bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring the Diffusional Pathlength and Area Within Membranes of Excised Human Stratum Corneum
Authors: Lieckfeldt Renate , Lee Geoffrey
Published: April 2011

By using lipid-free membranes it was possible to measure the extended diffusional pathlength (L*) and reduced diffusional area (A*) within samples of human stratum corneum.

The value of 883 obtained for the factor L*A/LA* (A = external membrane area and L = membrane thickness) compared well with previously published theoretical values. It was also consistent with measurements of lag-time and permeability made on both lipid-free and intact stratum corneum.

The geometrical barrier formed by the corneocytes was found to be quantitatively of equal importance to the extra-cellular lipid barrier for maintaining the overall barrier function of the stratum corneum.
Comparison of the Secretory Actions of 5-Hydroxytryptamine in the Proximal and Distal Colon of the Rat
Authors: Ayton B , Hardcastle J , Hardcastle P T , Carstairs J W M
Published: April 2011

The ability of 5-hydroxytryptamine (5-HT) to induce a secretory response in rat proximal and distal colon was examined both in-vivo and in-vitro by measuring transintestinal electrical activity.

In-vivo 5-HT caused a dose-dependent increase in the potential difference (PD) in both regions of the colon (maximum PD change = 7·2 ± 0·5 (n = 17)mV in proximal colon and 9·2 ± 0·7 (n = 17)mV in distal colon), an effect that was also observed in stripped (outer muscle layers removed) colonic sheets where the PD change was found to result from a rise in short-circuit current (SCC, maximum change = 150 ± 24 (n = 15)μA cm−2 in proximal colon and 126 ± 10 (n = 19)μA cm−2 in distal colon).

The effects of 2-methyl-5-hydroxytryptamine (2-Me-5-HT), a relatively selective agonist at 5-HT3 receptors, and 5-methoxytryptamine (5-MT), an agonist at all 5-HT receptors except 5-HT3, were also tested, their specificity of action being confirmed by their actions on cardiovascular function in-vivo. 2-Me-5-HT produced a similar response to 5-HT in proximal colon, but was less effective in the distal region, particularly in-vitro where it failed to induce any significant change in electrical activity. In contrast, 5-MT was more effective in the distal colon. Frusemide (10−3 M) inhibited the rise in SCC induced by both 2-Me-5-HT and 5-MT, indicating that, like 5-HT, these agonists stimulated electrogenic Cl· secretion. The 5-HT3 antagonist granisetron abolished the effects of 2-Me-5-HT, both in-vivo (8·6 times 10−8 molkg−1) and in-vitro (1·4 times 10−6M, 1·4 times 10−4M), but only caused a slight inhibition of the response to 5-HT in-vivo and no inhibition at all in stripped colonic sheets.

It is concluded that although 5-HT induces a secretory response in both proximal and distal colon, the mechanisms responsible differ, with 5-HT3 receptors making a greater contribution in the proximal region.
Effects of Atenolol, Labetalol and Methyldopa on Endogenous Antioxidants In-vitro
Authors: Chen G , Wilson R , Cumming G , Smith W E , Fraser W D , Walker J J , Mckillop J H
Published: April 2011

The aim of this study was to investigate whether atenolol, labetalol and methyldopa, which are commonly used for the treatment of hypertension in pregnancy, can induce antioxidant activity.

Reactive oxygen species scavengers (plasma thiol, red cell lysate thiol, red cell superoxide dismutase, red cell membrane thiol and plasma glutathione) were measured after incubation of peripheral blood with atenolol and methyldopa, respectively.

The results showed that atenolol and labetalol could significantly raise the levels of plasma thiol and membrane thiol but had no effects on lysate thiol, superoxide dismutase and glutathione. The effects on membrane thiol occurred after 60 min incubation and on plasma thiol after 120 min incubation.

The data also suggest that atenolol and labetalol at lower concentrations tend to have additive effects on reactive oxygen species scavengers but at higher concentrations do not.

Methyldopa had no significant effect on any of the parameters measured.

These findings suggest that atenolol and labetalol are able to induce higher levels of antioxidant activity.
Response of Rabbit Ear and Femoral Arteries to 5-Hydroxytryptamine During Cooling
Authors: Fernández N , García-Villalón A L , Monge L , Montoya J J , García J L , Gómez B , Diéguez G
Published: April 2011

The effects of cooling on the response of cutaneous and non-cutaneous arteries to 5-hydroxytryptamine (5-HT) were analysed.

Segments 2-mm long from rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries were prepared for isometric tension recording in an organ bath at 37 and 24°C (cooling). 5-HT (10−9-3 times 10−4 M) induced concentration-dependent contraction of the arteries. The sensitivity and maximal contraction of ear arteries and only the maximal contraction of femoral arteries to this amine were reduced at 24°C.

Endothelium removal or pretreatment with the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10−5  m) did not affect the response at 37°C but reversed the decreased sensitivity at 24°C in ear arteries, and neither procedure modified the reactivity at 24 or 37°C in femoral arteries to 5-HT. At both temperatures, the response of ear arteries to 5-HT was shifted to the right by phentolamine (10−6M) more than by the 5-HT antagonist, ketanserin (3 times 10−7M), and that of femoral arteries was shifted to the right by ketanserin or the 5-HT1/5-HT2 antagonist methysergide (3 times 10−7 M) more than by phentolamine, in arteries with and without endothelium.

