bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal Safety of Water-soluble β-Cyclodextrins in Paediatric Oral Solutions of Spironolactone: Effects on Human Intestinal Epithelial Caco-2 Cells
Authors: Tötterman Ann M , Schipper Nicolaas G M , Thompson Diane O , Mannermaa J-P
Published: April 2011

Effects of water-soluble β-cyclodextrins (βCDs) on intestinal epithelial integrity were investigated, to establish the safe use of these βSCDs as solubilizers of spironolactone in paediatric enteral solutions. Mannitol permeability and transepithelial resistance (TER) of human intestinal epithelial Caco-2 cell monolayers during exposure to dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD) and sulphobutyl ether β-cyclodextrin (SBEβCD) were followed. Staining methods were used to discern cells with damaged membranes and to study the integrity of cytoskeletal actin and tight junctions. Cytotoxicity of the βCDs was tested by effects on intracellular dehydrogenase activity.

Exposure to HPβSCD and SBEβCD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DMβCD clearly increased the epithelial permeability for the hydrophilic marker [14C]mannitol across Caco-2 monolayers, decreased TER and showed a dose-dependent cytotoxicity. According to staining, DMβCD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin.

HPβCD and SBEβCD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.
Modifications on Antioxidant Capacity and Lipid Peroxidation in Mice under Fraxetin Treatment
Authors: Martín-Aragón Sagrario , Benedí Juana M , Villar Angel M
Published: April 2011

Fraxetin belongs to an extensive group of natural phenolic antioxidants. We have investigated the modifications in endogenous antioxidant capacity; superoxide dismutase (SOD), catalase (CAT), total and selenium-dependent glutathione peroxidases (GPx) and glutathione reductase (GR) and stress index; glutathione disulphide (GSSG)/reduced glutathione (GSH) ratio and thiobarbituric acid-reactive substances (TBARs) in liver and brain supernatants of C57BL/6J male 12-month-old mice under fraxetin treatment for 30 days.

Liver SOD and GPx (total and Se-dependent) activities were not significantly affected by fraxetin, whereas they were increased in the brain compared with control animals. GR activity increased significantly only in the liver of treated mice. Fraxetin treatment-related decreases were shown for GSSG/GSH ratio and rate of accumulation of TBARs (not significant in TBARs) in both tissues.

We concluded that the net effect of fraxetin treatment on endogenous antioxidant capacity suggests that this compound might provide an important resistance to, or protection against, free-radical-mediated events which contribute to degenerative diseases of ageing.
Studies on the Inhibitory Effects of Analogues of Dapsone on Neutrophil Function In-vitro
Authors: Coleman Michael D , Smith Joanna K , Perris Alan D , Buck Nicola S , Seydel Joachim K
Published: April 2011

We have compared twelve sulphone analogues of dapsone in terms of inhibition both of zymosan-mediated human neutrophil respiratory burst and inhibition of interleukin-1-stimulated neutrophil adhesion to transformed human umbilical vein endothelial cells.

Overall, there was a good correlation between the respective rank orders of compound potency in the two test systems. The most effective compounds in terms of respiratory burst and adherence inhibition were the 2-nitro-4-amino-, 2-hydroxy-4-aminopropyl-, and 2-methoxy-4-aminoethyl- derivatives. In general, potency was inversely associated with lipophilicity; compounds with bulky side-chains, e.g. the 2-methyl-4-aminopentyl, 2-methyl-4-aminohexyl and the 2-hydroxymethyl-4-aminoethyl derivatives, were less potent. A 2-hydroxy-4-amino- derivative was the exception, however, with low lipophilicity and relatively low potency.

All of the compounds tested showed comparable or greater inhibition in both the neutrophil-mediated assays compared with dapsone. Some of the compounds might, because of their good tissue penetration and lower toxicity than dapsone, have the potential to undergo further development.
VB20B7, a Novel 5-HT-ergic Agent with Gastrokinetic Activity. I. Interaction with 5-HT3 and 5-HT4 Receptors
Authors: Ramirez M J , García-Garayoa E , Romero G , Monge A , Roca J , Del Río J , Lasheras B
Published: April 2011

This study describes the in-vitro interaction of the gastrokinetic agent 2[1-(4-piperonyl)piperazinyl]benzothiazole (VB20B7) with the 5-hydroxytryptamine 5-HT3 and 5-HT4 receptor subtypes, using functional as well as radioligand binding studies. The benzamide derivative cisapride was used as a comparison.

