bluuebunny/crossref_metadata_2025 huggingface dataset:
Affinity Constants and β-Adrenoceptor Reserves for Isoprenaline on Cardiac Tissue from Normotensive and Hypzrtensive Rats
Authors: Doggrell Sheila A , Petcu Eugen B , Barnett Carolyn W
Published: April 2011

To determine whether there are differences in cardiac β-adrenoceptor responsiveness, isoprenaline affinity constants and fractional β-adrenoceptor occupancy—response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-β-(2-hydroxyl-3-α-naphthoxypropylamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible β-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).

The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2–3 times 10−6M, which is as expected for isoprenaline at β1 or β2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2–4 times 10−8M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3–4% of the β-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25–35% and 55%, respectively, of the β-adrenoceptors to produce a 90% maximum response.

The SHR papillary muscles and left atrium had smaller β-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1–4 times 10−8M.

Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at β1 or β2-adrenoceptors, we suggest that atypical β-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower β-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.
A Study of the Anti-pyretic Effect of Quinine, an Alkaloid Effective Against Cerebral Malaria, on Fever Induced by Bacterial Endotoxin and Yeast in Rats
Authors: Santos F A , Rao V S N
Published: April 2011

The effect of quinine on fever induced by lipopolysaccharide and brewer’s yeast has been investigated in rats.

Oral administration of 50 or 100 mg kg−1 quinine, doses which had no effect on normothermic rats, significantly reduced lipopolysaccharide- (50 μg kg−1, i.m.) and yeast- (2 g kg−1) induced fever in rats. Pentoxifylline (100 mg kg−1), a tumour necrosis factor antagonist also attenuated the febrile response induced by lipopolysaccharide, but not that by yeast, in a manner similar to quinine. Piroxicam (5 mg kg−1), a cyclooxygenase inhibitor suppressed both types of fever with a longer duration of action. In addition to its anti-pyretic effect, quinine had a significant anti-inflammatory effect in the carrageenan model of acute inflammation in the hind-paw of rats.

The results indicate the anti-inflammatory and anti-pyretic potential of quinine which might be important in addition to its anti-plasmodial action in the therapy of cerebral malaria.
Polymeric Chitosan-based Vesicles for Drug Delivery
Authors: Uchegbu Ijeoma F , Schätzlein Andreas G , Tetley Laurence , Gray Alexander I , Sludden Julieann , Siddique Soryia , Mosha Erasto
Published: April 2011

A simple carbohydrate polymer glycol chitosan (degree of polymerization 800 approx.) has been investigated for its ability to form polymeric vesicle drug carriers. The attachment of hydrophobic groups to glycol chitosan should yield an amphiphilic polymer capable of self-assembly into vesicles. Chitosan is used because the membrane-penetration enhancement of chitosan polymers offers the possibility of fabricating a drug delivery system suitable for the oral and intranasal administration of gut-labile molecules.

Glycol chitosan modified by attachment of a strategic number of fatty acid pendant groups (11–16mol%) assembles into unilamellar polymeric vesicles in the presence of cholesterol. These polymeric vesicles are found to be biocompatible and haemocompatible and capable of entrapping water-soluble drugs. By use of an ammonium sulphate gradient bleomycin (MW 1400), for example, can be efficiently loaded on to these polymeric vesicles to yield a bleomycin-to-polymer ratio of 0.5 units mg−1.

Previously polymers were thought to assemble into vesicles only if the polymer backbone was separated from the membrane-forming amphiphile by a hydrophilic side-arm spacer. The hydrophilic spacer was thought to be necessary to decouple the random motion of the polymer backbone from the ordered amphiphiles that make up the vesicle membrane. However, stable polymeric vesicles for use in drug delivery have been prepared from a modified carbohydrate polymer, palmitoyl glycol chitosan, without this specific architecture. These polymeric vesicles efficiently entrap water-soluble drugs.
Novel Aryl-bis-quinolines with Antimalarial Activity In-vivo
Authors: Ismail F M D , Dascombe M J , Carr P , Mérette S A M , Rouault P
Published: April 2011

Three rationally designed isomeric aryl-bridged bis-quinolines, N1,Nx-bis(7-chloroquinolin-4-yl)phenylene-1,x-diamines, where x = 2, 3 or 4, i.e. o-, m- and p-substituted analogues respectively, were synthesized and evaluated against Plasmodium berghei in-vivo.

The compound with x = 2 had an ID50 of 30 mg kg−1, whereas the p-substituted analogue (x = 4) was not statistically schizonticidal at either of the two dose levels tested in olive oil-dimethylsulphoxide (5 and 25 mg kg−1, ID50 = 60 mg kg−1 approx.). When the delivery vehicle was changed to saline-DMSO, antimalarial potency increased for the p-substituted compound (ID50 17mg kg−1). In contrast, the m-substituted analogue had marked antimalarial activity (ID50 1.2 mg kg−1), which compares favourably with that of chloroquine diphosphate (ID50 = 4.3 mg kg−1). The data presented show that the amino-methylene side chain in amodiaquine can be successfully replaced by a 7-halo-4-aminoquinoline, establishing that carbon bridges containing less than four contiguous carbon atoms can be present within highly active aryl-substituted 4-aminoquinoline antimalarials.