These data concur with the proposition that the contraction to 5-HT is mediated mainly by α-adrenergic receptors in ear arteries and mainly by 5-HT-ergic receptors in femoral arteries, and suggest that cooling reduces the sensitivity of cutaneous, but not of deep arteries to 5-HT, probably by endothelium-nitric oxide-dependent mechanisms.
Captopril Induces Iron Release From Ferritin and Oxidative Stress
Authors: Lapenna Domenico , De Gioia Sergio , Ciofani Giuliano , Cuccurullo Franco
Published: April 2011

Captopril has been reported to possess reducing and iron-binding properties, which could favour iron delocalization from ferritin and oxidative stress.

In the present paper, we have found that the drug was effectively capable of inducing a significant mobilization of ferritin iron, which was apparently superoxide anion-independent. Once released from ferritin as a result of captopril action, iron became free in the reduced form and could induce oxidant damage, as evaluated by deoxyribose-oxidative degradation. This phenomenon was not antagonized by the reported oxygen radical-scavenging properties of the drug.

These data indicate that captopril is not always an antioxidant drug, and suggest that it may act as a pro-oxidant in the presence of ferritin in-vivo.
β-Adrenoceptor mRNA Levels Can Be Increased Via β-Adrenoceptor-independent Events
Authors: Gillespie David D , Duhl David M , Manier D Hal , Sulser Fridolin
Published: April 2011

The drug (-)-oxaprotiline has been used as a tool to study the regulation of the β-adrenoceptor in rat C6 glioma cells.

Treatment with (-)-oxaprotiline for 30 min results in an increase in steady-state β-adrenoceptor mRNA levels. The effect is β-adrenoceptor-independent, is not additive or synergistic with isoprenaline treatment, and does not involve activation of adenylate cyclase.

The data show that (-)-oxaprotiline can affect β-adrenoceptor mRNA levels via a mechanism that bypasses the receptor, perhaps involving direct activation of protein kinase A.
Hypoglycaemic Effect of Zizyphus jujuba Leaves
Authors: Erenmemisoglu Aydin , Kelestimur Fahrettin , Koker A Hulusi , Ustun Huseyin , Tekol Yalcin , Ustdal Muzaffer
Published: April 2011

Zizyphus jujuba leaves have been widely used as a hypoglycaemic agent by diabetics in some regions of Turkey. In this study, the effects of Z. jujuba leaves on plasma glucose levels in normo- and hyperglycaemic rats were investigated. In addition, the chronic toxicity of Z. jujuba leaves was investigated in normoglycaemic rats.

When 3 and 6% decoctions of Z. jujuba leaves were administered to rats, plasma glucose levels decreased significantly (P < 0.01). Biochemical and haematological parameters were not different from control groups (P > 0.05) and these parameters were within normal limits. No drug-related changes were observed in rats and there were no pathologic changes attributable to the drug in histopathologic examination of all tissues.
Properties of a Resiniferatoxin-stimulated, Calcium Inhibited but Phosphatidylserine-dependent Kinase, which is Distinct from Protein Kinase C Isotypes α, β1γ, δ, ε and η
Authors: Sharma Pawan , Ryves W Jonathan , Gordge Phil C , Evans A Tudor , Shaun N , Thomas B , Parker Peter J , Evans Fred J
Published: April 2011

We have separated a resiniferatoxin-stimulated histone-kinase activity from human neutrophils, elicited mouse macrophages and murine alveolar macrophages by hydroxyapatite chromatography.

The assay conditions for resiniferatoxin kinase were optimized as part of this study and in the presence of phosphatidylserine but absence of Ca2+ the Ka for histone IIIs phosphorylation by resiniferatoxin was calculated as 16 nm. Using a phosphate gradient of 20–500 mm, peaks of protein kinase C activity could be washed from the hydroxyapatite column in 300 nm phosphate and resiniferatoxin kinase recovered in 500 mm phosphate. At the optimum concentration of 160 nm, the ability of resiniferatoxin to induce enzyme activity was compared with a range of phorbol esters all at the same concentration. These related compounds failed to activate resiniferatoxin kinase although they have previously been shown to activate protein kinase C isotypes. Similarly sn-1,2,-dioleoylglycerol and the potent irritant capsaicin at 30 μm failed to activate the kinase. A Scatchard analysis of [3H] phorbol dibutyrate binding produced a linear plot (Kd 41·6 nm; Bmax 11·6 fmol unit−1) and binding was inhibited by resiniferatoxin and 12-O-tetradecanoylphorbol-13-acetate (TPA), with resiniferatoxin 700 times more potent than TPA in this respect. A radiolabeled resiniferatoxin binding assay was also used to demonstrate specific binding of [3H]resiniferatoxin which could be inhibited by unlabelled compound. Resiniferatoxin kinase activity was shown to be distinct from the protein kinase C isotypes α, β1, γ δ and ε by means of immunological analysis and from the η isotype, because that isotype was not stimulated by resiniferatoxin but was stimulated by TPA when a pseudosubstrate was used. In addition the resiniferatoxin-stimulated activity was inhibited in-vitro by the addition of Ca2+ (Ki 0·1-0·5 nm free Ca2+). Further purification of resiniferatoxin kinase by Superose chromatography indicated a major activity fraction of about 70–90 kDa.

