bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vivo Calibration of Microdialysis Probe by Use of Endogenous Glucose as an Internal Recovery Marker: Measurement of Skin Distribution of Tranilast in Rats
Authors: Hashimoto Yoshitaka , Murakami Teruo , Kumasa Chinami , Higashi Yutaka , Yata Noboru , Takano Mikihisa 
Published: April 2011

Abstract
To estimate the absolute concentration of substrates surrounding a microdialysis probe in-vivo, we developed a simple calibration method using endogenous glucose as an internal recovery marker and determined the skin distribution of tranilast (N-(3,4-dimethoxycinnamoyl)anthranic acid), an anti-allergic agent, in rats.
This calibration method was based on the assumption that the concentration of glucose in the extracellular fluid of skin tissues is the same as that in plasma and that the in-vivo recovery ratio of glucose to tranilast by microdialysis is the same as that estimated in-vitro. Based on these assumptions, the dialysate concentrations of tranilast and glucose recovered from cutaneous microdialysis, glucose concentration in plasma, and in-vitro recovery ratio of tranilast to glucose by microdialysis were determined for the estimation of absolute unbound concentration of tranilast in the extracellular fluid of skin tissues. In an in-vitro study employing plasma containing tranilast, the unbound concentration of tranilast in plasma estimated from the dialysate concentration was just comparable with that determined by ultrafiltration methods. Also in an in-vivo study under steady-state plasma concentration of tranilast in rats, the estimated concentration of tranilast in the skin extracellular fluid was the same level as the unbound concentration of tranilast in plasma. Using the present calibration method, the skin distribution of tranilast administered into the intestinal loop or transdermally was continuously monitored in a quantitative manner.
Influence of Nimodipine on Vasoconstrictor Responses Hindquarters Vascular Bed of the Cat
Authors: Champion Hunter C , Kadowitz Philip J 
Published: April 2011

Abstract
The beneficial effects of the calcium-entry blocking agent, nimodipine, on the cerebral circulation have been extensively studied but less is known about its peripheral vascular effects. In the present study, the effects of nimodipine on vasoconstrictor responses were investigated in the hindquarters vascular bed of the cat under constant-flow conditions.
Nimodipine decreased hindquarters vascular resistance and inhibited vasoconstrictor responses to BAY K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-phenyl)-pyridine-5-carboxylate) and noradrenaline, to the α1-adrenoceptor agonists phenylephrine and methoxamine, and the α2-adrenoceptor agonists BHT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]azepine dihydrochloride) and UK 14304 (5-bromo-6-(2-imidazoline-2-yl-amino)quinoxaline). In addition to inhibiting α-adreno-ceptor-mediated responses, nimodipine decreased responses to the vasoactive peptides angiotensin II and endothelin-1. Both the vasodilatory actions and inhibitory effects of nimodipine on vasoconstrictor responses were dose-dependent when the calcium antagonist was infused at rates of 0.1 and 1 μg min−1. The results of the present study suggest that vasoconstrictor responses to α-adrenoceptor agonists and to the vasoactive peptides are dependent, in part, on an extracellular source of calcium.
It is concluded that nimodipine and related dihydropyridine calcium-entry blocking agents may be effective in the treatment of peripheral vascular disorders in which adrenergic tone is increased or plasma levels of angiotensin II or endothelin-1 are elevated.
Tocolytic Effect of the Cyclooxygenase-2 Inhibitor, Meloxicam: Studies on Uterine Contractions in the Rat
Authors: Yousif Mariam H , Thulesius Olav 
Published: April 2011

Abstract
The objective of this study was to assess the tocolytic activity of meloxicam, a novel cyclooxygenase-2 inhibitor, in a comparative study with the non-steroidal anti-inflammatory drug, indomethacin.
The in-vitro tocolytic effect of meloxicam and indomethacin (10−9-10−5M) was evaluated on spontaneously-contracting uterine strips from non-pregnant rats and from rats at various stages of pregnancy. The rhythmic motility of the strips was reproducibly maintained over several hours. The effect of drugs was evaluated from the extent of inhibition of the frequency and amplitude of contractions. Both indomethacin and meloxicam induced dose-dependent inhibitory effects, with meloxicam being slightly more potent in all groups studied, particularly in early pregnancy.
These results suggest that meloxicam, which has fewer side-effects than cyclooxygenase-1 inhibitors, could be a potentially useful tocolytic agent in the treatment of premature labour.
Determination of Trace Lithium in Human Erythrocytes by Electrothermal Atomic-absorption Spectrometry with Pyrocoated Graphite Tubes and Integrated Platform
Authors: Decosterd L A , Buclin T , Dafflon M , Leeman C , Bélaz N , Magnin J-L , Biollaz J 
Published: April 2011

