bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolution and Electrophysiological Effects of Mexiletine Enantiomers
Authors: Turgeon Jacques , Uprichard Andrew C G , Bélanger Pierre M , Harron Dean W G , Grech-Bélanger Odette 
Published: April 2011

Abstract
Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(–)- and S-(+)-mexiletine were resolved with an optical purity &gt; 98 % (yield ∼ 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7–30 days after coronary ligation. R-(–)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0·5 mg kg−1, 1 after 8 mg kg−1); two animals died after 1 and 8 mg kg−1, respectively; one remained unchanged even at the highest dosage (16 mg kg−1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg−1); two died after 4 and 8 mg kg−1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg−1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0·5–16·0 mg kg−1). These results suggest that R-(–)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.
Investigation of the Different Types of Opioid Receptor Involved in Electroconvulsive Shock-induced Antinociception and Catalepsy in the Rat
Authors: Jackson Helen C , Nutt D J 
Published: April 2011

Abstract
The effects of novel opioid antagonists on the behavioural syndrome induced by electroconvulsive shock (ECS) in rats have been examined and compared with those of the established agent naloxone. A single ECS produced catalepsy and significantly increased tail immersion response times during the 15 min following the seizure. These responses were inhibited by a low dose of naloxone (1 mg kg−1, i.p.) and also by RX8008M (16-methylcyprenorphine; 1 mg kg−1, i.p.) which blocks μ- and δ- but not κ-opioid receptor function. In comparison, the antinociception and catalepsy induced by ECS was not attenuated by the selective δ-receptor antagonist naltrindole (1 mg kg−1, i.p.). These results suggest that ECS-induced antinociception and catalepsy may be mediated by endogenous opioids acting at μ-opioid receptors and are consistent with biochemical studies showing the release of β-endorphin in both animals and man following this procedure.
Changes in K+-induced contractions in ileal longitudinal smooth muscle of guinea-pig, induced by monoiodoacetic acid
Authors: Nasu T , Narimatsu H , Shibata H 
Published: April 2011

Abstract
The ileal responses to 40 min [K+]o were changed in the period after administration of monoiodoacetic acid (IAA). The phasic contraction to K+ appeared in the period before the development of a rigor, after the administration of 1 mM IAA. However, the response to K+ was absent during the development of a rigor to IAA during decreasing tissue ATP concentrations.
Lung Uptake of Liposome-entrapped Glutathione After Intratracheal Administration
Authors: Jurima-Romet M , Shek P N 
Published: April 2011

Abstract
The intratracheal delivery of glutathione (GSH), in liposome-encapsulated form, prolongs retention of the drug in the rat lung. This study has been designed to determine the extent and zime-course of pulmonary tissue uptake of administered 14C-labelled liposomes containing [3H]GSH. Liposomes, composed of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine each with or without 30 mol% cholesterol showed a clearance &gt;80% from the bronchoalveolar lavage, 24 h after intratracheal instillation. Lung tissue content of 14C-lipid increased with time: by 72 h, 42–56% of the administered dose was recovered from the tissue. [3H]GSH was present in pulmonary tissue in relatively constant amounts throughout the 72 h, ranging from 14–35% of the administered dose. Vesicles composed of DMPC had a low entrapment for GSH. There were only minor differences in GSH entrapment efficiency and lung tissue uptake between vesicles of the other lipid compositions.
Synthesis of Some Phenothiazine Derivatives as Potential Affinity Ligands for the Central Dopamine Receptors
Authors: Šoškić V , Maelicke A , Petrovic Gorica , Ristic Biljana , Petrović Jelena 
Published: April 2011