Thus resiniferatoxin kinase, isolated from human and mouse inflammatory cells is distinct from the known isotypes of protein kinase C and is a major resiniferatoxin receptor.
In-vitro Pharmacology of Sarpogrelate and the Enantiomers of its Major Metabolite: 5-HT2A Receptor Specificity, Stereoselectivity and Modulation of Ritanserin-induced Depression of 5-HT Contractions in Rat Tail Artery
Authors: Pertz H , Elz S
Published: April 2011

The new antiplatelet agent sarpogrelate (MCI-9042), its major metabolite (R,S)-1-[2-[2-(3-methoxyphe-nyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol ((R,S)-M-1) and the enantiomers of (R,S)-M-1 were studied as antagonists at 5-HT2A receptors, 5-HT1-like receptors, 5-HT3 receptors, α1-adrenoceptors, β-adrenoceptors, histamine H1 receptors, histamine H2 receptors and muscarinic M3 receptors in various functional in-vitro assays.

Sarpogrelate, (R,S)-M-1, (S)-M-1 and (S)-M-1, respectively, were competitive antagonists of 5-hydroxytryptamine (5-HT) at 5-HT2A receptors of rat tail artery with calculated pA2 values of 8·53, 9·04, 9·00 and 8·81, respectively. Sarpogrelate lacked prominent 5-HTt like, 5-HT3, β, Ht, H2 and M3 antagonist activity and weakly blocked α1-adrenoceptors (pKB = 6·30). (S)-M-1 showed weak affinity for 5-HT1-like receptors (pKB = 6·30), α1 (pKB = 6·80) and β (pKB = 6·54) adrenoceptors, while (R)-M-1 was a weak antagonist at histamine H1 receptors (pKB = 6·49).

Stereoselectivity of M-1 enantiomers was low. (R)-M-1 showed 1·6-fold, 2·3-fold and 2·5-fold higher antagonist activity than (S)-M-1 for 5-HT2A, H1 and M3 receptor, respectively. Affinity at β-adrenoceptors and 5-HT1-like receptors was 5-fold and 3-fold higher for (S)-M-1 than for (R)-M-1.

The depression of the maximum effect of 5-HT-induced contractions of rat-tail artery which amounted to 58–72% in the presence of ritanserin (1 nm), was totally prevented after preincubation with sarpogrelate (1 μm) and (R)- and (S)-M-1 (30 and 300 nm), respectively, and partially prevented after preincubation with (R)- and (S)-M-1 (0·3-3 nm). (R)- and (S)-M-1 failed to differ in restoring the ritanserin-induced depression of the 5-HT maximum response.

It is concluded that sarpogrelate, its major metabolite (R, S)-M-1 and M-1 enantiomers are specific antagonists of 5-HT at 5-HT2A receptors. The stereochemical configuration of the ligands does not seem to be crucial for binding to the 5-HT2A receptor. Like ketanserin, sarpogrelate and M-1 enantiomers appear to be allosteric activators of the 5-HT2A receptor system in rat tail artery.
Antiplatelet Effect of Gingerol Isolated from Zingiber officinale
Authors: Guh Jih-Hwa , Ko Feng-Nien , Jong Ting-Ting , Teng Che-Ming
Published: April 2011

The purpose of this investigation was to determine the antiplatelet mechanism of gingerol.

Gingerol concentration-dependently (0·5–20 μm) inhibited the aggregation and release reaction of rabbit washed platelets induced by arachidonic acid and collagen, but not those induced by platelet-activating factor (PAF), U46619 (9,11-dideoxy-9α,11 α-methano-epoxy-PGF2α) and thrombin. Gingerol also concentration-dependently (0·5–10μ m) inhibited thromboxane B2 and prostaglandin D2 formation caused by arachidonic acid, and completely abolished phosphoinositide breakdown induced by arachidonic acid but had no effect on that of collagen, PAF or thrombin even at concentrations as high as 300 μ m.

In human platelet-rich plasma, gingerol and indomethacin prevented the secondary aggregation and blocked ATP release from platelets induced by adenosine 5′-diphosphate (ADP, 5 μ m) and adrenaline (5 ä m) but had no influence on the primary aggregation. The maximal antiplatelet effect was obtained when platelets were incubated with gingerol for 30 min and this inhibition was reversible.

It is concluded that the antiplatelet action of gingerol is mainly due to the inhibition of thromboxane formation.
The Disposition of Morphine and Its Metabolites in the In-situ Rat Isolated Perfused Liver
Authors: Evans Allan M , Shanahan Kathryn
Published: April 2011

A specific HPLC method with UV detection was used to investigate the disposition of morphine and its metabolites in the in-situ rat isolated perfused liver preparation.

Livers of male Sprague-Dawley rats (n = 4) were perfused under single pass conditions with protein-and erythrocyte-free perfusate, containing 2·66 μm morphine, for up to 90 min. The concentration of morphine, normorphine and morphine-3-glucuronide (M3G) in outflow perfusate, and the biliary excretion of M3G and normorphine glucuronide, all reached steady-state levels within 15–20 min after commencing perfusion. At steady-state, the mean (± s.d.) extraction ratio of morphine was 0·87 ± 0·06 and clearance (26·0 ± 1·7 mL min−1) approached perfusate flow rate (30 mL min−1). Although M3G was the main metabolite, accounting for 72·8 ± 12·7% of eliminated morphine, a significant proportion (21·6 ± 13·5%) was N-demethylated to normorphine and was recovered as unchanged normorphine in outflow perfusate and normorphine glucuronide in bile. The biliary extraction ratio of hepatically-formed M3G was 0·61 ± 0·31.