In radioligand binding assays VB20B7 showed, like cisapride, a weak affinity at 5-HT3 receptors from rat cerebral cortex. The new compound lacked any affinity at other 5-HT receptors or at dopaminergic D2 receptors, whereas cisapride showed high affinity for the 5-HT4 receptors from guinea-pig hippocampus and moderate affinity at dopaminergic D2 receptors. In the non-stimulated guinea-pig ileum, the concentration-response curves to the specific 5-HT3 agonist 2-Me-5-HT and to 5-HT were shifted to the right by VB20B7. In the rat oesophagus tunica muscularis mucosae preparation (TMM), VB20B7 was evaluated for its activity at 5-HT4 receptors. VB20B7 behaved as a 5-HT4 receptor agonist, inducing a concentration-dependent relaxation of the preparation precontracted with carbachol. In this preparation, VB20B7 and cisapride were able to stimulate adenylate cyclase activity, an effect probably mediated through activation of 5-HT4 receptors, as can be inferred from the blockade by the 5-HT4 antagonist, tropisetron, of the enhanced cAMP formation. However, consistent with the lack of affinity at central 5-HT4 receptors, VB20B7 did not stimulate cAMP formation in guinea-pig hippocampal slices. VB20B7 also caused an increase in the twitch response of the transmurally stimulated guinea-pig ileum, although at a concentration higher than cisapride. This effect was blocked by desensitization of the 5-HT4 receptor with 5-MeOT and also by the 5-HT4 receptor antagonist tropisetron. Both VB20B7 and cisapride increased the K+-evoked acetylcholine release in this preparation.

The results show that VB20B7 possesses affinity for 5-HT4 receptors located in the rat TMM and guinea-pig ileum preparations, but is devoid of affinity at central 5-HT4 receptors. In addition, VB20B7 shows low to moderate affinity at both central and peripheral (enteric) 5-HT3 receptors The interaction of VB20B7 with the peripheral 5-HT4 and 5-HT3 receptors may be relevant for the gastrokinetic effects of the new compound.
Endothelium-dependent Vascular Responses in 1,3-Dipropyl-8-sulphophenylxanthine (DPSPX) Hypertensive Rats
Authors: Paiva M Q , Santos M J , Albino-Teixeira A
Published: April 2011

The study was undertaken to test the endothelium-mediated vascular responses in rats rendered hypertensive by chronic administration of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX). The relaxant effect of carbachol (an endothelium-dependent relaxing drug) and of sodium nitroprusside (an endothelium-independent relaxing drug) as well as the potentiation of the contractile effect of noradrenaline by NG-nitro-l-arginine methyl ester (l-NAME) were compared in aortic rings from normotensive and DPSPX-hypertensive rats.

Carbachol and sodium nitroprusside caused concentration-dependent relaxations in aortic rings precontracted by 1 μM noradrenaline. The relaxant effect of carbachol was significantly reduced in tissues of DPSPX-hypertensive rats: the maximal relaxant effect being 86 ± 3% and 64 ± 4% (of the pre-existing tone) in normal and hypertensive rats, respectively, while there were no significant differences in the relaxant effect of sodium nitroprusside. l-NAME (100 μM) significantly reduced the EC50 values of noradrenaline (3.71 ± 0.28 times, n = 8 and 2.96 ± 0.27 times, n = 7, in normal and hypertensive rats, respectively) and significantly enhanced the maximal contractile effect of noradrenaline (46 ± 8%, n = 8 and 35 ± 6%, n = 7, in normal and hypertensive rats respectively): the factors of reduction of EC50 values and the percentages of enhancement of the maximal contractile effect in the aorta of normal and hypertensive rats were not significantly different.

The results obtained provide evidence of functional impairment of the endothelium in DPSPX-hypertensive rats.
Interaction of Thrombin-activated Platelets with Extracellular Matrices (Fibronectin and Vitronectin): Comparison of the Activity of Arg-Gly-Asp-containing Venom Peptides and Monoclonal Antibodies Against Glycoprotein IIb/IIIa Complex
Authors: Sheu J R , Ko W C , Hung W C , Peng H C , Huang T F
Published: April 2011

Platelets adhere to fibronectin and vitronectin substrates following activation with physiological concentrations of thrombin. Adhesion of activated-platelets to either substrate is dependent upon the amount of fibronectin and vitronectin, and the duration of the adhesion assay. In this study, we showed that the Arg-Gly-Asp-containing peptides (including naturally occurring polypeptides, triflavin, trigramin and rhodostomin, synthetic peptides GRGDS, GRGDSPK, GRGDF, and GRGD and monoclonal antibodies, 7E3, 10E5 and AP2, raised against glycoprotein IIb/IIIa complex, inhibited the adhesion of activated-platelets to fibronectin and vitronectin-coated plates in a dose-dependent manner.

In fibronectin-coated plates, GRGDF was shown to be much more efficient than GRGDS, GRGDSPK and GRGD at inhibiting the adhesion of activated-platelets to immobilized fibronectin. On the other hand, there were no marked differences in the abilities of these three peptides (GRGDF, GRGDS and GRGDSPK) to inhibit platelet adhesion to immobilized vitronectin. Furthermore, the RGD-containing venom peptide, triflavin was more effective than rhodostomin and trigramin at inhibiting the adhesion of activated-platelets to either substrates. The monoclonal antibodies raised against glycoprotein IIb/IIIa complex (i.e., 7E3, 10E5 and AP2) inhibited platelet adhesion to fibronectin and vitronectin in a similar dose-dependent manner. Interestingly, we found that 7E3 was more efficient than 10E5 and AP2 in this reaction.