These results confirm that the presence of an OH group in the aryl bridge is not necessary for antimalarial activity and substantiate the view that, despite the appearance of resistant strains, new and existing aminoquinolines still have an important role in treating malaria.
Metabolism of Roxithromycin in the Isolated Perfused Rat Liver
Authors: Jarukamjorn Kanokwan , Thalhammer Therese , Gollackner Bernd , Pittenauer Ernst , Jäger Walter
Published: April 2011

Roxithromycin is a macrolide antibiotic with high clinical potency. N-Demethylation is considered to be one of the main pathways of roxithromycin metabolism in rats. We have studied the hepatic metabolism of roxithromycin in the isolated perfused rat liver.

After addition of roxithromycin (30 μM) to the perfusion medium the parent compound and one major metabolite were detected in bile by high-performance liquid chromatography. The metabolite was identified as monodesmethylated roxithromycin by mass spectrometric analysis. Onset of biliary excretion of native roxithromycin was fast, reaching a maximum (130.52 ±43.88 pmol g−1 min−1) after only 10 min, whereas excretion of the metabolite was delayed (maximum 75.83 ± 11.92 pmol g−1 min−1 at 30 min). The cumulative excretion of roxithromycin and its metabolite into bile during the 60 min of application amounted to only 1.09 ± 0.30 and 0.64 ± 0.22% of the roxithromycin cleared from the perfusate during the same time. The liver content was 0.48 μmol (g liver)−1, indicating high retention within the organ. No release of the metabolite into the perfusate was detected.

In conclusion, this study has demonstrated the importance of phase-I metabolism for the biliary excretion of roxithromycin in rat liver. These findings might be predictive of roxithromycin biotransformation and biliary excretion in man.
Effect of D-002 on the Pre-ulcerative Phase of Carrageenan induced Colonic Ulceration in the Guinea-pig
Authors: Noa Miriam , Mas Rosa
Published: April 2011

D-002 is a natural mixture of higher aliphatic primary alcohols, isolated and purified from beeswax which has anti-inflammatory properties, reduces leukotrienes (LTB4) and thromboxane B2 (TXB2) in exudated carrageenan-induced pleurisy, and has anti-ulcer activity in different experimental models. This study was conducted to determine the effect of D-002 on the pre-ulcerative phase of carrageenan-induced colonic ulceration in guinea-pigs.

Animals were randomly distributed among a negative control, a positive control group treated with the vehicle Tween 20 in H2O and two experimental groups receiving D-002 at 25 and 50 mg kg−1. All treated animals received degraded carrageenan for three days for induction of colonic ulceration. Significant reductions in wet weight, wall thickness, counts of infiltrating polymorphonuclear neutrophils and of macrophages, and histological index were observed in colonic mucosa of D-002-treated animals compared with controls.

It is concluded that D-002 has a protective effect on the pre-ulcerative phase of carrageenan-induced colonic ulceration in the guinea-pig.
Effects of the Ginsenosides Rgl and Rbl on Morphine-induced Hyperactivity and Reinforcement in Mice
Authors: Kim Hack-Seang , Hong Youn-Tack , Jang Choon-Gon
Published: April 2011

Recent studies have demonstrated that ginseng saponin inhibits the hyperactivity and conditioned place-preference response induced by psychostimulants and opiates. This seems to occur by direct or indirect modulation of dopaminergic activity. However, it is not known which components of ginseng saponin are active. These experiments were conducted to determine the effects of the ginsenosides Rb1 and Rg1, major components of the protopanaxadiol and protopanaxatriol fractions of ginseng saponin, on morphine-induced hyperactivity and conditioned place-preference.

Morphine-induced hyperactivity, but not apomorphine-induced climbing behaviour, was inhibited by both Rb1 and Rg1. These findings confirm the hypothesis that ginsenosides modulate catecholaminergic activity preferentially at pre-synaptic sites. Morphine-induced conditioned place-preference was inhibited by Rg1, but not by Rb1. It has previously been shown that at low doses Rb1 and Rg1 are equally effective at inhibition of catecholamine secretion at the pre-synaptic site, but that at high doses Rg1 is a more effective inhibitor. This observation might explain our finding that morphine-induced conditioned place-preference was inhibited by Rg1 only.

Our findings suggest that Rg1, a component of ginseng saponin with appropriate activity, might be a useful agent for prevention and treatment of the adverse effects of morphine.
Variability of Mitomycin C Adsorption by Activated Charcoal
Authors: Shah I A , Lindup W E , Mcculloch P G
Published: April 2011

A saline suspension of mitomycin C adsorbed on activated charcoal and administered intraperitoneally has been reported to be safe and effective in the treatment of gastric carcinoma. Activated charcoal specifically targets tumour and lymph-node tissues and the sustained higher local drug concentration is thought to be beneficial. The charcoal particles used in these suspensions have varied in size from > 147 μm to < 20 nm in diameter, but no data have been published to show how this might affect drug adsorption and delivery. Any variability in drug adsorption could pose a serious clinical risk for drugs with a narrow therapeutic index. We have, therefore, investigated the adsorption of mitomycin C on activated charcoal in-vitro.

