bluuebunny/crossref_metadata_2025 huggingface dataset:
Biocompatibility of wound management products: the effect of various monosaccharides on L929 and 2002 fibroblast cells in culture
Authors: Schmidt Richard J , Spyratou Olga , Turner Terence D
Published: April 2011

The effects of various monosaccharides on the growth of human 2002 and mouse L929 fibroblast cultures have been investigated. Eleven monosaccharides having acidic, neutral, and basic characteristics were evaluated in a bioassay procedure developed for the investigation of biocompatibility of wound management materials. Rate of growth in both cell lines was inhibited by D-galacturonic acid and by D-glucuronic acid. Although most neutral sugars produced no significant change in the growth rate or in the morphology of the cells, galactose produced a significant increase in the growth rate of both cell lines whilst L-fucose caused a significant decrease in growth of the L929 cells but did not significantly affect the growth of 2002 cells; xylose increased the growth rate of L929 but not 2002 cells. D-Glucosamine, a basic sugar, produced inhibition of growth which followed a different pattern from that produced by the acidic sugars; N-acetylglucosamine produced a species specific increase in cell growth of L929 cells. The results show that the effects produced by the monosaccharides on the cultured fibroblasts are related to their chemical structure and to cell line, and suggest that the use of galactose as a possible aid to wound healing should be investigated.
Effectiveness of insulin suppositories in diabetic patients
Authors: Nishihata Toshiaki , Kamada Akira , Sakai Kiyoshi , Yagi Toshihito , Kawamori Ryuzo , Shichiri Motoaki
Published: April 2011

Experimental insulin suppositories regulated postprandial hyperglycaemia in diabetic patients. The insulin suppositories seemed also to avoid hyperinsulinaemia. The formulation with more rapid dissolution of insulin, which contained a solid dispersed form of insulin, effectively reduced the insulin dose required.
The Uptake and Translocation of Latex Nanospheres and Microspheres after Oral Administration to Rats
Authors: Jani P , Halbert G W , Langridge J , Florence A T
Published: April 2011

Non-ionic and carboxylated fluorescent polystyrene microspheres (100, 500 nm, 1 and 3 μm in diameter), were fed by gavage (2·5% w/v; 1·25 mg kg−1) daily for 10 days to female Sprague Dawley rats. Peyer’s patches, villi, liver, lymph nodes and spleen of animals fed the non-ionic microspheres from 100 nm to 1 μm showed unequivocal evidence of uptake and translocation of the particles. Heart, kidney and lung showed no evidence of the presence of microspheres. Carboxylated microspheres were taken up to a lesser degree than the non-ionised particles. Experiments with 125I radiolabeled 100 nm and 1 μm particles showed a higher uptake of the smaller particles, which were concentrated in GI tissue and liver. Particles were not distributed randomly in the tissues, but were concentrated at the serosal side of the Peyer’s patches and could be seen traversing the mesentery lymph vessels towards the lymph nodes. The results demonstrate a need to re-examine the possibilities of particulate oral delivery, as well as the potential toxicity of ingested particulates.
Ionization constants, octanol partition coefficients and Cholinesterase inhibitor constants for chlorpromazine and its metabolites
Authors: Whelpton Robin
Published: April 2011

The relationship between the lipophilic character of chlorpromazine and seven of its metabolites and their ability to inhibit horse serum Cholinesterase (Ki) has been investigated. Log(1/Ki) values were correlated with log P octanol partition coefficients (r = 0·88, P < 0·01, n = 8). The inhibitor values ranged from 2·7 × 10−6 M for chlorpromazine to 48·6 × 10−6 M for monodesmethylchlorpromazine sulphoxide. Ionization constants were determined by limiting solubility, spectrophotometry and pH-partition characteristics. Demethylated metabolites were more basic than the tertiary amines and the sulphoxides were slightly less basic than the corresponding sulphides.
Apparent down-regulation of rat brain μ and κ-opioid binding sites labelled with [3H]cycloFOXY following chronic administration of the potent 5-hydroxytryptamine reuptake blocker, clomipramine
Authors: Benkelfat Chawki , Aulakh Charanjit S , Bykov Victor , Rice Kenner C , de Costa Brian R , Rothman Richard B
Published: April 2011

This study examined the effect of chronic clomipramine administration on opioid μ- and κ-binding sites. Clomipramine (5 mg kg−1 day−1) or saline was administered to rats via osmotic minipumps for 3 days or 28 days. Lysed-P2 brain membranes were prepared and preincubated for 60 min without (control membranes) or with 1 μM of the μ-selective acylating agent, 2-(4-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanato-benzimidazole-HCl (BIT), to deplete membranes of μ-binding sites. [3H]6-Desoxy-6β-fluoronaltrexone ([3H]cycloFOXY) was used to label μ and κ-binding sites. Weighted nonlinear least squares analysis of cycloFOXY binding surfaces permitted determination of the Kd and Bmax values of μ- and κ-binding sites in control and treated rats. Subacute (3 days) administration of rats with clomipramine had no significant effect on [3H]cycloFOXY binding. Chronic (28 days) administration of clomipramine produced a small (approximately 10%) but statistically significant decrease in the Bmax. These findings are discussed in reference to other studies that have examined the effect of chronic antidepressant administration on opioid receptors, and speculate that the endogenous opioid systems may play a role in obsessive-compulsive disorder.
Sustained release of buserelin acetate, a luteinizing hormone-releasing hormone agonist, from an injectable oily preparation utilizing ethylated β-cyclodextrin
Authors: Uekama Kaneto , Arima Hidetoshi , Irie Tetsumi , Matsubara Kazutaka , Kuriki Takeo
Published: April 2011

