bluuebunny/crossref_metadata_2025_split huggingface dataset:
EP1 receptor antagonist blocks the diarrheagenic, but not cytoprotective, actions of a synthetic prostaglandin
Authors: Lanthorn Thomas H. , Bianchi Robert G. , Perkins William E. 
Published: January 2005

AbstractNaturally occurring and synthetic prostaglandins acting at EP type receptors have a number of physiological actions, including cytoprotective and antisecretory effects, that are therapeutically useful. In addition they can produce other effects, such as diarrhea. It is possible that these actions are mediated by different EP receptor subtypes. The actions of a subtype‐selective prostaglandin agonist has suggested that diarrhea is not due to activity at the EP3 receptor, while cytoprotection and antisecretory actions may be. The recent development of a bioavailable EP1 antagonist, SC‐51089, has made it possible to examine this more directly. SC‐30249, the active isomer of misoprostol, protects against indomethacin‐induced gastric lesions and produces diarrhea in rats. SC‐51089, ig, shifted the dose‐response curve for SC‐30249‐induced diarrhea significantly to the right. ED50 values (assessed at 5 hr following administration of SC‐30249) were 13.8 μ/kg (0.036 μmol/kg) for SC‐30249 alone and 110.8 μg/kg (0.290 μmol/kg) for SC‐30249 plus SC‐51089. This antagonism of diarrhea was overcome by higher doses of SC‐30249. SC‐30249 dosedependently inhibited gastric lesions induced by indomethacin (ED50 = 3.4 μg/kg, 0.009 μmol/kg, ig). SC‐51089 did not reduce the cytoprotective effects of SC‐30249 (ED50 = 1.1 μg/kg, 0.003 μmol/kg, ig, SC‐30249 in combination with SC‐51089). These results are consistent with the hypothesis that the EP1 receptor subtype mediates the diarrheagenic effect of EP receptor agonists, but not their cytoprotective actions. These results provide a mechanistic basis for cytoprotective prostaglandins with greatly reduced side effects. © Wiley‐Liss, Inc.
Alzheimer's disease: Tacrine and tacrine metabolite concentrations in plasma and cognitive change
Authors: Davis Kenneth L. , Yang Ren‐Kui , Davidson Michael , Mohs Richard C. , Ryan Theresa M. , Schmeidler James , Knott Peter J. , Thal Leon J. , Gamzu Elkan R. 
Published: January 2005

AbstractIn a clinical trial of tacrine in patients with Alzheimer's disease, improvement, measured by changes on both total (ADAST) and the cognitive sub‐component (ADASC) of the Alzheimer's Disease Assessment Scale (ADAS) over a 6‐week period, correlated significantly with plasma levels of tacrine. Change on the ADAS (both total and the cognitive subcomponent) also correlated significantly with three monohydroxylated metabolites of tacrine 1, hydroxy‐tacrine (1‐OH‐THA), 2, hydroxy‐tacrine (2‐OH‐THA), and 4, hydroxy‐tacrine (4‐OH‐THA). However, changes of the relatively small non‐cognitive component of the ADAS were not significantly correlated with plasma levels of tacrine. Multiple correlational analysis revealed that the combined influences of these metabolites were no greater than the effects of tacrine alone in ameliorating the symptoms of Alzheimer's disease. An alternative measure of cognitive performance, the Mini Mental State Exam (MMSE) did not correlate significantly with plasma concentrations of tacrine or its metabolites. Tacrine and these metabolites are bound to plasma proteins. In 10 patients with Alzheimer's disease receiving tacrine, the percentage of tacrine, 1‐OH‐THA, 2‐OH‐THA, and 4‐OH‐THA, that was free in plasma was found to be 19.7 ± 3.3, 51.3 ± 7.7, 40.7 ± 6.9, and 42.4 ± 6.3 (mean ± SD), respectively. © Wiley‐Liss, Inc.
Impact of biophysical parameters on the biological assessment of peptide nucleic acids, antisense inhibitors of gene expression
Authors: Noble Stewart A. , Bonham Michele A. , Bisi John E. , Bruckenstein David A. , Brown Pamela H. , Brown Stephen C. , Cadilla Rodolfo , Gaul Micheal D. , Hanvey Jeffery C. , Fred Hassman C. , Josey John A. , Luzzio Michael J. , Myers Philip M. , Pipe Adrian J. , Ricca Daniel J. , Su Charles W. , Stevenson Cynthia L. , Thomson Stephen A. , Wiethe Robert W. , Babiss Lee E. 
Published: January 2005

