bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats
Authors: De Campos Rafael O P , Paulino Niraldo , Da Silva Célio H M , Scremin Amarilis , Calixto João B
Published: April 2011

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil.

The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg−1) or zymosan (40 mg kg−1) were inhibited to different extents by an extract of propolis (1–60 mg kg−1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg−1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg−1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg−1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg−1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg−1 i.p. or 25–100 mg kg−1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg−1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg−1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg−1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg−1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg−1 i.p., 30 min previously).

These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.
Effects of Copper-aspirin Complex on Platelet Aggregation and Thrombosis in Rabbits and Mice
Authors: Shen Z Q , Liang Y , Chen Z H , Liu W P , Duan L
Published: April 2011

The effects of intragastric and intraduodenal copper-aspirin complex on rabbit platelet aggregation were observed by Born’s method. Myers’s method was used to evaluate the antithrombotic effect of copper-aspirin complex in mice.

In-vitro copper-aspirin complex selectively inhibited arachidonic acid-induced platelet aggregation with an IC50 value (concentration resulting in 50% inhibition) of 13.2 μM (95% confidence limits 9.1–16.8 μM). Copper-aspirin complex (10 mg kg−1 given intragastrically or intraduodenally) was more potent than aspirin in inhibiting arachidonic acid-induced platelet aggregation. Copper-aspirin complex (10 mg kg−1) had a stronger inhibitory effect and a longer duration of action when given intragastrically than when given intraduodenally. It was shown by radioimmunoassay that copper-aspirin complex significantly reduced the level of thromboxane B2 in plasma while markedly increasing that of 6-ketoprostaglandin F1α (6keto-PGF1α). Copper-aspirin complex (10 mg kg−1 given intragastrically for 7 days) significantly reduced mouse mortality caused by intravenous injection of arachidonic acid.

The results suggest that both in-vitro and in-vivo copper-aspirin complex is more potent in selectively inhibiting arachidonic acid-induced platelet aggregation than aspirin. When given intragastrically the complex has a more potent antiplatelet effect and a longer duration of action than when given intraduodenally. The antithrombotic effect of the complex was more potent than that of aspirin.
Effects of Fluoxetine and Norfluoxetine on 5-Hydroxytryptamine Metabolism in Blood Platelets and Brain after Administration to Rats
Authors: Bourdeaux Roland , Desor Didier , Lehr Paul R , Younos Chafique , Capolaghi Bernard
Published: April 2011

The effects of intraperitoneal administration of fluoxetine (2.5, 5, 10 or 20 mg kg−1) and norfluoxetine (10 mg kg−1) on 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) metabolism were examined in the blood platelets and brain of rats killed 3 h after a single dose. Several experiments were performed to evaluate the effect of norfluoxetine.

Plasma 5-HT concentrations decreased significantly (48%) compared with control group results 3h after administration of a single dose of fluoxetine (10 or 20 mg kg−1). Similar plasma 5-HT levels, 0.54 ± 0.04 and 0.56 ± 0.09 mg L−1, respectively, were observed after administration of 10 mg kg−1 fluoxetine or norfluoxetine. In the same way 5-HIAA levels in whole brain were similar, 0.36 ± 0.03 and 0.34 ± 0.01 μg g−1, respectively, after administration of fluoxetine or norfluoxetine. There was a good correlation between plasma and brain levels of fluoxetine (0.962) and norfluoxetine (0.957).

The results suggest that fluoxetine and norfluoxetine lead to reduced levels of 5-HT in platelets and of 5-HIAA in the brain. Like the parent drug, norfluoxetine is a potent and selective inhibitor of 5-HT uptake.
Pharmacokinetic Interaction in Rabbits between a New Anticonvulsant, DL-3-Hydroxy-3-ethyl-3-phenylpropionamide, and Phenytoin
Authors: Medina L , García L , Pérez R , Fernández A , Jung H
Published: April 2011

The effect of phenytoin on the disposition of DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) has been studied in New Zealand white rabbits.

Plasma HEPP levels decreased when the drug was administered with phenytoin. The area under the plasma concentration-time curve was reduced by 56.49% (from 43.23 ± 7.0 to 18.81 ± 2.03 μg h mL−1), the elimination half-life was also significantly (P<0.01) reduced (from 2.68 ± 0.35 to 1.04 ± 0.07 h) and the clearance was increased (from 0.35 to 0.81 L h−1 kg−1). In-vitro protein binding to bovine serum albumin (BSA) and plasma was evaluated by equilibrium dialysis. Plasma protein binding was low (between 33.69 and 37.43% at concentrations ranging from 6.25 to 100 μg mL−1). The compound binds preferentially to albumin with an association constant (Ka) of 3.81 times 103 M−1 at 37°C.