Activated charcoal was ground and sieved to yield four size-fractions between 180 and 53 μm. Adsorption isotherms (n ≥ 3) were constructed and applied to the Freundlich model with 0–100 μg mL−1 mitomycin C measured by HPLC with detection at 365 nm. Adsorption of mitomycin C by activated charcoal varied by a factor of three under identical conditions at room temperature (21°C) and at 37°C. The specific adsorption (μg mitomycin C (mg activated charcoal)−1) was generally higher at 37°C than at room temperature. The variability of mitomycin C adsorption was greatly reduced by addition of the surface-active agent polyvinylpyrollidone, used to determine that adsorption of mitomycin C was independent of activated charcoal particle size.

The characteristics of adsorption of mitomycin C by activated charcoal are complex and should be thoroughly investigated to discover the critical controlling factors before submitting the suspensions for further clinical evaluation.
Pharmacokinetic Assessment of the Sites of First-pass Metabolism of BMS- 181101, an Antidepressant Agent, in Rats
Authors: Vachharajani Nimish N , Shyu Wen Chyi , Shah Vinod R , Barbhaiya Rashmi H
Published: April 2011

The relative contribution of the gut and the liver to the first-pass metabolism of BMS-181101 (3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-fluoro-1H-indole dihydrochloride), a potential antidepressant agent, has been evaluated in rats.

Nine male Sprague–Dawley rats were divided into three groups of three and each rat received a single 20 mg kg−1 dose of [14C]BMS-181101 via a 30 min constant-rate intravenous infusion, a 30-min constant-rate intraportal infusion or oral gavage. Serial blood samples were collected for 8 h after dosing and plasma was analysed for unchanged BMS-181101 and total radioactivity. Extraction ratios for BMS-181101 by the gut and liver were calculated on the basis of ratios of the area under the plasma BMS-181101 concentration–time curve. The gut had a high intrinsic capacity for metabolizing BMS-181101-extraction ratios were 93% and 10% for the gut and liver, respectively. After oral administration BMS-181101 is sequentially exposed to the gut then the liver. As a result, the contribution of the gut to the overall first-pass effect (ca. 93%) was significantly greater than that of the liver
HPLC on Chiralcel OJ-R for Enantiomer Separation and Analysis of Ketoprofen, from Horse Plasma, as the 9-Aminophenanthrene Derivative
Authors: Aboul-Enein Hassan Y , Van Overbeke An , Weken Guido Vander , Baeyens Willy , Oda Hirofumi , Deprez Piet , De Kruif Aart
Published: April 2011

Racemic ketoprofen is a non-steroidal anti-inflammatory drug used to treat musculoskeletal and colic conditions in horses. The enantioselective chiral inversion of ketoprofen administered to horses has been studied by use of cellulose tris(4-methylbenzoate), also known as Chiralcel OJ-R, as chiral stationary phase; acetonitrile − 0·02 m perchlorate buffer (pH 2·0) - methanol, 60:15:25 (v/v/v) was used as mobile phase. Before chromatography, to effect adequate chiral interaction with the chiral stationary phase ketoprofen was derivatized with 9-aminophenanthrene, under acid conditions, after solid-phase (C18) extraction and then liquid–liquid extraction, to ensure effective removal of endogenous plasma materials. The 9-aminophenanthrene derivative of S-ibuprofen was used as internal standard. The enantiomers of ketoprofen were separated to baseline (Rs = 6·44, α = 1·76) within a short analysis time.

The results indicate that the bio-inversion of R-ketoprofen to the S isomer is significant in equine species. However, considerable differences in pharmacokinetic parameters were observed, indicating large inter-animal variation.
Effect of Mn2+ on the Development of Tension Induced in Guinea-pig Taenia Coli by Bay K 8644
Authors: Nasu Tetsuyuki , Sasaki Miyori
Published: April 2011

We have studied the effects of Mn2+ on the contractile response induced by Bay K 8644, a dihydropyridine Ca2+ agonist, on guinea-pig taenia coli. Mn2+ (5 mm) completely inhibited Bay K 8644 (10−6  m)-induced rhythmic contraction and contracture to baseline values in normal Ca2+ medium; thereafter, the contraction progressively increased to about 90% of the K+ (60 mm)-induced tonic response. In Ca2+-free medium in the presence of Bay K 8644 Mn2+ also evoked contraction and a concomitant increase in Mn2+ influx into the cytoplasm.

These results suggest that during the opening of voltage-dependent Ca2+ channels activated by Bay K 8644, Mn2+ can enter cytoplasm through the channels and induce contraction in taenia coli.
Drug-delivery Products and the Zydis Fast-dissolving Dosage Form
Authors: Seager H
Published: April 2011

Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medication as prescribed. It is estimated that 50% of the population is affected by this problem which results in a high incidence of non-compliance and ineffective therapy. The difficulty is experienced in particular by paediatric and geriatric patients, but it also applies to people who are ill in bed and to those active working patients who are busy or travelling, especially those who have no access to water. Such problems can be resolved by means of the Zydis dosage form which does not require water to aid swallowing. The Zydis fast-dissolving dosage form is a unique freeze dried medicinal tablet, made from well known and acceptable materials. When Zydis units are put into the mouth, the freeze dried structure disintegrates instantaneously releasing the drug which dissolves or disperses in the saliva. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In these cases, the bioavailabilities of drugs from Zydis formulations are significantly greater than those observed from standard dosage forms.

