bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Synthesis and Some Pharmacological Actions of the Enantiomers of the K+-Channel Blocker Cetiedil
Authors: Roxburgh Craig J , Ganellin C Robin , Shiner Mark A R , Benton David C H , Dunn Philip M , Ayalew Yeshi , Jenkinson Donald H 
Published: April 2011

Abstract
Cetiedil ((±)-2−cyclohexyl-2-(3−thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1−yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca2+-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca2+-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (Kvol) of liver cells.
The enantiomers did not differ substantially in their ability to block the Ca2+-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 ± 0.2 (s.d.) times more active than the (–-) form. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 ± 0.54 (s.d.) μM; (–-)-cetiedil was 2.6 ± 0.8 (s.d.) times less active (IC50 of 5.2 ± 1.2 μM).
Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.
Antibacterial Activity of Xanthones from Guttiferaeous Plants against Methicillin-resistant Staphylococcus aureus
Authors: Iinuma Munekazu , Tosa Hideki , Tanaka Toshiyuki , Asai Fujio , Kobayashl Yasuko , Shimano Ryoyu , Miyauchi Ken-Ichi 
Published: April 2011

Abstract
Extracts of Garcinia mangostana (Guttiferae) showing inhibitory effects against the growth of S. aureus NIHJ 209p were fractionated according to guidance obtained from bioassay and some of the components with activity against methicillin-resistant Staphylococcus aureus (MRSA) were characterized.
One active isolate, α-mangostin, a xanthone derivative, had a minimum inhibitory concentration (MIC) of 1.57−12.5 μg mL−1. Other related xanthones were also examined to determine their anti-MRSA activity. Rubraxanthone, which was isolated from Garcinia dioica and has a structure similar to that of α-mangostin, had the highest activity against staphylococcal strains (MIC = 0.31−1.25 μg mL−1), an activity which was greater than that of the antibiotic vancomycin (3.13−6.25 μg mL−1). The inhibitory effect against strains of MRSA of two of the compounds when used in conjunction with other antibiotics was also studied. The anti-MRSA activity of α-mangostin was clearly increased by the presence of vancomycin; this behaviour was not observed for rubraxanthone.
The strong in-vitro antibacterial activity of xanthone derivatives against both methicillin-resistant and methicillin-sensitive Staphylococcus aureus suggests the compounds might find wide pharmaceutical use.
Influence of Pentobarbitone on In-vivo Local Disposition of Diclofenac in Rat Liver
Authors: Tabata Kenji , Yamaoka Kiyoshi , Yasui Hiroyuki , Fukuyama Takako , Nakagawa Terumichi 
Published: April 2011

Abstract
Because the liver is the main organ eliminating many drugs from the body and because pentobarbitone and other analogues can inhibit biliary secretion, the influence of pentobarbitone on hepatic local disposition of diclofenac has been investigated. Diclofenac was infused into the portal and femoral veins of non-anaesthetized rats (group A) and rats anaesthetized with pentobarbitone (group B) and the plasma concentration of diclofenac and the total amount of diclofenac excreted in the bile (in both cases intact diclofenac plus its glucuronide) were simultaneously monitored by HPLC at appropriate time intervals. The time-courses of plasma concentration and amount excreted in the bile were evaluated by moment analysis with trapezoidal integration. The hepatic recovery ratio (FH) was calculated by comparing the area under the curve (AUC) of plasma concentration after intravenous infusion with that after intraportal infusion. The mean biliary transit time (tb) was estimated by subtracting the mean residence time (MRT) of the plasma data from the mean biliary residence time (MRTb) of the biliary excretion data. The FH values of diclofenac were 0.664 in group A and 0.643 in group B. The biliary excretion ratio (Fb) of total diclofenac after intravenous administration was 27.0% in group A and 14.1% in group B. The t̄b values for total diclofenac were estimated to be 0.192 h (intravenous) and 0.159 h (intraportal) in group A, and 0.174 h and 0.238 in group B. Analysis of variance showed that differences among these four t̄b values were insignificant at the 5% level. The differences in the mean residence time (MRT), total clearance (CL) and distribution volume at steady state (VSS) were insignificant between groups A and B.
Whereas total and the hepatic clearance of diclofenac were not affected by pentobarbitone, biliary clearance was extensively reduced. It took a relatively long time for diclofenac to move from the sinusoid into the bile and the time was not affected by pentobarbitone.
Influence of Fatty Acids on the Binding of Warfarin and Phenprocoumon to Human Serum Albumin with Relation to Anticoagulant Therapy
Authors: Vorum Henrik , Honoré Bent 
Published: April 2011

