bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiarrhythmic and electrophysiologic effects of sublingual ibutilide fumarate
Authors: Buchanan Lewis V. , Thompson Dwayne D. , Hsu Chang‐Yuan L. , Walters Rodney R. , Gibson John K. 
Published: January 2005

AbstractIbutilide fumarate is a class III antiarrhythmic agent in phase III clinical trials. Due to rapid hepatic metabolism, ibutilide has a low oral bioavailability (< 10%). To assess alternate routes of administration, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mg/kg; 0.07, 0.2, and 0.7 m̈mol/kg) in pentobarbital anesthetized dogs. Peak significant increases in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 m̈mol/kg) ibutilide and were coincident with peak plasma ibutilide levels. The duration of significant effects ranged from 2 to 5 h. Peak effects were: QTc + 121 msec, MAPD90 + 71 msec, and VERP + 53 msec. The 0.3 mg/kg (0.7 m̈mol) dose significantly decreased heart rate 10 min post dosage through 5 h. The 0.03 mg/kg (0.07 m̈mol) dose increased MAPD90 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide was 2.8 h, with a 72% bioavailability relative to an equivalent intravenous dose. Based on the electrophysiologic results, we chose to test the 0.1 mg/kg (0.2 m̈mol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y‐shaped right atrial incisions. The administration of 0.1 mg/kg (0.2 m̈mol) sublingual ibutilide during sustained atrial flutter resulted in termination of atrial flutter in all cases (n = 4) after a mean time interval of 11.4 ± 0.8 min. Termination of atrial flutter was associated with ibutilide plasma levels of 19.6 ± 6.3 ng/ml, and 30 and 18 msec increases in atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, on at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levels to 2.3 ± 0.7 ng/ml. We conclude that sublingual ibutilide is rapidly absorbed and produces significant electrophysiologic and antiarrhythmic effects, and is a potential alternative to intravenous and oral therapy. ©1995 Wiley‐Liss, Inc.
Autoradiographic distribution of [3H]‐suriclone binding sites in the rat brain
Authors: Malgouris Christiane , Perrot Fabienne , Dupuis Marion , Kiosseff Thérèse , Daniel Marc , Blanchard Jean‐Charles , Doble Adam 
Published: January 2005

AbstractSuriclone is a potent non‐benzodiazepine anxiolytic belonging to the cyclopyrrolone family. This study examines the distribution and properties of [3H]‐suriclone binding sites in rat brain by autoradiography. The binding of [3H]‐suriclone to rat brain sections was displaced completely by 1 m̈M flumazenil; saturation experiments revealed a single class of binding sites with a KD value of 1.19 nM and a Bmax of 1.05 pmol/mg protein. The pharmacological specificity of [3H]‐suriclone binding was close to that of the benzodiazepine binding site on the GABAA receptor. Unlike benzodiazepine (BZ) agonists, [3H]‐suriclone binding to rat brain sections was not increased in the presence of GABA, and unlike imidazopyridines such as alpidem, suriclone was unable to discriminate between the BZ1 and BZ2 phenotype of the GABAA receptor. The autoradiographic distribution of [3H]‐suriclone binding sites in the rat brain was heterogeneous and relatively similar to that previously described for GABAA receptors labelled by benzodiazepines; some regions, however, such as certain cortical areas, displayed a different labelling.The highest densities were found in frontal, occipital, parietal, and cingulate cortices (layers I, II, III, IV), in the molecular layer of the cerebellum, in the superior colliculus and in the hippocampus. Moderate binding densities appeared in numerous areas such as the inferior colliculus, the central grey, the dorsal raphé, and the hypothalamus whereas caudate putamen, globus pallidus, and thalamic nuclei displayed a low density of [3H]‐suriclone binding sites. ©1995 Wiley‐Liss, Inc.
Evidence for multiple antiarrhythmic binding sites on the cardiac rapidly activating delayed rectifier K+ channel
Authors: Chadwick Christopher C. , Krafte Douglas S. , O'Connor Bernard , Volberg Walter A. , Ezrin Alan M. , Johnson Rober E. , Silver Paul J. 
Published: January 2005