This paper deals with the formulation and process technology of the Zydis dosage form. The bioavailability characteristics of Zydis products are summarized, and in particular, the design of Zydis products for the enhancement of oral bioavailability and the improvement of clinical activity, through transmucosal delivery and pregastric absorption, is discussed.
Kinetic Interaction between Fluoxetine and Imipramine as a Function of Elevated Serum Alpha-1-acid Glycoprotein Levels
Authors: Holladay John W , Dewey Michael J , Yoo Sun D
Published: April 2011

The effect of elevated serum alpha-1-acid glycoprotein (AAG) levels on the pharmacokinetic interaction between imipramine and fluoxetine has been examined by utilizing a novel strain of transgenic mice which express serum AAG levels several times greater than normal.

Before fluoxetine treatment, serum imipramine levels were approximately three times greater in transgenic mice than in control mice. Despite higher serum imipramine levels in transgenic mice, brain drug levels were lower than those found in control mice. Fluoxetine pre-treatment (20mg kg−1 for 5 days) resulted in an increase in serum imipramine levels in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (4.5-fold increase compared with 3.1-fold). Similarly, fluoxetine pre-treatment resulted in an increase in brain levels of imipramine in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (3.0-fold increase compared with 2.0-fold). Similar trends were observed for levels of desipramine in the serum and brain. Serum imipramine and desipramine levels did not correlate with their respective brain levels in the presence of elevated serum AAG levels before and after pre-treatment.

These findings indicate that the extent of increases in imipramine and desipramine serum and brain levels are greater during elevated serum AAG states than during normal AAG states when imipramine is co-administered with fluoxetine.
Is Arachis Oil a Solvent Only, or Does it also Have an Effect on the Central Nervous System?
Authors: Erden B Faruk , Ulak GüNer , Gacar Nejat , Özdemirci Sitki
Published: April 2011

Peanut (Archis hypogaea L.) seed, an important oil crop (arachis oil) throughout the world, is grown in large quantities in Africa, India and China. The oil is used in many edible products, including shortenings, margarines and mayonnaise, as a cooking and frying oil and as a salad oil. Arachis oil contains fatty acids and antioxidants. It has been shown to be unexpectedly atherogenic in the diets of experimental animals (Chow 1992).
Synthesis of Thiazolotriazine Derivatives and Their Antinociceptive Effects in Mice
Authors: Issartel Veronique , Coudert Pascal , Rubat Catherine , Nhamias Solange , Couquelet Jacques
Published: April 2011

A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro-thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity.

The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg−1. Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg−1, also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg−1. Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of μ-receptors in the antinociceptive effects of this drug. In addition, a non-opioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives.

These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.
Stereoselective Synthesis of Peptidyl Trifluoromethyl Alcohols and Ketones: Inhibitory Potency Against Human Leucocyte Elastase, Cathepsin G, Porcine Pancreatic Elastase and HIV-1 Protease
Authors: Amour Augustin , Reboud-Ravaux Michèle , de Rosny Eve , Abouabdellah Ahmed , Bégué Jean-Pierre , Bonnet-Delpon Danièle , Gall Marie Le
Published: April 2011

New fluorinated inhibitors have been designed to target two major proteases—human leucocyte elastase and HIV-1 protease.

Two series of β-peptidyl trifluoromethyl alcohols (TFMAs) Z-L-Val-NH-*CH(Y)-*CH(OH)-CF3, where *C is the chiral centre, varied in the nature of the substituent Y, a phenylethyl [-(CH2)2-C6H5] or an isopropyl [-CH(CH3)2] group. These TFMAs were first synthesized as two pairs of the syn and anti diastereoisomers. The inhibitory effects of these mixtures were then assessed on three serine proteases chosen on the basis of the aromatic and aliphatic nature of the substituents—human leucocyte elastase (HLE), human cathepsin G (HCG) and porcine pancreatic elastase (PPE). In the presence of detectable inhibition, each epimer at C2 was separated to determine its inhibition constant (Ki) towards HLE, HCG and PPE. The stereoisomerically pure TFMAs were then oxidized into peptidyl trifluoromethyl ketones = 5·65 × 10−4 M). The tested compounds also had structural properties compatible with recognition by HIV-1 protease. The inhibition of the enzyme was observed with TFMK only (IC50 = 15–200 μM). The phenylethyl substituent promoted inhibition by a factor of 10 (IC50 = 15μM) compared with the isopropyl substituent (IC50 = 200 μM) leading to selective inhibition of HIV-1 protease.

Isomerically pure TFMKs were more potent towards HLE than the alcohols from which they were obtained. However, an enantiomerically pure TFMA selectively inhibited HLE unlike its TFMK analogue which also inhibited PPE. This last result together with the selective inhibition of HIV-1 protease by TFMK with a phenylethyl substituent might be relevant to the design of specific HLE and HIV-1 inhibitors as therapeutic agents.
Effects of Epidermal Growth Factor Dosage Forms on Mice Full-thickness Skin Wound Zinc Levels and Relation to Wound Strength
Authors: Gönül B , Söylemezoglu T , Babül A , Celebi N
Published: April 2011

Epidermal growth factor (EGF) and zinc promote re-epithelization and reparative tissue strength by enhancing deposition of collagen at the site of the wound. In this study two EGF dosage forms were chosen to assess the effect of zinc levels on wound healing and for comparison with wound tear strengths.

