bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unequal Disposition of Enantiomers of the Organic Cation Oxyphenonium in the Rat Isolated Perfused Liver
Authors: Feitsma Karla G , Drenth Ben F H , de Zeeuw Rokus A , Oosting Roelof , Meijer Dirk K F 
Published: April 2011

Abstract
This paper describes the results of pharmacokinetic experiments in the rat isolated perfused liver with enantiomers of oxyphenonium. The study was performed with the [14C]methyl labelled compounds. In this preparation both metabolism and biliary excretion were significantly different for the (+)- and the (-)-isomer. Hepatic uptake rate was similar, but total biliary excretion (including metabolites) of the (-)-isomer was only 55% compared with the excretion of the (+)-isomer. In line with these data, after 2 h only 30% of the dose of the (+)-isomer and over 50% of the dose of the (-)-isomer was still found in the liver, predominantly in the form of metabolites. The metabolic profile was investigated using ion pair TLC. At least two metabolites were detected in bile for both enantiomers. However, unchanged (-)-oxyphenonium persisted for longer in bile, indicating either a more rapid canalicular transport of the (+)-isomer and/or a more rapid metabolism of (+)-oxyphenonium to cholephilic metabolites.
The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6-(1-Imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904), in Man after Single Oral Administration
Authors: Tanaka Makoto , Ono Kenji , Takegoshi Toshio , Shiozawa Tomoo , Suzuki Tomoyoshi , Nii Shigenori , Shibata Hisao 
Published: April 2011

Abstract
The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10–800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean ± s.e., n = 5) of 0·215 (± 0·041), 0·399 (± 0·037), 1·47 (± 0·22), 2·86 (±0·22), 4·66 (±0·58), 7·28(±0·72) and 16·9 (±2·6) μgmL−1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30–40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0·398 (±0·038) to 30·0 (±2·7) μgh. mL−1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0·930 and 0·960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied. The urinary excretion of DP-1904 was also independent of the administered dose, and about half of the dose was recovered in urine as unchanged form within 48 h after administration. The elimination of the drug was fast and almost complete within 6 h after dosing. On the other hand, only 0·5% of the dose was excreted into faeces as intact DP-1904 up to 48 h after 400 mg oral dose. Food intake delayed the absorption of DP-1904 but did not significantly modify its pharmacokinetics. Serum thromboxane B2 levels (the stable metabolite of thromboxane A2) were reduced more than 90% within 0·5 h after all doses studied. DP-1904 had a long duration of inhibitory activity and there was still more than 80, 90 and 95% suppression at 12 h after 200, 400, and 800 mg doses, respectively.
Dual Effects of Zinc Sulphate on Ethanol-induced Gastric Injury in Rats: Possibly Mediated by an Action on Mucosal Blood Flow
Authors: Cho C H , Chen B W , Poon Y K , Ng M M T , Hui W M , Lam S K , Ogle C W 
Published: April 2011

Abstract
The present study examines the protective effect of zinc sulphate against ethanol-induced gastric mucosal ulcers in rats. Absolute ethanol decreased the gastric mucosal blood flow and produced haemorrhagic lesions in the glandular mucosa. Zinc sulphate preincubation in an ex-vivo stomach chamber preparation prevented the formation of ethanol-induced lesions and attenuated the decrease of blood flow produced by ethanol. Subcutaneous injection of the same doses of the drug at 15 and 30 min before ethanol exposure, markedly reduced the blood flow and also aggravated ethanol-induced gastric injury; however, when injected at 23 and 24 h before ethanol administration, zinc sulphate protected against lesion formation but had no effect on the vascular changes induced by ethanol in the gastric glandular mucosa. These findings show that the antiulcer effect of zinc sulphate occurs only when the drug is given orally, or injected s.c. 23 and 24 h before ethanol challenge. Furthermore, this protective action is probably not entirely mediated by preservation of the gastric mucosal blood flow.
The influence of monoamine oxidase activity on the release of noradrenaline by tyramine
Authors: Brandão F , Araújo D , Monteriro J Guilherme 
Published: April 2011