AbstractWe have previously shown that [3H]dofetilide binds with high affinity to sites associated with the guinea pig cardiac rapidly activating delayed rectifier K+ (IKr) channel and that class III antiarrhythmic agents, including dofetilide, clofilium, quinidine, sotalol, and sematilide, competitively displace [3H]dofetilide with IC50 values that correlate with those for blockade of the IKr channel. In this report, we show that other class III antiarrhythmic agents, namely, E‐4031 (1‐[2‐(6‐methyl‐2‐pyridyl)ethyl]‐4‐(4‐methylsulfonylamidobenzoyl)piperidine) and L‐691, 121 (3,4‐dihydro‐1′‐[2‐(benzofurazan‐5‐yl)ethyl]‐6‐methanesfulonamidospiro[(2H)‐1‐benzopyran‐2,4′‐piperidin]‐4‐one), potently block guinea pig IKr channels with respective IC50 values of 29 and 8 nM, yet have a low potency for displacement of [3H]dofetilide. Moreover, WIN 61773‐2 [(R)(+)‐4,5‐dihydro‐4‐methyl‐1‐phenyl‐3(2‐phenylethyl)‐(1H)‐2,4‐benzodiazepine monohydrochloride] biphasically displaces [3H]dofetilide according to a two site competitive binding model (site 1 = 21% displacement, IC50 = 116 nM; site 2 = 79% displacement, IC50 = 50 m̈M) with correlation to IKr block in the first phase (IC50 = 92 nM). These findings suggest that E‐‐4031, L‐691, 121, and WIN 61773‐2 inhibit IKr channels by interacting at sites distinct from the high affinity [3H]dofetilide binding site. The partial displacement of [3H]dofetilide by low concentrations of WIN 61773‐2, correlated with complete block of IKr, suggests allosteric modulation of the dofetilide binding site by this agent. ©1995 Wiley‐Liss, Inc.
Antidiabetic agent pioglitazone increases insulin receptors on 3T3‐L1 adipocytes
Authors: Swanson Michael L. , Bleasdale John E. 
Published: January 2005

AbstractPioglitazone and other antidiabetic thiazolidinediones appear to overcome insulin resistance by affecting an unidentified early event in insulin action. Because attempts to determine changes in insulin receptors in tissues from thiazolidinedione‐treated diabetic animals are complicated by drug‐induced reduction of hyperinsulinemia and consequent receptor up‐regulation, 3T3‐L1 cells were utilized here as an in vitro model system. After the excess insulin required for optimal differentiation of 3T3‐L1 adipocytes was removed from the culture medium, there was an increase in specific binding of insulin to the cell surface that was further augmented 25 and 47% in cells treated with pioglitazone for 12 and 24 h, respectively (EC50 about 0.6 μM, maximal at 5–25 μM). Pioglitazone increased the number of insulin receptors without changing binding affinity. Specific IGF‐I binding was not affected by pioglitazone in the 3T3‐L1 cells. Glycerol 3‐phosphate dehydrogenase activity, a marker of adipocyte differentiation, was also increased in a dose‐dependent manner by pioglitazone (maximal at 10–25 μM). Tunicamycin, which inhibits the N‐linked glycosylation of newly synthesized insulin receptors that is required for their translocation to the cell surface, decreased specific insulin binding by about 50% after 24 h, and this decrease remained unchanged when pioglitazone was simultaneously present. Pioglitazone increased not only cell surface insulin receptors, but also total cellular insulin receptors (quantitated either by specific insulin binding or by immunoblotting) and insulin receptors mRNA. In addition, among several structurally related thiazolidinediones there was a positive correlation between in vivo antihyperglycemic activity and their ability to increase insulin binding in vitro, suggesting a possible common molecular mechanism for these actions. © 1995 Wiley‐Liss, Inc.
Canine plasma concentration‐cardiovascular effect relationships for bidisomide, a new antiarrhythmic drug, and disopyramide, cibenzoline, and propafenone
Authors: Garthwaite Susan M. , Schmidt Jennifer J. , Hatley Frida R. , Cook Chyung , Frederick Leo G. 
Published: January 2005

AbstractBidisomide (SC‐40230) is a unique new antiarrhythmic agent. In this study the canine intravenous (i.v.) antiarrhythmic doses of bidisomide (9 ± 1 mg/kg), disopyramide (8 ± 1 mg/kg), cibenzoline (8 ± 2 mg/kg), and propafenone (6 ± 0.5 mg/kg) were established in a 24 h coronary ligation ventricular arrhythmia model. Based on the canine therapeutic doses of the four agents, three cumulative i.v. doses (load/maintenance infusions) of each of these drugs and placebo were then studied in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7–3.0 μg/ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.9–7.0 μg/ml) and disopyramide (1.4–12.9 μg/ml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9–16.1 μg/ml) had the least potent effects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone increased JT (QT‐QRS). These experiments suggest that the antiarrhythmic plasma concentrations of bidisomide, in contrast to those of selected reference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs. © 1995 Wiley‐Liss, Inc.
Esterification improves antiarthritic effectiveness of lupeol
Authors: Kweifio‐Okai George , Field Barry , Rumble Baden A. , Macrides Theodore A. , De Munk Fred 
Published: January 2005

