bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation of the effects of potassium channel modulating agents on mouse intestinal smooth muscle
Authors: Yeung Chi-Kong , McCurrie Janice R , Wood Diana 
Published: October 2002

Abstract
The actions of agents which modulate ATP-sensitive potassium (KATP) channels in excitable cells were investigated in an in-vitro preparation of mouse ileum from which the mucosa was removed. A range of potassium channel openers of diverse structure, cromakalim (0.1–100 μM), pinacidil (0.1–200 μM) and its analogue P1060 (0.1–200 μM), SDZ PCO400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent-1-enyloxy)-2H-1-benzopyran-6-carbonitrile) (0.3–60 μM), caused concentration-related reduction in twitch height of electrical field stimulated ileum. P1060 and SDZ PCO400 were the most potent agents; diazoxide (0.1–100 μM) was without effect. The order of inhibitory potency, based on EC50 values (concentration of a relaxant producing 50% of the maximum inhibition of twitch) was: P1060 = SDZ PCO400 &gt; cromakalim &gt; pinacidil. The relaxant effect of the potassium channel openers was antagonised by the sulfonylureas glibenclamide (0.1-1.0 μM) and glipizide (3–30 μM) but the nature of the antagonism differed. Antagonism of P1060 and SDZ PCO400 by glibenclamide appeared to be competitive whereas the antagonism of relaxation induced by cromakalim and pinacidil was apparently not competitive. Both phentolamine (1–10 μM) and tolbutamide (100–300 μM) showed competitive antagonism of the actions of pinacidil while yohimbine (1–20 μM) did not antagonise relaxation and appeared to have actions at sites other than the KATP channel in this preparation. The relative effectiveness of the antagonists on pinacidil-induced relaxation was found to be: glibenclamide &gt;phentolamine &gt;tolbutamide &gt;yohimbine, which is in agreement with studies in other tissues. The results show that many structurally diverse potassium channel openers are potent relaxants of mouse ileum. These observations are consistent with the existence of ATP-dependent K+ channels in murine intestinal muscle which, however, differ somewhat in properties from those reported for vascular muscle and pancreatic β-cells.
Sensitivity of dissolution rate to location in the paddle dissolution apparatus
Authors: Healy A M , McCarthy L G , Gallagher K M , Corrigan O I 
Published: October 2002

Abstract
The aim of the present study was to determine the apparent diffusion boundary layer and dissolution rate constant for various surfaces of compacts and at various locations in the USP paddle dissolution apparatus. Benzoic acid compacts were coated with paraffin wax leaving only the surface under investigation free for dissolution. The dissolution rates for various surfaces at varying locations in the paddle dissolution vessel were determined from the slope of the dissolution profile (amount dissolved (mg) versus time (min)). The apparent diffusion boundary layer and dissolution rate constant were calculated and were found to vary depending on the surface of the compact from which dissolution took place and also on the location and size of the compact. It may be concluded that, in developing models to describe the dissolution from solid dosage forms, it is not accurate to assume constant hydrodynamics and mass transfer rates at all surfaces of the system, or in different locations within the test device. A more exact description of the hydrodyn amics would be necessary in order to precisely model drug dissolution in the paddle dissolution apparatus.
The study on organic nitrates, part V. New derivatives of piperazine potential NO donors
Authors: Korzycka Lucyna 
Published: October 2002

Abstract
We have obtained a series of non-symmetrical 1,4-disubstituted derivatives of piperazine, with the structure of organic nitrates, as potential NO donors. These compounds were obtained from respective hydroxyl derivatives of piperazine in an esterification reaction by fuming nitric acid. The obtained nitrates were tested in-vitro by reaction with a sulfhydryl compound. The structure of the most active nitrate and its hydroxyl analogue was used for the calculation of geometrical optimization with the determination of 3D-QSAR by a semi-empirical method PM3 using HyperChem 4.5.
Omeprazole increases permeability across isolated rat gastric mucosa pre-treated with an acid secretagogue
Authors: Hopkins Ann M , McDonnell Ciara , Breslin Niall P , O'Morain Colm A , Baird Alan W 
Published: October 2002