Abstract
Electrothermal graphite-furnace atomic-absorption spectroscopy with pyrocoated graphite tubes, integrated platform and matrix modification was used to determine submicromolar concentrations of trace lithium in human red blood cells.
Matrix-matched samples were used to establish calibration curves for concentrations up to 0.58 μM. (addition-calibration method) with satisfactory linearity (r2 &gt; 0.99) and intra-and inter-day variability (CV &lt; 11.4%). The median concentration of trace lithium in the cells of 40 healthy Caucasian volunteers devoid of medical or psychiatric history was 0.23 μM (inter-quartile range 0.20–0.30). The levels of trace lithium in the red blood cells correlated (r2 = 0.83) with plasma concentrations (median 0.13 μM, inter-quartile range 0.11–0.19) measured in the same blood sample. Dietary factors (e.g. consumption of lithium-containing mineral water) affected both levels. The red blood cell/plasma lithium ratio had a median value of 1.57 (inter-quartile range 1.16–2.07), implying that trace lithium is accumulated in erythrocytes. This contrasts with most reports of red blood cell/plasma ratio, measured during therapeutic treatment with lithium, for which the average value is 0.5–0.8, albeit for much higher concentrations of lithium (approx. 500–800 μM).
The proposed analytical method has the required sensitivity and accuracy for determination of trace lithium in red blood cells and makes it possible to perform epidemiological studies to assess human exposure to environmental lithium in diet and beverages, and inter-individual variations in trans-membrane and renal lithium kinetics at the submicromolar level.
Multiple Human Cytochromes Contribute to Biotransformation of Dextromethorphan In-vitro: Role of CYP2C9, CYP2C19, CYP2D6, and CYP3A
Authors: von Moltke Lisa L , Greenblatt David J , Grassi Jeffrey M , Granda Brian W , Venkatakrishnan Karthik , Schmider Jürgen , Harmatz Jerold S , Shader Richard I 
Published: April 2011

Abstract
Cytochromes mediating the biotransformation of dextromethorphan to dextrorphan and 3-methoxymorphinan, its principal metabolites in man, have been studied by use of liver microsomes and microsomes containing individual cytochromes expressed by cDNA-transfected human lymphoblastoid cells.
In-vitro formation of dextrorphan from dextromethorphan by liver microsomes was mediated principally by a high-affinity enzyme (Km (substrate concentration producing maximum reaction velocity) 3–13 μM). Formation of dextrorphan from 25 μM dextromethorphan was strongly inhibited by quinidine (IC50 (concentration resulting in 50% inhibition) = 0.37 μm); inhibition by sulphaphenazole was approximately 18% and omeprazole and ketoconazole had minimal effect. Dextrorphan was formed from dextromethorphan by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, −2C19, and −2D6 but not by those expressing CYP1A2, −2E1 or −3A4. Despite the low in-vivo abundance of CYP2D6, this cytochrome was identified as the dominant enzyme mediating dextrorphan formation at substrate concentrations below 10 μM. Formation of 3-methoxy-morphinan from dextromethorphan in liver microsomes proceeded with a mean Km of 259 μM. For formation of 3-methoxymorphinan from 25 μM dextromethorphan the IC50 for ketoconazole was 1.15 μM; sulphaphenazole, omeprazole and quinidine had little effect. 3-Methoxymorphinan was formed by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, −2C19, −2D6, and −3A4, but not by those expressing CYP1A2 or −2E1. CYP2C19 had the highest affinity (Km = 49 μM) whereas CYP3A4 had the lowest (Km = 1155 μM). Relative abundances of the four cytochromes were determined in liver microsomes by use of the relative activity factor approach. After adjustment for relative abundance, CYP3A4 was identified as the dominant enzyme mediating 3-methoxymorphinan formation from dextromethorphan, although CYP2C9 and −2C19 were estimated to contribute to 3-methoxymorphinan formation, particularly at low substrate concentrations.
Although formation of dextrorphan from dextromethorphan appears to be sufficiently specific to be used as an in-vitro or in-vivo index reaction for profiling of CYP2D6 activity, the findings raise questions about the specificity of 3-methoxymorphinan formation as an index of CYP3A activity.
Differential Efficacy of Vasodilators in Hypercholesterolaemic Rabbits
Authors: Rozsa Zsuzsanna , Pataricza Janos , Nemeth Jozsef , Papp Julius Gy 
Published: April 2011