Results from an additional six experiments, in which livers were perfused with 1·33 and 2·66 μm of morphine for 30 min each in a balanced cross-over manner, indicated that the disposition of morphine and its metabolites was approximately linear within this concentration range.
Determination of Octanol-water Partition Coefficients by an HPLC Method for Anticonvulsant Structure-activity Studies
Authors: Henczi Maria , Nagy Jeno , Weaver Donald F
Published: April 2011

Octanol-water partition coefficients have been measured and calculated for eight clinically relevant anticonvulsants.

For some compounds, these are the first experimentally available log P values. For the remainder of the molecules, new values have been suggested. The utility of the micro shake-flask experimental method and the ALOGP calculational method in determining anticonvulsant log P values has been demonstrated.
An Investigation into the Effects of Preparation Conditions and Storage on the Rate of Drug Release from Pharmaceutical Glyceride Bases
Authors: Sutananta Wanchai , Craig Duncan Q M , Newton J Michael
Published: April 2011

The effects of preparation conditions on the release of theophylline from Gelucires 50/13 and 55/18 have been investigated. Samples were prepared by melting physical mixes under controlled conditions, followed by either slow or fast (ambient) cooling to the solid state.

A rapid cooling rate was shown to result in a slower release rate for 2% w/w dispersions in Gelucire 55/18, with the slow- and fast-cooled systems resulting in drug release via a diffusion and a mixed diffusion/erosion mechanism, respectively. At higher drug loading (30% w/w), the cooling rate did not effect the release characteristics. The erosion of Gelucire 50/13 was found to be more rapid for slowly cooled samples.

Viscosity measurements were used as a means of assessing the chemical stability of the Gelucires, with evidence being found for degradation of Gelucire 55/18 on storage following heat treatment, while Gelucire 50/13 appeared to be stable.

The effects of storage on the dissolution profiles of ambiently cooled systems were studied, with drug release from both bases increasing on ageing for up to 180 days.
Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice
Authors: Liu Cheng-Hsiung , Ho Hsiu-O , Hsieh Meng-Chen , Sokoloski Theodore D , Sheu Ming-Thau
Published: April 2011

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design.

Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL−1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter.

There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.
Direct Drug Transport from the Rat Nasal Cavity to the Cerebrospinal Fluid: the Relation to the Molecular Weight of Drugs
Authors: Sakane Toshiyasu , Akizuki Motohiro , Taki Yoko , Yamashita Shinji , Sezaki Hitoshi , Nadai Tanekazu
Published: April 2011

To clarify the relationship between the direct transport from the rat nasal cavity to the cerebrospinal fluid (CSF) and the molecular weight of the drug, the transport of fluorescein isothiocyanate-labelled dextran (FD) with various molecular weights was investigated. FDs (average molecular weights 4400 (FD4); 9400 (FD10); 18 900 (FD20); 40 500 Da (FD40)) were administered nasally or intravenously to rats, and the concentrations in the plasma and the CSF were measured and compared.

None of the FDs were detected in the CSF after intravenous administration. However, FD4, FD10 and FD20 were observed to appear in the CSF after nasal administration, whereas the concentration in the plasma was much lower than that after intravenous administration. FD40 was not detected even after nasal administration. In addition, the concentration of these FDs in the CSF decreased with the increase in the molecular weight of FDs.

These findings show that drugs with a molecular weight up to at least 20 000 Da can be directly transported from the nasal cavity to the CSF and that the transport of FDs to the CSF is dependent on their molecular weights.
PEG-coated Poly(lactic acid) Nanoparticles for the Delivery of Hexadecafluoro Zinc Phthalocyanine to EMT-6 Mouse Mammary Tumours
Authors: Allemann Eric , Brasseur Nicole , Benrezzak Ouhida , Rousseau Jacques , Kudrevich Svetlana V , Boyle Ross W , Leroux Jean-Christophe , Gurny Robert , van Lier Johan E
Published: April 2011

Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(d,l-lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)-coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the salting-out procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 μmol kg−1 ZnPcF16.

Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC0–168, 57 μg h g−1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEG-coated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC0–168 227 μg h g−1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3·5 and 10·8, respectively.

Blood levels of ZnPcF16 after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC0–168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days.
Iloprost: Intracellular Ca2+-dependent Contractile Effect on Isolated Smooth Muscle Cells from Guinea-pig Ileum
Authors: Botella Alain , Jeanneton Olivier , Delvaux Michel , Frexinos Jacques , Bueno Lionel
Published: April 2011

Prostaglandin E2 (PGE2) and iloprost induced a concentration-dependent contraction of smooth muscle cells isolated from the circular layer of guinea-pig ileum. PGE2- and iloprost-induced contractions were inhibited by the selective EP1-receptor antagonist, SCI9220 (1-acetyl-2-(8-chloro-10, 11-dihydrodibenz (b,f) (1,4) oxazepine-10-carbonyl)-hydrazine), indicating the involvement of the EP1 subtype of the PGE2 receptor. When cells were incubated for 10 min in the presence of strontium (4 mm L−1), an inhibitor of the release of Ca2+ from intracellular store, the contractile effect of PGE2 and iloprost was inhibited. In contrast, incubation of cells in Ca2+-free medium, Ca2+-free medium plus EGTA, or in the presence of nifedipine, an organic Ca2+-channel blocker, did not alter the PGE2- and iloprost-induced contraction. These observations suggest that the myogenic effect of PGE2 and iloprost on intestinal smooth muscle is dependent on the release of intracellular calcium.
Angiostasis and Vascular Regression in Chronic Granulomatous Inflammation Induced by Diclofenac in Combination with Hyaluronan in Mice
Authors: Alam C A S , Seed M P , Willoughby D A
Published: April 2011

Angiostasis and vascular regression in chronic granulomatous inflammation was assessed in mice induced with diclofenac in combination with hyaluronan.