These studies suggest that the glycoprotein IIb/IIIa complex, present on activated-platelets, may interact with fibronectin and vitronectin substrates through the Arg-Gly-Asp-dependent mechanism. Since fibronectin and vitronectin are present in the subendothelial matrix, they may be involved in platelet-vessel wall interaction. The Arg-Gly-Asp containing peptide, especially triflavin, is an ideal therapeutic agent for inhibiting thrombus formation by interrupting platelet-platelet and platelet-subendothelium interactions.
Reversible Blockade of Retrograde Axonal Transport in the Rat Sciatic Nerve by Vincristine
Authors: MacFarlane B V , Wright A , Benson H A E
Published: April 2011

Altered axoplasmic transport has been implicated as a contributing factor in neuropathic pain states. Treatments which produce transient axoplasmic transport blockade have shown initial promise as therapeutic procedures in the management of chronic neuropathic pain. The present study evaluated the capacity of the vinca alkaloid, vincristine to produce reversible blockade of retrograde axoplasic transport.

Results indicated that intraneural administration of 10−5 M vincristine resulted in blockade of retrograde axoplasmic transport of [3H]leucine 24 h following administration. Importantly, the effect reversed over the next four days and axoplasmic transport was re-instated fully at day five.

The implications of these results are discussed in relation to the potential use of axoplasmic transport blocking agents in the management of chronic neuropathic pain.
Effect of Cationic Surfactant on Transport of Model Drugs in Emulsion Systems
Authors: Yoon Kyung Ae , Burgess Diane J
Published: April 2011

Excess surfactant present in emulsions can influence the rates of transport of incorporated drugs by micellar solubilization, alteration of the partitioning process and by drug-surfactant complexation. Cetyltrimethylammonium bromide (CTAB), a cationic surfactant was selected to investigate these phenomena as it forms relatively stable mineral oil–water (O–W) emulsions and has the potential for ionic interaction. Phenylazoaniline, benzocaine, benzoic acid and phenol were chosen as model drugs for this study.

The emulsion critical micelle concentration (CMC) for CTAB determined using a combination of a membrane equilibrium technique and surface-tension measurement was 10% w/v in 10% v/v% O-W emulsion systems. Ionic interaction between model drugs and surfactants and drug hydrophobicity affected their transport rates in the emulsion systems. The transport rates of the lipophilic drugs (benzocaine and phenylazoaniline) and the ionized hydrophillic drug (benzoic acid, pH 70) in the emulsion systems increased with increasing CTAB concentration up to 0–5% w/v micellar concentration and then decreased at higher concentrations. The rate of transport of phenol was not affected by the presence of micellar phase.

Ionic interaction between surfactant and model drugs affected transport rates of model drugs in emulsion systems. The micellar phase was considered to affect the overall transport rates of model drugs.
Oral Sustained-release Cisplatin Preparation for Rats and Mice
Authors: Nakano Kousuke , Ike Osamu , Wada Hiromi , Hitomi Shigeki , Amano Yukihiko , Ogita Ikuo , Nakai Nobuko , Takada Kanji
Published: April 2011

A new oral sustained-release solid-dispersion preparation of cisplatin (cis-diamminedichloroplatinum(II); cisplatin) has been developed for administration to small experimental animals such as mice. This preparation was obtained by formulating cisplatin with the water-insoluble polymer ethylcellulose and with stearic acid in different ratios.

In-vitro dissolution studies showed that cisplatin release characteristics were zero-order for the formulation cisplatin–ethylcellulose–stearic acid (1:10:5) and levels equilibrated 7 h after the start of the experiment. The availability of cisplatin from this preparation was evaluated both in rats and mice. The cisplatin preparation (20 mg kg−1) was administered orally to rats and the resulting curve of serum cisplatin levels against time was compared with that obtained after intravenous infusion (20 mg kg−1) to rats. By comparing the areas under serum concentration-time curves (AUCs), the bioavailability of cisplatin was estimated to be 31%. The mean residence time (MRT) of cisplatin solid dispersion was 6.13 ± 0.43 h, whereas the MRT of cisplatin administered by intravenous infusion was 3.89 ± 0.05 h. Serum cisplatin levels were maintained above 0.3 mg mL−1 (believed from our clinical studies to be the minimum effective concentration) for 24 h. The curve of serum cisplatin level against time suggested that cisplatin was released from the solid dispersion preparation in a sustained-release fashion. Similar levels were also maintained in mice for 24 h. The MRT of the cisplatin preparation was 10–16 h in mice, which is longer than that obtained after oral administration of the physical mixture. The serum free-cisplatin concentration was determined to be 0.10 mg mL−1 in mice serum in which the total cisplatin concentration was 0.30 mg mL−1. The free fraction of cisplatin in mice serum was the same as that in human patient serum. Pathological examination showed that this new sustained-release oral cisplatin preparation did not have any side effects on the gastrointestinal tract.

These results suggest usefulness of this new solid-dispersion preparation for oral cisplatin therapy in lung cancer patients.
Encapsulation, Stability and In-vitro Release Characteristics of Liposomal Formulations of Colchicine
Authors: Kulkarni Shirish B , Singh Mandip , Betageri Guru V
Published: April 2011

The severe toxicity and low therapeutic index of colchicine limit its therapeutic use. Encapsulation in liposomes might reduce these toxic effects. The objective of this study was to determine the factors influencing encapsulation of colchicine in liposomes and to optimize the encapsulation parameters.