Abstract
The effects of hypercholesterolaemia on the endothelium-dependent and -independent vascular reactivity of the superior mesenteric artery has been examined in anaesthetized rabbits in-vivo. Rabbits were fed with either standard or cholesterol-enriched diet for 24 weeks. Plasma lipids and changes in the endothelin content of plasma and vascular tissue were measured in the superior mesenteric artery and in the thoracic aorta. The functional severity of atherosclerosis was determined by examining vascular responses in the isolated thoracic aorta. The blood flow in the superior mesenteric artery was measured by transit-time flowmetry and drugs were injected through an intra-abdominal aortic catheter.
Acetylcholine (5, 10, 20 μg kg−1) elicited dose-dependent, mesenteric vasodilation in normocholesterolaemic rabbits. In hypercholesterolaemic animals the response to acetylcholine was completely abolished and even became a vasoconstriction. Endothelin levels in plasma and in the vascular tissue were significantly elevated in hypercholesterolaemic animals compared with controls. Cromakalim at a dose of 3 μg kg−1, elicited similar mesenteric vasodilation in hypercholesterolaemic and normocholesterolaemic animals.
These experiments show that the endothelium-dependent responses of the superior mesenteric artery to acetylcholine are functionally impaired by prolonged hypercholesterolaemia, that this altered vascular reactivity is associated with the elevation of endothelin levels in the circulation and in vascular tissues, and that in hypercholesterolaemia the mesenteric vasodilator effect of the K+-channel opener cromakalim is entirely preserved, suggesting that severe hypercholesterolaemia does not depress the function of ATP-sensitive potassium channels in mesenteric vascular smooth muscle.
Anti-inflammatory Effects of South American Tanacetum vulgare
Authors: Schinella Guillermo R , Giner Rosa-María , Recio MaríA Del Carmen , de Buschiazzo Perla Mordujovich , Ríos José-luis , Máñez Salvador 
Published: April 2011

Abstract
In recent years the role of phenolic compounds and sesquiterpene lactones, particularly parthenolide, in the anti-migraine and anti-inflammatory effects of Tanacetum parthenium (Asteraceae) has attracted much attention. However, the closely-related cosmopolitan species T. vulgare has remained outside the mainstream of research in this field.
After treating the aerial parts of T. vulgare with dichloromethane and methanol, and applying conventional column and thin-layer chromatographic techniques, it was possible to isolate from the moderately lipophilic fractions the principles responsible for the anti-inflammatory activity of this plant against the mouse-ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate. These were identified by ultraviolet and nuclear magnetic resonance spectroscopy as parthenolide (93% oedema inhibition at 0.5 mg/ear, ID50 (dose of drug inhibiting the oedema by 50%) = 0.18 μmol/ear) and the methoxyflavones jaceosidin (80% oedema inhibition at 0.5 mg/ear, ID50 = 0.50 μmol/ear), eupatorin, chrysoeriol and diosmetin.
Because in molar terms the potency of parthenolide was nearly three times greater than that of the most active of the flavones and because it is obtained from the plant in considerably larger amounts, the flavonoids must only be partially responsible, and to a minor extent, for the observed in-vivo anti-inflammatory local effect.
Poly(acrylamide-co-monoethyl Itaconate) Hydrog Devices for Cytarabine Release in Rats
Authors: Gomez C , Blanco M D , Bernardo M V , Sastre R L , Teijón J M 
Published: April 2011