Abstract
The influence of monoamine oxidase (MAO) activity on the kinetic characteristics of noradrenaline (NA) release evoked by tyramine has been examined. Dog splenic artery strips were incubated with [3H]NA after inhibition of catechol-O-methyl-transferase (COMT) and of extraneuronal uptake. In some experiments MAO was also inhibited. The strips were then perifused for 200 min. Some strips were exposed to tyramine (1·5, 40 and 3240 μmol L−1) from the 100th to the 200th min of perifusion. In control experiments (i.e. in the absence of tyramine) most of the [3H]NA accumulated in the strips (83% of tissue activity) and did not contribute to the efflux. The value of this “bound fraction” (the NA located at a site(s) from which it could not be displaced by a simple concentration gradient) was the same whether or not MAO was inhibited. At all concentrations, tyramine mobilized only one NA compartment. Increasing the concentration of tyramine resulted in a decrease of the “bound fraction”, which became negligible for the highest concentration of tyramine used (3240 μmol L−1), regardless of MAO being inhibited or not. However, for the lower concentrations of tyramine, MAO inhibition resulted in an increase in the amine’s releasing effect. The formation of 3,4-dihydroxy-phenylglycol (DOPEG) increased with increase of tyramine from the 1·5 to 40 μmol L−1 concentration, but not beyond. The ratio NA/DOPEG increased for all concentrations of tyramine. Thus, it was not possible to exclude an inhibitory effect of tyramine on MAO activity with the highest concentration used.
Methodology for a Better Evaluation of the Relation Between Mechanical Strength of Solids and Polymorphic Form
Authors: Kopp S , Beyer C , Graf E , Kubel F , Doelker E 
Published: April 2011

Abstract
In order to evaluate the role played by polymorphism in the mechanical strength of solid dosage forms (e.g. compressed tablets) and minimize the influence of other factors (such as compaction force, porosity, particle size, and possibly crystal habit), a melted disc technology was developed. With this technique, tablet-shaped discs of zero porosity were prepared by melting powder and subsequent crystallization in the desired modifications. Taking phenobarbitone as a model drug, different methods were used to get discs of forms I, II and III and the amorphous form. Mechanical properties of the discs were assessed, primarily through their bending strength. The Vickers hardness number was also determined for some specimen discs and monocrystals. Results showed that the amorphous form and form III of phenobarbitone gave the toughest discs and would be therefore the most suitable materials to manufacture coherent tablets. Moreover, the various preparation methods used resulted in discs of different internal structures. Both crystal size and crystal habit significantly affected the physical properties of the tested materials.
Lack of Mixed Agonist-Antagonist Properties of [Gln8-Gly31]-βh-EP-Gly-Gly-NH2 and [Arg9,19,24,28,29]-βh-EP in the Rat Vas Deferens Neuroeffector Junction: Studies with Naloxone, β-Funaltrexamine and ICI 174,864
Authors: Valenzuela Raúl , Li The Late Choh Hao , Huidobro-Toro J Pablo 
Published: April 2011

Abstract
The 1–27 truncated fragment of βh-endorphin (βh-EP) as well as [Gln8,Gly31]-βh-EP-Gly-Gly-NH2 or [Arg9,19,24,28,29]-β-EP exhibited opiate agonist activity in the rat vas deferens bioassay; the potency of these peptides was 3 to 6 times less than that of βh-EP. None of these compounds exhibited any degree of antagonism towards the inhibitory action of βh-EP. Naloxone antagonized and reversed the inhibitory action of βh-EP and its analogues though with varying potencies. The apparent naloxone-pA2 value for βh-EP was 8·94; that for [Gln8-Gly31]-βh-EP-Gly-Gly-NH2 was 8·08 and that for [Arg9,19,24,28,29]-βh-EP was 8·38. β-Funaltrexamine (β-FNA) potently antagonized the inhibitory action of βh-EP following non-equilibrium kinetics. Tissue preincubation with 10 nM β-FNA for 60 min followed by extensive washing caused a 10-fold increase in the βh-EP IC50. However, 10 nM β-FNA caused only a 1·2 increase in the IC50 of [Gln8,Gly31]-βh-EP-Gly-Gly-NH2 and a 4·1 -fold increase in the IC50 of [Arg9,19,24,28,29]-βh-EP. In contrast, preincubation of the tissue with 3 βM ICI 174,864 did not modify the potency of βh-EP or its structural analogues. However, a 60 min pretreatment with 10 μM β-FNA followed by the addition of 3 μM ICI 174,864 revealed a further decrease in the potency of the opiopeptins compared with tissues exposed to β-FNA alone or ICI 174,864 alone. In conclusion, the inhibitory action of these peptides is remarkably sensitive to β-FNA antagonism; in addition the peptides act as pure opiate agonists in marked contrast with the agonist-antagonist properties described in the CNS.
Distribution of dissociation constant values of muscarinic agonists
Authors: Lucchelli Adele , Boselli Cinzia , Grana Enzo 
Published: April 2011

