to 5 mg kg−1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2–5 and 5 mg kg−1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg−1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg−1 i.v.) and naloxone methylbromide (2 mg kg−1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the μ-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg−1 (and in all dogs except one at 5 mg kg−1) were below the detection limit (&lt; 20 ng g−1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 μg g−1. Concentrations in gastric juice after i.v. injection of fedotozine were 10 to 20 times higher than in the plasma, indicating passage of the drug from the blood into the lumen. These results indicate that fedotozine between 1 to 5 mg kg−1 orally or i.v. stimulates gastrointestinal motility in dog through peripheral opiate receptors. This peripheral activity is related to a high distribution of the drug at the target organ.
A Pharmacodynamic Model to Predict the Time Dependent Adaptation of Dopaminergic Activity During Constant Concentrations of Haloperidol
Authors: Cheng V F , Paalzow L K 
Published: April 2011

Abstract
The concentration-response relationship of the accumulation of brain homovanillic acid (HVA) has been studied by giving rats a shorter (12 h) and a longer (76 h) constant intravenous infusion of haloperidol, respectively, at rates aiming at different steady state blood concentrations of haloperidol of 5 to 30 ng mL−1. The observed response on brain HVA concentration vs increasing steady state blood concentration of the drug produced a bell-shaped type of curve during the 12 h infusion. When the infusion proceeded for 76 h a similar type of curve was obtained but it was shifted downwards compared with the 12 h infusion. The dopaminergic activity of the rat brain, as reflected by the HVA levels, therefore adapted to a lower activity during the prolonged exposure to haloperidol. To follow the time course of this adaptation, one steady state level of about 12 ng mL−1 was established and kept for 12, 28, 52 and 76 h. The result showed that the accumulation of brain HVA decreased over time compared with control animals given placebo. A pharmacodynamic model was set up to quantitatively describe the time-dependent adaptation of HVA accumulation in the whole rat brain during constant haloperidol administration. By fitting this model to all three sets of experimental data simultaneously, an adaptation half-time of about 38 h ± 14(s.d.) and a tolerance potency of about 7 ng mL−1 were obtained which could be used to calculate that, for example, at a constant blood level of 10 ng mL−1 haloperidol over 5 days the accumulation of brain HVA decreased by approximately 91% of the maximal decrease. Since the therapeutic effects of haloperidol take time to become apparent, the adaptation of HVA-accumulation seen in the present experiments and in the clinical literature could be related to the drug's antipsychotic effect. The adaptation half-time could be a useful parameter to describe and predict the rate of development of the desired therapeutic effect. Furthermore. the observed bell-shaped effect of increasing steady state blood concentrations of haloperidol on the accumulation of brain HVA corresponded to the clinically observed therapeutic haloperidol plasma concentrations of patients with schizophrenia.
Frusemide potentiates acetylcholine and carbachol in contracting the rat urinary bladder
Authors: Okpukpara J N , Akah P A 
Published: April 2011

Abstract
The interaction between acetylcholine and carbachol, and frusemide, a loop diuretic, have been studied on the rat isolated urinary bladder strip preparation. Acetylcholine (4.36 × 10−8–1.3 × 10−6 M) and carbachol (5.5 × 10−8–6.9 × 10−6 M) induced contractions and these were significantly potentiated by frusemide (3.02 × 10−6 M). The ratio of EC50 in the absence of frusemide to EC50 in the presence of frusemide was 1.58 ± 0.03 (s.e.m.) for acetylcholine and 1.86 ± 0.14 for carbachol. Potentiation of acetylcholine and carbachol contractions by frusemide was not observed in tissues treated with hexamethonium (2.5 × 10−5 M). Rhythmic contractions induced by frusemide alone were markedly reduced by hexamethonium (2.5 × 10−5 M) and tetrodotoxin (10−6 M) but they were not significantly reduced by atropine (1.7 × 10−6 M). The result suggests that frusemide increases the sensitivity of the bladder to acetylcholine and carbachol, and that it may have a nicotinic stimulant effect on the bladder. This extra-renal action may contribute to its prompt diuretic property.
Initial and Steady State Pharmacokinetics of Cilazapril in Congestive Cardiac Failure
Authors: Wiseman M N , Elstob J E , Francis R J , Brown A N , Rajaguru S , Steiner J , Dymond D S 
Published: April 2011