Abstract
This study has tested the application of three different copolymeric poly(acrylamide-comonoethyl itaconate; A/MEI) hydrogels, 90A/10MEI, 75A/25MEI and 60A/40MEI, on the release of cytarabine (ara-C).
The drug was incorporated in gels by placing it in the polymerization feed mixture and discs loaded with 5–50 mg ara-C were obtained. The amount of swelling at equilibrium in saline solution (NaCl, 0.9% w/w) was between 78 and 82% w/w, depending on the composition of the copolymer. The diffusion studies followed Fick’s second law. The diffusion coefficients for swelling of the gels were between 9.30 times 10−11 m2 s−1 and 37.42 times 10−11 m2 s−1; those for release of ara-C were between 3.42 times 10−11 m2 s−1 and 10.25 times 10−11 m2 s−1. The activation energies for swelling were in the range 16.60± 2.59-21.85± 1.78 kJ mol−1; those for ara-C release were 28.13±3.1–29.7±4.6 kJ mol−1. To determine the applicability of these copolymers, 75A/25MEI gel was subcutaneously implanted in rats and the plasma concentration of the drug was determined by high-performance liquid chromatography. The concentration of ara-C in plasma (range 17.67±5.68-10.76±2.15 μg mL−1) was maintained during the first stages (2–8 h) and no drug was detected after 32 h. This route of administration was compared with intraperitoneal injection of the drug.
In conclusion, ara-C can be incorporated in hydrogels and released in a pharmacologically active form. The concentration of ara-C in plasma is maintained for long enough to improve therapeutic results.
Resistance to Densification, Tensile Strength and Capsule-filling Performance of some Pharmaceutical Diluents
Authors: Nikolakakis I , Aragon O Ballesteros , Malamataris S 
Published: April 2011

Abstract
The purpose of this study was to compare some indicators of capsule-filling performance, as measured by tapped density under different conditions, and elucidate possible quantitative relationships between variation of capsule fill-weight (%CV) and gravitational and inter-particle forces (attractive or frictional) derived from measurements of particle size, true density, low compression and tensile strength. Five common pharmaceutical diluents (lactose, maize starch, talc, Emcocel and Avicel) were investigated and two capsule-filling methods (pouring powder and dosator nozzle) were employed.
It was found that for the pouring-type method the appropriateness of Hausner’s ratio (HR), Carr’s compressibility index (CC%) and Kawakita’s constant (α) as indicators of capsule fill-weight variation decreases in the order α &gt; CC% &gt; HR; the appropriateness of these indicators also decreases with increasing cylinder size and with impact velocity during tapping. For the dosator-type method the appropriateness of the indicators decreases in the order HR &gt; CC% &gt; α, the opposite of that for the pouring-type method; the appropriateness of the indicators increases with decreasing cylinder size and impact velocity. The relationship between %CV and the ratio of inter-particle attractive to gravitational forces calculated from measurements of particle size and true density (Fvdw/Wp) was more significant for the pouring-type capsule-filling method. For the dosator-type method a significant relationship (1% level) was found between %CV and the product of Fvdw/Wp and a function expressing the increase, with packing density (pf), in the ratio of frictional to attractive inter-particle forces derived from compression (P) and tensile-strength (T) testing, d(log(P/T))/d(pf).
The value of tapped density in predictions of capsule-filling performance is affected by the testing conditions in a manner depending on the filling method applied. For the pouring-type method predictions can be based on the ratio of attractive (inter-particle) to gravitational forces, whereas for the dosator-type method the contribution of frictional and attractive forces should, because of packing density change, also be taken into account.
Acid-catalysed Hydrolysis and Benzodiazepine-like Properties of 5-(Dialkylamino)- and 5-(Alkylthio)-substituted 8-Chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a][l,5]benzodiazepines in Mice
Authors: Caccia Silvio , Grossi Giancarlo , Fracasso Claudia , Nacca Angelo , Cagnotto Alfredo , Mennini Tiziana , Ghia Marco , Roma Giorgio 
Published: April 2011