The results suggest a pharmacokinetic interaction between phenytoin and HEPP, probably on the drug-metabolizing enzyme system in the liver.
Can Non-steroidal Anti-inflammatory Drugs Act as Metalloproteinase Modulators? An In-vitro Study-of Inhibition of Collagenase Activity
Authors: Barracchini Annalisa , Franceschini Nicola , Amicosante Gianfranco , Oratore Arduino , Minisola Giovanni , Pantaleoni Giancarlo , Di Giulio Antonio
Published: April 2011

The in-vitro effects of some non-steroidal anti-inflammatory drugs and some analgesic drugs on collagenase activity were studied by use of a self-quenched fluorogenic esapeptide as substrate. The increased fluorescence signal arising as a result of peptide cleavage by collagenase was recorded and related to the inhibitory potency of the drugs. The effective concentrations in collagenase modulation were also correlated with the levels of the drugs in the plasma and synovial fluids of patients receiving therapeutic doses.

Six of the tested drugs, nimesulide, piroxicam, tolmetin, meloxicam, sulindac and sodium meclofenamate, inhibited enzyme activity with IC50 values (concentrations resulting in 50% inhibition) ranging from 1.9 to 28.2 μM and Ki (apparent inhibition constant) ranging from 0.83 to 21.8 μM. Much of the activity was restored after dialysis of the enzyme-drug complex, demonstrating the reversibility of the effect.

Although these results indicate that some anti-inflammatory drugs could modulate enzymatic activity involved in the degradation of the extracellular matrix, their possible pharmacological involvement as collagenase inhibitors in collagen degradative diseases remains to be assessed by clinical studies.
Delayed Treatment with YM90K, an AMPA Receptor Antagonist, Protects against Ischaemic Damage after Middle Cerebral Artery Occlusion in Rats
Authors: Kawasaki-Yatsugi Sachiko , Shimizu-Sasamata Masao , Yatsugi Shin-Ichi , Yamaguchi Tokio
Published: April 2011

The neuroprotective effect of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride] has been examined in a rat middle cerebral artery occlusion model.

Intravenous infusion of YM90K (2·5–20mgkg−1h−1 for 4 h) starting immediately after occlusion of the middle cerebral artery significantly reduced the cortical infarct volume 24 h after occlusion compared with the control group. The protection at the highest dose was 39% (P<0·05). Similar protective effects were observed when YM90K (20mgkg−1h−1 for 4 h) was delayed up to 2 h after middle cerebral artery occlusion (45% reduction, P<0·05). CNS1102 [N-(1-naphthyl)-N′-(3-ethylphenyl)-N′-methylguanidine hydrochloride], a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also reduced the cortical infarct volume when 1·3mgkg−1 was administered by intravenous bolus injection immediately after middle cerebral artery occlusion, followed by intravenous infusion at 0·785 mgkg−1h−1 for 4 h (35% reduction, P<0·05). This neuroprotective effect was not observed when administration was delayed 1 h after middle cerebral artery occlusion.

These results suggest that AMPA receptors might play a more important role than NMDA receptors in the late development of neuronal cell damage after focal cerebral ischaemia and that AMPA receptor blockade would be one beneficial strategy in treating acute stroke.
The Pharmacokinetics and Bioavailability of Dihydroartemisinin, meether, Artemether, Artesunic Acid and Artelinic Acid in Rats
Authors: Li Qi-Gui , Peggins James O , Fleckenstein Lawrence L , Masonic Kelly , Heiffer Melvin H , Brewer Thomas G
Published: April 2011

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg−1. Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds.

Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21–41 mL min−1 kg−1) was slower than that of the other drugs for all three routes of administration (DQHS, 55–64 mL min−1 kg−1; AM, 91–92 mL min−1 kg−1; AS, 191–240 mL min−1 kg−1; AE, 200–323 mL min−1 kg−1). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19–35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3–72.7), then AE (3.4–15.9), AM (3.7–12.4) and AL (1.0–4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs.