A solution of EGF in 0.9% w/v NaCl and an EGF gel in 0.2% Carbopol 940 polymer (5 μL) were applied to full-thickness skin wounds of mice twice a day for 7 and 15 days. Wound zinc levels were higher on day 7 than on day 15, especially in wounds treated with EGF. The wound zinc levels of the gel + EGF group on day 15 were similar to those of normal control skin.

These results imply that there is a close connection, but no direct relationship, between EGF application in both dosage forms and wound zinc levels during healing.
Interrelationship of Cardiovascular Effects, Plasma Levels of Nicorandil, and Vascular cGMP Formation in Conscious Rats
Authors: Sakai Kazushige , Akima Michitaka , Kamachi Shinichi , Moriyasu Matsuko , Kitajima Shunichi
Published: April 2011

The relationship between the dual activity of nicorandil (KATP channel-opening activity and nitrate-like action), plasma levels, and changes in vascular cGMP levels and cardiovascular parameters was investigated in conscious rats.

Nicorandil (3 mg kg−1, p.o.) was rapidly absorbed and caused a significant reduction in blood pressure, lasting for at least 1 h, increases in heart rate and femoral blood flow, and decreases in femoral vascular resistance. These were entirely abolished by intravenous glibenclamide (20 mg kg−1). The plasma concentration of nicorandil reached a maximum 30 min after dosing. After administration of nicorandil, a correlation was observed between blood pressure and plasma nicorandil level or femoral vascular resistance. A significant increase (P < 0.05) in the cGMP content of the thoracic aorta occurred 15 min after administration of nicorandil, and persisted for at least 2 h.

These results imply that nicorandil induces vasodilatation by opening KATP channels in peripheral resistance vessels, leading to overt reduction of blood pressure, but acts on conductance vessels mainly through nitrate-like activity.
Endothelium-dependent Vasorelaxant and Anti-aggregatory Effect and Mechanism of Action of Some Antifibrinogen RGD (Arg-Gly-Asp-containing) Peptides
Authors: Torday Ladislaus L , Pataricza János , Balogh Gábor E , Zarándi Márta , Penke Botond , Papp Julius Gy
Published: April 2011

Vasorelaxation caused by some antifibrinogen RGD (Arg-Gly-Asp-containing) peptides and their basic mechanism of action was studied on rabbit isolated thoracic aortic rings preconstricted with 0.25 μM phenylephrine.

GRGDS (Gly-Arg-Gly-Asp-Ser-OH) and RGDV (Arg-Gly-Asp-Val-OH) caused dose-dependent relaxation. RGDS (Arg-Gly-Asp-Ser-OH) had a biphasic effect (a transient relaxation followed by a contraction) while GRGDS-[SE] (Gly-Arg-Gly-Asp-Ser(SO3)-OH) did not change the isometric tone of precontracted aortic preparations. GRGDS and RGDV exerted no relaxing effect on endothelium-denuded blood vessels suggesting that the vascular action of these peptides was entirely dependent on the presence of functionally intact endothelium. L-NG-Nitro-arginine (30 μM) attenuated the relaxation induced by GRGDS and abolished that induced by RGDV. All of the four RGD congeners inhibited ADP-induced aggregation of human platelets.

These findings indicate that the relaxant effect of RGDV is mediated exclusively by the nitric oxide pathway, but GRGDS could cause, besides nitric oxide release, the release of another substance which is different from nitric oxide. Because the rank order of the vasorelaxant potencies of RGD peptides differed from that found for their anti-aggregatory activities, a vascular effector mechanism mediated by an RGD-recognizing structure other than the known glycoprotein IIb/IIIa-like RGD-binding site is suggested.
Protective Effects of Selenomethionine against Cisplatin-induced Renal Toxicity in Mice and Rats
Authors: Rao Mahadev , Rao M N A
Published: April 2011

The effect of selenomethionine on the toxicity of cisplatin has been studied in mice and rats.

When selenomethionine (0.5–4 mg kg−1) was administered intraperitoneally to mice 1 h before intraperitoneal cisplatin (6 mg kg−1), the toxicity of cisplatin, as measured by loss of body weight and blood urea nitrogen and serum creatinine levels, was reduced significantly. The protection was dose-dependent but less when given orally. Similar results were obtained with rats. Deterioration of renal function was characterized by reduced creatinine clearance, and increased excretion of urinary protein was significantly reversed. Partial but significant protection was also observed against capsulation-induced reduction of white blood-cell count. Protective properties were further demonstrated by increased survival of mice pretreated with selenomethionine compared with the lethality observed for animals given cisplatin only.

These results suggested that selenomethionine protects against cisplatin-induced renal and other toxicity. The study has many clinical implications in cancer chemotherapy and needs further investigation.
Enhancement by Terpenes of 5-Fluorouracil Permeation through the Stratum Comeum: Model Solvent Approach
Authors: Moghimi H R , Williams A C , Barry B W
Published: April 2011

5-Fluorouracil permeates the stratum corneum through the intercellular pathway. 5-Fluorouracil is hydrophilic and, therefore, its partitioning from the aqueous region into the hydrocarbon interior of stratum corneum lipids is expected to be an important stage of its permeation and a target for some permeation enhancers. It has also been reported that complexation plays a role in the enhancement effect of some accelerants. These mechanisms have been investigated.