Colchicine was encapsulated in multilamellar liposomes and large unilamellar liposomes prepared using various phospholipids. The effects of method of preparation, type of vesicle, charge, and concentration of cholesterol on encapsulation of colchicine in liposomes were investigated. Also, stability of colchicine under stress conditions and at various temperatures, and in-vitro release characteristics were determined. A significant difference in encapsulation of colchicine in multilamellar liposomes was observed when prepared by two different methods. Induction of charge on the liposome surface increased encapsulation of colchicine in multilamellar liposomes, but did not affect large unilamellar liposomes. The liposome preparations could withstand simulated transport conditions and frequent changes in temperature. Particle size and concentration of colchicine did not change significantly during storage at various temperatures for six months. In order to retain encapsulated colchicine in liposomes, storage at or below room temperature was found to be suitable. In-vitro release of colchicine from large unilamellar liposomes was biphasic and was influenced by two rate-limiting barriers, the dialysis membrane and the liposome bi-layers.

For optimum encapsulation and stability of colchicine liposomes were prepared from a mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol and either stearylamine or dicetyl phosphate.
Experiences with the Rectal use of Trimethoprim
Authors: Sallai J , Vernyik Á , Regdon G , Gombkötõ S , Németh J , Regdon G
Published: April 2011

The possibility of rectal use of trimethoprim was studied. The in-vitro liberation of the drug from 24 different suppository bases was examined and the results used to select bases for in-vivo examination.

The in-vitro liberation from the suppositories containing 50–200 mg trimethoprim was studied by the method of dynamic diffusion, and the released drug content was measured spectrophotometrically. The in-vivo examinations were performed in anaesthetized rats. The concentration of trimethoprim in blood was determined by bioassay. The absorption of the drug in the form of oral suspension, rectal solution and suppository was also studied. The pharmacokinetic parameters obtained after blood-level curve fitting were compared by use of the MedUSA 1.6 program. The best in-vivo results were achieved with the lipohydrophilic Witepsol W 35 vehicle containing 10% polysorbate 20 and 10% polysorbate 61 (bioavailability = 63.8%) and with Witepsol W 35 containing 10% polysorbate 60 (bioavailability = 63.8%). The results for hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 were only slightly worse (bioavailability = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% polysorbate 20 and 10% polysorbate 61 content a significant negative exponential relationship was found between the administered doses and their respective bioavailability values; this tendency was also observed during in-vitro examinations.

When incorporated in the appropriate vehicle trimethoprim was absorbed well. With three vehicles the extent of absorption exceeded that for oral administration on the same model (bioavailability = 38.8%). Trimethoprim rectal suppositories, which are formulated with the vehicles having the best in-vitro and in-vivo results, are suitable for clinical pharmacological investigation.
Electrical and Mechanical Modulations by Oxygen-derived Free-radical Generating Systems in Guinea-pig Heart Muscles
Authors: Satoh Hiroyasu , Matsui Kazunori
Published: April 2011

The effects of free-radical generating systems and angiotensin-converting enzyme (ACE) inhibitors on the action potentials and contractile force in guinea-pig cardiac muscles were examined using conventional microelectrode and whole-cell voltage-clamp methods at 36°C.

Hydrogen peroxide (30–100 μm) prolonged 50%, 75% and 90% repolarization of action-potential duration (APD) approximately 15–25 min after its application. But the longer exposure reversed the APD shortening in a concentration-dependent manner. Other action-potential parameters were not altered to a significant extent. The contractile force was increased. Longer exposure inhibited the enhanced force (but it was still larger than control). The effects on the spontaneous action potential from right atrial muscle were almost the same. In whole-cell voltage-clamp experiments, H2O2 (100 μm) inhibited l-type Ca2+ current and enhanced delayed rectifier K+ current. The effects of light-activated rose bengal (10–100 nm) on the APD were similar to, but more potent than, those of H2O2. The response was observed rapidly after a light illumination. During exposure to rose bengal (100 nm), abnormal spontaneous action potentials or arrhythmias such as a bigeminy occurred, presumably because of early and delayed afterdepolarizations. The responses were irreversible. At 300 μm ACE inhibitors, captopril and enalapril, protected the changes induced by these free radicals.

These results indicate that H2O2 has a dual, time-dependent, action on the APD and rose bengal with light illumination produced the responses rapidly. The oxygen-derived free radicals increased [Ca]i and then cellular Ca2+ overload occurred. These responses were protected by ACE inhibitors.
Effects of ATP on Phosphoinositide Hydrolysis and Prostaglandin E2 Generation in Rabbit Astrocytes
Authors: Ishimoto Hiromi , Nakahata Norimichi , Matsuoka Isao , Nakanishi Hironori
Published: April 2011

Extracellular ATP secreted from stimulated nerves plays a role in neurotransmission. This study examined the effects of extracellular ATP on phospholipase A2 and C signalling pathways in rabbit astrocytes.