This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.
Comparative Analysis of the Vascular Actions of Diterpenes Isolated from Euphorbia canariensis
Authors: Miranda Francisco J , Alabadí José A , Ortí Marta , Centeno Jose M , Piáón Marta , Yuste Alberto , Sanz-Cervera Juan F , Marco J Alberto , Alborch Enrique
Published: April 2011

We have analysed the effects of 2,3-diepiingol 7,12-diacetate-8-isobutyrate (compound 1), ingenol-3-angelate-17-benzoate (compound 2), ingenol-3-angelate-17-benzoate-20-acetate (compound 3) and 3,5,7,8,9,15-hexahydroxyjatropha-6(17),11-dien-14-one-5,8-bis(2-methylbutyrate)-7-(2-methylpropionate) (compound 4), four diterpenes isolated from E. canariensis, on the isometric tension developed by isolated rabbit basilar and carotid arteries.

Concentration-response curves to these compounds were obtained cumulatively in both arteries at resting tension and active tone (KCl, 50 mM). At resting tension a concentration-dependent contraction was induced by the four compounds. In the basilar artery the order of potency was 3 = 1 > 2 = 4, without significant differences between Emax values. In the carotid artery the order of potency was 3 > 2 = 1 = 4 and there were no significant differences between the Emax (maximum effect) values of compounds 1–3, all of which were higher than that of compound 4. In pre-contracted basilar artery compounds 1–3 induced concentration-dependent relaxation and compound 4 was almost ineffective; the order of potency was 3 > 2 = 1 without significant differences between Emax values. In the carotid artery with active tone the four compounds tested induced further contractions; the order of potency was 3 > 2 = 4 > 1 without significant differences between Emax values.

These results show that the four diterpenes are potent active substances in rabbit basilar and carotid arteries and that there are regional differences between their action. The four compounds tested contract basilar and carotid arteries at resting tension. Compounds 1–3 relax pre-contracted basilar artery but not carotid artery.
Study of the Effects of Dispase in the Chemotherapy of Multicellular Tumour Spheroids of Small-cell Lung Carcinoma in Man
Authors: Matsuoka Hidehito , Okada Masayoshi , Ishii Noboru , Maeda Sakan
Published: April 2011

Multicellular tumour spheroids (MTS), diameter 650 μm, from PC-6, SBC-1 and NCL-H60 small-cell lung carcinoma cell-lines in man were prepared by the liquid overlay culture method and used to study the influence of treatment with dispase (bacterial neutral protease from Bacillus polymyxa, 1000 units mL−1) on the effectiveness of carboplatin, as determined by colony-forming assay.

When carboplatin alone was used on monolayers the curve of survival fraction against concentration was exponential in shape, indicating that the drug was active against the monolayer. When MTS were treated with medium concentrations (10−5 and 10−4  m) of carboplatin alone the survival fraction–concentration curve showed that the effectiveness of the treatment was less than that against the monolayer. On treatment of MTS with carboplatin and dispase the survival fraction–concentration curve was similar to that obtained for the monolayer and the survival fraction of the core of the MTS was also less than when carboplatin alone was used.

These results imply that dispase dissolves the intercellular matrix of the MTS enabling enhanced infiltration of carboplatin into the core of the MTS. Dispase thus indirectly increases the effectiveness of carboplatin.
Importance of Initial Environments in the Development of Ambulatory Sensitization to Methamphetamine and Cocaine in Mice
Authors: Kuribara Hisashi
Published: April 2011

Repeated administration of CNS stimulants such as amphetamines and cocaine induces behavioural sensitization which can be influenced by the animal’s environment. This study has evaluated the effect of restraint on the development and maintenance of ambulatory sensitization to methamphetamine and cocaine in mice.

Subcutaneous administration of the CNS stimulants methamphetamine (2 mg kg−1) and cocaine (20 mg kg−1) seven times at three-day intervals resulted in ambulatory sensitization when the mice were placed in 20-cm diameter activity cages after each dose of the drug. However, if methamphetamine or cocaine was administered when the mice were in small jars (6-cm diameter) in which expression of ambulation, but not of circling and rearing, was completely restricted, the development of ambulatory sensitization was retarded or inhibited, with circling behaviour concurrently increased, when subsequent repeated doses of the drug were administered in the activity cage. Subsequent repeated treatment of ambulatory-sensitized mice with the drug or saline when the mice were in the jars did not change the levels of the ambulatory sensitization or the circling behaviour.