For partitioning-permeation studies, isooctane was chosen as a model of the hydrocarbon interior of stratum corneum lipid bilayers and the effects of 26 different terpene enhancers on the solubility of 5-fluorouracil in isooctane were measured. Results were then compared with the effects of the same enhancers on the permeation of 5-fluorouracil through the epidermis in man. The stoichiometry of interaction of cineole and limonene with 5-fluorouracil were also studied to reveal possible complex formation. Solubility studies revealed good correlation between solubility and enhancement ratios for the majority of terpenes, indicating that one mechanism by which terpenes increase permeation of the stratum corneum by 5-fluorouracil is by improvement of partitioning. Stoichiometry studies showed that cineole can form 1:1 or higher complexes with 5-fluorouracil. With limonene, only a weak 1:1 complex was indicated. Data obtained using epidermis from man show that the enhancement effect of cineole toward 5-fluorouracil is much higher than that of limonene.

These data reveal that terpenes might increase the permeation of 5-fluorouracil through the stratum corneum as a result of complex formation and a form of facilitated transport.
N-Dealkylation of Chlorimipramine and Chlorpromazine by Rat Liver Microsomal Cytochrome P450 Isoenzymes
Authors: Valoti Massimo , Frosini Maria , Palmi Mitri , de Matteis Francesco , Sgaragli Gianpietro
Published: April 2011

The role of different cytochrome P450 isozymes (CYP) in the N-demethylation of chlorimipramine and chlorpromazine has been investigated in liver microsomes from rats by studying the effects of multiple subchronic doses of chlorimipramine, chlorpromazine, phenobarbital and β-naphthoflavone on the N-demethylation of ethylmorphine, mono-N-demethyl-chlorimipramine and chlorpromazine and on the hydroxylation of aniline.

With control microsomes, CYP-dependent metabolism of chlorimipramine and chlorpromazine (100 nmol; 30 min incubation) resulted in the formation of predominantly chlorimipramine (46.5 ± 4.9 nmol) whereas chlorpromazine (14.1 ± 0.9 nmol) accounted for only part of the overall metabolism of chlorpromazine. Multiple doses of chlorimipramine increased the capacity of microsomes to N-demethylate ethylmorphine (9.8 ± 0.73 and 6.08 ± 0.06 nmol min−1 (mg protein)−1 for chlorimipramine-treated and control rats, respectively) as well as itself (4.65±0.25 and 3.10±0.33 nmol min−1 (mg protein)−1, respectively). Multiple doses of chlorpromazine induced aniline-hydroxylase activity (1.11 ± 0.16 and 0.94 ± 0.06 nmol min−1 (mg protein)−1 for chlorimipramine and control microsomes, respectively) but the capacity to N-demethylate itself was unchanged. Phenobarbital treatment induced ethylmorphine N-demethylation activity, but did not affect N-demethylation activity, towards chlorimipramine and chlorpromazine. In control microsomes the N-demethylation capacity of chlorimipramine or chlorpromazine (0.160±0.025 and 0.015±0.003 nmol min−1 (mg protein)−1, respectively) was one order of magnitude lower than that of chlorimipramine or chlorpromazine. The capacity to N-demethylate either chlorimipramine or chlorpromazine was increased by treatment with either phenobarbital or β-naphthoflavone. In control microsomes, sulphaphenazole markedly inhibited both chlorimipramine-N-mono- and di-N-demethylation, whereas quinidine markedly inhibited the rate of formation of chlorpromazine.

The CYP2C and CYP2D subfamilies seem to be involved in the mono N-demethylation of chlorimipramine and chlorpromazine, respectively. Moreover the CYP1A and CYP2B subfamilies might participate in the N-demethylation of either chlorimipramine or chlorpromazine. This could have important implications in the clinical use of chlorimipramine and chlorpromazine in view of the genetic polymorphism of CYP2C and CYP2D isozymes in man.
Efflux Transport of Tolbutamide Across the Blood-brain Barrier
Authors: Takanaga Hitomi , Murakami Hideyasu , Koyabu Noriko , Matsuo Hirotami , Naito Mikihiko , Tsuruo Takashi , Sawada Yasufumi
Published: April 2011

In an attempt to determine the reason for the low brain distribution of tolbutamide, we have demonstrated the transport of tolbutamide from the brain to the blood via a non-P-glycoprotein efflux transport system which is inhibited by sulphonamides. We evaluated the directional transport of tolbutamide across the blood-brain barrier by means of an in-vivo brain-tissue distribution study and experiments on in-vitro transcellular transport and uptake in cultured mouse-brain capillary endothelial cells (MBEC4).