Abstract
Warfarin and phenprocoumon binding to human serum albumin was studied by equilibrium dialysis.
The first stoichiometric binding constant was 1.89 × 105 M−1 for warfarin and 2.40 × 105 M−1 for phenprocoumon. The affinity of warfarin was markedly increased on addition of up to 3 mol mol−1 albumin of palmitic, stearic, oleic or linoleic acids with energetic couplings for co-binding of one molecule of each of the fatty acids and one molecule of warfarin of 0.9, 1.1, 0.7 and 0.6 kJ mol−1, respectively. The affinity of phenprocoumon was only increased slightly on addition of palmitate with an energetic coupling of 0.3 kJ mol−1.
Six consecutive serum samples were obtained from each of 14 patients undergoing surgery. The serum affinity of the drugs varied considerably corresponding to free drug concentrations between 0.7 and 2.7% for warfarin and between 0.8 and 4.9% for phenprocoumon. The affinity of warfarin but not of phenprocoumon was correlated to the increasing plasma fatty acid concentration. Anticoagulant therapy with phenprocoumon may thus be less sensitive than warfarin to changes in the fatty acid concentration of plasma.
Local Tolerance of Subcutaneous Injections
Authors: Fransson J , Espander-Jansson A 
Published: April 2011

Abstract
Human insulin-like growth factor I (hIGF-I) has several possible clinical applications. Because subcutaneous administration of the drug can cause pain, local tolerance to injection of different formulations with or without hIGF-I has been investigated in man using isotonic saline solution as reference.
The formulations, made isotonic with NaCl, ranged in pH from 6 to 7 with phosphate buffer concentrations of 5 to 50 mM. The local tolerance after injection was assessed as injection pain on a visual analogue scale, pain duration and local tolerance (redness, paleness and oedema). The discomfort at the injection site was lowest with 10 mM phosphate, pH 7. Injection of buffer at pH 6 (50 mM phosphate) caused significantly more pain than using 10 mM phosphate, whereas the pain at pH 6 using 10 mM phosphate did not differ significantly from that experienced on injection of the solution at pH 7 using either 10 or 50 mM phosphate. hIGF-I itself did not seem to cause pain.
We concluded that for subcutaneous injections at non-physiological pH, the buffer strength should be kept as low as possible to avoid pain upon injection. We also hypothesize that when a non-physiological pH must be used for stability reasons, a lower buffer strength enables more rapid normalization of the pH at the injection site.
In-vitro Metabolism of YM17E, an Inhibitor of Acyl Coenzyme A: Cholesterol Acyltransferase, by Liver Microsomes in Man
Authors: Uchida Taisuke , Watanabe Takashi , Van Hoogdalem Ewoud J , Higuchi Saburo 
Published: April 2011

Abstract
Because YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]benzene dihydrochloride) inhibits acyl coenzyme A:cholesterol acyltransferase (ACAT) it has potential application in the treatment of hypercholesterolaemia. In man and animals YM17E is extensively metabolized, via N-demethylation, to five active metabolites (M1, M2-a, M2-b, M3 and M4). The main objectives of this study were to examine inhibition of YM17E metabolism by the products and identify the cytochrome P450 isoforms in liver microsomes which catalyse in-vitro YM17E metabolism in man.
In microsomes in man, N-demethylation of YM17E to M1 occurred enzymatically; for up to 45 s the rate was linearly proportional to the microsomal protein concentration. This reaction was inhibited by metabolites M2-a, M2-b, M3 and M4. Further, N-demethylation of [14C]-YM17E was also inhibited by its product, M1. These results showed that primary metabolism of YM17E was inhibited by its products, and supported the finding that the non-linear increase in plasma concentration of the parent drug and metabolites observed in an in-vivo study was due to inhibition by these products. Metabolic activity in microsomes from ten individual human livers demonstrated that YM17E N-demethylase activity correlated closely with testosterone 6β-hydroxylase activity. When cytochrome P450 isozyme-specific substrates and chemical inhibitors were used to inhibit YM17E N-demethylase activity, CYP3A-specific substrate and inhibitors such as nifedipine, ketoconazole and triacetyloleandomycin strongly inhibited this activity, whereas CYP1A-specific substrate or inhibitor, ethoxyresorufin and α-naphthoflavone, inhibited weakly. Other CYP inhibitors, in contrast, had few or no effects. An inhibition study using anti-rat CYP1A1, CYP2B1, CYP2C11, CYP2E1 and CYP3A2 antibodies demonstrated that only anti-rat CYP3A2 antibody inhibited YM17E metabolism, to 40% of control level, with no other antibodies showing an inhibitory effect. Of seven cDNA-expressed P450 isoforms in man (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 and CYP3A4), CYP3A4, CYP2D6 and CYP1A2 isozyme exhibited substantial catalytic activity of N-demethylation of YM17E.
These results indicate the predominant role of CYP3A4 in liver metabolism of YM17E in man.
Role of Na+/K+ ATPase on the Relaxation of Rabbit Ear and Femoral Arteries
Authors: GarcíA-Villalón A L , Monge L , García J L , Fernández N , Gómez B , Diéuez G 
Published: April 2011