These results suggest that the mice are sensitized to the behavioural effect of CNS stimulants which can be expressed in the environment in which the drug is administered. It is also considered that the established sensitization is strongly retained and is responsible for retardation or suppression of the development of sensitization to other behavioural stimulant effects.
The Non-peptide Neuroprotective Agent SR 57746A Interacts with Neurotrophin-3 to Induce Differentiation in- the PC 12 Cell-line
Authors: Fournier J , Boutot G , Keane P E , Maffrand J P , Fur G Le , Soubrié P
Published: April 2011

SR 57746A (1-(2β-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine hydrochloride) is a neuroprotective compound which potentiates nerve-growth factor (NGF)-induced differentiation in PC12 cells. We have evaluated the interaction of SR 57746A with the other members of the neurotrophin family in this cell-line.

In contrast with NGF, neurotrophin-3 did not increase the differentiation of PC12 cells. However, the association of SR 57746A with neurotrophin-3 significantly increased neurite outgrowth. No significant activity on neurite outgrowth was observed with brain-derived neurotrophic factor or neurotrophin-4, either alone or combined with SR 57746A.

These results indicate that as well as potentiating the effect of NGF SR 57746A enables neurotrophin-3, which alone is inactive, to increase the differentiation of these cells.
Effect of the Number of Samples on Bayesian and Non-linear Least-squares Individualization: A Study of Cyclosporin Treatment of Haematological Patients with Multidrug Resistance
Authors: Wu G , Pea F , Cossettini P , Furlanut M
Published: April 2011

We have studied whether the prediction of drug concentrations improves as the number of samples used for individualization is increased, and whether the Bayesian method of individualization is superior to the non-linear least-squares method. Data were obtained from ten adult haematological patients with multidrug resistance who were treated with cyclosporin. The predictions of blood–cyclosporin concentrations were made using the Abbott PKS program. The number of samples used for individualization was increased from 1 to 30 for the Bayesian method and from 4 to 30 for the non-linear least-squares method. Linear regression, percentage prediction error, and absolute and relative predictive performance were used to evaluate the predictions.

The results show that the Bayesian method affords greater precision than the non-linear least-squares method, but that the non-linear least-squares method is more accurate and results in less bias. Whereas for linear regression predictions improve as the number of samples is increased, other evaluations show improvement in the range from 5 to 11 samples; linear regression, percentage prediction errors and prediction bias support the opinion that the Bayesian method progressively becomes the non-linear least-squares method as the number of samples used for individualization is increased, but the accuracy and precision of prediction do not support this opinion.

The study supports the statement that Bayes’ law requires parameters from an infinite population, otherwise the advantage of the Bayesian method might be marginal.
Shenjincao (Palhinhaea cernua) Injection for Treatment of Experimental Silicosis of Rats
Authors: He Li-Zhong , Huang Ze-Hua , Wang Hui-Ru , Tu De-Yun , Mao Zheng-Fang
Published: April 2011

Shenjincao injection is a traditional Chinese medicine prepared from Palhinhaea cernua (L.) A. Franco et Vasc, by ultrafiltration. Its anti-silicosis action has been investigated both as a prophylactic and for treatment of the disease.

Wistar rats were injected intra-tracheally with quartz dust and then divided randomly into groups—treatment and control prophylactic groups and treatment and control disease groups. After five days or eight weeks, respectively, the silica-exposed rats of the two treatment groups were injected intraperitoneally three times a week with shenjincao injection, dose 2·0 mL, for five weeks or 11 weeks, respectively. The rats were then dissected, and the ceruloplasmin content of the serum and the fresh weight, dry weight, collagen content and pathological grade of the lungs were measured. Compared with the corresponding exposed control groups for the same treatment periods the values of these parameters were reduced by 62–8% to 30·7% for rats in the prophylactic treatment group (P<0·01 for all) and by 50·8% to 30-2% for the diseased group (P<0·01 for all). The values for the disease-treatment group were also reduced by 37·9% to 25·9% compared with values for the exposed control group before treatment (P<0·01 or P<0·05). The effective coefficients for prophylactic treatment were 82·6% to 56·0%; for disease treatment they were 68·8% to 39·8%.

These results show that shenjincao injection is efficacious against experimental silicosis not only when used prophylactically but also when used to treat the disease.
Contractile Action of Mn2+ via Ca2+ Channels Activated by Bay K 8644 in Guinea-pig Taenia Coli
Authors: Nasu Tetsuyuki , Sasaki Miyori
Published: April 2011

Mn2+ has been shown to inhibit K+-induced contraction of smooth-muscle, to induce contraction of smooth-muscle in Ca2+-free, K+ medium and to activate the contractile proteins of skinned fibres of smooth muscle cells. Further work has suggested that Mn2+ penetrates the cytoplasm through voltage-dependent Ca2+ channels when the cell membranes of smooth muscles are depolarized with K+. We have investigated whether in Ca2+-free medium, Mn2+ enters the cytoplasm through Ca2+ channels and induces contraction of guinea-pig taenia coli in the presence of Bay K 8644, a dihydropyridine Ca2+-channel agonist which prolongs the open state of the voltage-dependent Ca2+ channels in smooth-muscle cells.

