bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and brain entry of alaptide, a novel nootropic agent, in mice, rats and rabbits
Authors: Lapka R
Published: April 2011

Pharmacokinetics of a novel nootropic agent, alaptide, have been examined in plasma and brain of mice, rats and rabbits following an intravenous dose (1 mg kg−1). First-order equilibration rate constants between plasma and brain (kBO) were calculated by a two-compartment model with a linked compartment (brain). Brain alaptide equilibrates rapidly with the central compartment in mice and rats due to the high kBO/β ratio. In rabbits the equilibration is much slower (kBO/β∼ 1). Partition coefficients between brain and plasma calculated from areas under the brain and plasma concentration-time curves, are 0·479, 0·549 and 0·864, in mice, rats and rabbits, respectively.
Effect of Diltiazem and its Metabolites on the Uptake of Adenosine in Blood: an In-vitro Investigation
Authors: Yeung Pollen K F , Mosher Susan J , Macrae Dennis A , Klassen Gerald A
Published: April 2011

Using whole blood from man and rabbits, the effect of diltiazem, its metabolites, and other calcium antagonists on the uptake of adenosine has been described. The uptake and metabolism of adenosine was extremely rapid with a half-life in plasma of less than 30 s. Adenosine is rapidly and extensively metabolized to hypoxanthine. Metabolites of diltiazem, deacetyl diltiazem and deacetyl O-desmethyl diltiazem were considerably more potent than the parent drug. Diltiazem was one-tenth as active as verapamil, but more active than nifedipine or amlodipine. Dipyridamole was the most potent uptake-inhibitor tested (IC50 < 1 μm), whereas the angiotensin converting enzyme inhibitor enalapril was virtually devoid of any inhibitory activities (IC50> 1000 μm). The results obtained from both man and rabbit were similar.
Effects of a Polysaccharide Fraction from the Roots of Bupleurum falcatum L. on Experimental Gastric Ulcer Models in Rats and Mice
Authors: Sun X-B , Matsumoto T , Yamada H
Published: April 2011

Effects of an acidic polysaccharide fraction, BR-2, from the roots of Bupleurum falcatum L., on HCl-ethanol, ethanol and water immersion stress-induced gastric lesions in mice and pylorus-ligated ulcers in rats have been studied. Oral administration of BR-2 at doses of 50 to 200 mg kg−1 inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl-ethanol and ethanol, in a dose dependent manner. This protective effect was observed after oral, intraperitoneal, and subcutaneous administration of BR-2 (25–100 mg kg−1). BR-2 also inhibited the formation of gastric ulcers which were induced by water immersion stress or pylorus-ligation. Prostaglandin E2 in gastric juice from rats and in gastric mucosa from mice was not influenced by oral administration of BR-2. The protective action of BR-2 against HCl-ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin (20 mg kg−1, i.p.). The amount of alcian blue binding to mucosa also increased after administration of BR-2 (100 mg kg−1, p.o.); however, the amount of hexosamine and N-acetylneuraminic acid in mucosa did not change significantly.
A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein
Authors: Evans Allan M , Hussein Ziad , Rowland Malcolm
Published: April 2011

The residence-time distribution (RTD) of diclofenac in the rat single-pass isolated perfused in-situ liver (n = 4) was determined after bolus input into the hepatic portal vein. Addition of human serum albumin (5 g L−1) ensured extensive (>98%) binding of diclofenac within the perfusate. The one-compartment form of the axial dispersion model of hepatic elimination, which assumes instantaneous radial distribution of substrate within the accessible spaces of the liver, failed to describe adequately the RTD of diclofenac. In contrast, the two-compartment form of this model, which assumes that the radial transfer of unbound substrate between the vascular and cellular space is non-instantaneous, provided an excellent description of the diclofenac data. Moreover, the mean (±s.d.) value for the hepatic dispersion number (DN) for diclofenac (0·354 ± 0·076) compared well with that determined for simultaneously injected [125I]human serum albumin (0·456 ± 0·078) using the one-compartment dispersion model. These estimates of DN, a stochastic parameter which characterizes the axial spreading of individual elements during transit through the liver, were similar in magnitude to those reported for other tracers in the rat perfused liver. The findings suggest that common factors influenced the RTD of diclofenac and its binding protein, and indicate that the two-compartment dispersion model may be a valuable tool for interpreting hepatic impulse-response data for solutes whose hepatic distribution and elimination is influenced by membrane permeability.
Mechanism of paraquat-stimulated lipid peroxidation in mouse brain and pulmonary microsomes
Authors: Hara Shuichi , Endo Takahiko , Kurhwa Fumi , Kano Sadao
Published: April 2011

Paraquat-stimulated NADPH-dependent lipid peroxidation in mouse brain and pulmonary microsomes was inhibited by superoxide dismutase and singlet oxygen quenchers, but not by catalase or hydroxyl radical scavengers. MnCl2, which might form a salt with unsaturated lipid, inhibited the lipid peroxidation in brain microsomes, but not that in pulmonary microsomes. These findings suggest that activated oxygen species, especially superoxide and singlet oxygen, may play a major role in the stimulation of microsomal lipid peroxidation by paraquat in both brain and lung, and that the nature of the lipids exposed to peroxidative attack may be different in microsomes of the two organs.
Gastrointestinal absorption of quaternary ammonium compounds correlated to their binding to small intestinal brush border membrane in rat
Authors: Saitoh Hiroshi , Saitoh Nobutaka , Iseki Ken , Miyazaki Katsumi
Published: April 2011