Abstract
The frequency distributions of dissociation constant values of some muscarinic agonists (carbachol, muscarone and cis-2-methyl-5-trimethylammoniummethyl-1,3-oxathiolane) obtained on guinea-pig ileum and atria and rat urinary bladder have been examined to see if the means of the dissociation constant values and the statistical tests for their significance, should be based on geometric rather than on arithmetic means. For the three compounds the distributions on a logarithmic scale did not significantly deviate from normality while the distributions on an arithmetic scale tended to deviate from normality.
Hydrogel Patches for Transdermal Drug Delivery; In-vivo Water Exchange and Skin Compatibility
Authors: Boddé H E , van Aalten E A C , Junginger H E 
Published: April 2011

Abstract
Hydrogel patches based on water swellable polyacrylates have been developed for long-term transdermal drug delivery. Two properties, relevant to the performance of hydrogel patches in-vivo have been investigated in humans over five days. These were: (i) the kinetics of water exchange between the skin and the patches; (ii) the skin compatibility of the patches. It was found that initially there was a gradually increasing uptake of water from the skin by the patches, but after about 20 h the water exchange followed a regular fluctuating pattern, peaking once a day and once a night. The skin compatibility of the patches was satisfactory, in that no redness or pustulation was noticed throughout the five days. This was most likely due to the capability of the patches to exchange water with the skin.
Naloxone-insensitive Inhibitory and Excitatory Effects of Opioid Agonists in the Rat Isolated Uterus
Authors: Ohia S E , Laniyonu A A 
Published: April 2011

Abstract
Morphine (3 × 10−6−10−3 M) produced a concentration-dependent inhibition of both spontaneous rhythmic contractions and tonic contraction induced by potassium chloride (KCl) (50 mM) in rat isolated uterus. Uteri at the metoestrus phase were the most sensitive to the inhibitory effect of morphine. Morphine-induced relaxation was characterized by a post-wash tonic contraction. The μ-specific opioid agonist, D-alaglymepheglycol (DAGO) (4 × 10−8−1·2 × 10−5 M) did not affect spontaneous rhythmic contraction but produced a partial inhibition of the KCl depolarized uterus. There was no post-wash contraction following DAGO. In contrast to the inhibition produced by both morphine and DAGO, methionine enkephalin (8 × 10−7−2·4 × 10−5 M) produced a concentration-dependent contraction of the KCl depolarized uterus. Naloxone up to 100 μM, propranolol (10 μM), flurbiprofen (50 μM) and metiamide (10 μM) did not affect either the relaxation produced by morphine and DAGO or the contraction produced by methionine enkephalin. The results showed that the opioid agonists may have non-receptor mediated direct effects on the rat uterus.
Influence of streptozocin-induced diabetes on reductive metabolism of acetohexamide in rat liver
Authors: Imamura Yorishige , Kojima Yuichiro , Otagiri Masaki 
Published: April 2011

Abstract
Streptozocin-induced diabetes significantly decreased acetohexamide reductase activity of 10 000 g supernatant of liver homogenates from both male and female rats. However, the decrease in activity from female rats was smaller than that from male rats, thereby eliminating the sex difference in the activity of the 10 000 g supernatant. In male rats, the diabetes markedly decreased acetohexamide reductase activity only in the microsomal fraction of liver homogenate, whereas in female rats, it decreased the activity only in the cytosolic fraction. These results indicate that the mechanism for the decreasing effect of the diabetes on reductive metabolism of acetohexamide in 10 000 g supernatant differs between male and female rats.
Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B
Authors: Yu Peter H 
Published: April 2011