The possible use of heptakis (2,6-di-O-ethyl)-β-cyclodextrin (DE-β-CyD) as a parenteral sustained-release carrier for buserelin acetate, a luteinizing hormone-releasing hormone superagonist, has been examined. The in-vitro release of buserelin from the oily suspension was significantly retarded by the complexation with DE-β-CyD, mainly due to the poor water solubility of the complex. A single subcutaneous injection of the suspension containing the buserelin-DE-β-CyD complex to rats provided an effective continuous plasma level of buserelin lasting for at least one month, indicating a potential therapeutic efficacy for the treatment of the endocrine-dependent diseases. These results suggest that DE-β-CyD serves as an injectable sustained-release drug carrier suitable for chronic treatment with buserelin acetate.
An Infrared Study of Tautomerism in Acetohexamide Polymorphs
Authors: Girgis Takla Pamela , Dakas Christos J
Published: April 2011

Infrared data determined for known polymorphic forms and some new derivatives of acetohexamide and related compounds support the view that acetohexamide polymorphs exhibit keto-enol tautomerism. They indicate that type A polymorphs exist in the enol form, probably stabilized by intramolecular bonding between an O—H and S=O group to form a six-membered ring. Type B polymorphs exist in the keto form with the urea carbonyl group intermolecularly bonded to a sulphonamide N—H. The new evidence disputes previous interpretations of the data.
Evidence for a Postsynaptic Action of Neostigmine on Muscarinic Receptors in the Anococcygeus Muscle of the Rat
Authors: Smith J A , Spriggs T L B
Published: April 2011

In the rat anococcygeus muscle neostigmine induces atropine-sensitive, significant leftward displacements of the log concentration-response curves to both noradrenaline and 5-hydroxytryptamine. Responses to high K+ were also potentiated by neostigmine. However, high K+ elicited only small and irregular overflows of tritium from [3H]noradrenaline pre-incubated tissues, in contrast to the large overflow elicited by field stimulation. In addition guanethidine blocked responses to field stimulation but not those to high K+. This is consistent with the dose-related tension responses to high K+ being elicited postsynaptically. These results indicate that postsynaptic muscarinic receptors are involved in the potentiation by neostigmine of rat anococcygeus muscle responses to field stimulation or exogenous agonists, possibly by an action on receptor operated ion channels. Additional support for a postsynaptic site of action comes from the failure of neostigmine to potentiate tension responses to nerve or field stimulation in the chick expansor secundariorum, a muscle which is devoid of postsynaptic muscarinic receptors.
Relaxant Actions of Khellin on Vascular Smooth Muscle
Authors: Ubeda Amalia , Villar Angel
Published: April 2011

To clarify the mechanism of the vasodilatory action of khellin on calcium, we have investigated its relaxant action on base line and on K+ and noradrenaline-induced contractile tensions in rat aorta smooth muscle and on spontaneous contractile activity of rat portal vein. Khellin relaxed both of these preparations with a similar potency, which suggests a non-specific inhibition of calcium flux, without any difference related to the specific calcium channels. We have also studied the capacity of khellin to interfere with the loading and release mechanisms of caffeine and noradrenaline-sensitive calcium stores in Ca-free medium. Khellin’s Ca2+ loading reduction may be related with its capacity to inhibit calcium influx. Khellin applied during Ca2+ release also caused relaxation. We propose that this drug may enhance calcium extrusion or sequestration rather than the calcium release mechanism. These actions on calcium influx and intracellular mobilization can contribute to its vasorelaxant action.
Effects of opioid agonists on urine production in neonatal rats
Authors: Jackson Helen C , Kitchen I
Published: April 2011

The modulatory effects of opioids on urine production in adult rats have been well-documented. We report here the first investigation of the effects of these agents on urination in neonatal rats. The κ-agonists U50,488H (1, 10 mg kg−1) and (+)-tifluadom (10 mg kg−1) produced an increase in urine output in 10-day old pups whereas the (-)-isomer of tifluadom was ineffective in this model. The diuretic effects of the highest dose of U50,488H were attenuated by a 10 but not a 1 mg kg-1 dose of the opioid antagonist naltrexone. These findings suggest that κ-agonists, as in adult animals, produce diuresis in neonates by activity at κ-opioid receptors and also confirm the stereoselective nature of the response. The increase in urination produced by U50,488H (10 mg kg−1) was also reduced by the α-adrenoceptor antagonist phentolamine (1 mg kg−1), an observation which supports the hypothesis that κ-agonists—in addition to their well-established inhibitory effects on the release of antidiuretic hormone—may increase urination via an adrenergic mechanism at the level of the adrenal medulla. The μ-opioid agonist morphine (0·1–10 mg kg−1), in contrast to its observed effects in older animals, did not produce antidiuresis in either normally-hydrated or water-loaded 10-day old rat pups. The results of this study therefore show that the stimulatory effects of κ-agonists on urine production appear to be fully-functional at 10-days but the inhibitory effects of opioids on urination lag behind in development.
Employment of magnet-susceptible microparticles for the targeting of drugs
Authors: Kharkevich D A , Alyautdin R N , Filippov V I
Published: April 2011