The local injection of 0·1 mL HYAL EX-0001 (0·18% diclofenac in 2·5% hyaluronan) reduced granulomatous development after six days treatment from 150·4 ± 13·8 (0·18 saline) to 117·1 ± 17·8 mg (dry weight, n = 10), but not significantly when compared with 0·1 mL 2·5% hyaluronan alone or diclofenac in 0·1 mL saline. Diclofenac administered in saline had no significant effect when compared with saline control. The vascular density, expressed as carmine content per mg dry weight tissue, in those animals treated with HYAL EX-0001 was also significantly reduced to 5·27 ± 0·55 μg mg−1 (P < 0·1, n = 10) when compared with saline control (7·99 ± 1·0), hyaluronan alone (7·20 ± 1·0), and diclofenac in saline. (7·36 ± 1·28). A similar profile of activity was seen on topical application except that all treatments did not affect granulomatous tissue development.

On therapeutic dosing of mice daily with HYAL EX-0001 from day 7 after induction of the granulomatous tissue, the granulomatous tissue development was dramatically reduced from 111·67 ± 4·40 mg (n = 14 on day 7) to 60·23 ± 7·22 (P < 0·001, n = 8 on day 14) and 54·98 ± 7·88 (P < 0·001, n = 8 on day 21). HYAL EX-0001 after 14 days of application significantly reduced granulomatous tissue mass when compared with the hyaluronan-dosed control on day 21 (89·58 ± 7·49, P = 0·01, n = 8). The granulomatous tissue lost weight on the application of hyaluronan for 14 days by 19·8% (P < 0·01).

The vascular density of the tissues was 15·05 ± 0·63 μg mg−1, which HYAL EX-0001 significantly reduced to 11·96 ± 1·14 (P < 0·05) after 7 days application and 11·25 ± 1·21 μg mg−1 (P < 0·02) after 14 days application. The latter was significantly inhibited when compared with the day 21 hyaluronan control (14·02 ± 1·39 μg mg−1, P < 0·05). The day 7 vascular density was not significantly reduced by the topical application of hyaluronan from day 7 to 21.

The results suggest that hyaluronan is acting as a novel and effective drug delivery system, and may explain the therapeutic effectiveness of HYAL CT-1101 on basal cell carcinoma and actinic keratosis.
Semicarbazide-sensitive Amine Oxidase Activity in White Adipose Tissue of the Insulin-deficient Rat
Authors: Conforti L , Pirisino R , Ignesti G , Banchelli G , Raimondi L
Published: April 2011

We have investigated whether the effects in white adipose tissue due to insulin deficiency might also be related to an alteration of histamine levels which are regulated by semicarbazide-sensitive amine oxidase.

The lack of circulating insulin induced by streptozotocin produced, in rat white adipose tissue, a loss of affinity of the semicarbazide-sensitive amine oxidase for histamine oxidation. In parallel, a decrease of cell transformation, measured by glycerol-3-phosphate dehydrogenase activity and an augmented sensitivity to histamine lipolysis were observed.

These findings could contribute to the understanding of histamine metabolism and function in diabetic rats and to the knowledge concerning amine oxidases in this animal pathology.
Dexamethasone Reduces the Behavioural Effects Induced by Baclofen in Mice
Authors: Capasso A , Di Giannuario A , Loizzo A , Pieretti S , Sorrentino L
Published: April 2011

The present study examines the influence of dexamethasone on the behavioural effects induced by baclofen in mice. The behaviour elements considered were locomotor activity, motor co-ordination, catalepsy, stereotyped behaviour and antinociception.

Baclofen (1·0–4·0–6·0 mg kg−1, i.p.) induced a significant reduction of all behavioural elements studied and an antinociceptive effect was recorded. Dexamethasone alone (0·1–0·5–1·0 mg kg−1, i.p.) did not induce significant changes in the behaviour elements considered. On the other hand, when the steroid was injected immediately before baclofen a significant reduction of baclofen's behavioural effects was found.

Our results suggest a possible link between glucocorticoid and the GABA-ergic system.
Acid-base Properties of Terbutaline in Terms of Protonation Macro- and Microconstants
Authors: Takács-Novák Krisztina , Noszál Béla , Tökes-Kövesdi Márta , Szász György
Published: April 2011

The acid/base chemistry of terbutaline was characterized at the molecular level in terms of protonation macroconstants and microconstants. The macroconstants were measured by potentiometry and calculated by standard evaluation methods.