Abstract
Syntheses of several phenothiazine ligands as potential affinity probes for the D1- and D2-dopamine receptors derived from 4-(3-(10-(2-trifluorornethyl) phenothiazinyl) propyl)-1-(2-aminoethyl)-piperazine hydrochloride are described and their interactions with D1 and D2-dopamine receptors of the bovine caudate nucleus have been characterized. The bromoacetylamido-, maleinimido-, and isothiocyanato-derivatives expressed low selectivity and moderate affinity for both categories of dopamine receptors. 4-(3-(10-(2-Trifluoromethyl) phenothiazinyl)propyl)-1-(2-(isothiocyanatobenzoyl)ethyl)-piperazine hydrochloride did not discriminate among the two subclasses of the dopamine receptors, but showed an extremely strong irreversible binding to the D1-receptors and thus is promising as a highly specific affinity ligand for biochemical and pharmacological studies of the D1-dopamine receptors.
The role of the disulphide bonds in endothelin-1
Authors: Pelton John T , Miller Robert C 
Published: April 2011

Abstract
The smooth muscle contracting peptide endothelin-1 is characterized by the presence of two disulphide bonds and their importance for maintaining the agonist activity of the peptide was examined by synthesizing analogues of endothelin-1 lacking one or the other, or both, of these bonds. The circular dichroic spectra of these analogues (in which alanine residues replaced the appropriate cystines), [Ala1,15]-, [Ala3,11]- and [Ala1,3,11,15]-endothelin-l had features in common with that of endothelin-1. All three analogues exhibited at least some agonist activity in guinea-pig isolated trachea, but surprisingly endothelin-1 was a partial agonist in comparison with the analogue [Ala3,11]endothelin-1. The disulphide bonds are therefore not absolutely essential for maintaining the tertiary structure necessary for agonist activity at endothelin-1 receptors in all tissues.
Peripheral benzodiazepines potentiate the effect of adenosine in rat vas deferens
Authors: Escubedo Elena , Camarasa Jorge , Pallas Mercé , Adzet Tomás 
Published: April 2011

Abstract
Ro 5–4864, diazepam, clonazepam and PK 11195 inhibit the responses of rat vas deferens following electrical stimulation in the rank order Ro 5–4864 &gt; PK 11195 = diazepam &gt; clonazepam. The adenosine-inhibited electrically-induced response was potentiated by Ro 5–4864 or diazepam, but not by clonazepam or PK 11195. This potentiation is due to an inhibition of the adenosine uptake system.
Corticosterone and prolactin response to TFMPP in rats during repeated antidepressant administration
Authors: Poland Russell E , Frazer Alan 
Published: April 2011

Abstract
The corticosterone and prolactin response to acute administration of the 5-HT agonist 1-(m-trifluoromethylphenyl) piperazine (TFMPP) (10 mg kg−1) was assessed in rats treated for 10 days with either saline, amitriptyline (20 mg kg−1 day−1) or nialamide (40 mg kg−1 day−1). For all groups, TFMPP significantly increased both serum corticosterone and prolactin concentrations compared with control animals challenged with saline. However, the corticosterone response to TFMPP was attenuated significantly by nialamide pretreatment, while the prolactin response to TFMPP was enhanced significantly by amitriptyline pretreatment. These results support previous reports that antidepressants differentially affect 5-HT-ergic systems involved in the regulation of corticosterone and prolactin secretion.
Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes
Authors: Shahid M , Rodger I W 
Published: April 2011