AbstractAdult male Wistar rats were made arthritic by the subplantar injection of complete Freund's adjuvant. Oral treatment with the triterpenes lupeol, luepol palmitate, or lupeol linoleate (66 mg/kg BW every 2 days) from days 24 to 32 reduced synovial granulomatous growth (proximal interphalangeal foot joints) and its invasion of the synovial cavity and reduced the destruction of articular cartilage and subchondral bone (lupeol linoleate > lupeol palmitate > lupeol). Rats treated with the lupeol esters showed reduced periosteal bone erosion with bone repair in the form of periosteal new bone formation. Arthritic rat blood lymphocytes and serum levels of the joint degradative product, hyaluronate, which increased by 73% and 51%, respectively, were reduced by the triterpenes (lupeol linoleate > lupeol palmitate > lupeol) with lupeol linoleate restoring them to normal values. The antiarthritic effectiveness of lupeol was therefore increased by esterification with the long‐chain fatty acids. © 1995 Wiley‐Liss, Inc.
Caffeic acid prevents liver damage and ameliorates liver fibrosis induced by CCI4 in the rat
Authors: Reyes Maria T. , Mourelle Marisabel , Hong Enrique , Muriel Pablo 
Published: January 2005

AbstractIt has been postulated that during liver damage there is an arachidonic acid metabolism deflection toward lipoxygenase products and a simultaneous decrement of the synthesis of cytoprotective prostaglandins. Accordingly, we have demonstrated that leukotriene synthesis inhibition protects the liver from acute damage induced by CCI4. Thus, the aim of the present work was to study the effect of caffeic acid (a specific 5‐lipoxygenase inhibitor) on liver cirrhosis induced by CCI4 administration in the rat. Caffeic acid prevented significantly the increment of serum markers of liver damage, as well as lipid peroxidation and the depletion in glycogen content of the liver induced by chronic CCI4 intoxication. Collagen content increased fivefold in the CCI4‐treated rats. The group treated with the lipoxygenase inhibitor, in addition to CCI4, showed less collagen content than the group receiving only CCI4 (P ⩽ .05). Caffeic acid prevented liver damage significantly. The hepatoprotective effect of this compound could be attributed to its ability to inhibit 5‐lipoxygenase activity, and thus leukotriene production. © 1995 Wiley‐Liss, Inc.
Inhibition of 36CI− influx and [35S]TBPS binding in the rat brain by leumedins: A novel class of anti‐inflammatory agents
Authors: Jarvis Michael F. , Gant Daniel B. , Gessner George W. , Pendley Charles , Sutherland Charles , Martin Gregory E. 
Published: January 2005

AbstractThe leumedins, a series of N‐(fluorenyl‐9‐methoxycarbonyl) amino acids, are putative anti‐inflammatory agents that have been shown to inhibit leukocyte recruitment into inflammed tissue. While the exact mechanism of action of these agents is unknown, there are some reports suggesting that leumedins selectively block transmembrane ion flux in neutrophils. In order to examine the possibility that the leumedins may interact with chloride transport mechanisms, we evaluated representative leumedins for their ability to interact with the GABA/benzodiazepine chloride ionophore in rat brain. NPC 17923, at micromolar concentrations, was found to compete for 2 nM [35S]TBPS binding (IC50 = 16 μM) and inhibit 36CI— influx (IC50 = 133 μM) in rat brain. Saturation studies indicated that NPC 17923 inhibited [35S]TBPS binding in a noncompetitive fashion. Other less potent leumedins also inhibited [35S]TBPS binding in a concentration‐dependent fashion. The leumedins had no significant activity at other GABA/benzodiazepine recognition sites labeled by [3H]muscimol, [3H]flunitrazepam, or [3H]RO15‐4513. The two most potent leumedins effectively attenuated 36CI— influx into rat brain, while all of the leumedins examined blocked 36CI— influx into guinea pig neutrophils at moderate micromolar concentrations. The present data offer the first demonstration that the leumedins can block chloride flux at the rat brain GABA/benzodiazepine chloride ionophore and in guinea pig neutrophils at similar concentrations required to produce anti‐inflammatory actions on human neutrophils. These results show that while the leumedins can block chloride flux in both neurons and neutrophils, the relative low affinity of the leumedins to produce this effect suggests an apparent nonselective interaction at a number of different chloride transporters similar to that found with the disulfonic stilbene derivative chloride channel blockers. © 1995 Wiley‐Liss, Inc.
Comparative efficacy and safety of intravenous non‐steroidal anti‐inflammatory drugs in two animal models of pain
Authors: Rodriguez Rodolfo , Medina Martha , Rojas Yolanda 
Published: January 2005