It has been demonstrated in cats that magnet-susceptible microspheres and liposomes containing neuromuscular blocking agents (dipyronium, pyrocurinum and diadonium) caused a deeper inhibition of the neuromuscular transmission in the limb placed in the magnetic field than in the control limb located beyond the field. The microparticles containing a short-acting neuromuscular blocking agent diadonium appeared to have the highest selectivity of action. The present method allows a pronounced neuromuscular block in a target area to be achieved without noticeable effect on PCO 2 of the exhaled air.
The Material Tensile Strength of Convex-faced Aspirin Tablets
Authors: Pitt K G , Newton J M , Richardson R , Stanley P
Published: April 2011

The material tensile strength of a range of convex-faced tablets, compacted under controlled conditions at pressures of 40 and 320 MPa from a size fraction of acetylsalicylic acid, has been assessed. The calculation of the tensile strength σt, from observed fracture loads obtained in diametral compression testing, is based on the equation derived by Pitt et al (1988), namely:

where P is the fracture load, D is the tablet diameter, t is the overall tablet thickness and W is the central cylinder thickness. The strength of a tablet of a given shape compacted at 320 MPa was between two and four times greater than that of a similar tablet compacted at 40 MPa. For the thicker tablets (W/D ≥0·2) the material tensile strength was practically independent of shape. For the thinner tablets (W/D = 0·1) the material tensile strength varied considerably with face-curvature, showing a maximum for each of the two compaction pressures at a D/R value of 0·67.
Effect of β-Casomorphins on Intestinal Propulsion in the Guinea-pig Colon
Authors: De Ponti Fabrizio , Marcoli Manuela , Lecchini Sergio , Manzo Luigi , Frigo Gian Mario , Crema Antonio
Published: April 2011

β-Casomorphins are a family of opioid peptides originally isolated from β-casein. In view of a possible physiological significance of these milk-derived compounds, the effects of bovine β-casomorphin-5 (β-CM-5), β-casomorphin-4 (β-CM-4) and D-Ala2-β-casomorphin-4-NH2 (D-Ala2-β-CM-4-NH2) have been investigated on the peristaltic reflex in the guinea-pig isolated colon and compared with morphine. β-CM-5 and D-Ala2-β-CM-4-NH2 each dose-dependently inhibited the velocity of propulsion of an intraluminal bolus; β-CM-4 was ineffective. IC50 values were 0·30, 5·21 and 0·29 μfor morphine, β-CM-5 and D-Ala2-β-CM-4-NH2, respectively. The potency ratios vs morphine were 0·06 and 0·96 for β-CM-5 and D-Ala2-β-CM-4-NH2, respectively. Blockade of the peristaltic reflex by β-CM-5 or D-Ala2-β-CM-4-NH2 was reversed by the opioid antagonist naloxone. D-Ala2-β-CM-4-NH2 also dose-dependently inhibited resting acetylcholine output (IC50 = 5·69 μM; potency ratio vs morphine: 0·63). In conclusion, certain β-casomorphins inhibit intestinal propulsion and cholinergic neurotransmission in the guinea-pig colon, probably by acting at opioid receptors.
The Effect of Diazepam on Ventricular Automaticity Induced by a Local Injury. Evidence of Involvement of “Peripheral Type” Benzodiazepine Receptors
Authors: Ruiz F , Hernández J , Pérez D
Published: April 2011

The effect of diazepam on ectopic cardiac automaticity has been examined in rats. We also investigated whether “central” or “peripheral type” benzodiazepine receptors are involved, as well as the role of calcium, on the possible effect of diazepam, by studying the interaction of this drug with either GABA, Picrotoxin, RO 15–1788, PK 11195, diltiazem or Bay K 8644. A local injury of the rat isolated right ventricle produced a sustained abnormal rhythm which was completely abolished by diazepam (30–50 μu). This effect was not modified by the presence of either GABA (100 μM) Picrotoxin (2 μM) or RO 15–1788 (5 μM.) but it was reduced by the antagonist of “peripheral type” benzodiazepine receptors PK 11195 (0·1 μu). On the other hand the calcium channel blocker diltiazem (5 μM) and the calcium channel activator Bay K 8644 (3 nM), respectively, potentiated and reduced the effect of diazepam. It is concluded that diazepam effectively reduces ectopic cardiac automaticity in the rat. The “central type” benzodiazepine receptors are not involved in this effect, but it seems to be, at least, partially mediated by “peripheral type” receptors and is a calcium-dependent phenomenon.
Effects of Trimebutine Maleate on Electrical Activities of Isolated Mammalian Cardiac Preparations
Authors: Igawa Osamu , Kotake Hiroshi , Hirai Shozo , Hisatome Ichiro , Hasegawa Junichi , Mashiba Hiroto
Published: April 2011

The effects of trimebutine maleate on electrical activity in guinea-pig isolated papillary muscles and rabbit sino-atrial nodes have been studied by means of a standard microelectrode method. In papillary muscles, trimebutine (above 10 μM) decreased the maximum rate of rise (V̇max) and the action potential duration at 90% repolarization (APD90), whereas the resting potential was not significantly altered. As to a decrease in V̇max, trimebutine produced a negative shift of the curve relating V̇max to the resting potential along the voltage axis. Trimebutine also depressed the slow action potentials of papillary muscles produced by 27 mM K and 0·2 mitt Ba. In spontaneously beating sino-atrial node preparations, trimebutine (above 10 μ) decreased the heart rate, V̇max and the rate of diastolic depolarization. These results indicate that trimebutine maleate possesses a depressant action on the electrical activities of the fast- and slow-response fibres of the heart mainly due to inhibitions of both fast Na+ and slow Ca2+ channels.
Continuous shear rheometry of o/w emulsions; control of evaporation in cone/plate geometry
Authors: Orafidiya Lara O
Published: April 2011