AbstractPeptide nucleic acids (PNA) are oligodeoxynucleotide (ODN) analogs in which the sugar phosphate backbone of the ODN has been replaced by one derived from units of N‐ethylaminoglycine. PNAs recognize DNA and RNA in a sequence specific manner and form complexes that can be characterized by biophysical methods. The binding motif is context dependent; homopyrimidine PNAs combine with complementary polypurine targets to form stoichiometric 2:1 complexes, whereas PNAs containing both purine and pyrimidine bases afford a 1:1 heteroduplex with mis‐match sensitivity comparable to that found in dsDNA. These complexes mediate the antigene and antisense effects of PNAs via the steric blockade of enzyme complexes responsible for DNA transcription, cDNA synthesis, and RNA translation. PNAs, like ODNs, are taken up by cells via endocytosis leading to their entrapment within intracytoplasmic vesicles. Under circumstances where agent delivery is solved by cell microinjection, PNAs can effect selective inhibition of endogenous and exogenous genes. The impact of biophysical parameters on the biological assessment of PNAs as antisense inhibitors of gene expression is presented and discussed. © 1995 Wiley‐Liss, Inc.
Biological activity of WIN 63759, an orally bioavailable inhibitor of human neutrophil elastase
Authors: Silver Paul J. , Gordan Robert J. , Pagani Edward D. , Johnson Judith A. , Maycock Alan L. , Dunlap Richard P. , Ferguson Edward W. , Franke Catherine A. , Drozd Marion L. , Robinson David T. , Mark Eickhoff W. , Baizman Eugene R. , Subramanyam Chakrapani , Desai Ranjit C. , Hlasta Dennis J. , Newton John F. 
Published: January 2005

AbstractThe proteolytic activity of human neutrophil elastase (HNE) has been implicated in a number of pulmonary diseases. We report on the activity of an orally bioavailable, selective HNE inhibitor, WIN 63759 [6‐methoxy‐4‐(1‐methylethy)‐3‐oxo‐1,2‐benzisothiazol‐2(3H)‐yl]methyl 2,6‐dichloro‐3‐[2‐(4‐morpholinyl)ethoxy] benzoate S, S dioxide. WIN 63759 is a potent inhibitor of HNE (Ki = 14 pM) and is at least 70,000‐fold selective for HNE relative to other serine proteases or receptors. In vivo, WIN 63759 produces dose‐related inhibition of HNE‐induced pulmonary hemorrhage following either intravenous (ED50 = 3 mg/kg; 4.5 μmol/kg) or subcutaneous (ED50 = 19 mg/kg; 28.5 μmol/kg) administration in hamsters. WIN 63759 selectivity inhibits HNE in vivo (relative to chymotrypsin or trypsin), and is equally efficacious following acute or chronic administration in the hamster. WIN 63759 is not orally bioavailable in hamsters, rats, or monkeys, and this lack of bioavailability is related to rapid in vitro metabolism in liver, jejunum, or blood. In contrast, WIN 63759 is stable in canine tissues in vitro and is orally bioavailable in dogs. Bioavailability is enhanced in fed relative to fasted dogs. Bronchoalveolar lavage studies indicate that WIN 63759 is present in the target organ (lung) at concentrations 3–5 X higher than those found in plasma following oral administration of 3–100 mg/kg (4.5–150 μmol) in dogs. These data show that WIN 63759 is a potent, selective, and orally bioavailable inhibitor of HNE. Since oral bioavailability was predictable based on in vitro metabolism, and since in vitro metabolism in humans is similar to that observed with dogs, WIN 63759 and other members of this chemical series may be orally bioavailable inhibitors of neutrophil elastase in man. © 1995 Wiley‐Liss, Inc.
Skilled incompetence in the management of R & D
Authors: Jensen Ivan , Jorgensen Stig , Sapienza Alice M. 
Published: January 2005

AbstractWe use the term skilled incompetence to describe a situation characterized by a mismatch between technical and managerial competence and caused by inadequate, inappropriate, or missing second‐order feedback on managerial behavior. Based on our collective experience with the pharmaceutical industry, we believe that skilled incompetence is prevalent in the management of R & D. In this commentary we explore, using a hypothetical case study as illustration, how skilled incompetence arises and persists. We define the cost of skilled incompetence as the cost of delayed drug development times and thus lost opportunities in the market. We discuss how skilled incompetence manifests itself, how it can be diagnosed, and what general rules should guide any interventions. © 1995 Wiley‐Liss, Inc.
Interaction of three sponge‐derived macrocyclic lactone polyethers (spongistatin 3, halistatins 1 and 2) with tubulin
Authors: Ludueña Richard F. , Roach Mary Carmen , Prasad Veena , Pettit George R. , Cichacz Zbigniew A. , Herald Cherry L. 
Published: January 2005