ATP caused prostaglandin E2 (PGE2) generation and phosphoinositide hydrolysis in a time- and concentration-dependent manner. A P2y purinoceptor-selective agonist, 2-methylthio-ATP also caused phosphoinositide hydrolysis, but not PGE2 generation. A P2x purinoceptor-selective agonist, α,β-methylene-ATP did not cause either phosphoinositide hydrolysis or PGE2 generation. Although pertussis toxin had no effect on 2-methylthio-ATP-induced phosphoinositide hydrolysis, it markedly decreased ATP-induced PGE2 generation, with significant inhibition of phosphoinositide hydrolysis. Dexamethasone and indomethacin which potently inhibited ATP-induced PGE2 generation, caused partial inhibition of phosphoinositide hydrolysis, suggesting that pertussis toxin-sensitive component of ATP-induced phospholipase C activation is mediated by cyclo-oxygenase metabolites of arachidonic acid.

These results suggest that a stimulation of P2y receptor results in phospholipase C activation in a pertussis toxin-insensitive manner, and that a P2 receptor other than the P2y or P2x subtypes is involved in ATP-induced phospholipase A2 activation via a pertussis toxin-sensitive G protein.
Some Histamine-related Compounds Interacting with the Benzylamine-oxidizing Activity of Rat White Adipocytes
Authors: Raimondi Laura , Conforti Laura , Banchelli Grazia , Sgromo Lucia , Pirisino Renato
Published: April 2011

In rat white adipocytes histamine is oxidized by a semicarbazide-sensitive amine oxidase which has benzylamine or preferential substrate (Bz-SSAO). To determine whether Bz-SSAO could control the extracellular levels of histamine and other histamine-related compounds active in lipid mobilization, a series of histaminergic compounds was screened as possible substrates or inhibitors of Bz-SSAO activity.

Histaminergic compounds with imidazolo or thiazolo groups are oxidized by rat white-adipocyte Bz-SSAO whereas S-isothiourea derivatives, with two- or three-carbon-atom alkyl chains between the isothiourea and the N,N-dimethyl residue are, instead, inhibitors of the enzyme. Amtamine has been identified as a selective, high affinity substrate for rat white adipocyte Bz-SSAO. This enzymatic degradation might represent a catabolic pathway for the drug.

These results show that the histaminase property of the rat white-adipocyte enzyme Bz-SSAO also extends to other histamine derivatives active at histamine receptors.
Mechanisms Involved in the Antinociceptive Effect in Mice of the Hydroalcoholic Extract of Siphocampylus verticillatus
Authors: Trentin Ana P , Santos Adair R S , Miguel Obdúlio G , Pizzolatti Moacir G , Yunes Rosendo A , Calixto João B
Published: April 2011

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract.

The hydroalcoholic extract of S. verticillatus (60–1000 mg kg−1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and ∼1000 mg kg−1, respectively. In the formalin test, the extract (100–1000 mg kg−1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg−1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60–1000 mg kg−1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg−1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg−1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg−1, s.c.) and the extract (300 mg kg−1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with l-arginine (600 mg kg−1, i.p.) significantly attenuated the antinociceptive effects of NG-nitro-l-arginine (l-NOARG) (75 mg kg−1, i.p.), of the hydroalcoholic extract (600 mg kg−1, i.p.) or of morphine (5 mgkg−1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg−1, i.p.) in the formalin-induced pain.

These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the l-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.
Analysis of Rabbit Vascular Responses to DBI, an Ingol Derivative Isolated from Euphorbia canariensis
Authors: Miranda Francisco J , Alabadí José A , Pérez Pedro , Ortí Marta , Centeno Jose M , Yuste Alberto , Sanz-Cervera Juan F , Marco J Alberto , Alborch Enrique
Published: April 2011

We have analysed the effects of 7,12-O-diacetyl-8-O-benzoil-2,3-diepiingol (DBI), an ingol derivative isolated from E. canariensis, on isometric tension developed by isolated rabbit basilar and carotid arteries.

Concentration-response curves to DBI (10−8 - 3 × 10−5 m) were obtained cumulatively in both arteries at resting tension and active tone (KC1, 50 mm). At resting tension, DBI induced a concentration-dependent contraction, which was not inhibited in Ca2+-free medium. H7 (1-(5-isoquinoline sulphonyl)-2-methylpiperazine dichloride) (10−4 m) inhibited the DBI-induced contraction both in basilar and in carotid arteries. Calmidazolium (10−4 m) inhibited the maximum contraction of the carotid artery to DBI, and completely abolished the response in the basilar artery. In pre-contracted basilar arteries DBI induced a concentration-dependent relaxation that was not modified by incubation with NG-nitro-l-arginine (l-NOARG; 10−5 m) or indomethacin (10−5 m). In the carotid artery with active tone DBI induced further contractions, which were not significantly modified by l-NOARG (10−5 m) and were potentiated by indomethacin (10−5 m).