Volatile solvents may evaporate during cone/plate viscometry so that false rheograms develop. This surface evaporation was prevented in a cod-liver oil-in-water emulsion stabilized with zanthoxylum gum by layering a film of cod-liver oil on the exposed surface of the emulsion test sample. The oil layer effectively prevented evaporation and did not alter significantly the rheological behaviour of the test material.
The effects of dipyridamole and indomethacin on methotrexate cytotoxicity in LoVo human colon cancer cells
Authors: Gaffen J D , Chambers E A , Bennett A
Published: April 2011

Dipyridamole and indomethacin were studied for their effects in the in-vitro response of LoVo colon cancer cells to methotrexate (MTX) using a dye elution method. Dipyridamole 0·5–5 μg mL−1 or indomethacin 1 μg mL−1 alone had little or no effect on cell growth. The tumour cells were refractory to even high concentrations of MTX (2·5–10 μg mL−1) alone or with indomethacin 1 μg mL−1. In contrast, dipyridamole 0·5–5 μg mL−1 sensitized the cells to MTX 5 μg mL−1 (their growth was reduced by 25 to 69%), possibly by inhibiting thymidine salvage.
2-[125I]Iodomelatonin binding sites in hamster and chick exhibit differential sensitivity to prazosin
Authors: Pickering D S , Niles L P
Published: April 2011

Binding of 2-[125I]Iodomelatonin to putative receptors for melatonin has been well documented in chicken and hamster tissues. Differences in the potency of N-acetyl-5-hydroxytryptamine in these tissues suggested distinct central and peripheral binding sites. Prazosin was found to be much more potent (Ki = 6–5 nm) in hamster hypothalamus than in chick retina (Ki = 740 nm). N-acetyl-5-HT also was more potent in hamster hypothalamus (Ki = 14 nm) than in chick retina (Ki = 1050 nm). A comparison of hamster hypothalamus to chick forebrain revealed a similar difference in potency for prazosin. In light of these findings, the dissimilarity between the potencies of N-acetyl-5-HT and prazosin in hamster and chick would appear to be due to a species difference as the central and peripheral sites seem alike within either species.
A study of β-adrenoceptors in rat lung parenchymal strip
Authors: Candenas Maria L , Anselmi Elsa
Published: April 2011

The aim of the present study was to characterize the β-adrenoceptor population in rat lung strip. For this purpose, Schild plots were obtained for the β-adrenoceptor antagonists atenolol (β1-selective), butoxamine (β2-selective) and propranolol (nonselective), using three different agonists: isoprenaline (non-selective), salbutamol (β2-selective) and noradrenaline (β11-selective). The slopes of these Schild plots were close to the theoretical value of unity, and pA2 values determined with isoprenaline, salbutamol and noradrenaline as agonists were: for propranolol, 7·86 ± 0·22, 7·72 ± 0·15 and 7·89 ± 0·23; for atenolol, 5·19 ± 0·05, 5·33 ± 0·07 and 5·47 ± 0·22 and for butoxamine, 6·31 ± 0·11, 6·34 ± 0·03 and 5·99 ± 0·23, respectively. These data suggest that pharmacological responses of rat isolated lung strip to β-adrenoceptor agents are mediated by a homogeneous population of β2-adrenoceptors, although the presence of a minor population of β1-adrenoceptors undetected by the agonists used cannot be excluded.
Interaction of Nefopam and Orphenadrine with the Cytochrome P-450 and the Glutathione System in Rat Liver
Authors: Leurs R , Donnell D , Timmerman H , Bast A
Published: April 2011

Nefopam, a cyclic analogue of orphenadrine, exhibits a type I (substrate) and a type II (ligand) interaction with ferri-cytochrome P-450 in control and phenobarbitone induced rat hepatic microsomes respectively. In-vitro metabolism of nefopam in phenobarbitone-induced microsomes leads to the production of a reactive metabolite which complexes with cytochrome P-450. In contrast to the known complexation of orphenadrine, complexation by nefopam can be inhibited by glutathione (GSH, 0·1-1·0 mm). However, in-vivo administration of nefopam to rats does not diminish the GSH content of liver cytosol nor increase oxidized glutathione levels nor alter the activities of GSH transferase and GSH peroxidase. In-vivo administration does not lead to cytochrome P-450 induction nor cytochrome P-450 complexation as has been shown for orphenadrine. Finally, nefopam inhibits the NADPH dependent endogenous H2O2 production in both control and phenobarbitone-induced microsomes.
Specific Age-dependence in Capacity-limited Uptake of Propranolol by Isolated Rat Lung
Authors: Iwamoto Kikuo , Watanabe Jun , Yonekawa Hina
Published: April 2011