AbstractMacrocyclic lactone polyethers of marine origin include a series of compounds which bind to tubulin, the subunit protein of microtubules, and inhibit microtubule assembly and vinblastine binding to tubulin. We have previously studied two of these compounds: halichondrin B and the very similar homohalichondrin B. We have found that halichondrin B enhances the time‐dependent exposure of hydrophobic areas on the tubulin molecule without affecting the exposure of the sulfhydryl groups, while homohalichondrin B has no effect on exposure of hydrophobic areas and slightly suppresses exposure of sulfhydryl groups. The spongistatins (isolated from the marine sponge Spongia sp.) resemble the halichondrins, except for having a smaller ring; spongistatin 1 inhibits vinblastine binding to tubulin and blocks microtubule assembly. Here, we have examined the effect of the closely related spongistatin 3 on the exposure of tubulin sulfhydryl groups and hydrophobic areas. We have found that spongistatin 3 inhibits formation of the same intrachain cross‐link in tubulin as is inhibited by vinblastine. Unlike vinblastine, however, spongistatin 3 has no effect on the exposure of either sulfhydryl groups or hydrophobic areas on the tubulin molecule. In short, spongistatin 3 resembles maytansine in its effects on tubulin more than it does either halichondrin B or homohalichondrin B. We also examined the interaction of tubulin with halistatins 1 and 2, which are close structural analogues of halichondrin B and homohalichondrin B, respectively. Halistatins 1 and 2 are isolated, respectively, from the marine sponges Phakellia carteri and Axinella carteri. We find that both halistatins resemble halichondrin B in that they have no effect on the exposure of sulfhydryl groups. Our results suggest that very small structural changes in these compounds can significantly alter the pattern of their effects on the tubulin molecule. © 1995 Wiley‐Liss, Inc.
Combinatorial chemistry: A conservative perspective
Authors: Lyttle Matthew H. 
Published: January 2005

AbstractLarge biotechnology based initiatives, like the Human Genome Project, in addition to accelerating scientific progress and improving the understanding of basic biological process, are responsible for an increased demand for high quality drug candidates. In this regard, combinatorial libraries have become a subject of intense interest, as chemists and biologists attempt to generate large numbers of compounds that bind to the increasing number of newly discovered and potentially medically relevant proteins. Now that a variety of exploratory combinatorial chemistry efforts have been reported, it is appropriate to evaluate the utility of these procedures which have often outpaced conservative chemical characterization regarding composition and purity of products. The use of assay formats dictated by the needs of the synthetic protocol have also often circumvented disciplined evaluation of how relevant the assay data is to realistic drug‐target interactions. This commentary examines procedural details whereby commonly used combinatorial practices can generate less useful information than anticipated. Concrete, practical suggestions are made for using combinatorial chemistry in a more focused manner in lead generation and development, so that disappointing results can be avoided and the high potential of this technology more effectively realized. © 1995 Wiley‐Liss, Inc.
A‐80426, a potent α2‐adrenoceptor antagonist with serotonin uptake blocking activity and putative antidepressant‐like effects: I. Biochemical profile
Authors: Hancock Arthur A. , Buckner Steven A. , Oheim Karen W. , Morse Patricia A. , Brune Michael E. , Meyer Michael D. , Williams Michael , Kerwin James F. 
Published: January 2005

AbstractA‐80426 (N‐[2‐(benzofuran‐6‐yl)ethyl]‐N‐[(R)−( + )‐5‐methoxy‐1,2,3,4‐tetrahydronaphthalen‐1‐yl methyl]‐N‐methylamine) is a novel compound with potential antidepressant activity. A‐80426 inhibits synaptosomal serotonin (5HT) uptake (IC50 = 13 nM) more potently than fluoxetine (IC50 = 308 nM), and blocks [3H]‐paroxetine binding (K1 = 3.8 nM) to 5HT uptake sites. A‐80426 inhibits [3H]‐rauwolscine binding to α2‐adrenoceptors (K1 = 2.0 nM), blocks α2‐adrenoceptors (pEC30 = 7.4–7.5) in electrically stimulated rat atria and vas deferens, and increases electrically stimulated [3H]‐NE overflow from brain slices. A‐80426 lacks significant activity at isolated tissue models of α1‐ or β‐adrenergic sites or at M3 muscarinic or H1 histaminergic receptors. A‐80426 has negligible radioligand binding activity at 5HT1 and β‐adrenergic receptors, but exhibits a K1 value of 144 nM at 5HT2 receptors. A‐80426 interacts with both dopamine D1 (K1 = 744 nM) and D2 (K1 = 51.5 nM) receptors. Functionally, the compound antagonizes dopamine‐induced changes in cyclic AMP formation with K1 values of 133 nM and 185 nM at D1 and D2 receptors, respectively. The potent α2‐adrenoceptor blocking activity of A‐80426 in radioligand binding assays is not reflected in isolated tissue bioassays, and may thus have less functional consequence in determining the in vivo profile of the compound. Accompanying behavioral data [Giardina et al., 1995], while indicating activity in the olfactory bulbectomized rat model of antidepressant action, shows a marked reduction in the α2‐antagonistic properties of A‐80426 in other in vivo models, suggesting that the antidepressant‐like activity may be caused primarily by inhibition of 5HT uptake. © 1995 Wiley‐Liss, Inc.
Nitric oxide‐associated vasorelaxing effect of an anti‐ulcer agent, benexate hydrochloride betadex
Authors: Iwasaki Takanori , Matsunaga Kazuki 
Published: January 2005