In Ca2+-free medium the application of 5 mM Mn2+ in the presence of Bay K 8644 caused contraction of and concomitant increase in Mn2+ uptake in guinea-pig taenia coli smooth muscle. In the presence of Bay K 8644 nifedipine, a dihydropyridine Ca2+ channel antagonist, dose-dependently inhibited both manganese uptake and the contraction induced by Mn2+.

These results suggest that Mn2+ enters the cytoplasm through dihydropyridine-sensitive, voltage-dependent Ca2+ channels activated by Bay K 8644 and then induces contraction in taenia coli.
Transdermal Iontophoretic Delivery of Hydrocortisone from Cyclodextrin Solutions
Authors: Chang Shu-Lun , Banga Ajay K
Published: April 2011

Enhanced skin penetration of hydrocortisone can be desirable for treatment of several diseases. Transdermal iontophoretic delivery of hydrocortisone solubilized in an aqueous solution of hydroxypropyl-β-cyclodextrin (HP-β-CyD) was investigated and compared with chemical enhancement of co-solvent formulations.

The passive permeation of hydrocortisone through human cadaver skin was higher when delivered from propylene glycol than when delivered after solubilization in an aqueous solution of HP-β-CyD. However, the iontophoretic delivery of the 1% hydrocortisone-9% HP-β-CyD solution was higher than the amount delivered passively by the 1% hydrocortisone-propylene glycol formulation, even if oleic acid was used as a chemical enhancer. Iontophoretic delivery of 1% hydrocortisone with 3% or 15% HP-β-CyD was lower than that of the 9% HP-β-CyD solution.

These data suggest that free hydrocortisone rather than complexes is predominantly delivered iontophoretically through the skin and the HP-β-CyD complex serves as a carrier to replenish depletion of hydrocortisone. HP-β-CyD prevents hydrocortisone from forming a skin reservoir. Iontophoresis provides better enhancement of transdermal delivery of hydrocortisone than the chemical approach when just sufficient HP-β-CyD is added to solubilize the hydrocortisone.
Goniodomin A, an Antifungal Polyether Macrolide, Increases the Filamentous Actin Content of 132IN 1 Human Astrocytoma Cells
Authors: Mizuno Kouichi , Nakahata Norimichi , Ito Emiko , Murakami Masahiro , Yamaguchi Katsumi , Ohizumi Yasushi
Published: April 2011

Goniodomin A, a polyether macrolide isolated from the dinoflagellate Goniodoma pseudogoniaulax, caused morphological change in 1321N1 human astrocytoma cells.

Observation by scanning electron microscopy revealed that the shape of the cell became refractile from flat in response to goniodomin A. This morphological change was accompanied by the outgrowth of a needle-like structure from the cell surface. Goniodomin A increased the intracellular content of filamentous actin in a concentration- and time-dependent manner. It also caused the change in filamentous actin distribution in the cells. The elongation of filamentous actin was observed in goniodomin A-treated cells. These results suggest that goniodomin A induces morphological change by increasing the content of filamentous actin in non-muscle cells.
Single- and Multiple-dose Mibefradil Pharmacokinetics in Normal and Hypertensive Subjects
Authors: Welker Horst A
Published: April 2011

Mibefradil is a single-enantiomer calcium antagonist belonging to a new class, the tetralol derivatives. The recommended doses for treatment of hypertension and chronic stable angina pectoris are 50 or 100 mg. Mibefradil is metabolized via parallel pathways of esterase-catalysed hydrolysis and cytochrome P450 3A4-mediated oxidation. Mibefradil also inhibits cytochrome P450 3A4 and consequently inhibits its own metabolism, a property illustrated by three studies performed early in the drug’s development.

