bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Feasibility Study of the Multiple-peak Approach for Pharmacokinetic Screening: Population-based Investigation of Valproic Acid Relative Clearance Using Routine Clinical Pharmacokinetic Data
Authors: Yukawa Eiji 
Published: April 2011

Abstract
The multiple-peak approach was used to evaluate the effect of age, body mass, dose and gender on the population estimates of valproic acid relative clearance.
Routine clinical pharmacokinetic data (n = 474) was collected from 250 patients receiving valproic acid and no other drug. The data was analysed according to a simple steady-state pharmacokinetic model using NONMEM, a computer program designed for population pharmacokinetic analysis allowing pooling of data.
The final regression model for relative clearance (CL, mL kg−1 h−1) was:
CL = 18.9 x body weight−0.276. daily dose0.142. gender
where gender = 1 for males, 0.877 for females.
NONMEM estimates suggested that the rate of valproic acid clearance decreased nonlinearly with increasing body weight in the maturation process, and increased nonlinearly with increasing valproic acid dose (mg kg−1 day−1). The clearance in females was about 11% less than in males. These estimates were similar to those detected from previous studies.
The Analysis of Drug Release from Diluted Water/oil/water Emulsions by a Model of the Rupture of Oil Membrane
Authors: Hino T , Takeuchi H , Niwa T , Kitagawa M , Kawashima Y 
Published: April 2011

Abstract
The release behaviour of theophylline encapsulated in the inner aqueous phase of a water/oil/water emulsion was investigated by two methods. A cellulose tube containing a sample of the emulsion was placed in a rotary basket and was stirred in a dissolution medium (Method A), or the w/o/w emulsion was dispersed in a dissolution medium and the system was stirred by a paddle, allowing the drug to permeate into a cellulose tube placed in the dispersing medium (Method B).
In Method A, the drug release rate from the emulsion decreased with increase in the concentration of sodium chloride co-formulated with the drug in the inner aqueous phase. The drug release rate in the dissolution test medium No. 1 or No. 2 of the JP XII was greater than that in purified water and was increased with the ionic strength of the dissolution medium. The drug was released more rapidly in Method B than in Method A, because the emulsion was destroyed more easily using the former method. As this destruction of emulsion structure occurred immediately after dilution with dissolution medium, the influence of the dissolution medium on the release profile could not be detected using Method B.
The experimental data of drug release were satisfactorily explained by the destruction model of the oil membranes of the water/oil/water emulsions.
Measuring the Diffusional Pathlength and Area Within Membranes of Excised Human Stratum Corneum
Authors: Lieckfeldt Renate , Lee Geoffrey 
Published: April 2011

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 0.01). Biochemical and haematological parameters were not different from control groups (P &gt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt; 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter &lt; 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

Abstract
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.