Abstract
The role of Na+/K+ ATPase in vascular relaxation has been studied by determining its inhibitory effects on 2-mm segments from rabbit central ear and femoral arteries, mounted for isometric tension recording.
Acetylcholine (10-8-10-4 M), the nitric oxide donor sodium nitroprusside (10-8-3 × 10-4 M), the potassium channel agonist cromakalim (10-8-3 × 10-5 M), histamine (10-8-10-4 M) in the presence of the H1 antagonist chlorpheniramine (10-5 M), and papaverine (10-6-3 × 10-4 M) all produced arterial relaxation in ear and femoral arteries precontracted with endothelin 1. Addition of potassium (6 × 10-3- 1.2 × 10-2 M) caused relaxation of the same arteries preincubated in potassium-free medium.
Ouabain (10-5 M) an inhibitor of Na+/K+ ATPase, reduced the relaxation of ear arteries, but not of femoral arteries, in response to acetylcholine; it also reduced the response to sodium nitroprusside, cromakalim or histamine, and abolished the relaxation to potassium, but did not modify the response to papaverine, in both types of artery.
These results suggest that Na+/K+ ATPase might play a role in the relaxation of ear and femoral arteries to nitrovasodilators, to potassium channel openers and to activation of histamine receptors, and that Na+/K+ ATPase might play a role in the cholinergic relaxation of ear, but not femoral arteries, suggesting that the mechanism of cholinergic relaxation might differ in each type of artery.
Nicotinic Acid Transport Mediated by pH-dependent Anion Antiporter and Proton Cotransporter in Rabbit Intestinal Brush-border Membrane
Authors: Takanaga Hitomi , Maeda Hiroshi , Yabuuchi Hikaru , Tamai Ikumi , Higashida Haruhiro , Tsuji Akira 
Published: April 2011

Abstract
In order to determine whether the vitamin nicotinic acid is absorbed via an anion antiporter, intestinal epithelial cell membrane transport mechanisms for nicotinic acid were characterized using isolated rabbit jejunal brush-border membrane vesicles.
The uptake of nicotinic acid by the membrane vesicles showed an overshoot phenomenon in the presence of an outwardly directed bicarbonate gradient or an inwardly directed proton gradient and the uptakes were two times and six times greater, respectively, than that in the absence of any ion gradient. The bicarbonate-dependent initial uptake of nicotinic acid was increased at acidic pH, showing pH-dependent transport activity. An inhibitor of anion transport, 4,4′-diisothiocyanostilbene-2,2′-disulphonic acid, specifically reduced bicarbonate-dependent transport of nicotinic acid. The initial uptakes of nicotinic acid via the anion antiporter and the proton cotransporter were specifically inhibited by monocarboxylic acids such as acetic acid, benzoic acid, D- and L-lactic acid, pravastatin and valproic acid, but not by di- or tricarboxylic acids, bile acids or amino acids. Nicotinic acid uptake activity was, furthermore, expressed in a Xenopus laevis oocyte system after injection of messenger RNA (mRNA) derived from rabbit intestinal epithelial cells.
These observations demonstrate that nicotinic acid is absorbed by two independent active transport mechanisms from small intestine, i.e. a proton cotransporter and an anion antiporter. The pH-dependence observed in the intestinal absorption of nicotinic acid might, therefore, be ascribed partly to pH-sensitive and partly to carrier-mediated transport mechanisms in the brush-border membrane.
Simple HPLC Determination of the Concentrations of Epiroprim in the Serum and Brains of Mice
Authors: Lee How Sung , Chang Hernan R , Khoo Yok Moi 
Published: April 2011