Abstract
Triple therapy using proton-pump inhibitors (PPIs) in combination with oral antibiotics for the treatment of Helicobacter pylori-associated gastritis has shown increased efficacy for reasons that are still poorly understood. Possible explanations include a direct antibacterial effect of the PPIs or a PPI-mediated increase in bacterial susceptibility to antibiotics. Using an in-vitro model of rat gastric mucosa, we examined fluxes of a radiolabelled marker molecule through the interepithelial tight junctions under normal conditions and under the influence of an acid secretagogue (50 μM histamine) and a PPI (100 μM omeprazole). Paracellular fluxes of the radiolabel (represented by calculation of apparent permeability coefficients) were linear over 2 h. Fluxes of the marker increased significantly after treatment with histamine followed by omeprazole, but were unaltered in paired preparations exposed to the same drugs given in reverse order. Enhancements in paracellular permeability were mirrored in separate experiments using a detergent (Triton X-100), a bile salt (deoxycholate) and an agent that disrupts the cytoskeleton (cytochalasin D) to interfere with tight junctional integrity. The results suggest that exposure of acid-secreting gastric mucosa to omeprazole widens the interepithelial spacing in a manner that may facilitate enhanced macromolecular transport. Increases in antibiotic delivery from the blood to the gastric lumen via such a mechanism may account for the greater eradication rates observed with PPI-based triple therapy in H. pylori-associated gastritis.
Anti-inflammatory and antioxidant properties of Helichrysum italicum
Authors: Sala Araceli , Recio María del Carmen , Giner Rosa María , Máñez Salvador , Tournier Horacio , Schinella Guillermo , Ríos José-Luis 
Published: October 2002

Abstract
The anti-inflammatory and antioxidant activities of the aerial part of Helichrysum italicum extracts have been established in various in-vivo and in-vitro experimental models. The results obtained on the acute oedemas induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) and ethyl phenylpropiolate in the mouse ear, by serotonin and phospholipase A2 (PLA2) in the mouse paw, on chronic inflammation induced by repeated application of TPA in the mouse ear and on the delayed-type hypersensitivity induced by sheep red blood cells suggest that said anti-inflammatory activity is due to the effects of compounds expressed via a corticoid-like mechanism. In addition, the antioxidant activity of the extracts seems to be implicated in this anti-inflammatory activity, as the former inhibits enzymatic and non-enzymatic lipid peroxidation and has free-radical scavenger properties. We conclude that the anti-inflammatory activity of Helichrysum italicum can be explained by multiple effects, including inflammatory enzyme inhibition, free-radical scavenging activity and corticoid-like effects.
1-0-Hexyl-2,3,5-trimethylhydroquinone inhibits IκB phosphorylation and degradation-linked inducible nitric oxide synthase expression: beyond antioxidant function
Authors: Liu Wei , Itoigawa Masataka , Miki Tokutaro , Nishikawa Hiroshi , Sugiyama Satoru , Ishikawa Naohisa 
Published: October 2002

Abstract
Inducible nitric oxide (NO) production in macrophages plays an important role in atherosclerosis, the protective effects of vitamin E and its derivatives perhaps being partly mediated by alteration in this parameter. We have investigated the influence of a novel synthesized vitamin E derivative, 1-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ), on NO production in the RAW 264.7 mouse macrophage cell line. HTHQ dose-dependently inhibited lipopolysaccharide (LPS)-induced NO production through reducing LPS-triggered inducible nitric oxide synthase (iNOS) expression. The phosphorylation and subsequent degradation of IKB caused by LPS in RAW 264.7 cells was markedly blocked. The free radical scavenging activity of HTHQ was only 2-fold that of vitamin E, whereas its inhibition of NO production was found to be nearly 500-fold stronger. Our results indicated that HTHQ suppressed NO production in macrophages by blocking IKB degradation and thus inhibiting iNOS expression. The inhibitory activity of HTHQ on NO production did not parallel its free radical scavenging activity, implying a possible involvement of additional functions.
Synthesis and spasmolytic action of 2-substituted thienopyrimidin-4-one derivatives
Authors: Santagati Natale Alfredo , Prezzavento Orazio , Bousquet Ennio , Ronsisvalle Giuseppe , Spampinato Santi 
Published: October 2002