Abstract
Twenty one patients with NYHA class II—III congestive heart failure received single ascending doses of 0·5, 1·25 and 2·5 mg cilazapril daily followed by the minimum effective dose for six weeks. Fifteen patients completed the study, but the data from only 11 were sufficiently complete for kinetic evaluation. The pharmacokinetics of the metabolite, cilazaprilat, after a single dose of 0·5 mg cilazapril were similar to previous observations in healthy volunteers at identical dosage. Repeat administration, however, led to greater accumulation than previously observed in volunteers at the higher dosages of 1·25 or 5 mg given for 8 days. Seven patients experienced adverse events. Four were severe, leading to withdrawal of the patients from the study, but only one event was related to cilazapril. Of the other three, one suffered a myocardial infarction and subsequently died due to worsening congestive heart failure. One other patient was withdrawn with two adverse events probably related to cilazapril. No other deaths occurred amongst the study population, and there were no significant abnormalities in haematology or blood chemistry.
Acute Effects of Beclamide on Brain Regional Monoamine Concentrations, their Metabolites and Radioligand Binding Studies
Authors: Darmani N A , Sewell R D E , Nicholls P J 
Published: April 2011

Abstract
The effects of beclamide on regional brain monoamine levels and radioligand binding have been studied in rats. One hour oral pre-treatment with beclamide (400 mg kg−1) increased rat striatal dopamine turnover by increasing the levels of its major metabolites (DOPAC and HVA) three-fold. Simultaneously the drug reduced the concentration of striatal dopamine by a similar factor, and the concentrations of 5-hydroxytryptamine, (5-HT), 5-hydroxyindoleacetic acid, (5-HIAA) and 3-methoxytyramine in the striatum were reduced below the detection limits of the assay. In the frontal cortex, beclamide depleted the dopamine, 5-HT and 5-HIAA content whilst having no significant effect on the noradrenaline level. The concentrations of bioamines and their metabolites in the hypothalamus were unaffected by such acute beclamide treatment. In radioligand binding studies beclamide lacked affinity and failed to displace radioligands from α2, β, 5-HT, 5-HT2 and dopamine D2 sites in selective loci of the rat brain.
H+ coupled transport of orally active cephalosporins lacking an α-amino group across brush-border membrane vesicles from rat small intestine
Authors: Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi 
Published: April 2011

Abstract
The effect of an inwardly directed H+ gradient on the transport characteristics of ceftibuten, cefixime and analogues of ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [(6R, 7R)-(7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carba-moyloxy-methyl-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H + gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.
Subcellular distribution of metformin in rat liver
Authors: Wilcock Carol , Wyre N D , Bailey C J 
Published: April 2011

Abstract
The subcellular localization of metformin was studied in livers of 18 h fasted rats treated orally with [14C]metformin 20 μCi kg−1, 50 mg kg−1. Sequential determination of 14C radioactivity showed that maximum concentrations of metformin in plasma (about 15 μmol L−1) and liver (about 50 μmol kg−1) were achieved at 30–60 min and approximately half-maximal concentrations were achieved at 4 h. At 30 min and 4 h after administration of [14C]metformin, livers were removed and homogenized. Nuclear, mitochondrial and lysosomal, mixed membrane, and cytosolic fractions were separated by ultra-centrifugation. Distribution of 14C was similar at both time points, being greatest in the cytosolic fraction (78% of total radioactivity, and 60–69% of relative specific activity). Small amounts of 14C were associated with the other fractions. The total radioactivity and relative specific activity were respectively 2–3% and 7–8% in the nuclear fraction, 9–10% and 7–10%) in the mitochondrial and lysosomal fraction, and 8–9% and 13–14% in the mixed membrane fraction. The higher concentration of metformin in liver compared with plasma suggests that metformin enters hepatocytes via a specific mechanism, and is distributed mainly within the cytosol.
Microemulsions as topical drug delivery vehicles: in-vitro transdermal studies of a model hydrophilic drug
Authors: Osborne D W , Ward A J I , O'Neill K J 
Published: April 2011