To investigate the effect of age on the pulmonary uptake of propranolol, minced tissue (0·4 g) of lungs isolated from 3- to 104-week-old rats was incubated with the drug (1 to 500 ng μL−1) prepared in oxygenated, pH 7·4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BS A for 60 min at 37°C. In any age-group the metabolism of propranolol was not significant (i.e. less than 0·6% of any initial load) under the present in-vitro conditions. The extent of uptake after the incubation with 2·5 μ mL−1 of the drug was largest in the 7 weeks (i.e. 82% of the initial load) and relatively small in the 3(64%), 24(61 %), 52(51%) and 104(48%) week old rats. Similar, specific age-dependence was observed in the tissue-to-medium concentration ratio of the drug. In any age-group, the initial uptake rate obtained in the first 5 min of the incubation was found to be a combination of apparently linear transport and saturable (capacity-limited) processes. There was a marked, specific age-dependence in the capacity-limited uptake rate. Although Km′ value was almost equivalent in any age-group (i.e. 24·4 to 25·4 μg mL1), Vmax exhibited a specific age-dependence by yielding the highest value in 7 weeks (0·726 ± 0·101 mg g−1 min−1) and relatively low values in 3 (0·501 ±0·082 mg g−1 min−1), 52 (0·410 ± 0·088 mg−1 g−1 min1) and 104 (0·397 ± 0·074 mg g−1 min−1) weeks.
Pharmacokinetics of 8-phenyltheophylline in the rat
Authors: Wormald A , Bowmer C J , Yates M S , Collis M G
Published: April 2011

The pharmacokinetics of the adenosine antagonist 8-phenyltheophylline (8-PT) have been investigated in the rat. After intravenous administration to male rats with normal renal function, 8-PT was rapidly cleared from plasma with a t 1/2 of about 14 min. Its apparent volume of distribution was some 76 mL/100 g and plasma clearance was 3·5 mL min−1 g. Injection via the carotid artery did not alter the kinetics of 8-PT, but when given through the porta) vein a first-pass effect was observed. Moreover, 8-PT could not be detected in plasma following intraperitoneal injection. The kinetics of 8-PT were not altered in male rats with acute renal failure and no difference was noted between male and female animals with respect to the kinetics of 8-PT following intravenous injection. It is concluded that the pharmacokinetic properties of 8-PT are likely to complicate its use in-vivo.
Rapid production of ulcerative disease of the colon in newly-weaned guinea-pigs by degraded carrageenan
Authors: Marcus A J , Marcus S N , Marcus R , Watt J
Published: April 2011

In a dose-response study, degraded carrageenan (Eucheuma spinosum) was supplied in the drinking fluid at 1,2 and 3% concentrations over two weeks to young adult guinea-pigs. Ulceration of the large bowel was produced in 100% of animals, the severity and extent of damage probably being dose-related. In a time-course study, 3% degraded carrageenan solution supplied to newly-weaned guinea-pigs produced in 100% of animals ulceration in the caecum by four days and in the ascending colon by seven days. The onset of ulceration occurred as early as the second day. This model is convenient and economic for the screening of drugs of potential therapeutic value in human ulcerative colitis.
Inhibition of Dapsone-induced Methaemoglobinaemia by Cimetidine in the Presence of Trimethoprim in the Rat
Authors: Coleman M D , Russell R M , Tingle M D , Park B K
Published: April 2011

Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P < 0·05) in measured methaemoglobin levels (46·2±24% Met Hb h) compared with administration of dapsone alone (124·5 ± 24·4% Met Hb h). The elimination half-life of dapsone (814 ± 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 ± 160 min, P < 0·05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 ± 2249 μg min mL−1) in the presence of dapsone compared with trimethoprim alone (2122 ± 552 μg min mL−1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19·1±6·9 vs 60·8 ± 21·0 mL min−1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 ± 120 vs 292 ± 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 ± 1501 μg min mL−1) compared with trimethoprim alone (2122 ± 552 μg min mL−1). There was also a corresponding reduction in the clearance of trimethoprim in the presence of cimetidine (61·2 ± 21·2 vs 17·8 ± 9·3 mL min−1) compared with control. However, there was no significant change in the elimination half-life of trimethoprim after the administration of cimetidine (273 ± 136 vs 215 ± 109 min). Administration of either trimethoprim or cimetidine alone did not cause methaemoglobin levels to exceed control values. The administration of trimethoprim with dapsone and cimetidine resulted in a significant increase in AUC (2122 ± 552 vs 5744 ± 3289 μg min mL−1), a fall in clearance (17·8 ± 9·3 vs 60·8 ± 21 mL min−1), but no change in half-life (252 ± 134 vs 273 ± 136 h) of trimethoprim. The co-administration of cimetidine significantly reduced dapsone-mediated methaemoglobin formation in the presence of trimethoprim, whilst the AUC of trimethoprim was significantly increased in the presence of both cimetidine and dapsone.
Effect of a Perfluorochemical Emulsion on the Rat Hepatic Mixed Function Oxidase System
Authors: Ravis William R , Ramakanth Swayampakula , Brzozowski Diane M , Hamrick Maynard E
Published: April 2011

The perfluorochemical components of synthetic oxygen transporting emulsions may persist in hepatic tissue. After a single 30% blood exchange with the perfluorochemical emulsion, Fluosol-DA 20%, the effects on the microsomal metabolism of 7-methoxycoumarin and 7-ethoxycoumarin were studied over a 9 week period. Fluosol-DA treated animals were compared with controls (sham) and hetastarch-treated controls. Changes in dealkylase activities were compared with induction by phenobarbitone and 3-methylcholanthrene. The liver to body weight ratio increased by 49% in Fluosol-DA-treated rats over the controls at 1 week and the microsomal protein was increased in the Fluosol-DA-treated rats after 4 and 9 weeks. Fluosol-DA treatment induced 7-methoxycoumarin demethylase with peak differences occurring at 1 week and a Vmax 75% greater than controls. Fluosol-DA was a more potent inducer of demethylase than phenobarbitone. In addition, 7-ethoxycoumarin de-ethylase was induced by Fluosol-DA with a peak induction at 4 weeks. The Vmax at 4 weeks in Fluosol-DA-treated rats was 122% greater than control. In this case, Fluosol-DA produced less induction in de-ethylase than 3-methylcholanthrene. These studies show that Fluosol-DA induces more than one form of cytochrome P450 and the effects resemble those of phenobarbitone more than those of 3-methylcholanthrene. Hetastarch, a plasma expander, did not affect liver weights, microsomal protein content, or the cytochrome P450 system.
Studies on an Oral Iron Chelator: 1,2-Dimethyl-3-hydroxy-pyrid-4-one (DMHP). Mechanism of Intestinal Absorption in Rabbits
Authors: Railkar Aruna M , Awni Walid M , Camp Richard J , Rahman Yueh-Erh
Published: April 2011