Abstract
In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-onederivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-oneisomers with therapeutic potential. These substances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 μM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20–25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7–41.4 μM) or histamine (IC5041.5–63.4 μM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55 ± 0.08 and 5.14 ± 0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15 ± 0.07 and 5.76 ± 0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.
Concentration-dependent disposition of glucuronide metabolite of valproate
Authors: Yu Hsiu-Ying , Shen Yu-Zen 
Published: October 2002

Abstract
The glucuronide conjugation metabolism of valproate (VPA) has been assessed to be non-linear within the therapeutic concentration range. However, disposition of its metabolite, valproic acid glucuronide (VPAG), in relation to VPA doses is unclear. The purpose of this study was to elucidate the characteristics of dose-related disposition of VPAG. Guinea-pigs were treated with an intravenous bolus dose of sodium valproate at 20, 100, 500 or 600 mg kg−1. Plasma was sampled on a pre-selected time schedule, and bile and urine were collected. Concentrations of VPA and VPAG in plasma, bile and urine were determined by gas chromatography. The pharmacokinetics of VPA and VPAG both were dose-dependent. However, the plasma concentration-time profiles of VPAG and VPA were not parallel. At a usual dose of VPA (20 mg kg−1) plasma VPAG declined with plasma VPA, whereas at a high dose of VPA (&gt; 500 mg kg−1) plasma VPAG was elevated against the decline of plasma VPA, which suggested accumulation of plasma VPAG possibly owing to saturated elimination. The biliary and urinary clearances of VPA (vCLb and vCLu) were independent of dose. However, the clearances of plasma VPA (vCLp), plasma VPAG (gCLp), biliary and urinary VPAG (gCLb and gCLu) all were decreased against the increase in VPA doses. The dose-dependent decrease of gCLu (from 3.19 to 1.12 mL min−1) was less pronounced than that of gCLp (from 6.72 to 0.86 mL min−1) and the gCLu turned to exceed the gCLp at high doses of VPA (&gt; 500 mg kg−1). These results suggest that the excess urinary VPAG might be produced in kidney. In conclusion, at a high dose of VPA, plasma VPAG is accumulated. The concentration-dependent biliary and urinary recovery of VPAG might be governed by a saturable elimination process rather than by saturable hepatic biotransformation rate. Glucuronide conjugation metabolism of VPA in kidney is speculated, which might be minor at low levels of plasma VPA, but more obvious after saturation of hepatic glucuronidation.
Multiple dose pharmacokinetics of fiduxosin under fasting conditions in healthy elderly male subjects
Authors: Dutta Sandeep , Zhang Yiming , Daszkowski Daniel J , Granneman G Richard , Verlinden Marleen 
Published: October 2002

Abstract
Selective α1a-adrenoceptor antagonists are effective agents for treatment of benign prostatic hyperplasia, a disorder occurring in middle-aged and elderly males. The objective of this study was to determine the pharmacokinetics of fiduxosin, a novel α1a-adrenoceptor antagonist, following multiple dose administration. This was carried out in a Phase I, randomized, double-blind, placebo-controlled, parallel group, multiple oral dose study of fiduxosin. Single once-daily oral doses of 30, 60, 90 or 120 mg of fiduxosin or placebo were administered to healthy elderly male subjects (n = 48; 8 active and 4 placebo per dosing group) for 14 consecutive days. Fiduxosin plasma concentration-versus-time prof les for days 1, 7 and 14 were used to assess fiduxosin pharmacokinetics. Steady state was achieved by day 7. At steady-state mean Tmax (time to maximum plasma concentration), CL/F (apparent oral clearance) and Vβ/F (apparent volume of distribution) ranges were 1.8-7.8h, 27.3–47.2 L h−1 and 846-1399L, respectively. Tmax and Vβ/F were independent of dose. Cmax (maximum plasma concentration), Cmin (minimum plasma concentration) and AUC24 (area under plasma concentration vs time curve from 0 to 24 h) for days 7 and 14 were linearly proportional with dose over the 30–120 mg/day dose range and were unchanged from day 7 to day 14. It was concluded that fiduxosin multiple-dose pharmacokinetics were dose-independent and time-invariant over the 30–120 mg/day dose range under fasting conditions.
Pharmaceutical quality of different Ginkgo biloba brands
Authors: Kressmann S , Müller W E , Blume H H 
Published: October 2002