AbstractIn this study, the antinociceptive activity of five non‐steroidal anti‐inflammatory drugs (NSAIDs) was determined in two animal models of different pain intensity and compared with their capacity to produce motor incoordination and death. Intravenous clonixine, diclofenac, dipyrone (metamizole), ketorolac, and piroxicam produced dose‐dependent antinociception in the acetylcholine‐induced writhing test with ED50 values ranging from 14 (clonixine) to 205 (dipyrone) μmol/kg. The behavioral responses in the 55°C hot plate assay were also inhibited in a dosedependent manner, but significantly higher doses were required to display antinociceptive activity, the ED50 values ranging from 116 (clonixine) to 2, 263 (dipyrone) μmol/kg. In the writhing test, the antinociceptive effects of NSAIDs were present at doses far below those producing toxic effects. In contrast, their ED50 values against a more intense nociceptive stimulus approached those producing lethal effects so that the therapeutic ratios were very small, ranging from 1.3 (diclofenac) to 3.0 (dipyrone). The antinociceptive activity of the reference drug morphine is striking, since both types of nociceptive responses were eliminated at doses substantially lower than those producing death (therapeutic ratios of 502 and 121). Morphine exhibited the highest antinociceptive efficacy, followed by dipyrone, ketorolac, clonixine, and piroxicam. Diclofenac showed a more limited efficacy. These findings imply potential risks for patients treated iv with this class of drugs and suggest caution in the use of high doses of NSAIDs. Future development of injectable NSAID formulations should include a detailed analysis of adverse reactions following iv administration of high doses. © 1995 Wiley‐Liss, Inc.
Performance of baby monkeys on the Hebb‐Williams closed field maze learning task
Authors: Zimmermann Robert R. 
Published: January 2005

AbstractInfant monkeys, 15 to 120 days of age, were tested in a Hebb‐Williams maze. Age was a significant variable affecting error scores, and the relationship between age and performance on this test might best be described as U‐shaped. The operation of changing motor and motivational systems appears to be a crucial factor in determining performance of infant monkeys in this task, rather than learning abilities.
The effect of criterion level on the acquisition and retention of a 1‐way avoidance response in young and old rats
Authors: Potash Marc , Ferguson H. Bruce 
Published: January 2005

AbstractYoung (23–25 days old) and adult (80–84 days old (rats) n = 8, per group) were trained on an active‐avoidance task to a criterion of 0, 5, or 15 consecutive correct trials and then tested for retention 30 days later. In original training, both age groups acquired the response in about the same number of trials when the criterion was set at 5/5 but young subjects required significantly more trials than older subjects to learn the response under the 15/15 criterion. In retraining, both age groups performed equally well when original training was to the 15/15 criterion although adults retained significantly better than weanlings when original training was to 5/5 correct responses.
Alleviation of separation distress in 3 breeds of young dogs
Authors: Pettijohn T. F. , Wong T. W. , Ebert P. D. , Scott J. P. 
Published: January 2005

AbstractTwenty‐four puppies (8 each of Shetland sheepdogs, Telomians, and beagles) served as subjects in this experiment which was designed to examine the effectiveness of 12 stimulus conditions (food, toys, canine contact, and human contact) on alleviation of separation‐induced distress vocalization. Testing consisted of a prestimulus trial, stimulus trial, and post‐stimulus trial each session 3 times a week from 4 to 8 weeks after birth. Overall results showed human contact to be the most effective, followed by canine contact, toys, and food. Breed differences were significant in only 2 of the stimulus conditions. In the typical case of effective treatment, the vocalization rate declined from the prestimulus trial to a low point in the stimulus trial and then increased again in the post‐stimulus trial.
The effect of visual deprivation in the rat on transfer effects after form discrimination training
Authors: Tees Richard C. , Bruinsma Yvonne , Midgley Glenda 
Published: January 2005