AbstractThe vasorelaxing effect of benexate hydrochloride betadex (BHB) was examined in rat thoracic aortic ring with and without endothelium. BHB at 1∼100 μM caused concentrationdependent vasorelaxation in both endothelium‐intact and ‐denuded aortas precontracted with phenylephrine (1 μM), with its relaxing effect being significantly more potent in the endotheliumintact aorta. This partial endothelium‐dependent vasorelaxation by BHB was significantly inhibited by Nω‐nitro‐L‐arginine methylester (100 μM), an inhibitor of nitric oxide (NO) synthase, and hemoglobin (10 μM), an NO scavenger, but not by indomethacin (5 μM), an inhibitor of cyclooxygenase. The content of c‐GMP, a second messenger of NO, in endothelium‐intact aorta treated with BHB (30 μM) significantly increased by about twofold of the control level. NO synthase (NOS) activity by the treatment of BHB at 100 μM increased to about the same level by the treatment of L‐arginine at 10 μM. Taken together, these results suggest that the vasorelaxing effect of BHB is, in part, associated with NO synthesis and release from the endothelium but not with the prostaglandin system. The mechanism of NO synthesis and release from the endothelium by BHB might be NOS activation by the effect as a substrate of NOS. © 1995 Wiley‐Liss, Inc.
Antiarthritic mechanisms of lupeol triterpenes
Authors: Kweifio‐Okai George , De Munk Fred , Macrides Theodore A. , Smith Phil , Rumble Baden A. 
Published: January 2005

AbstractThe triterpenes lupeol (L), lupeol‐3‐palmitate (LP), and lupeol‐3‐linoleate (LL) have previously been shown to reduce joint destruction in adjuvant arthritic rats. In order to explain the relative antiarthritic effectiveness (LL>LP>L), the triterpenes were tested on the release of collagenase by rat osteosarcoma (bone tumor) cells, on the release of 5 lipoxygenase inflammatory products by human neutrophils, and on CCl4‐induced hepatotoxicity in rats. The rat osteosarcoma cells released collagenase which digested type I (bone) native collagen. The collagenase release, unaffected by 50 μM lupeol, decreased in the presence of lupeol linoleate and lupeol palmitate by 97% and 78%, respectively. The 30% inhibitory concentrations (IC30) of lupeol linoleate, lupeol palmitate, and lupeol on LTB4 release by the neutrophils were 27 μM, 94 μM, and μ100 μM, respectively. All the triterpenes equally reduced hepatic fatty degeneration in CCl4 rats, but only the triterpene esters significantly reduced LDH release (34% LL; 25% LP) and accelerated hepatic cell regeneration (LL>LP). The effectiveness of the triterpenes in the models of inflammatory and arthritic processes employed here corresponded with their relative antiarthritic effectiveness in adjuvant arthritic rats. © 1995 Wiley‐Liss, Inc.
Effects of typical, atypical, and novel antipsychotic drugs on amphetamine‐induced place conditioning in rats
Authors: Hoffman Diane C. , Donovan Hilary 
Published: January 2005