The relationship between absorption of quaternary ammonium compounds (QACs) from rat intestine and their in-vitro binding to isolated brush-border membrane has been examined, using a series of n-alkyltrimethylammoniums. The binding of these QACs gradually increased with each extension of unbranched hydrocarbon chain from octyltrimethylammonium to tetradecyltrimethylammonium. However, hexyltrimethylammonium and heptyltrimethylammonium failed to bind to the membrane. On the other hand, the disappearance of these QACs from rat jejunal loop also increased with the length of hydrocarbon chain over the range of 8·9 to 71·3%. A good correlation was found between binding to the brush-border membrane and disappearance from jejunal loop. From these results, it was suggested that the size of the hydrophobic part of a QAC molecule was a principal determinant of both absorption and membrane binding, and that the absorption of QACs, with an appropriate sized hydrophobic part, was closely associated with the degree of binding to the membrane.
Effects of nifedipine on renal responses to several diuretic agents in rats
Authors: Rao V S , Fonteles M C
Published: April 2011

The influence of the dihydropyridine calcium antagonist nifedipine has been studied on the diuretic response to frusemide, acetazolamide and hydrochlorothiazide in water-loaded (25 mL kg−1) conscious rats. Oral administration of nifedipine (10 mg kg−1) markedly inhibited frusemide- and hydrochlorothiazide-induced diuresis as evidenced by a reduction in 5 h urine volume and urinary sodium and potassium elimination. However, it neither significantly enhanced nor limited urine and electrolyte excretion promoted by acetazolamide. Nifedipine, 5 and 10 mg kg−1 but not 1 mg kg−1, significantly (P < 005) inhibited the diuretic response of hydrochlorothiazide. At doses which affect hydrochlorothiazide diuresis (5 and 10 mg kg−1), nifedipine was found to depress the mean arterial pressure by 32% in normotensive rats. These results are of interest in view of the often reported clinical side effect of nifedipine in promoting peripheral oedema in hypertensive patients and its use in combination with a thiazide or loop diuretic.
Instrumentation of a Gravity Feed Extruder and the Influence of the Composition of Binary and Ternary Mixtures on the Extrusion Forces
Authors: Baert L , Fanara D , De Baets P , Remon J P
Published: April 2011

A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.
Distribution of Protein Kinase C in the Hippocampus of the Gerbil and Rat: Autoradiographic Analysis by [3H]Phorbol 12,13-Dibutyrate
Authors: Kawagoe Jun-Ichi , Hara Hideaki , Kogure Kyuya
Published: April 2011

In-vitro quantitative receptor autoradiography with [3H]phorbol 12,13-dibutyrate (PDBu) was used to determine the affinity constant (Kd) and the maximum number of receptor sites (Bmax) for protein kinase C (PKC) in subregions of the gerbil hippocampus, and to compare the distribution of [3H]PDBu binding sites in the gerbil hippocampus with that in the rat hippocampus. The Kd and Bmax values in the subregions of the gerbil hippocampus were estimated at 2·6–3·8 nM and 2·38–2·54 pmol (mg tissue)−1, respectively. The distribution of hippocampus [3H]PDBu binding sites was uniform in the gerbil but not in the rat. The [3H]PDBu binding activities in the strata oriens of the CA1 and CA3 subfields and the molecular layer of the dentate gyrus in the rat hippocampus were significantly higher than in the gerbil hippocampus. However, binding activity in the stratum lacunosum-moleculare of the rat CA1 subfield was statistically lower. These data demonstrate a difference in the distribution of [3H]PDBu binding activity in the hippocampus between the gerbil and rat.
In-vivo Release of a GnRH Agonist from a Slow-release Poly(lactide-glycolide) Copolymer Preparation: Comparison in Rat, Rabbit and Guinea-Pig
Authors: Heinrich Nadja , Fechner Klaus , Berger Hartmut , Lorenz Dorothea , Albrecht Erika , Rafler Gerald , Schäfer Heinz , Mehlis Burkhard
Published: April 2011

Different batches of 50:50 poly((±)-lactide-glycolide) copolymer (PLG) were used as biodegradable carriers for D-Phe6-gonadotropin-releasing hormone (GnRHa) in the form of injectable long-acting implants loaded with 10% GnRHa and tracer amounts of [125I]GnRHa. After their injection subcutaneously into rats, rabbits, and guinea-pigs, the release kinetics of the peptide were determined by counting the radioactivity remaining in the implants (i) after recovery from the rats after death or (ii) directly on the skin above the injection site of rabbits and guinea-pigs in-vivo. No significant differences in the release pattern of the peptide amongst the three species whether the release process was controlled by diffusion or by degradation of the polymeric matrix were found. It is concluded that the results of in-vivo release tests using laboratory animals are valid for man and that enzymes are not involved in the degradation of the polymeric matrix. The results may be of general importance for the use of long-term release PLG formulations of highly active drugs, especially peptides and proteins.
Differential Effects of Potassium Channel Blockers on Dopamine Release from Rat Striatal Slices
Authors: Boireau Alain , Richard Fabien , Olivier Valérie , Aubeneau Michel , Miquet Jean-Marie , Dubédat Pierre , Laduron Pierre , Doble Adam , Blanchard Jean-Charles
Published: April 2011