Abstract
Ginkgo biloba-containing brands are one of the top sellers within the growing market for herbal remedies in many European countries as well as in the USA. In the consumers' interest, these brands should feature a certain quality and should be transparent in quality claims. In this investigation, a variety of products on the USA market was studied with respect to pharmaceutical quality, such as quantity of constituents and in-vitro dissolution. In terms of the content of active substances, flavone glycosides ranged from 24% to 36% and terpene lactones from 4% to 11%. With ginkgolic acids, there was a very large range, from &lt; 500 ppm to about 90 000 ppm. Comparing the dissolution rates of terpene lactones and flavone glycosides within the single products, most were approximately the same. Thus, terpene lactones and flavone glycosides were released from these products and dissolved at the same rate in most cases. Furthermore, most of the products investigated released more than the required 75% of the content of both components within 30 min. However, several products showed clear and relevant differences in dissolution rates to the rest (e.g. &lt; 75% within 30 min or even less than 25% after 60 min in one case, indicating much poorer pharmaceutical quality). Beside the comparability respectively standardisation of the extracts used, the in-vitro dissolution of the relevant constituents should be similar to other drugs to guarantee comparable in-vivo performance of herbal products. An important step in standardising pharmaceutical quality is the pharmacopoeial monograph for Ginkgo biloba extract in Germany, standardising the content of pharmacologically relevant substances (flavone glycosides 22–27% and terpen-lactones 5–7%, 2.8-3.4% ginkgolides A, B, C and 2.6-3.2% bilobalide thereof). Many of the investigated products, which refer to the German Commission E (of the Federal Institute for Drugs and Medicinal Devices) monograph, are not in accordance with this specification. Thus, they can not be considered to be pharmaceutically equivalent.
Mechanism of the vasodilator effect of 12-O-methylcurine in rat aortic rings
Authors: Guedes Diego N , Barbosa-Filho José M , Lemos Virgínia S , Côrtes Steyner F 
Published: October 2002

Abstract
The vasodilator effects of 12-O-methylcurine (OMC), a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae), and its respective mechanism of action were investigated in rat aorta. In either endothelium-intact or endothelium-denuded aortic rings, OMC induced concentration-dependent relaxation in vessels pre-contracted with 0.1μM phenylephrine (IC50 = 63.2 ± 8.8 μM and 73.9 ± 5.3 μM, respectively), 100 μM 5-hydroxy-tryptamine (IC50 = 49.6 ± 13 μM and 49.9±10μM, respectively) and 50 mM KCl (IC50 = 19.9 ± 6.8 μM and 21.1 ± 4.5 μM, respectively). OMC also inhibited in a concentration-dependent and non-competitive manner the concentration-response curves induced by CaCl2 in high K+ (IC50 = 16.7 ± 1.6 μM). In addition, OMC (100 μM) strongly inhibited phenylephrine-induced contractions dependent on calcium influx in the absence and presence of nifedipine (10 μM). In Ca2+-free medium, the transient contractions induced by phenylephrine (0.1 μM) were strongly inhibited by OMC (100 μM), whereas those induced by caffeine (20 mM) were not altered. H-89 (1 μM) and Rp-8-pCPT-cGMPs(3 μM), selective inhibitors of protein kinase A and G, respectively, did not change the relaxant effect of OMC in aortic rings pre-contracted with phenylephrine. Finally, OMC induced a concentration-dependent relaxation (IC50 = 62.8 ± 12.5 μM) of the sustained contractions induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate in normal, but not in Ca2+-free, solution. The above results suggest that OMC induces a vasodilator effect in rat aortic rings by a mechanism independent of the presence of functional endothelium and dependent on the influx of calcium ions through voltage- and receptor-operated calcium channels. Furthermore, it can also be suggested that the inhibition of calcium influx activated by protein kinase C is involved in the vasodilator effect of OMC.
In-vitro release of fluoropyrimidines from PLGA film implants
Authors: Dorta M Jesús , Oliva Alexis , Munguía Obdulia , Llabrés Matías , Fariña José B 
Published: October 2002