Over the last 30 years, desferrioxamine has been the only iron chelator in clinical use. This chelator is expensive and must be given by injection. A new class of chelators, namely 1-alkyl-2-methyl-3-hydroxypyrid-4-ones, have been shown to be orally effective. Using 1,2 dimethyl-3-hydroxy-pyrid-4-one (DMHP), we have carried out a study to clarify the mechanism of intestinal absorption of this new class of drug, using an in-situ system of the intestine from rabbit. The major site of DMHP absorption is in the intestine and is linear with increasing drug concentration. DMHP absorption per unit length of jejunum and ileum is similar; however, due to the larger surface area of jejunum, the absorption by ileum segment is more effective per unit surface. l-Proline, l-tryptophan (amino acids), 2-deoxyglucose, and sodium iodoacetate (metabolic inhibitors) have no effect on DMHP absorption, but l-phenylalanine, an amino acid with a 6-member carbon ring, significantly inhibits the DMHP absorption from the intestinal segment. We conclude that the mechanism of DMHP absorption in the intestine is mainly by simple passive diffusion based on the linear relationship found between drug concentration and absorption. However, the inhibitive effect of l-phenylalanine suggests that the co-existence of a facilitated uptake cannot be ruled out.
Accumulation of 5-Ethyl-2′-deoxyuridine and its 5,6-Dihydro Prodrugs in Murine Lung and its Potential Clinical Application
Authors: Cheraghali A Majid , Morin Kevin W , Kumar Rakesh , Knaus Edward E , Wiebe Leonard I
Published: April 2011

The accumulation of 5-ethyl-2′-deoxyuridine (EDU), (–)-trans-(5S, 6S)-5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2′-deoxyuridine [(5S, 6S)-BMEDU], (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2′-deoxyuridine [(5R, 6R)-BMEDU], (+)-trans-(5.R, 6R)-5-bromo-5-ethyl-6-ethoxy-5, 6-dihydro-2′-deoxyuridine (BEEDU), (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5′-O-valeryl-2′- deoxyuridine (VBEEDU) and (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-3′-5′-di-O-valeryl-2′-deoxyuridine (DVBEEDU) in lung and other tissues was investigated in male Balb-C mice following intravenous injection of the corresponding 4-14C-labelled compounds.

EDU showed a rapid distribution into liver and lung immediately after injection, and the overall levels of radioactivity in blood, liver and lung were similar. The distribution of radioactivity in lung after injection of [4-14C](5S, 6S)-BMEDU and [4–14C](5R, 6R)-BMEDU were substantially different from one another and also from that of [4-14C]EDU. The radioactivity level present in lung samples after injection of both [4-14C](5S, 6S)-BMEDU and [4-14C](5R, 6R)-BMEDU was substantially higher than that in blood samples. Radioactivity levels present in lung samples taken at 18 min after injection of [4-14C]BEEDU were significantly higher (P < 0·05) than those for liver and blood samples. Although the radioactivity present in lung samples after injection of [4-14C]VBEEDU was significantly higher (P < 0·05) than those of liver and blood samples, [4-14C]VBEEDU did not provide a higher radioactivity level in lung samples than did [4-14C]BEEDU. The level of radioactivity in lung samples following injection of [4-14C]DVBEEDU was also higher than that of blood samples. EDU undergoes glycosidic bond cleavage to form EU in lung following intravenous injection into Balb-C mice.

The concentrations of EDU and 5-ethyluracil (EU) following intravenous injection of EDU, and its prodrugs BEEDU and VBEEDU, were quantitated in lung and blood samples. In contrast to lung samples, EU was not detected in blood samples at 120 min post injection of EDU. The concentrations of both EDU and EU in lung tissues after injection of BEEDU and VBEEDU were substantially higher than those in blood samples.
Pharmacological Profile of Rat Pleurisy Induced by Bothrops jararaca Venom
Authors: Búrigo A C , Calixto J B , Medeiros Y S
Published: April 2011

Bothrops jararaca venom (30 μg/site) triggered a marked inflammatory reaction in the pleural cavity that was long-lasting and reproducible.

In the first 1 h after pleurisy induction, a significant decrease of total and differential cell count was observed in comparison with control values, despite the gradual enhancement of fluid leakage. A significant increase of cell migration was observed after 3 h of pleurisy induction, due to mononuclear and neutrophil cells that peaked 8 h later and this was followed by a gradual decrease, remaining elevated up to 24 h. In parallel with cell influx, a significant increase of fluid leakage that peaked between 1 and 8 h was observed, being completely abolished after 12 h following pleurisy induction. This inflammatory response was not associated in parallel with significant changes in circulating leucocyte cells and it was significantly inhibited by compound 48/80, cyproheptadine, pyrilamine, dexamethasone, indomethacin and phenidone. Preheating of the venom (100C) caused a significant decrease of both leakage of fluid and cell migration in the pleural cavity 8 h after pleurisy induction. Previous exposure to the venom (30 μg/site, 5 days before) produced a significant decrease of both cell migration and fluid leakage 4 h after triggering pleurisy with the same dose of the venom. Otherwise, prior daily treatment with the venom (10 μg/site, 4 days) resulted only in marked fluid leakage reduction 1 h after treating the animals with BJV (30 μg/site).