Abstract
Epiroprim, an analogue of trimethoprim, has been shown to potentiate the efficacy of dapsone in experimental parasitic infections. A simple and accurate HPLC method has been developed to estimate epiroprim in serum and brain
Blood and brains from mice were sampled 0, 30, 75, 120 and 240 min after 50 or 100 mg kg−1 oral gavage. The drug and added internal standard metoprine in serum and brain supernatant were isolated by solid-phase extraction (Supelclean LC-SCX). The HPLC system consisted of a 150 × 4.6 mm Hypersil 5 μm ODS column. The mobile phases contained various proportions of acetonitrile, methanol and phosphate buffer (0.1 M). Peaks were detected by UV absorbance at 210 run. Serum concentrations (mean ± s.e.m.) of epiroprim were highest at 30 min for both 50 and 100 mg kg−1 doses, 173 ± 20 and 207 ± 25 ng mL−1, respectively, falling to 8 ± 5 and 18 ±6 ng mL−1, respectively, at 240 min. Epiroprim concentrations in the brain correlated well with those in the serum, with levels of 223 ±69 and 265 ±21 ng g−1 falling to 10 ± 10 and 31 ± 11 ng g−1, respectively.
Epiroprim is rapidly absorbed and distributed to the brain.
Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus
Authors: Park Kwang J , Yoon Woo H , Shin Wan G , Lee Myung G 
Published: April 2011

Abstract
Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg−1) to control and alloxan-induced diabetes mellitus rats (AIDRs).
After intravenous administration of azosemide to the AIDRs, the area under the plasma concentration-time curve (AUC) increased considerably (3120 compared with 2520 μg min mL−1; P &lt; 0.135) and the total body clearance decreased considerably (3.20 compared with 3.96 mL min−1 kg−1; P &lt; 0.0593). The considerable reduction in time-averaged total body clearance in the AIDRs was a result of the significant decrease in renal clearance (1.01 compared with 1.55 mL min−1 kg−1) in the AIDRs, the non-renal clearance being comparable between the two groups of rats. After intravenous administration, the 8-h urinary excretion of azosemide (29.5 compared with 40% of intravenous dose; P &lt; 0.0883) and one of its metabolites, M1 (2.15 compared with 2.60% of intravenous dose, expressed in terms of azosemide; P &lt; 0.05) decreased in the AIDRs because of the impaired kidney function. The diuretic, natriuretic, kaliuretic and chloruretic efficiencies increased significantly in the AIDRs. After oral administration of azosemide, AUC decreased significantly in the AIDRs (115 compared with 215 μg min mL−1) possibly because of the reduced gastrointestinal absorption of azosemide in the AIDRs. After oral administration of azosemide, the 8-h urine output decreased significantly in the AIDRs (9.32 compared with 16.1 mL per 100 g body weight) because of the significantly reduced 8-h urinary excretion of azosemide (3.00 compared with 9.14% of oral dose).
After both intravenous and oral administration some pharmacokinetic and pharmacodynamic parameters of azosemide were significantly different in AIDRs.
Toxicological Effects of Teucrium stocksianum after Acute and Chronic Administration in Rats
Authors: Tanira M O M , Wasfi I A , Homsi M Al , Bashir A K 
Published: April 2011