The brain-to-unbound-plasma concentration ratio of [14C]tolbutamide increased in the presence of high concentrations of unlabelled tolbutamide or sulphonamide at steady-state in-vivo. The brain-to-blood concentration ratios of [14C]tolbutamide were very low compared with that of [3H]propranolol obtained by in-vivo integration plot analysis. From the in-vitro transcellular transport study using a monolayer of MBEC4 cells, we found that the abluminal-to-luminal flux of [14C] tolbutamide was higher than the reverse flux. Both luminal-to-abluminal and abluminal-to-luminal transport of tolbutamide were saturable. The maximum transport rate (Jmax), the half-saturation concentration (Kt), and the first-order rate constant (kd) were 65.9 ± 29 pmol min−1 (mg protein)−1, 7.54 ± 4.4 μM, and 4.89 ± 0.34 μL min−1 (mg protein)−1, respectively, for luminal-to-abluminal transport, and 128 ± 66 pmol min−1 (mg protein)−1, 5.59 ± 4.2 μM, and 4.43 ± 0.86 μL min−1 (mg protein)−1, respectively, for abluminal-to-luminal transport. At therapeutic plasma concentrations of tolbutamide (1–16.9 μM), the efflux rate would be faster than the influx rate. The estimated net efflux was consistent with the very low in-vivo brain distribution of tolbutamide. The efflux process observed in MBEC4 cells was inhibited by sulphonamides such as sulphaphenazole, sulphamethoxazole and sulpha-dimethoxine whereas the steady-state uptake of [14C]tolbutamide was not affected by either cyclosporin or verapamil, specific inhibitors of P-glycoprotein.

These findings suggest that tolbutamide is partly transported from the brain via the non-P-glycoprotein-efflux transport system, which is inhibited by sulphonamides.
Effects of KW-5092 on Antroduodenal Coordination and Gastric Emptying in Guinea-pigs
Authors: Kishibayashi N , Karasawa A
Published: April 2011

KW-5092 (2-[1-[2-[[5-(piperidinomethyl)-2-furanyl]methylamino]ethyl]imidazonylidin-2-ylidenene]malononitrile fumarate) is a novel gastroprokinetic agent with both acetylcholine release facilitatory and acetylcholinesterase inhibitory activity. We have investigated the effects of KW-5092 on antroduodenal coordination and gastric emptying in guinea-pigs.

In the guinea-pig isolated gastroduodenal preparation, KW-5092 at 3 times 10−7 to 3 times 10−6 M significantly increased antroduodenal coordination. The effect of KW-5092 was almost completely inhibited by atropine or tetrodotoxin. Cisapride, a gastroprokinetic agent with acetylcholine release facilitatory activity, also increased coordination whereas neither acetylcholine nor the acetylcholinesterase inhibitor neostigmine affected it. In-vivo, KW-5092 and cisapride enhanced gastric emptying whereas neostigmine delayed it.

These results suggest that acetylcholine release facilitation, but not acetylcholinesterase inhibition, is involved in the enhancement by KW-5092 of antroduodenal coordination and gastric emptying.
Plasma and Muscle Polyamine Levels in Aerobically Exercised Rats Treated with Salbutamol
Authors: Cepero M , Cubría J C , Reguera R , Balaña-Fouce R , Ordónez C , Ordóñez D
Published: April 2011

The induction of hypertrophy of cardiac and skeletal muscles has been studied after treatment with two different salbutamol dosages, therapeutic and doping.

Treatment of rats subjected to a physical training schedule with repeated doses (16 μg kg−1 per day or 3 mg kg−1 per day) of salbutamol, a specific β-adrenergic agonist, induced a marked increase in both skeletal and heart-muscle weight, whereas total body weight did not change significantly. Adrenergic involvement of salbutamol-linked muscle hypertrophy was demonstrated by co-administration of the non-specific β-adrenergic antagonist, propranolol (20 mg kg−1 per day). Salbutamol-induced muscle hypertrophy was associated with an increase in serum, skeletal-muscle and heart levels of the naturally occurring polyamines putrescine, spermidine and spermine.

These observations suggest the involvement of polyamines in muscle hypertrophy and the possible role of blood polyamines as exposure biomarkers in β-adrenergic-muscle hypertrophy.
Concentration- and Region-dependent Intestinal Permeability of Fluvastatin in the Rat
Authors: Lindahl Anders , Sandström Rikard , Ungell Anna-Lena , Lennernäs Hans
Published: April 2011

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intestine in the rat. In-situ single-pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (Peff) of fluvastatin, antipyrine and D-glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 μM). The effect of lovastatin acid on the bi-directional transport of fluvastatin across the ileal mucosa was also studied.

The Peff of fluvastatin was found to be dependent both on the intestinal region and on the concentration in the intestinal lumen (P < 0.001). Fluvastatin had the lowest Peff (0.55±0.10 times 10−4 cm s−1) in the jejunum at 1.6 μM, and the highest Peff (1.0±0.16 times 10−4 cm s−1) in the colon at 160 μM. The highest concentration of fluvastatin increased the average absorption of water from the intestine by 209% (P < 0.05), and the average Peff of D-glucose by 29% (P < 0.05). The presence of excess lovastatin acid (100 μM, compared with fluvastatin 1.6 μM) at the luminal side increased the average absorption of water by 218% (P < 0.001), and the Peff of fluvastatin in the ileum and the colon by 44 and 50%, respectively (P < 0.05). The presence of lovastatin acid on the luminal side in the ileum also increased the blood-to-lumen transport (exsorption) of fluvastatin by 43% (P < 0.001).

The increased intestinal absorption of fluvastatin at higher concentrations does not suggest that substantial absorption occurs by any carrier-mediated process in the absorptive direction. The increased bi-directional transport when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent increase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.
Intestinal Uptake of Particulate Material by Dexamethasone-treated Rats: Use of a Novel Technique to Avoid Intestinal Mucosal Contamination
Authors: Limpanussorn J , Simon L , Dayan A D
Published: April 2011

The aim of this study was to investigate the effect of immune suppression on the uptake of particles across the wall of the intestine and the dissemination of the particles to systemic organs.