These results show that the venom elicits pro-inflammatory effects in the rat pleural cavity which involve the participation of several mediators, including histamine, 5−hydroxytryptamine and products of arachidonic pathways.
Regioselectivity and Substrate Concentration-dependency of Involvement of the CYP2D Subfamily in Oxidative Metabolism of Amitriptyline and Nortriptyline in Rat Liver Microsomes
Authors: Masubuchi Yasuhiro , Iwasa Takashi , Fujita Shoichi , Suzuki Tokuji , Horie Toshiharu , Narimatsu Shizuo
Published: April 2011

Kinetic analysis of the metabolism of amitriptyline and nortriptyline using liver microsomes from Wistar rats showed that more than one enzyme was involved in each reaction except for monophasic amitriptyline N-demethylation. The Vmax values particularly in the high-affinity sites for E-10-hydroxylation of both drugs were larger than those for Z-10-hydroxylations. Their E- and Z-10-hydroxylase activities in Dark-Agouti rats, which are deficient for CYP2D1, were significantly lower than those in Wistar rats at a lower substrate concentration (5 μM). The strain difference was reduced at a higher substrate concentration (500 μM). A similar but a smaller strain difference was also observed in nortriptyline N-demethylase activity, and a pronounced sex difference (male > female) was observed in N-demethylation of both drugs in Wistar and Dark-Agouti rats. The reactions with the strain difference were inhibited concentration-dependently by sparteine, a substrate of the CYP2D subfamily, and an antibody against a CYP2D isoenzyme. The profiles of these decreased metabolic activities corresponded to that of the lower metabolic activities in Dark-Agouti rats.

These results indicated that a cytochrome P450 isozyme in the CYP2D subfamily was involved in E- and Z- 10-hydroxylations of amitriptyline and nortriptyline in rat liver microsomes as a major isozyme in a low substrate concentration range. It seems likely that the CYP2D enzyme contributes to nortriptyline N-demethylation.
Potential Irreversible Ligands for Opioid Receptors. Cinnamoyl Derivatives of β-Naltrexamine
Authors: Derrick Ian , Lewis John W , Moynihan Humphrey A , Broadbear Jillian , Woods James H
Published: April 2011

Cinnamoyl derivatives of β-naltrexamine (β-NTA) have been prepared and evaluated as potential irreversible opioid antagonists.

In receptor binding assays, isolated tissue preparations and mouse antinociception assays the p-methylcinnamoyl derivative BU42 was similar to the standard opioid ligand β-funaltrexamine (β-FNA). The main features were reversible κ agonism and irreversible μ antagonism. Surprisingly the p-chlorocinnamoyl derivative BU59 showed only modest competitive antagonist activity in-vivo despite appearing to bind irreversibly to μ receptors in the guinea-pig ileum (GPI) preparation. BU60, the dihydrocinnamoyl analogue of BU59, like BU59 displayed reversible κ agonism in GPI but in mouse antinociception assays its agonism was mediated by κ and β receptors rather than κ.

The surprising changes of profile attributable to substitution in the aromatic ring of the cinnamoylamido group in this small series suggests that a larger range of substituted cinnamoylamido derivatives should be studied to further elucidate the effects of Michael acceptor activity and other factors.
Knowledge, attitude and practices of Qatari patients with type 2 diabetes mellitus
Authors: Kheir Nadir , Greer William , Yousif Adil , Al Geed Hajer , Al Okkah Randa
Published: April 2011

Objectives

Patient compliance with their medications and their ability for self-management in type 2 diabetes mellitus (T2DM) is a growing cause of concern to healthcare providers. Knowledge about diabetes, attitude towards the condition and time management with respect to the condition (practice), collectively known as KAP, are known to affect compliance and play an important part in diabetes management. We aimed to describe the knowledge, attitude, practice and psychological status of adult Qatari patients with T2DM, and to explore the interaction between these and other patient-related factors which could impact on the ability of the patients to manage their diabetes and to achieve desirable health outcomes.

Methods

A questionnaire (the Diabetes Habits and Beliefs Questionnaire, DHBQ) was used to investigate the level and relationship between knowledge, attitude, general practice and psychological status of patients with T2DM. The data was collected in face-to-face interviews with patients visiting the diabetic clinic at a tertiary hospital in Qatar during the period January 2008 to March 2009.

Key findings

There were significant differences in attitude and knowledge between educational levels. Knowledge and attitude were highly correlated and the psychological status of the patient was positively associated with both knowledge and attitude. There was generally poor practice of regularly inspecting feet to detect signs of neuropathy, taking medication in relation to meals, modifying doses when necessary and setting goals for therapy.