These results suggest that DBI contracts rabbit basilar and carotid arteries by a mechanism that is independent of extracellular Ca2+ and involves the participation both of protein kinase C and of calmodulin. DBI relaxes basilar but not carotid arteries by a mechanism independent of the liberation of nitric oxide and prostacyclin. In the carotid artery prostacyclin but not nitric oxide partially counteracts the contractile action of DBI.
Peter Howard El worthy (1933–1995): a Biographical Note
Authors: Florence A T
Published: April 2011

Peter Elworthy had a considerable influence on pharmaceutical science, education and practice, in the UK. He died in December 1995 at the early age of 62, but he had retired from full time academic work from his post as Professor of Pharmacy and Head of the Department of Pharmacy in the University of Manchester twelve years earlier. Concerned about his health but also not a little disillusioned by the multiple pressures placed even then on senior academics, he foresaw the era of cuts and the central oversight and restrictions. His heart was elsewhere. In his 1976 Harrison Memorial Lecture (reproduced in this issue) he said: “Looking back, I have the feeling of having been very lucky. ‘Much have I travell'd in the realms of gold, and many goodly states and kingdoms seen.’ My main interest has been in the phenomenon of micellization. The subject has been of absorbing interest, and continually shows new bright facets which lead to new scientific advances. Travelling in the realms of gold has nothing to do with gold, but to me it means travelling in sunlight, which illuminates things brightly, and makes visible new facts, which have been invisible before. Occasionally dark clouds form; they are the disappointments and frustrations, but we need them in order to be able to recognize the sunlight by contrast.”
Variation in Cetostearyl Alcohol and Lecithin from Different Sources: Evaluation by Dielectric Analysis
Authors: Rowe R C
Published: April 2011

Dielectric analysis has been used to evaluate the variation with source of both cetostearyl alcohol (when used in aqueous gels prepared with cetostearyl alcohol and cetrimide) and lecithin (when used in oil-in-water emulsions).

In both examples differences in the dielectric response were detected for samples prepared using excipients from different sources, despite the failure of other tests to detect any difference.

The differences seen could be related to changes in the structures of the samples.
Aggregation and Surface Properties of Synthetic Double-chain Non-ionic Surfactants in Aqueous Solution
Authors: Lawrence M Jayne , Lawrence Simon M , Barlow David J
Published: April 2011

Double-chain non-ionic surfactants have been synthesized with the general formula 2CnMPEG750, where n is the number of carbons in the alkyl chains and 750 is the molecular weight of the monomethoxypolyoxyethylene (MPEG) head group. The aggregation and surface properties in dilute aqueous solution (<1.0% w/w) of surfactants with n = 8, 10 and 12 have been determined.

Each of the surfactants formed clear, foaming, non-birefringent solutions. Total-intensity light scattering indicated the presence of micelles with aggregation numbers of 36, 68 and 74 for the 2C8, 2C10 and 2C12 surfactants, respectively, whereas photon-correlation studies yielded radii, assuming spherical aggregates, of 59–103 Å. Surface-tension measurements gave critical micelle concentrations for the surfactants in the range 1–15–7–24 × 10−6 m; these, as expected, decreased when the number of carbon atoms in the alkyl chains was increased.

Such studies are important in the design of new surfactants as vehicles for drug delivery because it is imperative to be able to predict the type of aggregate formed by a surfactant.
The Influence of Gamma Irradiation on the Physicochemical Properties of a Novel Triblock Copolymer of β-Caprolactone and Ethylene Oxide
Authors: Martini Luigi , Collett John H , Attwood David
Published: April 2011

A novel triblock copolymer of ε-caprolactone (CL) and ethylene oxide (E), CL6E90CL6, intended for use in implantable drug-delivery systems, has been subjected to gamma irradiation, in the solid state and in aqueous solution, under different controlled environmental conditions, to assess its stability to a radiation sterilization process.

When copolymer matrices were irradiated with doses of irradiation up to 72 kGy in the presence of oxygen, negligible changes were observed in the molar mass, molecular mobility (assessed by pulsed nuclear magnetic resonance spectroscopy) and thermal properties. However, irradiation of matrices in the absence of oxygen (anoxia) induced the formation of cross-links, as indicated by a reduction in the molecular mobility of the copolymer, but without affecting its molar mass and thermal properties. Gamma irradiation of aqueous solutions of CL6E90CL6 in the presence of oxygen induced random polymer chain scission, as evidenced by a reduction in the molar mass, and the formation of a distribution of copolymer chain lengths in solution. Nuclear magnetic resonance relaxation studies showed that irradiation of solutions of CL6E90CL6 at concentrations greater than 4% w/v under anoxic conditions with doses of 54 kGy produced polymer gels with a network structure.

These differences in the effects of gamma irradiation on the physicochemical properties of CL6E90CL6 might be germane to the method selected for sterilization of the polymer before its use in implantable drug-delivery systems.
Influence of Hydroxypropyl β-Cyclodextrin on the Stability of Benzylpenicillin in Chloroacetate Buffer
Authors: Ong J K , Sunderland V B , McDonald C
Published: April 2011

Hydroxypropyl β-cyclodextrin (HPβCyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HPβCyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20.

At penicillin G: cyclodextrin molar concentration ratios from 1:1 to 1:10, HPβCyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (kobs) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HPβCyD concentration. Degradation of penicillin G complexed with HPβCyD (penicillin G-HPβCyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HPβCyD have also been evaluated. The negative standard enthalpy change (ΔH°) for the complexation implied that the penicillin G-HPβCyD complex would be predisposed towards enhanced stability, and thus the kobs value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (ΔH‡) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (ΔS‡) for these hydrolytic reactions.