Abstract
Microemulsions with a 58:42 weight ratio of dioctyl sodium sulphosuccinate: octanol and containing 15, 35, and 68% water have been tested for their ability to transport glucose across human cadaver skin. A flow-through multisample skin diffusion cell showed that both the 35 and 68% water microemulsions caused enhanced (approximately 30-fold) transport of glucose. No transport was discernible for the 15% water microemulsion. Differences in percutaneous glucose transport were shown to parallel differences in the diffusion of water within the microemulsion vehicles before application to the skin.
Isomerization of Lactose in Solid-state by Mechanical Stress During Grinding
Authors: Otsuka Makoto , Ohtani Hiro , Kaneniwa Nobuyoshi , Higuchi Shigesada 
Published: April 2011

Abstract
Isomerization during grinding of solid-state α-monohydrate, α-anhydrate and β-anhydrate of lactose was investigated. Samples were ground in an agate centrifugal ball-mill at 270 rev min−1 at room temperature (20°C). The crystallinity of ground lactose was measured by Hermans' method from the powder X-ray diffraction profiles. The α-and β-lactose content of the ground lactose was obtained from the specific rotation measured by using angular rotation spectrophotometry. The crystalline lactose samples were transformed into non-crystalline solids by mechanical stress during grinding. After grinding, the water content of all ground lactose samples increased, and the samples had about 2 mol water per lactose after 10 h grinding. After 10 h grinding of α-monohydrate and α-anhydrate, 10 and 15%, respectively, of α-lactose was transformed into β-lactose by the mechanical treatment. After 10 h grinding of β-lactose, 20% of β-lactose was transformed into α-lactose. The results suggest that crystalline lactose was transformed into a non-crystalline solid, and water was adsorbed on the non-crystalline lactose. The non-crystalline solids of α-or β-lactose were then transformed into their counterparts by the mechanochemical effects of grinding.
Lipid-itraconazole Interaction in Lipid Model Membranes
Authors: Brasseur R , Goormaghtigh E , Ruysschaert J-M , Duquenoy P H , Marichal P , Bossche H Vanden 
Published: April 2011

Abstract
Itraconazole, a lipophilic, fungal sterol-biosynthesis inhibitor, does not disturb membrane organization parameters measured by differential scanning calorimetry and infrared spectroscopy. Conformational analysis studies suggest that the molecular volume and the position of itraconazole in the lipid membrane is similar to that of dipalmitoyl phosphatidylcholine. The mean energy of interaction between itraconazole and the phospholipid is-60.6 kJ mol−1 whereas this energy in the pure lipid matrix is-54.3 kJ mol−1. The mean molecular area of itraconazole calculated by projecting the molecule on the lipid-water interface is equal to that occupied by the pure lipid (60 Å2/molecule).
Analgesic effect of μ-and κ-opioid agonists in beige and CXBK mice
Authors: Muraki Takamura , Oike Nobuko , Shibata Yoshie , Nomoto Teruko 
Published: April 2011