The effects of different potassium channel blockers on tritiated dopamine ([3H]DA) release were investigated in rat striatal slices in the presence of pargyline and nomifensine (10 μM each). 4-Aminopyridine (4-AP; 10 and 30 μM) and 3,4-diaminopyridine (3,4-DAP; 30 μM) markedly increased the basal tritium outflow, whereas tetraethylammonium (TEA; 100–1000 μM) was without effect. The facilitating effect of 4-AP (10 μM) on spontaneous release was Ca2+- and K+-dependent. Moreover, the 4-AP-induced increase in spontaneous release was abolished in the presence of tetrodotoxin, indicating that voltage-dependent Na+ channels were involved in the release mechanism. 4-AP (10 and 30 μM) induced a dose-dependent decrease in K+-evoked [3H]DA release. This effect was confirmed with 3,4-DAP (30 μM). When striatal slices were depolarized with veratridine (5 μM), these two aminopyridines increased the evoked release of [3H]DA. TEA increased both K+- and veratridine-evoked [3H]DA release. These biochemical results are consistent with electrophysiological differences between the mechanism of action of aminopyridines and that of TEA.
The plasma kinetics of digoxin-specific Fab fragments and digoxin in the rabbit
Authors: Timsina M P , Hewick D S
Published: April 2011

The plasma kinetics of total and free digoxin, and digoxin-specific antibody fragments (DSFab) in rabbits which had been given [3H]digoxin one hour before DSFab has been studied over a 5 day period. Injection of DSFab caused a 4- to 5-fold rise in total digoxin and reduced elimination half-life (t½β), apparent volume of distribution at steady-state (Vdss) and systemic clearance (CL) by 40, 90 and 75% respectively. Early in the experimental period, DSFab reduced free digoxin concentration (measured by ultrafiltration) from 4·1 ng mL−1 to a minimum of 1·3 ng mL−1 at 15 min. However, the concentration had rebound to 2·5 ng mL−1 by 60 min. Subsequently, free digoxin fell to 0·63 ng mL−1 and remained relatively constant over a 7 to 90 h period. The distribution half-life, t½β, Vdss and CL for DSFab (concentrations measured by enzyme-linked immunosorbent assay) were 0·3 h, 3·2 h, 185 mL kg−1 and 57 mL kg−1 h−1, respectively. A considerable molar excess (about 5) of DSFab in the plasma was necessary to maintain minimum free digoxin concentrations. When the DSFab:digoxin molar ratio was less than 4 during the initial treatment period, free (toxicologically active) concentrations increased. With the elevation in total digoxin, however, an opposite situation appeared to apply. By 24 h the relatively short DSFab t½β meant that the plasma DSFab concentration was < 0·05 μg mL−1 giving a DSFab:digoxin molar ratio of below 006, yet the antibody-induced rise in total digoxin concentration was still detectable at 100 h.
Influence of standard and nicotine-reduced cigarette smoke on plasma concentrations of isosorbide dinitrate and its metabolites in rats
Authors: Gomita Yutaka , Furuno Katsushi , Araki Yasunori
Published: April 2011

Rats dosed orally with isosorbide dinitrate (1 mg kg−1) were exposed to smoke from standard and nicotine-reduced cigarettes for 8 min using a smoking machine. Plasma concentrations of isosorbide dinitrate and 5-isosorbide mononitrate, one of its major metabolites were approximately equal in the exposed groups, but were lower than in the non-smoking control group. The 2-isosorbide mononitrate concentration was also lower in the group exposed to smoke from standard cigarettes. Since the pharmacokinetics were influenced by smoke from both types of cigarette smoke, the effect may be attributed in large part to non-nicotine components of the smoke.
Effect of Age on the Gastrointestinal Absorption of Acyclovir in Rats
Authors: Fujioka Yūko , Mizuno Nobuyasu , Morita Emiko , Motozono Hitomi , Takahashi Koichi , Yamanaka You , Shinkuma Denji
Published: April 2011

Drug elimination from the body after intravenous administration of acyclovir (20 mg kg−1) was delayed in 1-week-old rats but the pharmacokinetic data for 2–5-week-old rats were the same as those for 8-week-old rats. The areas under the plasma concentration-time curves at 0–∞ h (AUC) after oral administration of acyclovir (20 mg kg−1) decreased with increasing age. The absolute bioavailabilities for 1-, 2·5-, 3- and 8-week-old rats were 77·59, 51·52, 14·61 and 7·30%, respectively. The gastrointestinal absorption of poorly absorbed acyclovir was good for rats younger than 2·5 weeks but dropped abruptly between 2·5 and 3 weeks of age. The intestinal membrane permeability of acyclovir was studied using the everted sac method. The rate of transfer of an initial concentration of 10 μm acyclovir from the mucosal to the serosal side was constant until 60 min in rats of different ages while the rate in 2–5-week-old rats was significantly greater than that in 3-, 4- and 8-week-old rats. Abrupt in-vivo and in-vitro changes were observed in the experimental results between 2·5- and 3-week-old rats; this period coincided with the weaning period of the rat. The membrane transport mechanism of acyclovir in 2·5- and 8-week-old rats was also studied. Cumulative transferred amounts of acyclovir were linear (r = 0·99) over the range 5 μm–1 min and dose-independent. The influence of metabolic inhibitors (sodium azide, 2,4-dinitrophenol, ouabain), purine and pyrimidine analogues (2-deoxyguanosine, guanine, adenine, uridine) and temperature on the permeation of acyclovir was studied. The permeation of acyclovir was inhibited only by 2-deoxyguanosine and guanine in 2·5-week-old rats. These results suggest that throughout the maturation period, the gastrointestinal absorption mechanism of acyclovir is predominantly via passive diffusion with little or no active or facilitated transport. The abrupt change that occurs during the weaning period is attributable not to facilitated transport but to a change in the factors regarding passive transport.
The Effect of Aminoguanidine Treatment, With or Without Food Restriction on the Liver, Stomach and Small Intestine of the Rat
Authors: Marway Jaspaul S , Preedy Victor R
Published: April 2011