The results indicate that HPβCyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.
Isolation of a polysaccharide with antiproliferative, hypoglycemic, antioxidant and HIV-1 reverse transcriptase inhibitory activities from the fruiting bodies of the abalone mushroom Pleurotus abalonus
Authors: Wang Chang Rong , Ng Tzi Bun , Li Le , Fang Jin Cen , Jiang Yun , Wen Ting Yi , Qiao Wen Tao , Li Ning , Liu Fang
Published: April 2011

Objective

The intent of this study was to purify and characterize a polysaccharide named LA from the fruiting bodies of the edible mushroom Pleurotus abalones.

Methods

The 120-kDa polysaccharide was obtained by extraction with boiling water, ethanol precipitation, ion exchange chromatography on Diethylaminoethyl-cellulose and gel filtration on Sephadex G-200.

Key findings

The LA was composed of glucose, rhamnose, glucuronic acid, xylose, galactose and arabinose in the molar ratio of 26.3 : 2.7 : 1 : 1.4 : 1.8 : 1.2. The FITR and 1H-NMR spectrum of LA disclosed that it was a saccharide with an α-configuration. Its 13C-NMR spectrum revealed that its main chain was [→6)-α-d-Gly(1→]n. The LA exhibited antioxidant activities, especially in scavenging 1,1- diphenyl-2-picryl-hydrazyl radicals and hydroxyl radicals. It manifested antiproliferative activity towards breast cancer MCF7 cells with an IC50 of 3.7 µm, and also exerted some antiproliferative activity against HepG2 cells. It manifested a hypoglycemic action on diabetic mice. It inhibited HIV-1 reverse transcriptase with an IC50 of 8.7 × 10−2 µm.

Conclusions

The polysaccharide from the abalone mushroom.
Dichotomous cellular properties of mouse orexin/hypocretin neurons
Authors: Schöne Cornelia , Venner Anne , Knowles David , Karnani Mahesh M. , Burdakov Denis
Published: April 2011

Non‐technical summary  Orexin/hypocretin neurons are widely projecting, ‘multi‐tasking’ brain cells that promote alertness, reward seeking and feeding. They are vital for stable consciousness in higher mammals. Loss of orexin/hypocretin cells produces narcolepsy. It was originally assumed that orexin/hypocretin neurons are one uniform population of cells, but recent studies hinted that they may be split into subsystems. To explore this, we performed unbiased statistical analysis of electrical properties of orexin/hypocretin cells in combination with 3‐D analysis of their shape. Our results pointed to an existence of two subgroups of orexin/hypocretin neurons, that have unique ‘electrical fingerprints’ and distinct ways of receiving information from other neurons.
Correlation Between Speciated Hydrocarbon Emissions and Flame Ionization Detector Response for Gasoline/Alcohol Blends
Authors: Wallner Thomas
Published: April 2011

The U.S. renewable fuel standard has made it a requirement to increase the production of ethanol and advanced biofuels to 36 billion by 2022. Ethanol will be capped at 15 billion, which leaves 21 billion to come from other sources such as butanol. Butanol has a higher energy density and lower affinity for water than ethanol. Moreover, alcohol fueled engines in general have been shown to positively affect engine-out emissions of oxides of nitrogen and carbon monoxide compared with their gasoline fueled counterparts. In light of these developments, the variety and blend levels of oxygenated constituents is likely to increase in the foreseeable future. The effect on engine-out emissions for total hydrocarbons is less clear due to the relative insensitivity of the flame ionization detector (FID) toward alcohols and aldehydes. It is well documented that hydrocarbon (HC) measurement using a conventional FID in the presence of oxygenates in the engine exhaust stream can lead to a misinterpretation of HC emissions trends for alcohol fuel blends. Characterization of the exhaust stream for all expected hydrocarbon constituents is required to accurately determine the actual concentration of unburned fuel components in the exhaust. In addition to a conventional exhaust emissions bench, this characterization requires supplementary instrumentation capable of hydrocarbon speciation and response factor independent quantification. Although required for certification testing, this sort of instrumentation is not yet widely available in engine development facilities. Therefore, an attempt is made to empirically determine FID correction factors for oxygenate fuels. Exhaust emissions of an engine fueled with several blends of gasoline and ethanol, n-butanol and iso-Butanol were characterized using both a conventional FID and a Fourier transform infrared. Based on these results, a response factor predicting the actual hydrocarbon emissions based solely on FID results as a function of alcohol type and content is presented. Finally, the correlation derived from data presented in this study is compared with equations and results found in the literature.
Explicit Numerical Methods for Solving Stiff Dynamical Systems
Authors: Zhang Suying , Li Jiangdan
Published: April 2011

The precise integration method can give precise numerical result for linear invariant dynamical system, and can be used to solve stiff linear invariant dynamical system. In this paper, precise integration is compounded with Runge–Kutta method and a new effective integration method is presented for solving nonlinear stiff problems. The numerical examples are given to demonstrate the validity and effectiveness of the proposed method.
Transformation of a Mismatched Nonlinear Dynamic System into Strict Feedback Form
Authors: Mathieu Johanna L. , Hedrick J. Karl
Published: April 2011