AbstractIn 3 experiments the performances of light‐reared (LR) and dark‐reared (DR) 90‐day‐old rats were compared on a variety of transfer tests following acquisition of 3 discriminations involving patterns of small squares (dots). Though no significant difference due to rearing condition was found in acquisition of those discriminations consisting of single lines of dots in various orientations, transfer tests did reveal subtle differences in the way LR and DR rats analyze contour information. Significant differences due to rearing were also observed on the acquisition of a complex dot pattern (∇ vs X) and, in spite of overtraining, on subsequent stimulus equivalence tests. Anomalous transfer effects were not observed in any of these test situations.
Behavioral effects of unilateral basal gangliar lesions in neonatal rats
Authors: Van Hartesveldt Carol , Lindquist David 
Published: January 2005

AbstractTwo‐day‐old rats were given unilateral lesions of the caudate‐putamen, globus pallidus, or hippocampus and their postural orientation was observed for 30 min immediately after surgery. All groups with damage to the caudate‐putamen and/or globus pallidus showed a significant postural deviation toward the side ipsilateral to the lesion. At this age, neurogenesis in the basal ganglia is complete but synapses, neurotransmitters, and enzymes for neurotransmitter synthesis are far below adult levels. These results indicate that the basal ganglia have a role in motor function prior to their full maturation as measured by neuroanatomical and biochemical techniques.
Effects of undernutrition and litter size on material variables and pup development
Authors: Jen Kai‐Lin Catherine , Wehmer Francine , Morofski Jan 
Published: January 2005

AbstractDifferential effects of maternal nutrition and litter size variation were examined in a 2 × 2 factorial design in which undernourished or ad lib fed mothers nursed litters of 4 or 12. Litter size accounted for a greater proportion of pup body weight at weaning than did maternal nutrition. When the mother was fed ad lib, birth weight of individual pups and later body weight were correlated regardless of litter size. When the mother was undernourished, these correlations were not found. Enlargement of litter size increased the pup weight coefficient of variability only when the mother was fed ad lib. Size of the litter did not influence the maternal variables under study: open field behavior, adrenal weight, and body weight.
The ontogeny of exploration in the rat: Habituation and effects of handling
Authors: File Sandra E. 
Published: January 2005

AbstractExploration, measured by head‐dipping in a holeboard, was tested in male rats at 16, 21, 28, 56, and 84 days of age. Headdipping increased with increasing age from Day 16 to Day 84, and so did the number of rears made. At all ages handled rats showed more head‐dipping and made more rears than did their unhandled litter‐mates. The age differences in exploration cannot be explained by different patterns of habituation: rats showed significant within‐session habituation of head‐dipping at all ages tested (Days 16, 21, and 28). Day 16 rats also showed significant between‐session habituation.
The interstimulus interval in classical autonomic conditioning of young infants
Authors: Ingram Eben M. 
Published: January 2005

AbstractConditioned auditory discrimination and extinction of the skin potential response were attempted in 4‐month‐old infants using interstimulus intervals of 1500, 3500, 5500, and 7500 msec. Half of the infants in each of the interstimulus interval groups were defined as high magnitude orienters and half were low magnitude orienters. Conditioning was successful with the 5500‐ and 7500‐msec interstimulus intervals, but not with the 1500‐ and 3500‐msec intervals. Analysis of individual subject data indicated that individual differences in conditionability were related to interstimulus interval and orienting response magnitude. Also, those subjects discriminating at the longer intervals tended to be high magnitude orienters. In other words, longer interstimulus intervals interacted with a high magnitude of orienting to facilitate conditioning. The results were taken as evidence that individual differences in the magnitude of the orienting response reflect different individual needs in stimulus information processing time.
Directional responses by kittens to an auditory stimulus
Authors: Clements Maureen , Kelly Jack B. 
Published: January 2005

AbstractSix kittens were tested in a 2‐choice maze to determine if they would execute directional approach responses to an auditory stimulus. Tests were done at various postnatal ages (4–10, 11–17, 18–24, and 25–31 days) and comparison was made with responses of 5 kittens tested without auditory stimulation. At the earliest ages no evidence was seen for auditory approach responses but by 18–24 days consistent approach responses were found.