Abstract
The release of two low-molecular weight water-soluble fluoropyrimidines, 5-fluorouracil and 5-fluorouridine, from implants of PLGA films was modulated by varying the area (diameter) and number of layers of film per implant. The aim was to achieve continuous release without burst effect for at least a month. The film implants were prepared by the solvent evaporation technique. Except with 5-fluorouracil films, the in-vitro release profiles were in all cases triphasic, indicating that release proceeds by a combination of diffusion and polymer erosion. The experimental data fit the equation resulting from the sum of two exponentials, one direct and the other inverse. 5-fluorouridine release from simple films presented a relatively minor burst effect (24–28%). In contrast, the delivery of both compounds from sandwich-type implants occurred continuously without a burst effect, and lasted for 17–20 days. During the first phase, both 3- and 5-mm sandwiches released 55% of the dose of 5-fluorouridine, at rate constants of 0.037 ± 0.021 h−1 (n = 3) and 0.009±0.003 h−1 (n = 3), respectively. In the second phase, release was gradual from both simple Alms (k2 = 0.011-0.015 h−1) and sandwiches (k2 = 0.018-0.058 h−1). According to the analysis-of-variance results, neither the area nor type of implant influenced the rate constants significantly. The release profiles of 5-fluorouracil from simple films showed a severe burst effect (64–71%). Release of 5-fluorouracil was gradual only from sandwiches, 5 mm in diameter, showing a lag time unobserved in the 3-mm sandwiches. In the second phase, release was gradual (k2 = 0.014 ± 0.003 h−1) from 3-mm implants. However, the high variability in results for 5-mm implants prevents conclusions being drawn about the model parameters. Therefore, the sandwichtype film implants showed their utility for releasing water-soluble drugs for a prolonged time, without burst effect.
Introduction of poly-L-lactic acid microspheres into the skin using supersonic flow: effects of helium gas pressure, particle size and microparticle dose on the amount introduced into hairless rat skin
Authors: Uchida Masaki , Jin Yi , Natsume Hideshi , Kobayashi Daisuke , Sugibayashi Kenji , Morimoto Yasunori 
Published: October 2002

Abstract
A micro particulate bombardment system loaded with DNA- and RNA-coated gold and tungsten micro particles (diameter 1–3 μm; density about 19 g cm−3), the Helios gene gun system (Helios gun system), has been used to deliver a gene into cells by accelerating the micro particles to high velocity using a supersonic flow of helium gas. To investigate whether drug-loaded microspheres, &gt; 20 μm in diameter and about 1.0 g cm−3 in density, could be delivered in powder form quantitatively into the skin using the Helios gun system equipped with a cartridge container fitted with a rupture membrane, we investigated the effect of the helium gas pressure in accelerating indometacin-loaded poly-L-lactic acid (PLA) microspheres, as well as the particle size and the bombardment dose on delivery into the skin. Introduction of indometacin (i.e. indometacin-loaded PLA microspheres) after bombardment, with 3.0 mg indometacin-loaded PLA microspheres of a particle size of 20–38, 44–53 and 75–100 μM at a helium pressure of 100, 200 and 300 psi, of the abdomen of hairless rats increased in parallel with the helium pressure and it was also affected by the particle size, being highest at a diameter of 75–100 μm. However, introduction of higher amounts of PLA microspheres resulted in more severe skin erythema (skin damage) as monitored by the Draize score. Using lower bombardment doses (0.5 and 1.0 mg), the efficiency of introduction was improved and the skin damage markedly reduced. Moreover, discrete bombardment with a low dose provided a more efficient introduction of indometacin and less skin damage. These results suggest that bombardment injection of drug-loaded microspheres in a powdered form by the Helios gun system appears to be a very useful tool for the quantitative delivery of a variety of drugs and an alternative to parenteral injection by needle, especially for delivering water-soluble macromolecules.