The stepwise macroconstant values were log K1 = 11·01, log K2 = 9·89, and log K3 = 8·57 at 250°C and 0·2 m ionic strength. The microconstants were deduced using the relationships between macro- and microconstants and an appropriate data set of model compounds (resorcinol and phenylephrine). The molecule of terbutaline contains three ionizable functional groups. In the unprotonated form of the molecule, the two identical phenolate groups are slightly more basic than the secondary amino group, whereas the amino basicity significantly exceeds that of the phenolate site, when the other phenol is protonated. This is due to the large phenolate-phenolate intramolecular interaction. The phenolate-phenolate and the phenolate-amino interactivity parameters were found to be −1·21 and −0·41 log E units, respectively.
Acid-base Equilibria of 1,4-Benzodiazepine 4-Oxides by Spectrophotometry
Authors: Yang Shen K
Published: April 2011

Chlordiazepoxide (a 1,4-benzodiazepine 4-oxide) is an anxiolytic/hypnotic drug in clinical use. It was reported to be predominantly protonated at the N-oxide oxygen in acidic aqueous solutions at pH ≪ 4·6 (pKa). We have studied the acid-base equilibria of three 1,4-benzodiazepine 4-oxides (chlordiazepoxide, diazepam 4-oxide, and nordiazepam 4-oxide) by ultraviolet-visible spectrophotometry. The results indicate that chlordiazepoxide is not protonated at the N-oxide oxygen, but rather at the nitrogen of an imine bond between C2 carbon and its nitrogen substituent in acidic media.
An In-vitro Evaluation of Silicone Elastomer Latex for Topical Drug Delivery
Authors: Li Luk Chiu , Vu Ngocoanh Thi
Published: April 2011

A silicone elastomer latex was evaluated as a topical drug-delivery system.

With the addition of a fumed silica and the removal of water, the latex produced elastomeric solid films. The water vapour permeability of the solid film was found to be a function of the film composition. An increase in silica content and the incorporation of a water-soluble component, PEG 3350, rendered the silicone elastomer-free film even more permeable to water vapour. The release of hydrocortisone from the elastomer film can be described by a matrix-diffusion-controlled mechanism. Drug diffusion is thought to occur through the hydrophobic silicone polymer network and the hydrated hydrophilic silica region in the film matrix. Silicone elastomer film with a higher silica content exhibited a faster drug-release rate. The addition of PEG 3350 to the film further enhanced the drug-release rate.
Pseudo-ternary Phase Diagrams of Lecithin-based Microemulsions: Influence of Monoalkylphosphates
Authors: Trotta Michele , Ugazio Elena , Gasco Maria Rosa
Published: April 2011

The formation of macroscopically homogeneous, stable, fluid, optically transparent, isotropic solutions (microemulsions) was delineated, at 25°C, for systems containing water, soybean lecithin, sodium monoalkylphosphate (hexyl or octyl), alcohol and isopropyl myristate. Six straight or branched alcohols (1-butanol, 2-butanol, isobutanol, 1-pentanol, 2-pentanol, 3-pentanol) were investigated as co-surfactants. A constant lecithin/alcohol mixing ratio was used, while the aqueous phase consisted of a solution of alkylphosphates at different concentrations.

An increase of the microemulsion domain was seen by increasing the concentration of the alkylphosphate. With 0·2 m hexylphosphate, as aqueous phase, the microemulsion domain consisted of a single, region, that, in the presence of butylic alcohols, spanded the greater portion of the phase diagram. In the presence of amyl alcohols the area of this region was much smaller. With 0·2 m octylphosphate the realm of existence of the microemulsions, except for 1-pentanol, consisted of two regions separated by a liquid-crystal region. With all the alcohols examined, the liquid-crystal phase solubilized a larger amount of oil in the presence of octylphosphate than in the presence of hexylphosphate.

The stability ranges of microemulsions in systems containing soybean lecithin, alcohol, water, and isopropyl myristate can be greatly increased by using a second hydrophobic amphiphile, such as hexylphosphate, to adjust the hydrophilic-lipophilic balance or the spontaneous peaking properties of lecithin-alcohol systems.
Absorption Enhancement of a Hydrophilic Model Compound by Verapamil After Rectal Administration to Rats
Authors: Noach Arthur B J , Blom-Roosemalen Margret C M , de Boer Albertus G , Breimer Douwe D
Published: April 2011

The use of verapamil as an absorption enhancer for the paracellular route in-vivo was studied using FITC-labelled dextran (molecular weight 4000) (FD-4) as a hydrophilic model compound for transport enhancement.

The kinetics of FD-4 after intravenous doses of 1 or 10mg could be described by a two-compartment model with a systemic clearance of approximately 2mL min−1 and a terminal plasma half-life of approximately 36 min. Rectal administration to rats, performed as a rectal infusion of 10 mg FD-4 together with 7 mm verapamil, resulted in a 10-fold increase in the percentage of the dose absorbed over a 5-h period compared with the control and a 6-fold increase compared with a bolus administration, although the total amount absorbed remained relatively low (approx. 3% maximum). Large inter-animal variation in effect values were noted.

The data indicate that although verapamil is able to enhance the absorption of hydrophilic compounds in-vivo, practical application of verapamil for this purpose does not seem feasible.
Zinc Sulphadiazines: Novel Topical Antimicrobial Agents for Burns
Authors: Lee A R , Huang W H
Published: April 2011

Two new zinc sulphadiazine (Zn(SD)2)-amine complexes, zinc sulphadiazine-methylamine (Zn(SD)2(CH3NH2)2) and zinc sulphadiazine-ethylenediamine (Zn(SD)2(C2H8N2)3·H2O), were prepared and compared with silver sulphadiazine (AgSD). The compounds were readily obtained by reaction of zinc nitrate hexahydrate with sulphadiazine or its salt in methylamine and ethylenediamine, respectively.