Abstract
Because of the widespread use of T. stocksianum (Boiss) in herbal medicine and reports of the toxicity of Teucrium chamaedrys to man, the effects of acute (2 and 4 g kg−1, single dose) and chronic (4% in lieu of drinking water for 48 days) administration of an aqueous extract of T. stocksianum has been studied in rats.
After acute administration no change was found in reduced liver glutathione content, plasma total protein concentration or the enzyme activities of aminotransferase or gamma glutamyl transferase. After chronic administration, no change was noticed in the plasma concentrations of total protein, total bilirubin, creatinine, urea, glucose, triglycerides, calcium or phosphorus or the enzyme activities of aminotransferase, alanine aminotransferase, creatinine kinase, gamma glutamyl transferase or lactate dehydrogenase. There was no change in food or water intake or output of urine or faeces; the body weight of the treated animals was, however, slightly reduced. No change was observed in the weight of vital body tissues. Histological examination revealed occasional hepatic ‘apoptosis’ and cerebral neuronal loss in the cortex and hippocampus in treated animals; focal loss of Purkinje cells in the cerebellum was particularly noticed.
The results did not indicate a major hepatotoxic effect of acute or chronic administration of T. stocksianum, unlike other Teucrium spp. We report a neurotoxic effect, however, which warrants monitoring of neurological function in people taking this plant.
Sucrose Laurate Gels as a Percutaneous Delivery System for Oestradiol in Rabbits
Authors: Vermeire An , De Muynck Christian , Vandenbossche Geert , Eechaute Willy , Geerts Marie-Louise , Remon Jean Paul 
Published: April 2011

Abstract
In this study sucrose laurate was formulated in hydrogels and investigated as a suitable transdermal penetration enhancer for oestradiol. Using rabbits as an animal model, the absolute bioavailability and the skin irritation were evaluated after single and multiple application. Three hydrogels containing 60 mg% oestradiol were evaluated: Oestrogel, and two hypromellose gels containing 5 and 15% sucrose laurate (w/w), respectively.
No stability problem of the sucrose laurate was detected during a storage period of four months at 7 ± 2°C. After single application no significant difference (P &lt; 005) was observed between the bioavailability parameters of Oestrogel and the 5% sucrose laurate gel. The values obtained for the 15% sucrose laurate gel were significantly higher than for the other gels. When applied on day 7 after a 6-day treatment, twice daily with the respective placebo gel, no significant difference was seen amongst the three formulations for any of the parameters evaluated. When the results after multiple application were compared with those after single application, a significant increase in oestradiol bioavailability was seen for the gel containing 30% ethanol and a significant decrease in oestradiol bioavailability was seen for the 5 and 15% sucrose laurate gels. Histological evaluation of the untreated and treated skin biopsies, showed a significantly higher incidence of infiltrate for all treated skin biopsies in comparison with the untreated ones. A significant increase in skinfold thickness was seen for the skin biopsies treated with gel containing 15% sucrose laurate.
It can be concluded that sucrose laurate shows a potential as an absorption enhancer for percutaneous drug delivery.
Differential Binding of Warfarin to Maternal, Foetal and Non-pregnant Sera and its Clinical Implications
Authors: Bajoria Rekha , Sooranna Suren R , Contractor Soli F 
Published: April 2011

Abstract
The object of this study was to determine whether differential binding of sodium warfarin in paired maternal and cord sera accounts for its adverse effects on the foetus.
In-vitro binding of sodium warfarin to human serum albumin in maternal, foetal, and non-pregnant (control) subjects was determined by equilibrium dialysis at 37°C. Our data suggest that at therapeutic concentrations, sodium warfarin has a single high affinity binding site on human serum albumin with an association constant of 1–65 × 10-3 M. Serum albumin concentration in the control sera (4.42 ± 0.08 g dL−1) was comparable with that in the cord sera (4.54 ± 0.26 g dL−1) but was significantly higher (P &lt; 0.01) than the maternal levels (4.03 ± 0.21 g dL−1). Binding data indicate that the fraction of unbound warfarin in the foetal sera (6.8 ± 1.9 g dL−1) was significantly higher than in the maternal (3.60 ± 1.3 g dL−1; P &lt; 0.01) and non-pregnant sera (1.96 ± 0.6 g dL−1; P &lt; 0.001). The maternal and foetal fractions of free warfarin were directly proportional to the concentrations of free fatty acids (y = 1268 − 110 x; r = 0.93; P &lt; 0.001), and bilirubin (y = 8.7 + 1.4x; r = 0.91; P &lt; 0.001), respectively.
This study indicates that warfarin was more strongly bound in the maternal sera than in the foetal sera; this was probably because of the competitive and allosteric effect of free fatty acid and bilirubin in the maternal and foetal sera, respectively. The clinical significance of this observation is discussed in this paper.