After single intravenous doses of 2.5 to 80 mg to healthy male subjects, pharmacokinetics are linear. At the representative 40 mg intravenous dose mean pharmacokinetic parameters were clearance 241 ± 76 mL min−1, terminal exponential half-life 15.0h and volume of distribution at steady state 213 L. After single oral doses of 10 to 320 mg, reduced first-pass metabolism occurs with increasing dose. This effect is accompanied by increasing absolute bioavailability as the dose is increased. In an oral multiple-dose study of healthy male volunteers mibefradil doses of 100, 150 or 250 mg (from tablets) were administered once daily for 28 days. Reduction of the first-pass effect was noted, although the data suggested that a maximum was reached for doses of 150 mg or more. In a study of the effect of hypertension on mibefradil pharmacokinetics, 12 patients received oral mibefradil once daily at doses of 50, 100, 150, or 200 mg in 100 mL orange juice for 8 days. Steady state was reached within 3 days and accumulation generally ranged from three- to sevenfold. Single-dose non-linearity was observed in the first-pass effect, although for multiple dosing oral clearance values were dose-independent and lower than for single doses. After multiple dosing at the recommended dosage of 50 and 100 mg once daily, oral clearance of mibefradil stabilizes to approximately the same value for both doses. Hence, the single-dose non-linearity has little clinical relevance but demonstrates the self-inhibition of metabolism seen with mibefradil.

Studies so far suggest that self-inhibition of its oxidative metabolic pathway leads to a low clearance and long half-life, enabling once-daily dosing and conferring low intra- and inter-patient variability in pharmacokinetics.
Pharmacokinetics and Tissue Distribution of (±)-3′-Azido-2′,3′-dideoxy-5′-O-(2-bromomyristoylythymidine, a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT) in Mice
Authors: Parang Keykavous , Wiebe Leonard I , Knaus Edward E
Published: April 2011

The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine (1, AZT), 2-bromomyristic acid (2) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine (3) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver.

The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g−1 min; CL (blood clearance) = 10.5 ± 1.1 mL min−1 kg−1) and its ester prodrug (3, βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g−1 min; CL = 17.6 ± 4.8 mL min−1 kg−1) were compared after intravenous injection of equimolar doses (0.3 mmol kg−1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g−1) and AUC (12.3 μmol min g−1) were lower than observed after AZT administration (peak concentration 0.36 μmol g−1; AUC 29.1 μmol min g−1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g−1; respective AUCs 42.5 and 12.7 μmol min g−1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g−1) and AUCs (2.8 compared with 1.4 μmol min g−1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself.

In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.
First-pass Metabolism of Peptide Drugs in Rat Perfused Liver
Authors: Taki Yoko , Sakane Toshiyasu , Nadai Tanekazu , Sezaki Hitoshi , Amidon Gordon L , Langguth Peter , Yamashita Shinji
Published: April 2011

To elucidate the extent and mechanisms of the first-pass metabolism of peptide drugs in the liver after oral administration, a liver perfusion study was performed in rats using metkephamid, a stable analogue of methionine enkephalin, and thyrotropin-releasing hormone (TRH), as model peptides.

The fraction of intact metkephamid recovered after single-pass constant perfusion through rat liver reached steady-state very quickly, and it was concluded that metkephamid was hydrolysed enzymatically at the surface of hepatocytes or endothelial cells of microvessels, or both, rather than being taken up by hepatocytes. The fraction of metkephamid recovered intact was approximately 40% under protein-free conditions but increased to 70–75% on addition of bovine serum albumin (BSA) to the perfusate. The fraction of metkephamid bound to BSA was approximately 50% under these conditions, implying that only the free fraction of metkephamid in the plasma was metabolized in the liver. Calculations based on the tube model showed that approximately 30–35% of metkephamid absorbed from the intestine undergoes first-pass metabolism before entering the systemic circulation in-vivo. In contrast, the fraction of TRH metabolized in the liver was less than 10%, indicating a remarkably low contribution of first-pass metabolism to the bioavailability of TRH.

These results show that hepatic first-pass metabolism of metkephamid contributes to its low systemic bioavailability. After intestinal absorption free metkephamid is rapidly hydrolysed on the surface of hepatocytes or endothelial cells, rather than being taken up by hepatocytes. This information has important implications in the oral delivery of many kinds of peptide.
Changes in Thyroid Hormone Concentrations after Administration of Ashwagandha Root Extract to Adult Male Mice
Authors: Panda Sunanda , Kar Anand
Published: April 2011

The importance of ashwagandha root extract in the regulation of thyroid function with special reference to type-I iodothyronine 5′-monodeiodinase activity in mice liver has been investigated.