Structure was established by X-ray crystallography and ultraviolet-visible, infrared and nuclear magnetic resonance spectroscopy. The products were effective, in-vitro, against Gram-positive and Gram-negative bacteria as well as fungus. However, their activity is partially reversed by p-aminobenzoic acid. Further investigations in burned mice revealed that these compounds displayed a potential value in the prevention and treatment of wound healing, and diminution of mortality and weight loss. The toxicity of Zn(SD)2 derivatives was much lower than that of AgSD. The better aqueous solubility and skin permeability may explain the reason for their superiority over AgSD in the efficacy for topical therapy.

Zn(SD)2(CH3NH2)2 was consistently more potent and was chosen for further development in clinical uses. The similarity in complexation between Zn(SD)2(CH3NH2)2 and AgSD may be significant to distinguish that from any other Zn(SD)2 derivative in bioactivity.
Antitumour Effects and Pharmacokinetics of Combination of Vinblastine with a Staurosporine Derivative, NA-382, in P388/ADR-bearing Mice
Authors: Miyamoto Ken-Ichi , Takeda Keiko , Koga Kenjiro , Ohshima Taeyuki , Wakusawa Shinya
Published: April 2011

The effects of a staurosporine derivative, N-ethoxycarbonyl-7-oxostaurosporine (NA-382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug-resistant P388/ADR-bearing mice.

At first, the in-vitro experiments indicated that NA-382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 μ kg−1) into P388/ADR-bearing mice, NA-382 in a suspension form (10 mg kg−1) prolonged the life-span of the mice near to that of P388/S-bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg−1) barely affected the in-vivo antitumour effect of vinblastine.

When simultaneously administered with vinblastine to P388/ADR-bearing mice, NA-382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time-intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid.

This study indicates that NA-382 is more effective against multidrug-resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug-resistant tumours.
Influences of Immobilization and Footshock Stress on Pharmacokinetics of Theophylline and Caffeine in Rats
Authors: Okazaki Masatoshi , Eto Kohei , Furuno Katsushi , Oishi Ryozo , Gomita Yutaka
Published: April 2011

The influences of immobilization and footshock stress on pharmacokinetics of theophylline (20 mg kg−1) and caffeine (30 mg kg−1) administered orally were examined in rats.

The immobilization stress for 30 min or 1 h immediately after oral administration caused marked immobilization period-related decreases in plasma theophylline concentrations during the absorption phase, but did not affect plasma caffeine concentrations. The ka and Cmax values for theophylline were significantly decreased, and the tmax was significantly increased. On the other hand, when the immobilization stress was loaded for 1 or 3 h before the oral administration, the plasma theophylline or caffeine concentrations were not affected. The footshock stress for 30 min immediately after oral administration did not significantly decrease plasma theophylline concentrations during the absorption phase.

These results suggest that the pharmacokinetics of theophylline are influenced by strong stress, possibly due to the inhibition of its absorption from the gastrointestinal tract, but the pharmacokinetics of caffeine are not influenced by stress, probably due to its central action.
Comparison of Procedures for Measuring the Quaternary N-Glucuronides of Amitriptyline and Diphenhydramine in Human Urine with and without Hydrolysis
Authors: Fischer Dorothee , Breyer-Pfaff Ursula
Published: April 2011

The activities of β-glucuronidases from Helix pomatia, Escherichia coli and rat towards the N-glucuronides of amitriptyline and diphenhydramine were considerably lower than those towards standard substrates.

The two N-glucuronides were analysed in urine samples by the following procedures: HPLC of the intact conjugate after solid-phase extraction on a cation exchanger cartridge or after direct injection of urine; HPLC of the aglycone after hydrolysis with β-glucuronidase from H. pomatia or E. coli or after alkaline hydrolysis. Solid-phase extraction led to the highest recovery and precision, and sensitivity can be improved by extracting a larger volume of urine.

On application to samples from patients under treatment with amitriptyline, the results of all procedures except alkaline hydrolysis were in good agreement. When diphenhydramine N-glucuronide was analysed in urine samples of volunteers, solid-phase extraction, hydrolysis by E. coli glucuronidase and alkaline hydrolysis resulted in similar values.
Compression of Lactose, Glucose and Mannitol Granules
Authors: Juppo Anne Mari , Kervinen Lasse , Yliruusi Jouko , Kristoffersson Eeva
Published: April 2011

The effect of the amount of granulation liquid, compression speed and maximum compression force on the compressibility and compactibility of lactose, glucose and mannitol granules was studied. The porosity based on the geometrical shape and the uniformity of weight of tablets was also studied.

Lactose and mannitol granules showed a greater compressibility than glucose granules. Mannitol granules produced the hardest tablets and lactose and glucose the weakest. The change in the amount of granulation liquid caused changes both in the granule porosity and in the amount of binder; this was attributed to differences in tablet strength. All parameters studied were relatively insensitive to changing speeds of compression in the range used, except for the breaking force of mannitol tablets, which was greatest with the lowest speed of compression. All granule masses showed a relatively good continuous flow suitable for tablet production. Tablets compressed from lactose granules had the best uniformity of weight of the tablets studied.
Particle Size Studies for Subcutaneous Delivery of Poly(lactide-co-glycolide) Microspheres Containing Ovalbumin as Vaccine Formulation
Authors: Uchida Takahiro , Goto Shigeru , Foster Todd P
Published: April 2011

The primary objectives of the present study were to produce poly(lactide-co-glycolide) (PLGA) microspheres with different diameters, to characterize these microspheres which were loaded with a model antigen, ovalbumin and to evaluate the effect of microsphere particle size on the serum antibody levels following administration to mice.