A comparative investigation has been made into the effects of aminoguanidine treatment (60 mg kg−1 day−1) with or without dietary restriction (i.e. 50% reduction in food intake) on the protein, RNA and DNA composition of the liver, small intestine and stomach of young rats (0·1 kg body weight). After 3 weeks of dietary restriction the wet weights of the liver and small intestine decreased by 56 and 52%, respectively. There were significant reductions (approx 50%) in total hepatic and intestinal protein, RNA and DNA. Changes in ratios of RNA/protein, RNA/DNA and protein/DNA were only significant for intestinal RNA/DNA, where a 15% reduction was observed. In contrast, stomach wet weight and total protein content were unaltered by dietary deprivation. Stomach RNA and DNA contents were reduced by only 18–21%, and the protein/DNA ratio increased by 22%. Similar responses of liver, small intestine and stomach to dietary deprivation were observed in aminoguanidine-treated rats. Aminoguanidine-treatment of rats on an unrestricted diet for three weeks had no effect on the wet weights, total protein, RNA or DNA contents of the liver, stomach or small intestine. In dietary-restricted rats, the liver and stomach were unaffected by the treatment. However, aminoguanidine treatment of dietary-restricted rats caused significant increases in the amounts of intestinal protein, RNA and DNA by approximately 15%. The treatment abolished the dietary restriction-induced decrease in total intestinal DNA/body weight. The wet weights of the lung, diaphragm, kidney, spleen and testes of both fed and dietary-restricted rats were also unaffected by aminoguanidine. It was concluded that the stomach is protected against the deleterious effects of nutritional deprivation; the data derived from the small intestine of dietary-restricted rats suggests aminoguanidine may have some potential therapeutic properties as a trophic agent.
Effect of Hydroxyethyl Rutosides and Related Compounds on Lipid Peroxidation and Free Radical Scavenging Activity. Some Structural Aspects
Authors: Rekka Eleni , Kourounakis Panos N
Published: April 2011

Four hydroxyethyl rutosides, 7,3′,4′-trihydroxyethyl quercetin, quercetin and a commercial standardized mixture of hydroxyethyl rutosides were investigated on non-enzymatic lipid peroxidation, for hydroxyl radical scavenging activity and interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH). It was found that the tested compounds exhibited a considerable inhibition of microsomal lipid peroxidation. They were less active than the reference compound quercetin, and this was attributed to their structural characteristics. They were also found to be potent hydroxyl radical scavengers and to interact with DPPH. As hydroxyl radical scavengers, they were more potent than the known hydroxyl radical scavengers mannitol and dimethyl sulphoxide. These properties could be considered as a useful and exploitable combination.
The lipid peroxidation product 4-hydroxy-2,3-trans-1 nonenal decreases rat intestinal smooth muscle function in-vitro by alkylation of sulphydryl groups
Authors: Van Der Vliet A , Van Der Aar E M , Bast A
Published: April 2011

The effects of the lipid peroxidation product 4-hydroxy-2,3-trans-1 nonenal (HNE) on intestinal smooth muscle function have been studied. Exposure of rat isolated small intestinal segments to HNE (0·1–0·5 Mm) led to decreased muscarinic and β-adrenergic responses. The maximal response to the muscarinic agonist methacholine and its pEC50 decreased in a dose dependent manner. The response to the β-adrenoceptor agonist isoprenaline was affected in a similar manner, but at slightly higher concentrations of HNE. As HNE has been described to be sulphydryl-reactive these effects were compared with the effects of the sulphydryl-reactive agent N-ethylmaleimide (NEM). Incubation of intestinal segments with NEM had similar effects on pharmacological responses to methacholine, indicating that the effects of HNE like that of NEM are likely to be caused by alkylation of sulphydryl groups. Dithiothreitol, a compound which reduces oxidized sulphydryl groups, was unable to restore the effects of HNE or NEM, which suggests that the effects of HNE and NEM are irreversible.
Toxicity of amphotericin B emulsion to cultured canine kidney cell monolayers
Authors: Lamb K A , Washington C , Davis S S , Denyer S P
Published: April 2011

The effect of amphotericin B in an emulsion formulation on the integrity of monolayers of kidney cells has been studied. Whereas a conventional solubilized amphotericin formulation (Fungizone, Squibb) caused a loss in monolayer integrity at concentrations above 1 μg mL−1, the emulsion formulation had no measurable effect on confluence at amphotericin concentrations up to 100 μg mL−1. The emulsion retained a comparable antifungal activity to that of Fungizone against Saccharomyces cerevisiae in suspension culture. These results parallel the observed erythrocyte lysis data obtained previously using amphotericin B emulsions, and suggest that the emulsion formulation may have a lower toxicity and improved therapeutic potential over existing formulations.
Thromboxane-mimetic U46619 causes depressor responses in anaesthetized rats
Authors: Hui S-C G , Ogle C W
Published: April 2011

