bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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&lt;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&lt;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&lt;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

Abstract
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

Abstract
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 &gt; 2 = 4, without significant differences between Emax values. In the carotid artery the order of potency was 3 &gt; 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 &gt; 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 &gt; 2 = 4 &gt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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&lt;0·01 for all) and by 50·8% to 30-2% for the diseased group (P&lt;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&lt;0·01 or P&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.