Four kinds of ovalbumin-loaded PLGA microspheres with different diameters (1·2, 3·5, 7·0 and 14·3 μm as mean volume diameter) were manufactured by a w/o/w emulsion/solvent evaporation method. Low loading percent (0·08%-0·25%w/w) and efficiencies (8–25% w/w) were observed. Examination using scanning electron photomicrographs showed smooth spherical particles. The in-vitro release of ovalbumin from microspheres showed an expected burst release with all batches and the extent of the burst release increased with decreasing diameters of spheres; PLGA microspheres with the smallest diameter (1·2/μm) showed an 80% burst release within one day. Approximately 10–60% of ovalbumin remained unreleased 30 days later.

The single subcutaneous administrations of ovalbumin-loaded PLGA microspheres with different diameters to mice induced good antibody responses above ovalbumin saline negative controls at 3, 6, 9, and 12 weeks after inoculation. Especially, 0·16% ovalbumin-loaded PLGA microspheres having mean volume diameter of 3·5 /μm exhibited the best immune responses with values greater than those obtained after inoculation with adjuvants such as complete Freund's adjuvant or alum as positive control.

The strong adjuvant activity of PLGA microspheres as vaccine formulation was suggested.
The Transfer of Polystyrene Microspheres from the Gastrointestinal Tract to the Circulation after Oral Administration in the Rat
Authors: Eyles J , Alpar H O , Field W N , Lewis D A , Keswick M
Published: April 2011

Factors relating to the transfer of latex microspheres of 0·87 μm mean diameter from the gastrointestinal tract (GIT) to the circulation have been investigated.

The rapidity of appearance and the number of particles increased when the volume of water used as a suspending vehicle was increased. This was probably due to barrier cell integrity being compromised so that the movement of particles across the enterocytes would be enhanced. Particles were swept into these channels by the waterflow. The tonicity of the fluid was important as isotonic and hypertonic saline were not as affective as water in transferring particles. Particles were transferred from GIT segments adjacent to the stomach which may in part explain the rapid appearance of particles in the circulation. Particle uptake was blocked by cytochalasin B which suggests an active component may also be involved.
The Effect of Lysine, a Water-structure Breaker, on the Stability of Phospholipid-stabilized Emulsions
Authors: Lutz O , Groves M J
Published: April 2011

Phospholipid-stabilized emulsion properties were studied in the presence of lysine, a water-structure breaker, using two unrelated procedures, photon correlation spectroscopy and a light obscuration instrument. Commercial Intralipid was used as a control.

Lysine 0·125, 0·25 and 0·5 M induced changes in the size distribution of a non-heated model emulsion system, irrespective of any changes produced by environmental pH. Some of the laboratory-prepared emulsions containing lysine were more stable than the corresponding commercial heat-sterilized product Intralipid, once heated.

The results suggest that lysine is producing an effect on the nascent oil-water interface that controls the physical stability of the system. Once the heat-induced interfacial rearrangement of the individual phospholipid molecules occurs, the influence of lysine becomes diminished.
Effects of Ageing on the Oral Absorption of d-Xylose in Rats: Analysis of Gastrointestinal Disposition
Authors: Yuasa Hiroaki , Kawanishi Koji , Watanabe Jun
Published: April 2011

The effects of ageing on the oral (gastrointestinal) absorption of d-xylose were investigated by analysing the gastrointestinal disposition after oral administration to young (9 weeks) and old (53 weeks) rats. A linear model assuming first-order gastric emptying followed by first-order intestinal absorption was fitted to remaining fraction vs time profiles for the stomach and small intestine to estimate the gastric emptying rate constant (kg) and the intestinal absorption rate constant (ka).

In young and old rats, kg values were 0·087 ± 0·008 and 0·070 ± 0·007 min−1, respectively, and ka values were 0·020 ± 0·002 and 0·018 ± 0·002 min−1 suggesting an insignificant effect on ageing on the rate of oral absorption. The average intestinal lumen volume (Vav) was unchanged with ageing, and so was the apparent intestinal membrane permeability clearance (CLapp) as the product of ka and Vav. However, the small intestinal transit time (Tsi) was suggested to be twice that in older rats (171 min) than in young rats (78 min) by the analysis of gastrointestinal disposition of inulin, a non-absorbable marker. It was also shown that our preceding finding of an increase in the fraction absorbed of D-xylose with ageing can be solely ascribable to the delay in intestinal transit.

Thus, among various determinants of oral absorption, only Tsi was found to be altered with ageing. The CLa,app and ka of passively absorbed drugs such as D-xylose may be generally unchanged, and the fraction absorbed may increase with ageing by the delay in intestinal transit.
Effect of Oleanolic Acid on Complement in Adjuvant- and Carrageenan-induced Inflammation in Rats
Authors: Kapil Aruna , Sharma Shalini
Published: April 2011

The present work was aimed at evaluating the influence of oleanolic acid on complement-related inflammation.

In adjuvant-induced arthritis and carrageenan-induced paw oedema in rats, oleanolic acid was found to possess significant anti-inflammatory and complement-inhibitory activities. The intraperitoneal injection of oleanolic acid (60 mg kg−1, twice a day), before and after Freund's Complete Adjuvant challenge and thereafter repeated for several days, significantly reduced foot-pad thickness of experimental animal models and simultaneously reduced complement activity. Oleanolic acid also produced marked reduction in complement levels and inflammatory effects on carrageenan-induced paw oedema in rats when injected intraperitoneally (60 mg kg−1 twice a day).