Intravenous (i.v.) or intra-arterial injections of U46619, a thromboxane A2 (TxA2)-mimetic agent, into chloralose-anaesthetized rats dose-dependently decreased the arterial blood pressure. Indomethacin (8 mg kg−1) or atropine (1 mg kg−1), given i.v. 30 min beforehand, attenuated the hypotensive effect of U46619 i.v. whereas methysergide pretreatment (5 mg kg−1 i-v.) was without action. Pretreatment with AH23848 (5 mg kg−1 i.v.), a specific TxA2-receptor antagonist, completely abolished the depressor responses to U46619. The findings suggest that the vasodepressor effect of U46619 appears to be mediated via TxA2-receptor activation, with the release of prostacyclin and/or acetylcholine both of which produce vasodilatation.
Pharmacological characterization of the inhibitory activity of βh-endorphin (βh-EP),[Arg9,19,24,28,29]-)βh-EP,[Gln8,Gly31]-βh-EP-Gly-Gly-NH2, in the neuroeffector junction of the mouse vas deferens
Authors: Valenzuela Raúl , Li Choh Hao , Huidobro-Toro J Pablo
Published: April 2011

The inhibitory opioid activities of βh-endorphin (βh-EP), its structurally related peptide analogues [Gln8, Gly31]-βh-EP-Gly-Gly-NH2 (Gly-Gly-βh-EP), [Arg9,19,24,28,29]-βh-EP (Arg-βh-EP) and methionine enkephalin have been examined in the electrically stimulated mouse vas deferens bioassay. All four peptides behaved as full agonists; methionine enkephalin was the most potent followed by Arg-βh-EP, βh-EP and Gly-Gly-βh-EP. Neither Gly-Gly-βh-EP nor Arg-βh-EP antagonized the inhibitory action of βh-EP or methionine enkephalin. An hour of tissue exposure to 30 Nm β-funaltrexamine followed by thorough washing, displaced to the right, in a parallel fashion, the concentration-response curves of βh-EP and analogues. Whereas the displacement of the concentration response curves was 8 to 10-fold for βh-EP and Arg-βh-EP, it was only about 3-fold for Gly-Gly-βh-EP and methionine enkephalin. Naltrindole was the most potent antagonist of methionine enkephalin with an apparent pA2 of 9·4; its potency as an antagonist of βh-EP and related analogues was approximately one-tenth of this with pA2 values approximately 8·5. Norbinaltorphimine also antagonized the action of the opioid peptides with pA2 values close to 7·8.
Permeability of the blood-brain barrier for atenolol studied by positron emission tomography
Authors: Agon Philippe , Goethals Patrick , Van Haver Dirk , Kaufman Jean-Marc
Published: April 2011

The permeability of the blood-brain barrier for atenolol, a hydrophilic β-adrenergic blocking agent, has been assessed in dogs, by studying the distribution of [11C]atenolol in brain tissue with positron emission tomography. The passage of atenolol into the brain was very limited, but a measurable small net influx into the brain tissues did occur. Osmotic opening of the blood-brain barrier resulted in a marked increase of the atenolol concentrations in brain tissue. The approach described, with sequential non-invasive measurements in brain tissue, is applicable to pharmacokinetic studies of atenolol in man.
Salt Formation of Lactic Acid Oligomers as Matrix for Sustained Release of Drugs
Authors: Wada Ryoichi , Hyon Suong-Hyu , Ikada Yoshito
Published: April 2011

The calcium and sodium salts of l- and d, l-lactic acid oligomers were obtained by immersion of the oligomer powders (weight average mol. wt 3000–10000) in aqueous solutions of CaCl2 and NaCl, respectively, at room temperature (22°C). The salt formation was analysed by atomic absorption measurement. The thermal properties, including glass transition temperature, melting temperature, and softening temperature, were altered by conversion of the terminal free acid of the oligomer to its salt. An in-vitro release test of an anti-cancer drug from the oligomer beads showed that the drug was released more rapidly from the beads prepared from the non-converted oligomers than those prepared from the salts when the release test was carried out in media containing no calcium and no sodium ions.
Effect of Cigarette Smoking on Theophylline Pharmacokinetics in Rats
Authors: Gomita Yutaka , Furuno Katsushi , Eto Kohei , Okazaki Masatoshi , Suemaru Katsuya , Araki Yasunori
Published: April 2011

The effect of acute cigarette smoke inhalation on the plasma levels of theophylline administered orally and parenterally to rats has been studied. The animals were exposed to smoke containing low- or high-nicotine/tar concentration for 10 min immediately after oral, intraperitoneal (i.p.) or intravenous (i.v.) administration of theophylline. The plasma levels of theophylline when administered orally (20 mg kg−1) were lower in the two cigarette smoke-inhaling groups than in the non-smoking restrained control group, with the lowest values in the high-nicotine/tar group. The plasma levels (8 and 12 h after administration) in the high-nicotine/tar group when theophylline was administered i.p. (10 mg kg−1), were also slightly lower than in the non-smoking restrained control group but this was not significant. When theophylline was administered i.v. (5 mg kg−1), there was no difference between the high-nicotine/tar group and the nonsmoking restrained control group. These data indicate that cigarette smoke inhalation causes suppression or delay of theophylline absorption from the gastrointestinal tract.
Development of Tolerance to the Plasma Amino Acid-Decreasing Effect of Ethanol in the Rat
Authors: Hagman Mats , Eriksson Tomas
Published: April 2011