Abstract
The inotropic activity of amrinone and its effects on cyclic nucleotide levels in rabbit papillary muscles with normal and depressed contractile function have been compared. The effects of amrinone on the cyclic (c) AMP hydrolytic activity of cyclic nucleotide phosphodiesterase (PDE) isoenzymes were also examined. Amrinone (2.4 × 10−4-1.2 × 10−3 M) produced a relatively weak (maximal increase 11%) positive inotropic effect in papillary muscles stimulated at the near optimal stimulation frequency of 1 Hz. In contrast, large positive inotropic responses (maximal 138–200%) were obtained with amrinone in papillary muscles in which contractile force had been depressed by: (a) lowering stimulation frequency to 0.4 Hz, (b) reducing extracellular Ca2+ concentration from 2.5 × 10−3 M to 6.3 × 10−4 M, (c) prior addition of sodium pentobarbitone (6.5 × 10−4 M). The EC50 values for amrinone under conditions (a), (b), and (c) were 3.0 × 10−3, 2.6 × 10−3, and 2.8 × 10−3 M, respectively. Force-frequency curves in rabbit papillary muscles were compared at normal (2.5 ×10−3 M) and low (6.3 × 10−4 M) extracellular Ca2+ concentration. Contractions at low frequencies of stimulation (&lt; 0.4 Hz) were less sensitive to removal of extracellular Ca2+ than higher stimulation rates indicating that in the former situation, recycling of intracellular Ca2+ is more important for maintaining contractile force. The positive inotropic effects of amrinone in normal and papillary muscles with depressed contractile force were associated with similar increases in both cAMP (1.6-2.5 fold) and cGMP (2.6-4.0 fold) levels, despite marked differences in the degree of inotropy in these muscles. The cGMP inhibited cAMP-PDE (PDE III) was selectively inhibited by amrinone (IC50 9.9 × 10−5 M), whilst the activities of Ca2+/calmodulin-stirnulated PDE, cGMP-stimulated PDE and cGMP-insensitive PDE were only weakly affected (IC50 &gt; 2.5 × 10−4 M). The results show an involvement of cAMP in the mechanism underlying the positive inotropic action of amrinone in cardiac muscle with depressed contractile force. Furthermore, it is suggested that there may be an enhanced effectiveness of cAMP on intracellular Ca2+ mobilization in depressed cardiac muscle.
Effect of Some Cationic Amphiphilic Drugs on Phospholipid Methylation in the Central Nervous System of Rats
Authors: Nocon Halina , Melzacka Miroslawa 
Published: April 2011

Abstract
Imipramine, desipramine, citalopram and chlorpromazine in concentrations which corresponded with their concentration in the central nervous system of rats after pharmacological doses, potentiated phospholipid methylation in the synaptic cortical membranes of naive rats in-vitro. Chronic administration of imipramine, desipramine or citalopram induced changes in the activity of phospholipid methyltransferases since none of these drugs stimulated phospholipid methylation in the synaptic cortical membranes of rats treated with these antidepressants for two weeks. In contrast, chronic treatment with chlorpromazine did not change the sensitivity of phospholipid methyltransferases to the stimulating effect of chlorpromazine, whereas addition of haloperidol to the synaptic cortical membranes of rats treated chronically with haloperidol led to a decrease of phospholipid methylation.
Reconsideration of inhibitory effect of metformin on intestinal glucose absorption
Authors: Wilcock Carol , Bailey Clifford J 
Published: April 2011

Abstract
New evidence that metformin increases intestinal glucose metabolism has necessitated a re-examination of the effect of metformin on intestinal glucose absorption. Normal 18 h fasted mice received an intragastric bolus of metformin 2 h before preparation of everted gut sacs from the proximal, middle and distal regions of the jejunum and ileum. Net mucosal glucose transfer from the intestinal lumen into the tissue was reduced by 15 and 28% after 50 and 250 mg kg−1 metformin, respectively (ANOVA, P &lt; 0.05). Net glucose transfer into the serosal fluid was reduced by 12 and 70% after 50 and 250 mg kg−1 metformin respectively (ANOVA, P &lt; 0.05 and P &lt; 0.01). The inhibitory effect of metformin on both the mucosal and serosal glucose transfer mechanisms was greatest in the middle portion of the small intestine. The results suggest that metformin decreases intestinal glucose absorption in a dose-dependent manner by effects on mucosal and serosal glucose transfer.
Electrochemical determination of the permeability of porcine mucus to model solute compounds
Authors: Desai M A , Nicholas C V , Vadgama P 
Published: April 2011

Abstract
An electrochemical approach to the determination of permeability through native mucus gel of simple electrochemically active solutes is reported. For all the the solutes studied, a reduction in effective diffusion coefficients was observed, with retardation of solute flux by a factor of at least two. However, NADH and the dicarboxylic acid derivative of ferrocene demonstrated a substantial, almost ten-fold, reduction in permeability through mucus. Results for the controls were in reasonable agreement with literature values where available. No consistent effect of molecular weight was evident with regard to the barrier properties of mucus over the molecular weight range of solutes investigated (34–660 daltons). The results suggest that mucus is acting more than as a gel support for an unstirred water layer.
Concentration of ibuprofen in cervical mucus
Authors: Salas-Herrera I G , Pearson R M , Turner P 
Published: April 2011