AbstractBecause amphetamine‐induced place conditioning is believed to be mediated by dopamine (DA) receptors within the nucleus accumbens, this behavioral model may be useful for detecting drugs with antipsychotic efficacy. To test the selectivity and specificity of the model, the present study examined whether amphetamine‐induced place conditioning is reversible in rats pretreated with the classical antipsychotic haloperidol, the atypical antipsychotic clozapine, and the novel antipsychotics raclopride and risperidone. The non‐antipsychotic drugs baclofen and prazosin were also tested. Male Sprague‐Dawley rats received d‐amphetamine (5.4 μmol/kg ip) paired with one side of a two‐compartment box and saline paired with the other side. During these pairings, locomotor activity was measured. On the test day, the amount of time drug‐free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug‐paired side from pre‐ to postconditioning, indicating a place preference. Pretreatment with the highest dose of either haloperidol (0.026, 0.13, 0.26 μmol/kg sc), clozapine (3, 15, 30, 60 μmol/kg sc), raclopride (0.1, 0.2, 1.0 μmol/kg), or risperidone (0.12, 0.24, 1.2 μmol/kg sc) prior to amphetamine significantly blocked the establishment of place conditioning. Treatment with the antipsychotic alone did not support place conditioning (preference or aversion). On conditioning days, haloperidol, clozapine, raclopride, and risperidone significantly decreased amphetamine‐induced locomotor activity. Pretreatment with either baclofen or prazosin failed to disrupt amphetamine‐induced place conditioning despite significant decreases in locomotor activity on the conditioning days. These data provide preliminary support for amphetamine place conditioning as a rodent model for detecting drugs with antipsychotic efficacy. © 1995 Wiley‐Liss, Inc.
Development of gross electrical activity in the hippocampus of the guinea pig
Authors: Stenberg Dag , Vehaskari Matti 
Published: January 2005

AbstractHippocampal and neocortical EEG activity was recorded from 48 unanesthetized, intra‐uterine, guinea‐pig fetuses of 35 to 65 days gestational age. The earliest hippocampal electrical activity appeared at around 35 days (i.e., at approximately the same time as such activity appears in the lower brain stem, and earlier than it appears in the neocortex). This indicates that functional maturation of the brain begins almost simultaneously in large parts of the so‐called old brain, not only in its bulbar parts, and spreads to more superficial structures with age. The first activity had a random frequency distribution, whereas more regular periodicity developed later. From 44 days hippocampal bursts and spindles were recorded, especially during hypoxia or fetal distress. The bursts seemed to bear a relation to the reanimation process after hypoxia.
Some amino acids in the developing visual system
Authors: Davis J. M. , Himwich W. A. , Agrawal H. C. 
Published: January 2005

AbstractGlutamic acid, glutamine, GABA, aspartic acid, and alanine have been determined throughout the ontogenetic development of the rabbit visual system, i.e., occipital cortex, superior colliculi, lateral geniculate bodies, and retina. At 11 days of age, when the rabbits' eyes were opening, many of the amino acids had decreased significantly in the individual parts, and then later increased to more mature levels. The amino acid level appeared to be fully developed by 30 days of life with glutamic acid having the highest concentration in the cortical area and GABA in the subcortical ones.
Norepinephrine and dopamine in the developing chick brain
Authors: Kobayashi Kenichi , Eiduson Samuel 
Published: January 2005

AbstractAppearance, concentration, and distribution of catecholamines (dopamine and norepinephrine) in embryonic and postnatal chick brain regions were studied. The highest amount of DA was found in cerebral hemispheres and increased gradually to adult levels, whereas in other parts of the brain the concentrations of DA fluctuated during the post‐hatch period. The remainder contained the largest amount of NE, whereas the cerebral hemispheres contained relatively small amounts of NE. Relatively high amounts of NE were found in the cerebellum. A single dose of L‐3, 4‐dihydroxyphenylalanine (DOPA) injected into the 3‐day‐old embryo had no significant effect upon the levels of DA and NE either in the embryonic stages or in the postnatal period. In the 7‐day‐old chick, combined treatment of JB‐516 (catron) and L‐DOPA (IP) induced about a 10‐fold and 2‐fold increase of the brain level of DA and NE respectively about 30 min after injection, and these levels decreased rather rapidly within 2 hr. A group of chicks injected with DOPA at the 3‐day‐old embryonic stage and a group injected with saline were exposed one month post‐hatch to three visual discrimination tasks. There was no significant difference in the performance between these two groups.
The effects of separation and reunion on the behavior of mother and infant squirrel monkeys
Authors: Kaplan Joel 
Published: January 2005

AbstractMother and infant squirrel monkeys that lived together in a socially restricted environment were separated for a period of seven days after the infants had become relatively independent, and were then reunited. Behavioral observations before, during, and after separation indicated that (1) female infants became independent of their mothers earlier than males, (2) neither mothers nor infants were severely affected by separation, and (3) an increase in attachment occurred following reunion only when the mother had a limited history of maternal experience. These results suggest that (1) certain characteristics in the maternal behavior of the squirrel monkey facilitate readjustment in mothers and infants following maternal separation, (2) maternal experience can influence the mother‐infant relationship following a period of separation, and (3) the independence of infants from their mothers may be a function of both sex and species.