Abstract
The analgesic effects of μ-and κ-opioid agonists, including morphine, FK33,824, U50,488H, tifluadom and bremazocine, have been determined in C57BL/6J-bgJ (beige) and CXBK mice which are hyporesponsive to μ-opioid receptor-mediated analgesia compared with those of control mice (C57BL/6J (C6J), C57BL/6By (C6By), BALB/cBy (BALB)) using an abdominal constriction assay. The analgesic effect of subcutaneously administered morphine and FK33,824 in both beige and CXBK mice was significantly reduced compared with the controls and the analgesic effect of U50,488H and tifluadom in beige mice was significantly reduced compared with the wild strain (C6J). No reduction of analgesic effect of U50,488H and tifluadom was seen in CXBK compared with its progenitor strains, C6By and BALB, except for a reduction of the effect of tifluadom in CXBK compared with C6By. There was no strain difference in the bremazocine-induced analgesia. These results suggest that the beige mouse has a deficit in analgesia mediated by both μ-and κ-opioid receptors, whereas the CXBK is deficient only in the μ-opioid receptor-mediated analgesia.
Effects of Compaction Variables on Porosity and Material Tensile Strength of Convex-faced Aspirin Tablets
Authors: Pitt K G , Newton J M , Stanley P 
Published: April 2011

Abstract
The porosity and tensile strength of convex-faced aspirin tablets formed under a compaction pressure in the range 40–320 MPa and at punch velocities in the range 0.008 to 500 mm s−1 have been determined. The material tensile strength, σf, was calculated from the observed fracture load, Ps, using the equation of Pitt et al (1988): σf=10PsπD2(2⋅84tD−0⋅126tW+3⋅15WD+0⋅01)−1 where D is the tablet diameter, t is the overall tablet thickness and W is the central cylinder thickness. Tablets formed at lower compaction pressures had a higher porosity and lower tensile strength than those formed at higher compaction pressures. Tablets of face curvature ratio (D/R) in the range 0.25-0.67 and a normalized cylinder length (W/D) of 0.2 had the optimum tensile strength. (R is the radius of curvature of the tablet face.) Tablets formed at high compaction rates were significantly weaker than those formed at lower compaction rates.
Percutaneous Absorption of Indomethacin from Transparent Oil/Water Gels in Rabbits
Authors: De Vos F , De Muynck C , Geerts M , Remon J P 
Published: April 2011

Abstract
The percutaneous absorption of indomethacin from transparent oil in water gels (TOW gels) has been studied in rabbits and compared with absorption from a hydrophilic gel and from a spray formulation. The area under the curve and the Cmax values in plasma were significantly higher for the TOW gels in comparison with the other formulations after single application. The pH of the aqueous phase of the TOW gels did not significantly influence the bioavailability. After multiple application the TOW gels induced a larger increase in AUC (vs first application) in comparison with the other formulations. None of the formulations without drug damaged the skin after multiple application. For indomethacin formulations skin damage was more pronounced with the hydrophilic gel than for the TOW gels and spray formulation.
Leucine Modulates Peptide Transport System-1 Across the Blood-brain Barrier at a Stereospecific Site within the Central Nervous System
Authors: Banks William A , Kastin Abba J 
Published: April 2011

Abstract
Previous results have shown that leucine injected into a cerebral ventricle (i.c.v.) can act as an allosteric regulator of peptide transport system-1 (PTS-1), the system that transports Tyr-Pro-Leu-Gly-NH2 (Tyr-MIF-1) and the enkephalins out of the central nervous system (CNS). D-Leucine appeared more potent than L-leucine. In the current study, dose-response curves were constructed for each compound after both intravenous (i.v.) and i.c.v. injection. Based on ED50 values after i.c.v. injection, D-leucine was about 200 times more potent than L-leucine in its inhibition of PTS-1, thereby confirming stereospecificity of the allosteric site, D-and L-Leucine were also more potent when given i.c.v. than when given i.v., suggesting that the site is located on the CNS side of the blood-brain barrier (BBB). The finding that D-leucine was less potent than L-leucine when given i.v. is also consistent with a CNS site of action because the L-isomer of leucine has been shown to be preferentially transported into the brain. These findings agree with the previous suggestion that some of the neurotoxic effects of leucine may be mediated through PTS-1 and could help explain how D-amino acids can exert opiate-related effects on the CNS.