Abstract
Concentrations of an acidic drug, ibuprofen, in cervical mucus and serum have been measured by HPLC after oral administration in six healthy volunteers. After an 800 mg single dose of ibuprofen, the concentration reached in cervical mucus was less than 4% of that in serum. It is postulated that because ibuprofen is an acidic drug which is not subject to ‘ion-trapping’ in the acidic environment of cervical mucus, it is not concentrated in this secretion.
Analogues of Triprolidine: Structural Influences upon Antihistamine Activity
Authors: Casy A F , Ganellin C R , Mercer A D , Upton C 
Published: April 2011

Abstract
The synthesis of some geometrical isomers related to triprolidine is reported. Previous configurational assignments, by UV and proton NMR, are validated by high field nuclear Overhauser enhancement methods and the isomeric purity of tested E- and Z-isomers was greater than 99.5% as assessed by an HPLC method developed for these compounds. Affinity constants for triprolidine (E and Z) in guinea-pig ileum showed a potency ratio of ∼600 whereas at cerebellar sites this ratio was only ∼100, suggesting that the H1 receptor in these two tissues may not be identical. In-vivo tests using a lethal dose of compound 48/80 (a potent histamine-releasing agent) demonstrated that triprolidine itself was the most active compound to protect the animal among all the isomeric compounds tested: in all isomeric pairs the E-configuration possessed superior activity over Z. The disposition of the aryl groups in these geometrically constrained compounds mimics that seen in the structurally related chiral pheniramines which are sp3 hybridized and whose absolute stereochemistry is known.
Binding Potency of Paroxetine Analogues for the 5-Hydroxytryptamine Uptake Complex
Authors: Mathis Chester A , Gerdes John M , Enas Joel D , Whitney John M , Taylor Scott E , Zhang YI , Mckenna Dennis J , Havlik Sona , Peroutka Stephen J 
Published: April 2011

Abstract
The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4′≅ 3′-≅ 2″-&gt;2′-≅ 1- &gt;5″-&gt; 6″-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4′-,3′-, and 2″-methyl derivatives were 1·9, 2·2 and 2·2, respectively. The 4′- and 2″-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4′- and 2″-fluoromethyl derivatives were determined to be 2·0 and 3·5, and those of the 4′- and 2″- fluoroethyl analogues were 5·2 and 6·2, respectively. The 2″-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies. The 4′-fluoromethyl derivative was stable in aqueous solutions and, based upon its relatively high affinity, is a candidate for radiolabelling with 18F for in-vivo positron emission tomography studies of the 5-HT re-uptake site.
In-Vivo Pharmacological Studies of 2-N-Carboxamidinonormianserin, a Histamine and 5-Hydroxytryptamine Antagonist Lacking Central Effects
Authors: Leitch I M , Boura A L A , Edwards P , King R G , Rawlow A , Rechtman M P 
Published: April 2011

Abstract
The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1, 2, 3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-α)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30–100 μg kg−1, i.v.) caused long-lasting (&gt;1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (≤lmg kg−1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11α,9α-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0·3–1·0 mg kg−1, i.v.). Higher doses of FCC5 (3 mg kg−1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0·1–1·0 mg kg−1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0·1–0·3 mg kg−1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0·76 mg kg−1, i.p.; and 2·7 mg kg−1, p.o.). In decerebrate rats which had been spinalized at T6–8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0·36 mg kg−1, i.p.) but not by FCC5 (≤3mg kg−1, i.p.). Head twitches in carbidopapretreated mice induced by l-5-hydroxytryptophan were inhibited by mianserin (ID50 0·11 mg kg−1, i.p.), but not by FCC5 (≤30 mg kg−1, i.p.). It is concluded that FCC5 possesses antihistamine and anti-5-HT properties and is orally effective. No evidence was found for central effects.
The Calcium Channel Blocker LAS 30538, Unlike Nifedipine, Verapamil, Diltiazem or Flunarizine, Potently Inhibits Insulin Secretion In-vivo in Rats and Dogs
Authors: Gristwood R W , Furman B L , Llenas J , Jauregui J , Berga P 
Published: April 2011