Male Sprague-Dawley rats were treated for one month with daily intraperitoneal injections of ethanol (2 g kg−1), or saline. After this pretreatment, animals from each group were given acute doses of ethanol (2 g kg−1) or saline. Plasma amino acid concentrations and brain tyrosine, tryptophan, dopamine, 5-HT and 5-HIAA concentrations were measured in samples collected 1 h after the injections. Acute administration of ethanol induced a dramatic fall in the concentrations of 18 out of 20 plasma amino acids in animals pretreated with saline. In animals chronically pretreated with ethanol this decrease was much smaller. Furthermore, the decrease was significantly lower for 6 of the measured amino acids in the chronic ethanol group compared with the saline-treated control group. Tolerance to the plasma amino acid decreasing effect of ethanol had thus developed. This acquired tolerance might be explained by both pharmacokinetic and pharmacodynamic mechanisms. Chronic administration of ethanol induced increased concentrations of tyrosine and dopamine in the brain, probably due to increased transport of tyrosine into the brain caused by an increase in the ratio of tyrosine to large neutral amino acids in plasma.
The Synthesis, and Structure-activity Relationships of some Long Chain Acyl Carnitine Esters on the Coronary Circulation of the Rat Isolated Heart
Authors: Criddle D N , Dewar G H , Radniknam M , Wathey W B , Woodward B
Published: April 2011

The synthesis of the isopropyl ester of carnitine and a series of fatty acid derivatives with fatty acid lengths C8-C30 is described. Bolus doses of these compounds (0·03–300 nmol) showed coronary vasodilator activity in the rat isolated heart. Increasing fatty acid chain length from C8 to C16 resulted in an increased vasodilator potency. Longer lasting vasodilation was observed with the C20 compound. Increasing fatty acid chain length to C30 was associated with a small dilator response preceded by vasoconstriction.
M3-Muscarinic Receptor Mediates Prejunctional Inhibition of Noradrenaline Release and the Relaxation in Cat Femoral Artery
Authors: Fernándes Filomena A , Alonso María J , Marín Jesús , Salaices Mercedes
Published: April 2011

The aim of the present study was to analyse the muscarinic receptors involved in the vasodilation elicited by acetylcholine (ACh) and the carbachol inhibition of electrically-evoked [3H]noradrenaline (NA) release in cat femoral artery. For this purpose, the following receptor antagonists were used, atropine, pirenzepine (M1-antagonist), AF-DX 116 (M2-antagonist) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3-antagonist). The order of potency (pA2 values) of these drugs at postjunctional level was: atropine (9·7) ≥ 4-DAMP (9·6) > pirenzepine (7·2) > AF-DX 116 (6·0), and at prejunctional level (pIC50 values) was: 4-DAMP (9·3) > atropine (8·5) > AF-DX 116 (7·1) > pirenzepine (5·9). These findings indicate that the muscarinic receptors mediating the vasodilation induced by ACh and the carbachol inhibition of NA release are of the M3-subtype.
The Influence of α1-Acid Glycoprotein on Quinine and Quinidine Disposition in the Rat Isolated Perfused Liver Preparation
Authors: Mansor S M , Ward S A , Edwards G , Hoaksey P E , Breckenridge A M
Published: April 2011

We have studied the effect of 0·5 and 2·0 g L−1 of α1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2·0 g L−1) resulted in a significant decrease in clearance [quinine study (control: 9·6 ±2·9 vs test: 31 ± 1·2 mL min−1); quinidine study (control: 9·8 ± 2·4 vs test: 3·5±1·1 mL min−1)] and volume of distribution [quinine study (control: 1198 ± 416 vs test: 466 ± 95 mL); quinidine study (control: 1352 ± 459 vs test: 317 ± 24 mL)] but not the elimination half-life compared with control. At the lower concentration (0·5 g L−1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0·5 to 2·0 g L−1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0·5 g L−1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.
Acoustic emission during the deformation of α-lactose monohydrate and anhydrous α-lactose monocrystals
Authors: Wong D Y T , Waring M J , Wright P , Aulton M E
Published: April 2011

During the deformation of single crystals of α-lactose monohydrate and anhydrous α-lactose in a crushing strength rig, their acoustic activity was monitored using a portable activity meter. The acoustic parameters measured were the average signal level (ASL), count rates and total acoustic counts. Both types of lactose, even though deformed by fragmentation, differed fundamentally in the degree and nature of this fragmentation. Close correlation was observed between the ASL, count rate profiles and the force-displacement profiles. The monohydrate form is acoustically more active than the anhydrous form during deformation. Small internal fractures which were neither visually observed nor detected in the force-displacement profiles (in particular the anhydrous α-lactose) were detected by monitoring the acoustic signals during the deformation of these crystals. This work illustrates the potential of using the acoustic emission technique as an aid in the assessment of the deformation characteristics of pharmaceutical materials during single crystal compression studies.
Antihaemostatic and antithrombotic effect of some antiplatelet agents isolated from Chinese herbs
Authors: Teng Che-Ming , Ko Feng-Nien , Wang Jih-Pyang , Lin Chun-Nan , Wu Tian-Shung , Chen Chien-Chih , Huang Tur-Fu
Published: April 2011