Normal and dexamethasone-immunosuppressed rats were dosed orally with 0.5 mL distilled water or fluorescent polystyrene latex particle suspension containing 2.33 times 109 2-μm diameter particles. One hour after particle dosing, the animals were killed by CO2 asphyxiation. The intestinal tissues and systemic organs were sampled for particle quantitation. To avoid contamination by particles adherent to intestinal mucosa the epithelium of intestinal tissue samples was removed before quantification. The number of fluorescent particles in tissues was determined by fluorescence microscopy of digests of selected samples. The uptake of particulate material across the intestinal wall was significantly (P < 0.05) increased in rats treated with dexamethasone but the number of particles transferred to systemic organs did not differ from values found for control animals.

The results suggest that although dexamethasone increased intestinal permeability the apparatus or mechanisms involved in particle transport to distal sites were not affected during immune suppression.
OBSERVATIONS ON THE COLOUR VISION OF SCHOOL CHILDREN
Authors: TUCKER A. WINIFRED
Published: April 2011

Object: the comparison of the colour vision of English children with that of primitive peoples. Methods: matching with Holmgren's wools, naming, tintometer. Resemblance of children to primitive peoples in character of discrimination. With tintometer general raising of thresholds, but not more for blue than for other colours. Influence of pigmentation and general intelligence.
THE FALL‐HAMMER, CHRONOSCOPE AND CHRONOGRAPH
Authors: DUNLAP KNIGHT
Published: April 2011

Criticisms on the Wundt fall‐hammer.—Defects in the Zimmermann model and their correction.—Reliability of the break spark in chronograph records.—Latency of magnetic markers shown by spark method. —Timing fall‐hammer from break to break of current.—Timing from break of current through supporting magnet.—Effect of occasional reversal of current on Hipp chronoscope.—Spark method of recording movements of chronoscope armature.—Effects of unreversed current on chronoscope.—Advisability of never reversing.—Lower winding for Magnets.
TOWARDS AN INFORMATION‐FLOW MODEL OF HUMAN BEHAVIOUR*
Authors: MACKAY DONALD M.
Published: April 2011

This paper is concerned with behaviour possible in an information‐flow system intended explicitly as a hypothetical model for comparison with human information‐handling system. A statistically self‐organizing system is described in which not only normal homeostatic behaviour but also such activities as invention of fruitful hypotheses, imagination of fictitious situations, and like would find a natural place. Discussion is confined mainly to manner of concept‐formation and concept‐handling in such a system. It has been suggested that correlate of perception (as distinct from reception) is activity which organizes an outwardly directed internal matching response to signals from receptors. This organizing activity amounts logically to an internal representation of feature in incoming signals to which it is adaptive, i.e. feature which is thus ‘perceived’.

A hierarchic structure is postulated wherein much of organizing activity is concerned with modifying probabilities of other activity. Abstract concepts and hypotheses are represented by ‘sub‐routines’ of such organizing activity. These can in principle be evolved as a result of experience in a manner analogous to‐or at least fruitfully comparable with‐process of learning and discovery; and it is not necessary for designer to predetermine, nor possible for him to foresee, all conceptual categories in terms of which information received by system may be structured. Particular attention is directed to conditions under which such a process of concept‐formation could take place with sufficient rapidity.

Some of symptoms of psychopathology find apparent correlates in possible modes of malfunction of such a system. But in this, as in other respects, it is not intended to press resemblances; intention is rather to stimulate critical comparisons, in order that differences between information‐flow model and real thing may continually lead to progressive refinement and enlarged understanding.
BOUNDARIES BETWEEN PERSON AND WORLD*
Authors: MURPHY GARDNER
Published: April 2011

In contrast to widespread opinion that organism and environment (or person and world) can be sharply distinguished, thesis is propounded that one often melts into other. Data from physiology, genetics, behaviour psychology, psychology of immediate experience, social psychology and parapsychology all suggest that ‘gradient’ from person to world may be either ‘steep’ or very gradual.
SEX DIFFERENCES IN PREFERENCES FOR SHAPES: A CROSS‐CULTURAL REPLICATION
Authors: JAHODA G.
Published: April 2011

A shape‐preference test was designed by McElroy on basis of ‘a possible corollary of psychoanalytic theory’ and administered to Scottish schoolchildren. In accordance with predictions there was a significant tendency, increasing with age, for boys to prefer round shapes (disguised female symbols) and for girls to prefer rectilinear ones (disguised male symbols). McElroy suggested alternative hypotheses that might, in his view, account equally well for effects obtained.

In present study McElroy's main alternative hypotheses were examined and it appeared that, as formulated by him, they could not be used to predict results in Accra. It was shown, however, that psychoanalytic hypothesis did permit a definite prediction: in a cultural situation where there is less repression, one would expect sex differences to be smaller. test was given in a modified form, which made more detailed analysis possible. A greatly reduced, but still significant, sex difference was in fact obtained. Age changes, contrasting with those found in Scotland, were also shown to be consistent with psychoanalytic hypothesis. It was further suggested that some of specific Freudian interpretations of symbols may have to be reconsidered.