Abstract
The effects of a novel calcium channel blocker, LAS 30538 (1-[2-(2,6-dimethylphenoxy)ethyl]-α,α-bis-(p-fluorophenyl)-4-piperidine methanol), were studied on glucose tolerance and insulin secretion in rats and dogs in-vitro and in-vivo. Some comparisons were made with nifedipine, verapamil, diltiazem, flunarizine, diazoxide, cromakalim and minoxidil. LAS 30538, like a number of calcium channel blockers, was found to inhibit insulin secretion in-vitro, but was 1000-fold more potent than verapamil or diltiazem in this respect. LAS 30538 differed from the other calcium channel blockers studied in that it also potently inhibited insulin secretion and impaired glucose tolerance in-vivo. The evidence that LAS 30538 is more potent than diazoxide as a hyperglycaemic agent in-vivo suggests that this could be a useful drug for the treatment of hyperinsulinaemia in man.
Effects of cupric chloride and tamrabhasma, a traditional Indian preparation of copper, on eicosanoid production by human gastric and colonic mucosa
Authors: Goel R K , Tavares I A , Bennett A 
Published: April 2011

Abstract
Tamrabhasma is a traditional copper oxide-containing Indian preparation which has anti-ulcer activity. We have studied the effect of tamrabhasma and CuCl2· 2H2O on prostaglandin formation by human gastric and colonic mucosa and submucosa, as prostaglandins have mucosal protective activity, and their release may contribute to the anti-ulcer effect. With the gastric mucosa, tamrabhasma 10 μg mL−1, but not 01 or 1 μg mL−1, increased prostaglandin E (PGE) concentration by 38% (P &lt; 0·005), with little or no effect on 6-keto-PGF1α, thromboxane B2 or the leukotriene (LT) LTC4/LTD4. CuCl2-2H2O (10 μg mL−1) increased 6-keto-PGF,α by 46% (P &lt; 0·05), but 0·1, 1, 50 and 250 μg mL−1 did not significantly affect any of the prostanoids, and only the highest concentration reduced the amount of LTC4/LTD4. In the colon mucosa, tamrabhasma (0·1–10 μg mL−1) or CuCl2 · 2H2O (10–50 μg mL−1) increased all the prostanoids and this effect was greater than in the gastric mucosa but there was no significant change in LTC4/LTD4. CuCl2-2H2O showed a bell-shaped concentration-effect curve, with no significant effect at lower and higher amounts. Indomethacin (0·1–10 μg mL−1) caused a concentration-dependent reduction in the prostanoid amounts. The effect of tamrabhasma was probably not only due to the presence of Cu2+, as tamrabhasma was more effective than CuCl2-2H2O alone; in addition the solubility of CuO is very low. Increased prostanoid levels might explain, at least partly, the gastric mucosal protection by tamrabhasma. The results in the colon, however, raise the possibility that tamrabhasma should be examined for the treatment of inflammatory bowel disease.
Calcium Antagonism by Cobalt Ions on Contraction of Guinea-pig Taenia Coli
Authors: Nasu Tetsuyuki 
Published: April 2011

Abstract
In guinea-pig taenia coli, cobalt ions (Co2+) inhibited the tonic response to a highly concentrated K+ solution (high-K+, 40 Mm) more strongly than the phasic response. Co2+ displaced Ca2+ concentration-response curves to the right, inhibited the increase in tissue calcium content caused by high-K +, and inhibited Ca2+ binding at low affinity sites more than at high affinity sites. After treatment with Co2+, the tonic tension caused by high-K+ was not restored by a wash with normal medium, but it was restored by a wash with EDTA. The cobalt remaining in muscles was almost completely eliminated after a 20–30 min wash with EDTA. The results suggest that Co2+ binds chiefly to the surface membrane of taenia coli. Co2+ probably reduced the tension in response to high-K+ mainly by inhibiting Ca2+ influx rather than by affecting Ca2+ release.