Five antiplatelet agents have been isolated from Chinese herbs. Apigenin and magnolol are inhibitors of thromboxane synthesis, while osthole, protopine and norathyriol are inhibitors of phosphoinositide breakdown. Thirty min after intraperitoneal (i.p.) administration of these drugs, tail bleeding time of mice was prolonged markedly in a dose-dependent manner by norathyriol, protopine, osthole and magnolol, but not by apigenin. However, the antiplatelet agents (up to 200 mg kg−1, i.p.) could not prevent acute thromboembolic death in mice. In endotoxin-induced experimental disseminated intravascular coagulation in rats, norathyriol (50–100 mg kg−1, i.p.) prevented the decrease in platelet counts and fibrinogen, and the prolongation of plasma prothrombin time. Norathyriol (100 mg kg−1, i.p.) also suppressed ex-vivo platelet aggregation induced by collagen and ADP in rat plasma.
α-Methyl analogues of acetylenic amines as striatal muscarinic antagonists
Authors: Sethy Vimala H , Heier Richard F , Moon Malcolm W
Published: April 2011

The effect of acetylenic amines, with or without α-methyl substitution, on striatal acetylcholine (ACh) concentration in rats was investigated. Oxotremorine, oxotremorine-1, and U-77053 (trimethyl (4-(1-pyrrolidinyl)-2 butynyl)-urea), the unsubstituted amines, increased striatal ACh concentration. On the other hand, the corresponding α-methyl substituted analogues, α-methyl-oxotremorine, BM-5, and α-methyl U-77053, decreased the concentration of ACh in the striatum. The results indicate that substitution of α-methyl in acetylenic amines converts compounds from agonists to antagonists for striatal muscarinic receptors.
The Effect of Site of Administration in the Gastrointestinal Tract on the Absorption of Insulin from Nanocapsules in Diabetic Rats
Authors: Michel C , Aprahamian M , Defontaine L , Couvreur P , Damgé C
Published: April 2011

Isobutylcyanoacrylate nanocapsules have been used as drug carriers for the enteral absorption of insulin. Their absorption has been studied by measuring fasted glycaemia in streptozotocin-induced diabetic rats after a single administration of encapsulated insulin (100 units kg−1) at various sites along the gastrointestinal tract. Glycaemia decreased from the second day, the intensity and duration depending on the site of administration (65% ileum, 59% stomach, 52% duodenum and jejunum, 34% colon). This hypoglycaemic effect lasted up to the 18th day after administration for ileum and jejunum, the 15th day for stomach and duodenum, and the 13th day for colon. In-vitro, nanocapsules protect insulin against proteolysis from pepsin, chymotrypsin and trypsin. These results suggest (i) that insulin is protected by nanocapsules in the gastrointestinal tract, (ii) that it is absorbed in an active form, and (iii) that ileum is he most potent site of absorption.
Orally Active Carbamate Prodrugs of the Selective Dopamine Agonist N-0437: In-vivo Activities in the 6-OHDA Turning Model and In-vitro Activities
Authors: den Daas Izaak , De Boer Peter , Tepper Pieter G , Rollema Hans , Horn Alan S
Published: April 2011

The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11–15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37°C, while the other test compounds were hydrolysed relatively slowly, with t 1/2 values ranging from 1.5–6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1–12 times more lipophilic than N-0437). The potential Cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak Cholinesterase inhibitors.
Effects of Calcium Antagonists on the Erythrocyte Membrane
Authors: Abe Hiroko , Katada Keiko , Orita Machiko , Nishikibe Masaru
Published: April 2011

The effects of dihydropyridine compounds nimodipine, nicardipine and NB818 (isopropyl methyl-6-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-1,4-dihydro-2-methyl-3,5-pyridine-dicarboxylate) on erythrocyte membranes have been studied. These compounds showed protective effects against hypotonic haemolysis, but not against heat-induced haemolysis. An increase in deformability of erythrocytes by these calcium antagonists was observed using a capillary tube centrifugal method. The erythrocytes showed slight stomatocytosis after 30 min of incubation with calcium antagonists, but did not show significant changes in mean corpuscular volume and ATP levels.
Two highly effective V1/V2 antagonists of vasopressin containing novel thioacids at position 1
Authors: Lammek B , Wang Y X , Franco R , Gavras I , Gavras H
Published: April 2011

In an attempt to develop more effective and selective V1/V2 antagonists of arginine vasopressin (AVP), two analogues have been designed and synthesized. In position 1 they contain thioacids that include a heteroatom in the cyclohexane ring. The 4-thio-4-tetrahydrothiopyraneacetic acid modification of position 1 used in one of them had advantages over the 1-mercaptocyclohexaneacetic acid substituted compound used as reference. The new compound was weaker at lower doses, but elicited a greater response at higher doses, whereas the reference compound reached its plateau earlier. Although the 4-thio-4-tetrahydropyraneacetic acid substitution used in the second compound resulted in a less potent analogue on a weight basis, this substitution also confers enhanced overall efficacy in terms of magnitude of effect.
Avoidance learning during antidepressant withdrawal in mice
Authors: Sansone Mario , Battaglia Mario , Ekblom Jonas , Nalepa Irena , Vetulani Jerzy
Published: April 2011