Conclusions

The data provided can assist pharmacists and other healthcare practitioners in tailoring educational programmes aimed at improving diabetes control.
Eukaryotic initiation factor 2B epsilon induces cap‐dependent translation and skeletal muscle hypertrophy
Authors: Mayhew David L. , Hornberger Troy A. , Lincoln Hannah C. , Bamman Marcas M.
Published: April 2011

Non‐technical summary  Skeletal muscle comprises ∼40% of total body mass, and the control of muscle mass has significant effects on overall health. Skeletal muscle mass is determined by the balance of protein synthesis and degradation within muscle cells. We sought to determine which cellular proteins that control protein synthesis within muscle cells are associated with muscle growth after resistance exercise, a potent growth stimulus. We identified two proteins that were associated with muscle growth in humans: p70S6K and eIF2Bɛ. Follow up studies determined that eIF2Bɛ alone is sufficient to induce muscle growth. This is the first study to determine that this protein can induce skeletal muscle growth. These results further our understanding of how skeletal muscle responds to resistance exercise.
The most common cystic fibrosis‐associated mutation destabilizes the dimeric state of the nucleotide‐binding domains of CFTR
Authors: Jih Kang‐Yang , Li Min , Hwang Tzyh‐Chang , Bompadre Silvia G.
Published: April 2011

Non‐technical summary  Cystic fibrosis is a genetic disease caused by the malfunction of a chloride channel called cystic fibrosis transmembrane conductance regulator (CFTR). The most common disease‐associated mutation is the deletion of the phenylalanine residue at position 508 (ΔF508), which result in channels with poor membrane expression and defective function. Opening of CFTR channels is controlled by ATP binding at two intracellular domains, called nucleotide‐binding domains (NBDs), and subsequent NBD dimerization. Our previous studies revealed that ΔF508‐CFTR channels open very infrequently, raising the possibility that the mutation perturbs NBD dimerization although the mutation is not located near the dimer interface. In this paper, we employed a functional assay to assess the stability of the NBD dimer. Our data suggest that the ΔF508 mutation significantly destabilizes the NBD dimer, supporting the hypothesis that the mutation disrupts the dimer interface. Our results provide structural insights that are potentially useful for drug design.
Intrinsic membrane properties of spinal dorsal horn neurones modulate nociceptive information processing in vivo
Authors: Reali Cecilia , Fossat Pascal , Landry Marc , Russo Raúl E. , Nagy Frederic
Published: April 2011

Non‐technical summary  The dorsal horn of the spinal cord is the first site in the central nervous system where painful sensory information is processed before transmission to the brain. In vitro recordings in spinal slices established that this processing relies on both plasticity of synaptic connections and intrinsic electrical properties of dorsal horn neurones (DHNs). DHNs may generate plateau potentials, which underlie intense discharges and long‐lasting after‐discharges in response to a brief stimulation, and represent a putative endogenous mechanism for amplification of painful sensory inputs. Using patch‐clamp recordings in the anaesthetized adult rat, we show that DHNs do generate plateau potentials in vivo, which shape their responses to natural sensory stimulation. Moreover, we give direct evidence for the involvement of these amplification properties in both short‐term (windup) and long‐term sensitisation associated with neuropathic pain, raising the possibility that plateau potentials could be putative therapeutic targets to control spinal component of neuropathic pain.
Wave Power Statistics for Sea States
Authors: Myrhaug Dag , Leira Bernt J. , Holm Håvard
Published: April 2011

This paper provides a bivariate distribution of wave power and significant wave height, as well as a bivariate distribution of wave power and a characteristic wave period for sea states, and the statistical aspects of wave power for sea states are discussed. This is relevant for, e.g., making assessments of wave power devices and their potential for converting energy from waves. The results can be applied to compare systematically the wave power potential at different locations based on long term statistical description of the wave climate.
A Parametric Study of Fuel Lattice Design for HTR-10
Authors: Wang Meng-Jen , Peir Jinn-Jer , Chi Chen-Wei , Liang Jenq-Horng
Published: April 2011

In this study, the multiplication factor and neutron spectrum behaviors were investigated against the moderator-to-fuel ratio, the fuel loading height, and the detector location in high-temperature gas-cooled reactor (HTR)-10. The MCNP5 computer code (version 1.51) was employed to perform all the simulation computations. The results revealed that the multiplication factor varies significantly depending on the moderator-to-fuel ratio and the fuel loading height due to the competition among the neutron moderation and absorption abilities of the moderator as well as the neutron production ability of the fuel. Due to its inherent stability, HTR-10 is deliberately designed such that the multiplication factor decreases and the neutron spectrum softens as the moderator-to-fuel ratio increases. The average neutron energy level in the HTR-10 fuel balls is approximately 240 keV and ranges from smallest to largest at the middle, bottom, and top of the reactor core, respectively.
Application of a Negative Capacitance Circuit in Synchronized Switch Damping Techniques for Vibration Suppression
Authors: Ji Hongli , Qiu Jinhao , Cheng Jun , Inman Daniel
Published: April 2011

In the synchronized switching damping (SSD) techniques, the voltage on the piezoelectric element is switched synchronously with the vibration to be controlled using an inductive shunt circuit (SSDI). The inherent capacitance and the inductance in the shunt circuit comprise an electrically resonant circuit. In this study, a negative capacitance is used in the shunt circuit instead of an inductance in the traditional SSD technique. The voltage on the piezoelectric element can be effectively inverted although the equivalent circuit is capacitive and no resonance occurs. In order to investigate the principle of the new SSD method based on a negative capacitance (SSDNC), the variation of the voltage on the piezoelectric element and the current in the circuit are analyzed. Furthermore, the damping effect using the SSDNC is deduced, and the energy balance and stability of the new system are investigated analytically. The method is applied to the single-mode control and two-mode control of a composite beam, and its control performance was confirmed by the experimental results. For the first mode in single-mode control, the SSDNC is much more effective than SSDI. In other cases, the SSDNC is also more effective than the SSDI, although not significantly.