Abstract
Monoamines with from 1 to 18 straight chain carbon atoms have been analysed as rat liver monoamine oxidase substrates. Methylamine and ethylamine are clearly not substrates of monoamine oxidase (MAO). n-Propylamine, n-butylamine, n-dodecylamine and n-octadecylamine are relatively poor substrates, i.e. with high Km and low Vmax values for the enzyme. n-Pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine and n-decylamine are all very good MAO substrates. All these aliphatic amines are found to be typical type B substrates according to the sensitivities of the enzyme towards the selective MAO-B inhibitor selegiline and the MAO-A inhibitor, clorgyline. The sensitivity towards selegiline with respect to these amines is even higher, i.e Ki = 1 × 10−9 M for butylamine, than that of the typical type B substrate β-phenylethylamine (Ki = 1 × 10−8 M). The sensitivity towards selegiline decreases slightly with increasing chain length of these aliphatic amines.
Controlled Release of LHRH Agonist, Leuprolide Acetate, from Microcapsules: Serum Drug Level Profiles and Pharmacological Effects in Animals
Authors: Ogawa Yasuaki , Okada Hiroaki , Heya Toshiro , Shimamoto Tsugio 
Published: April 2011

Abstract
The pharmacokinetic behaviour of leuprolide acetate from a controlled release parenteral dosage form has been studied in rats and dogs. The release of the drug in rats after a single subcutaneous injection exhibited pseudo-zero-order kinetics for one month in doses ranging from 0·0135 to 1·35 mg/rat; the release rate at a dose of 1·35 mg/rat was 2·8% of dose/day; after intramuscular injection the response was similar. In rats, the serum leuprolide acetate levels increased sharply immediately after injection by either route as a consequence of the initial release of the drug; subsequently, the levels attained a plateau for two weeks. The serum level profiles in dogs showed essentially the same pattern as those in rats. When the dosage form was injected into rats, the serum testosterone level (a pharmacological index) sharply peaked, abruptly decreased to below the normal level, and then was sustained at a suppressed level for over six weeks at a dose of 1·35 mg/rat (equivalent to 3 mg kg−1) and higher, while the serum testosterone level after an injection of 0·0135 and 0·135 mg/rat was not sufficiently suppressed. The profiles in dogs showed essentially the same pattern as those in rats. With multiple administrations (once every 4 weeks), serum testosterone levels in dogs did not show any sharp rise after the second and third injections. Changes in rat reproductive organ weights agreed well with the serum testosterone profile in the suppression. The results demonstrate that this dosage form releases the drug at a constant rate for one month and has a long-acting potency.
A high dose of MPTP overcomes the protective effect of selegiline against dopaminergic neurotoxicity
Authors: Fuller Ray W , Hemrick-Luecke Susan K 
Published: April 2011

Abstract
1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) at 90 mg kg−1 s.c., a dose lethal in non-pretreated mice, was well tolerated in selegiline ((—)-deprenyl)-pretreated mice and produced persistent depletion of striatal dopamine and its metabolites one week after the last of four daily injections. The protective effect of selegiline against dopaminergic neurotoxicity of MPTP can thus be overridden by a high dose of MPTP that would be lethal without selegiline pretreatment.
Effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin and [D-Ala2,D-Leu5]enkephalin on ion and amino acid transport in rabbit ileum
Authors: Meyer G , Botta G , Tavani A , Algeri S , Cremaschi D 
Published: April 2011

Abstract
The selective μ-opioid agonist [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAGO) (10 μM) reduced the short circuit (Isc) and the L-valine induced increase of the transepithelial potential difference and Isc(δVms and δsc) measured in-vitro in rabbit ileum, with a mechanism antagonized by naloxone (1 μM). [D-Ala2, D-Leu5]enkephalin (DADLE) (10 μM) had no significant effect on the transepithelial potential difference (Vms), Isc, δVms and δIsc. In the ileum deprived of the serosa and muscolaris, DAGO reduced the δVms and δIsc, but not the Vms and Ics, suggesting localization of the receptors responsible for this latter effect in the myenteric plexus and/or the muscularis mucosae. These preliminary results suggest that in the rabbit ileum opioids influence electrolyte and amino acid transport and these effects may be at least partly mediated by μ-receptors.
α-Blockade on Blood Pressure and on Cardiac Noradrenaline Content in SHR and DOCA-salt Rats
Authors: Sanchez Adela , Torres Andres , Saiz Jesus 
Published: April 2011