Shuttle-box avoidance acquisition, locomotor activity and density of adrenoreceptors in the cerebral cortex have been evaluated, in CD-I mice, during withdrawal from repeated treatment with desipramine or mianserin (5 or 14 daily injections of antidepressant drug, 10 mg kg−1). Withdrawal from mianserin did not produce any behavioural or neurochemical change. Mice withdrawn from desipramine exhibited avoidance facilitation, when training started 24 h (but not 72 or 120 h) after the last injection. Locomotor activity was not affected and no change was found in the density of β-adrenoreceptors. An up-regulation of α2- and, to a lesser extent, of α1-adrenoreceptors, occurred 72 h following desipramine withdrawal. However, the assessment of the role played by these neurochemical changes in the avoidance facilitation observed during withdrawal from the antidepressant treatment requires further study.
Inhibition of [3H]dopamine uptake by platelets by the dopamine-D2 receptor agonist RU 24926
Authors: Dean Brian , Srikanthan Preethi , Copolov David L
Published: April 2011

We have examined the effect of the dopamine-D2 receptor agonist RU 24926 (N-n-propyl-di-β(3-hydroxy-phenyl)-ethylamine HCl) on [3H]dopamine uptake by human platelets. RU 24926 reduced the uptake of [3H] dopamine by platelet-rich plasma and this affect was not reversed by the dopamine-D2 receptor antagonist haloperidol, or the dopamine-D1 receptor antagonist SCH 23390 (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol). These data suggest that RU 24926 reduces [3H]dopamine uptake by platelets by competing for the dopamine uptake mechanism on the platelet and not by activation of the dopamine-D2 receptor.
Effect of 8-methoxypsoralen in the dark on proliferation of stimulated lymphocytes
Authors: Górski G , Antosz H , Gawron A
Published: April 2011

The effect of 8-methoxypsoralen (8-MOP) in the dark on proliferation of phytohaemagglutinin-stimulated human lymphocytes has been examined, using total blood leucocytes, the lymphocyte fraction and the T-lymphocyte subpopulation. 8-MOP (1 μg mL−1) increased [3H]TdR incorporation and caused a rise in the blastic and mitotic index in all experimental cultures. The lymphocyte proliferation in these experiments was effected by a comitogenic effect of 8-MOP on T-lymphocytes.
DNA strand breakage by peroxidase-activated mitoxantrone
Authors: Fisher Geoffrey R , Patterson Laurence H
Published: April 2011

Spectroscopic evidence demonstrates that the alkylaminoanthraquinone mitoxantrone is a substrate for horseradish peroxidase in the presence of hydrogen peroxide and that the result of this interaction is the formation of an air-stable mitoxantrone-derived free radical. The mitoxantrone-derived free radicals or their further oxidation products appear to extensively cross-link with plasmid DNA by a reaction that is mitoxantrone concentration-dependent. Oxidative activation of mitoxantrone to a DNA-damaging species may contribute to the mechanism of action of this antitumour agent.
In-vitro Dissolution Properties of Indomethacin Extended-release Capsules
Authors: Komuro Tetsuo , Yomota Chikako , Kimura Toshio
Published: April 2011

In-vitro dissolution properties of indomethacin extended-release capsules, from samples available on the Japanese market, have been investigated using a continuous flow, column-type dissolution apparatus and the results compared with those obtained by the paddle and the rotating basket methods. A plot of the percent of drug dissolved against the square root of time gave a straight line with the flow-through method but not with the paddle or the rotating basket methods. The results suggest an advantage of the flow-through method over the other two methods when extended-release products are tested by in-vitro dissolution.
Effect of an Anti-SRS-A Agent, NZ-107, on Airway Responses Induced by Ovalbumin and A23187 in the Guinea-pig
Authors: Yamamoto Akiko , Shikada Ken-Ichi , Iwama Takehisa , Sakashita Mitsuaki , Hibi Morihide , Tanaka Sakuya
Published: April 2011

The effects of the anti-SRS-A agent NZ-107 on antigen-(ovalbumin) and calcium ionophore A23187-induced airway responses in the guinea-pig have been investigated. In the presence of 5 μM indomethacin, NZ-107 (3 μM) did not affect the peak response in ovalbumin-induced contraction but did inhibit the prolonged response following the peak response in the tracheal strip. A higher concentration of NZ-107 (10 μM) completely blocked both peak and prolonged responses. Inhibitory effects of NZ-107 on ovalbumin responses were less in the lung parenchymal strip. The potency of NZ-107 in inhibiting ovalbumin-induced tracheal contraction was not changed in the absence of indomethacin but was reduced in the presence of 45 mM serine-borate, an inhibitor of the conversion of LTC4 to LTD4. NZ-107 inhibited A23187-induced contractions in both tracheal and parenchymal strips but in both cases the inhibitory potency was less than that on ovalbumin response. NZ-107 was a more potent inhibitor of ovalbumin-induced SRS-A release than histamine release in lung fragments but was ineffective in inhibiting A23187-induced SRS-A and histamine release. NZ-107 at a concentration of 10 μM more effectively inhibited LTC4-and histamine-induced tracheal contractions than it did LTC4 in the presence of 45 mM serine-borate. These results suggest that NZ-107 selectively inhibits antigen-induced SRS-A responses in airway tissues of the guinea-pig.