Abstract
The in-vitro and in-vivo hydrolysis of two benzodiazepine compounds has been studied to evaluate their in-vivo activity in mice.
Compounds RL 218 and RL 236, selected as representative examples of N,N-dialkyl-8-chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines (1) and of their 5-(alkylthio) substituted analogues (2), were rapidly hydrolysed to the corresponding 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5(6H)-one 3 (RL 214) in aqueous acidic solution at pH 1.5. This reaction also occurred extensively in mice when compounds RL 218 and RL 236 were given orally but not intraperitoneally. Both compounds were active against pentylenetetrazole-induced lethal convulsions in mice only when administered orally. After administration of pharmacologically effective oral doses (ED50, the dose protecting 50% of mice), at the time of assessment of the antipentylenetetrazole activity, mean brain concentrations of RL 218 and RL 236 were below the limits of sensitivity of the analytical procedure whereas brain concentrations of their metabolite RL 214 were comparable with that present after an oral equiactive dose of this compound itself. RL 214 but not RL 218 or RL 236 had in-vitro affinity for brain benzodiazepine receptors.
These results indicate that the anticonvulsant activity of RL 218 and RL 236 in mice depends essentially on their in-vivo transformation into the common active metabolite RL 214 which most probably arises as a result of acid catalysed hydrolysis in the gastric juice.
Transepithelial Transport of Large Particles in Rat: a New Model for the Quantitative Study of Particle Uptake
Authors: Limpanussorn J , Simon L , Dayan A D 
Published: April 2011

Abstract
The transport of large particles across the intestinal mucosa and the mechanisms of transfer of the particles into the body are still little understood.
Fluorescent polystyrene latex particles (2 μm diam.) were administered orally to young male Sprague-Dawley rats in doses of 2.33 times 103, 2.33 times 106 and 2.33 times 109 particles. After 60 min, Peyer’s patches and Peyer’s patch-free tissues were collected from the small intestine and colon. A novel technique was used to exclude non-translocated particles adherent to the mucosal surface; the intestinal epithelium was stripped from the intestine by immersion in Hanks’ balanced salt solution containing 1.5 mM EDTA. Particles in solubilized samples of intact and epithelium-stripped Peyer’s patches and Peyer’s patch-free intestinal tissue and colon were quantified by fluorescence microscopy. The location of particles within the intact and epithelium-stripped gut samples was revealed by confocal microscopy. Particles were shown to have been taken up along the entire length of the small and large intestines via both Peyer’s patches and the normal intestinal epithelium. The number of particles detected in the distal region was greater than in the proximal part of the small intestine, although the difference was not statistically significant.
This study has revealed that large numbers of non-translocated particles adhered to the mucosal surface resulting in a high background count. The assay system was considerably improved by the epithelium-stripping technique. The process of transepithelial uptake is a potentially important route of uptake of toxic, immunologically active and radioactive substances. These particles are much larger than the conventionally accepted upper limit for absorbed materials.
Influence of Ammonium Chloride on the Tissue Distribution of Anticholinergic Drugs in Rats
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Ohkuma Shoji , Ichimura Fujio 
Published: April 2011

Abstract
Ammonium chloride (NH4***C1) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated.
The tissue-plasma concentration ratios (Kp) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH4***C1. Treatment with NH4***C1 reduced the Kp values for both drugs, causing the largest reduction in Kp in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (Kp,sf) was reduced by treatment with NH4***C1, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in Kp,sf after NH4***Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945).
These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.
Possibility of Partial Absorption of Nicardipine by Routes Other Than the Hepato-portal System After Oral Administration in Rats
Authors: Mizumura Junko , Watari Nobutoshi , Higuchi Shigesada 
Published: April 2011

Abstract
The systemic availability of nicardipine after different routes of administration has been examined in rats, with particular attention to differentiating oral absorption from intestinal and hepatic metabolism. The quantities of nicardipine and its metabolite were determined by capillary column gas chromatography.
A linear relationship was shown between the hepatic first-pass effect and dose after hepato-portal administration of nicardipine; the hepatic first-pass effect was calculated to be approximately 80%. However, the availability after oral and rectal administration was found to be more than twice that observed after hepato-portal administration. Partial avoidance of the hepatic first-pass effect after oral and rectal administration are estimated to be 37.3% and 35.2%, respectively, assuming that all absorbed molecules pass through the liver.
These findings suggest that the absorption of nicardipine after oral administration also occurs by routes other than the hepato-portal system.