Dynamic surface control is a robust nonlinear control technique. It is generally applied to mismatched dynamic systems in strict feedback form. We have developed a new method of defining states and state-dependent disturbances to transform a mismatched dynamic system into strict feedback form. We apply this method to a multi-input multi-output (MIMO) extended-state kinematic model of a bicycle. We show how a dynamic surface controller can be used for position tracking of the bicycle. The performance of the dynamic surface controller is compared with that of a controller designed using feedback linearization. Transformation of the dynamic system into strict feedback form allows us to successfully apply dynamic surface control. Both the dynamic surface controller and the feedback linearization controller perform well in the absence of disturbances. The dynamic surface controller is more robust when disturbances are introduced; however, a large control effort is required to reject the disturbances. Our method of defining new states and state-dependent disturbances to transform mismatched nonlinear dynamic systems into strict feedback form could be used on other systems requiring robust nonlinear control.
New Composite Materials for Decreasing of Radioactive Molecular Iodine in the Water Coolant on the Working and New Developed NPPS
Authors: Kulyukhin S. A. , Mizina L. V. , Tishina A. A.
Published: April 2011

The sorption of 131I−, 131IO3−, I2 and CH3131I from water solutions at 25°C on new composite materials obtained by modifying of cation-exchange resin KU-2 was investigated. It was established, that the given materials are capable to absorb I2 both from distilled water, and from a water coolant of the WWER-type NPPs, with distribution factors Kd more than 103 cm3/g at V/m = 100. Thus, it was found, that practically full I2 absorption (more than 95.0%) was achieved for 15 min. It was shown, that anion-exchange resin AV-18 is capable to adsorb CH3131I from a water solutions with distribution factors Kd more than 300 cm3/g at V/m = 100.
A Novel Point Estimate Procedure for IVR Calculations in Core-Molten Severe Accident
Authors: Zhang Yapei , Qiu Suizheng , Su Guanghui , Tian Wenxi
Published: April 2011

In-Vessel Retention (IVR) of core melt is a key severe accident management strategy adopted by operating nuclear power plants and advanced light water reactors (ALWRs), AP600, AP1000 etc. External Reactor Vessel Cooling (ERVC), which involves flooding the reactor cavity to submerge the reactor vessel in an attempt to cool core debris relocated to the vessel low head, is a novel severe accident management for IVR analysis. In present study, IVR analysis code in severe accident (IVRASA) has been proposed to evaluate the safety margin of IVR in AP600 with anticipative depressurization and reactor cavity flooding in severe accident. For, IVRASA, the point estimate procedure has been developed for modeling the steady-state endpoint of core melt configurations. Furthermore, IVRASA was developed in a more general fashion so that it is applicable to compute various molten configurations such as UCSB FInal Bounding State (FIBS) etc. The results by IVRASA were consistent with those of the UCSB and INEEL. Benchmark calculations of UCSB-assumed FIBS indicate the applicability and accuracy of IVRASA and it could be applied to predict the thermal response of various molten configurations.
Primary Design and Operation Analysis of the ITER Transfer Cask System
Authors: Wang Haitian , Li Ge , Qin Shijun
Published: April 2011

The ITER is an international collaborative project aimed at demonstrating the scientific and technological feasibility of fusion energy for peaceful purposes. China as one of the seven parties takes part in the ITER, and wishes to grasp the remote handling technology, which is one of the four key technologies related to the future fusion reactors for electric power generation. The transfer cask system (TCS) is one subsystem of ITER remote handling system, which provides the means for the remote transfer of (clean/activated/contaminated) in-vessel components and Remote Handling Equipment between Hot Cell Facility and Vacuum Vessel through dedicated galleries and lift in the ITER buildings. The TCS can work in the nuclear radiation environment and can be fully driven by self powered electricity with high energy density batteries. Its driving force is provided by nearly twenty servo motors. The remote handling technology can lay the foundation for developing demonstration nuclear fusion power plant in China on self-reliance. Due to the gamma irradiation and the hazard material in these ITER parts, all required maintenance of the port plug and the inner components are being carried out by the TCS, which offers confinement boundaries to these components. The ITER Tokamak building includes three floors, including upper port level, equatorial port level and lower port level, linked by a lift. Due to limited Tokamak building space which is frozen and can not be changed presently, the TCS penetrates its cable tray for about 300 mm. According to the configuration each port level and the mass of the corresponding plug, the dimensions of the TCS envelope in three levels are different. The basic components and the basic parameters of the TCS are presented. Furthermore, according to each port level configuration and the safety requirement of the TCS, the radius of the curvature with the TCS trajectory is optimized, and a trajectory of each port level is determined by the positioned guidance beacons. At last, the results of the computer aided design (CAD) shows that the present conflict between TCS and Tokamak building can be designed compatible with the proposed variable structure cable tray in the ITER Tokamak building and the TCS based on a fleet of server motor driven system.
Root Cause Analysis of the Power Generation Capability Decrease After the 5th Refuelling Outage of Ling Ao 2
Authors: Chi Zhiyuan , Chai Weidong , Zhang Dayong , Dong Kang , Wang Guoyun , Wang Chun
Published: April 2011

The power generation capability of Unit 2 of Ling Ao Nuclear Power Plant has been decreased about 6MW after its fifth refueling outage in 2008. This paper investigates the activities which may influence the unit capability in the outage, compares the related parameters before and after the outage, and then analyzes its root causes. From the root cause analysis, it can be found that the replacement of orifices which measure the feedwater flow was the main reason for the capability decrease. Finally, some modification measurements have been provided to recover the unit capability.