Although the root extract (1.4 g kg−1) administered daily for 20 days by gastric intubation increased serum 3,3′,5-triiodothyronine (T3) and tetraiodothyronine (T4) concentrations and hepatic glucose-6-phosphatase activity, hepatic iodothyronine 5′-monodeiodinase activity did not change significantly. Furthermore, ashwagandha root extract significantly reduced hepatic lipid peroxidation, whereas the activity of antioxidant enzymes such as superoxide dismutase and catalase were increased.

These findings reveal that the ashwagandha root extract stimulates thyroidal activity and also enhances the antiperoxidation of hepatic tissue.
The Absence of Stereoselective P-Glycoprotein-mediated Transport of R/S-Verapamil Across the Rat Jejunum
Authors: Sandström Rikard , Karlsson Anders , Lennernäs Hans
Published: April 2011

We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ.

A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (Peff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L−1. The Peff of each enantiomer was also determined at 400 mg L−1 when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of Peff from 0.42 times 10−4 cm s−1 to 0.80 times 10−4 cm s−1 (P < 0.05) at concentrations from 4 to 400 mg L−1, respectively. The observed concentration-dependent jejunal Peff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal Peff increased to 1.47 times 10−4 cm s−1. There was no difference between the Peff of the two enantiomers in any of these experiments. The efflux of R/S-norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte.

In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-norverapamil is formed inside the enterocytes.
Circadian Changes in the Pharmacokinetics and Pharmacodynamics of Azosemide in Rats
Authors: Han Kye S , Lee Myung G
Published: April 2011

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg−1) to rats at 1000 or 2200 h.

After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CLR) of azosemide was significantly faster (2.86 compared with 1.76 mL min−1 kg−1) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CLR of azosemide was significantly faster (3.64 compared with 0.79 mL min−1 kg−1) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats.

If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.
THE RELATION OF MIND AND BODY1 I.
Authors: LATTA R.
Published: April 2011

Problem considered as one of method—Parallelist and animist theories—Parallelism an a priori extension of mechanical hypothesis to mind—Animist theories teleological as regards mind—Psychical and physical worlds remain separate on both views—But if they are real systems they must have immanent teleology—Distinction of physical from psychical is a distinction within one system.
THE INFLUENCE OF MARGINS ON THE PROCESS OF BISECTION: ADDITIONAL EXPERIMENTS WITH OBSERVATIONS ON THE AFFECTIVE CHARACTER OF THE DETERMINATIONS
Authors: SMITH W. G. , KENNEDY‐FRASER D. , NICOLSON WILLIAM
Published: April 2011

The objects and methods of the investigation. Results regarding the magnitude and course of the marginal illusion: modifications due to the special mode of presenting distances. The definite character of the transition from ‘far’ to ‘near’ judgments. The time taken in the process of judgment. The feelings connected with the various forms of judgment; the course of affective values in connexion with the succession of stages in the series. Judgments of equality and the accompanying feelings.
SOME OBSERVATIONS ON LOCAL FATIGUE IN ILLUSIONS OF REVERSIBLE PERSPECTIVE
Authors: FLÜGEL J. C.
Published: April 2011

Local fatigue as manifested in the ‘Windmill’ or ‘Revolving Cross’ Illusion. McDougall's observations confirmed. Local fatigue not manifested by all subjects. Differences of local fatigability in the same subject. Experiments showing the extremely specific nature of this local fatigue. Local fatigue unaffected by other simultaneous mental processes. The rôle of local fatigue in illusions of reversible perspective. The general interest of local fatigue. Summary.
IS CONSCIOUSNESS A BRAIN PROCESS?
Authors: PLACE U. T.
Published: April 2011

thesis that consciousness is a process in brain is put forward as a reasonable scientific hypothesis, not to be dismissed on logical grounds alone. conditions under which two sets of observations are treated as observations of same process, rather than as observations of two independent correlated processes, are discussed. It is suggested that we can identify consciousness with a given pattern of brain activity, if we can explain subject's introspective observations by reference to brain processes with which they are correlated. It is argued that problem of providing a physiological explanation of introspective observations is made to seem more difficult than it really is by ‘phenomenological fallacy’, mistaken idea that descriptions of appearances of things are descriptions of actual state of affairs in a mysterious internal environment.
A THEORY OF INSIGHT, REASONING AND LATENT LEARNING
Authors: DEUTSCH J. A.
Published: April 2011

types of performance to be explained, i.e. reasoning and latent learning, are briefly delimited. type of structure which would exhibit such behaviour is outlined. assumption of such a structure is then shown to explain relevant experimental data. Some predictions are also made.
EFFECTS OF PROPAGANDA ON RECALL, RECOGNITION AND BEHAVIOUR
Authors: BELBIN EUNICE
Published: April 2011