Abstract
The current study was designed to explore the effects of peripherally administered α-adrenoceptor inhibiting drugs (either prazosin or yohimbine) in spontaneously hypertensive (SHR) and DOCA-salt hypertensive rats before the development of established hypertension, as well as to characterize changes induced by prazosin and/or yohimbine in the cardiac noradrenaline (NA) content that might be responsible for the development of hypertension in these strains. The α-adrenoceptor blockade can prevent hypertension in DOCA and salt-treated animals in such a way that their blood pressure stabilizes at levels significantly lower than those observed in similarly treated normotensive controls. Significantly lower cardiac NA content was observed in DOCA-salt rats under basal and experimental conditions. The blood pressure of the treated rats and the heart NA content of the SHR were unaltered by treatment. Thus, administration of the α-adrenoceptor blocking agents, prazosin and/or yohimbine, throughout the developmental stage of SHR hypertension failed to alter either the progressive rise in blood pressure or in NA content. There may be differences between the cardiac adrenergic mechanisms responsible for the development of hypertension in each of these two models of hypertension.
The role of vagal adrenergic activity in the mechanism of gastric acid secretion after pylorus-ligation in the rat
Authors: Salim Aws S 
Published: April 2011

Abstract
The role of the vagus nerve and adrenoceptor stimulation in acid secretion after pylorus-ligation in the rat has been examined. All drugs were administered intraperitoneally. Atropine (5 mg kg−1) depressed the H+ output (111 μmol ± 33·8 vs 412·5 μmol ± 62·2, mean ± s.e.m., n = 10, P&lt;0·001); Cimetidine (40 mg kg−1) did not enhance this action, while vagotomy was more effective than atropine (32·7 μmol ± 4·9, mean ± s.e.m., n = 10, P&lt;0·05). Atropine (10 mg kg−1) produced a similar depression to the 5 mg kg−1 dose. Cimetidine (100 mg kg−1) depressed the H+ output (248·5 μmol ± 46·8, mean ± s.e.m., n = 10, P&lt;0·05). Propranolol (5–20 mg kg−1) had no significant effect on the H + output but dose-dependent inhibition was produced by phenoxybenzamine or phentolamine; an inhibition similar to that achieved by vagotomy was seen with the 20 mg kg−1 dose. Both these drugs (5 or 10 mg kg−1) had no significant effect on the H+ output when given with atropine (5 mg kg−1) but the H+ output was significantly lower than that produced by either drug at the same dose given alone. Atropine (5 mg kg−1) with phenoxybenzamine or phentolamine (20 mg kg−1) produced H + output not significantly different from that with vagotomy or either α-adrenoceptor given alone at 20 mg kg−1, but the result was significantly (P&lt;0·05) lower than the H+ output with atropine (5 mg kg−1) alone. The results suggest that pylorus-ligation in the rat produces vagal α-adrenoceptor delivery to the stomach causing cholinergic and non-cholinergic stimulation to acid secretion.
Comparison of Transport Characteristics of Amino β-Lactam Antibiotics and Dipeptides Across Rat Intestinal Brush Border Membrane
Authors: Iseki Ken , Sugawara Mitsuru , Saitoh Hiroshi , Miyazaki Katsumi , Arita Takaichi 
Published: April 2011

Abstract
The transport characteristics of amino β-lactam antibiotics, ampicillin and cephradine, have been examined and compared with that of glycylglycine using brush border membrane vesicles isolated from rat small intestine. The initial rate of glycylglycine uptake was markedly stimulated in the presence of an inward H + gradient compared with the uptake rates in the absence of an H + gradient. With the same H + gradient the stimulation of cephradine uptake was lower and ampicillin uptake was not altered. Cephradine uptake, however, was greater than that of glycylglycine in both vesicular conditions ((pH)i &gt; (pH)0 and (pH)i = (pH)0). Inhibitory effects of dipeptides, ampicillin and cephradine on the initial uptake of glycylglycine were also examined. Glycylglycine uptake was significantly decreased in the presence of L-phenylalanylglycine or carnosine. Ampicillin and cephradine did not alter the uptake of glycylglycine. These results suggest that the contribution of the inward H+ gradient to the permeation of ampicillin, cephradine and glycylglycine across the rat small intestinal brush border membranes is different for each of the substances examined.