Two experiments are described in which effects of propaganda were assessed by standard forms of recall and recognition tests as well as by any change in overt behaviour following propaganda. first, a field experiment, using road‐safety propaganda presented in a Children's Cinema Club, showed that there was no positive relationship between effects of propaganda as shown by tests of recall or recognition on one hand and behaviour on roads on other. A second experiment was conducted in laboratory where an attempt was made to influence a subject's choice of fast or slow speed on a mechanical task by means of incidental propaganda. ‘effect’ of propaganda varied according to whether its influence was assessed by its attention value, its intelligibility, by how much could be described or recognized, or by its capacity to influence behaviour. Some subjects had only attended to individual items of display and, although they were able to recall or recognize these, they were not able to understand implication of propaganda and were not influenced by it. Others understood and recalled propaganda but were not influenced by it. Finally, there were those subjects who understood propaganda and were influenced by it but who could not remember it. Thus it seems that information which has been learned from propaganda can become apparent in two distinct forms: (a) in recall or recognition, and (6) in subsequent behaviour. reasons why these different effects were more marked in some subjects than in others will be examined in second part of this paper.
A STUDY OF CHILDREN'S INTERESTS AND COMPREHENSION AT A SCIENCE MUSEUM
Authors: BROOKS JOYCE A. M. , VERNON PHILIP E.
Published: April 2011

As part of an attempt to increase attractiveness and usefulness of a Children's Gallery in a Science Museum, an inquiry was made into numbers and types of children who visit it, their behaviour there, and extent to which they comprehend what they have seen. Methods of investigation included a sampling survey of attendances at different times of day and periods of year, stopwatch recording of times spent at different exhibits and charts of movements, and an oral questionnaire dealing with background of one hundred children and their understanding of selected exhibits. data throw some light on evolution of genuine scientific interests (mainly in boys) from superficial curiosity, and on suitable and unsuitable exhibits and methods of display and labelling.
THE STATISTICAL THEORY OF FIGURAL AFTER‐EFFECTS AND ACUITY
Authors: DEUTSCH J. A.
Published: April 2011

Osgood & Heyer explain shift of a contour by prolonged inspection of another in vicinity by assuming a spread of excitation in cortex, associated with each contour. This spread of excitation is normally distributed. contour itself is ‘perceived’ at peak of distribution. shift in second contour occurs because of an area of depressed excitability, left by first, which will tend to skew second distribution of excitation, and its peak, away from locus of first. It is argued that if two distributions are to subtract from each other successively, they will add up to a single peak if placed on cortex simultaneously. Thus any interaction will occur only if two contours are below threshold of separation and any shift will be a mere fraction of this threshold. Various amendments are considered which might enable theory to evade this consequence. neurophysiological basis (Marshall & Talbot) for Osgood & Heyer's theory is also questioned. A hypothesis to explain figural after‐effects and after‐effects of seen movement is briefly suggested.
A THEORY OF PERCEPTUAL CONSTANCY
Authors: TAYLOR J. G. , PAPERT S.
Published: April 2011

A terminology is developed for perceptual constancy which permits useful mathematical treatment. This is illustrated by discussing a particular form of constancy for which mathematics is particularly simple. Other cases which need more elaborate mathematics can be discussed in same way.

This formulation of constancy problem enables empiricist approach to perception to be formulated more concretely. Instead of saying simply that learning is involved we are able to go some way towards saying what has to be learnt.

It is suggested that constancy can be established by conditioning each element of an ‘ equivalence class’ of states of stimulation to same group of responses. This idea needs much more elaboration and investigation (Taylor, 1956), and we do not maintain that it is only possible mechanism.

Experimental results on protracted wearing of distorting spectacles are reported and discussed in light of above principles.
SOME EXPERIMENTS ON PAVLOV'S THEORY OF SUGGESTION*
Authors: INGHAM J. G.
Published: April 2011

Pavlov's theory implies that some degree of inhibition should be present following a period of suggestion and that amount of inhibition will to some extent determine response to suggestion. Experiments were carried out to determine whether changes in auditory sensitivity following suggestion were in accordance with this theory. As predicted, suggestions of arm movement were followed by increased thresholds. A period of prose reading of same duration and intensity produced same effect but casual conversation did not. Correlations between suggestibility and threshold increment were, on whole, positive but not large enough to justify a definite conclusion. threshold increment was greater in subjects who had been taking sedative doses of sodium amytal for one week.