bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analgesic profile of the sodium salt of pemedolac
Authors: Chau Thuy T. , Walter Thomas , Katz Alan , Weichman Barry M. 
Published: January 2005

AbstractPemedolac Na, 1‐ethyl‐1,3,4,9‐tetrahydro‐4‐(phenylmethyl)‐pyrano [3,4‐b] indole‐1‐acetic acid sodium salt, exhibited equipotent analgesic effects after oral, iv, and im administration, suggesting that it is well absorbed. In mouse writhing models, the ED50 values ranged from 0.3 mg (0.81 μmol)/kg (vs. acetylcholine) to 4.3 mg (11.6 μmol)/kg (vs. paraphenylbenzoquinone [PBQ]). In the rat Randall‐Selitto model, the ED50 o the compound was approximately 0.001 mg (2.7 nmol)/kg, with a flat dose response curve. The peak effects lasted for 7–9 h, 10–18 h, and 5 h following oral, im, and iv injections, respectively. Intracerebroventricular (i.c.v.) injections of pemedolac Na inhibited the PBQ‐induced writing in mice with an ED50 of 43.5 μg (0.12 μmol)/mouse, and this effect was not antagonized by naloxone. It was inactive in the hot plate and tail flick tests, demonstrating that pemedolac Na does not act via an opiate mechanism. These results indicate that pemedolac Na is a viable parenteral and oral analgesic, typified by high analgesic potency, a rapid onset and long duration of action, and an extremely wide safety index. © Wiley‐Liss, Inc.
Oxiracetam and aniracetam increase acetylcholine release from the rat hippocampus in vivo
Authors: Giovannini Maria Grazia , Rodinò Paola , Mutolo Donatella , Pepeu Gincarlo 
Published: January 2005

AbstractThe effect of two nootropic drugs, oxiracetam and aniracetam, on cholinergic neurotransmission in vivo was investigated in the rat by means of the transversal microdialysis techique. The basal release of acetylcholine (ACh) from the hippocampus and parietal cortex was 2.93 ± 0.17 and 3.10 ± 0.18 pmol/min (mean ± s.e.m.), respectively, and remained stable for at least 3 h, while the initial efflux of choline was 51.9 ± 2.6 and 42.8 ± 6.4 pmol/20 min (mean ± s.e.m.), respectively, and decreased by about 50% during the first 60 min of collection. Oxiracetam, tested at doses of 50, 100, and 300 mg/kg ip, elicted a 63% increase in ACh release from the hippocampus at the dose of 100 mg/kg only. This effect of oxiracetam was inhibited by perfusion with tetrodotoxin (TTX), 5 × 10−7 M. In oxiracetam‐treated rats the decrease in choline efflux was less pronounced than in controls (‐23% of the initial value) at the dose of 100 mg/kg. Aniracetam (100 mg/kg, orally) elicited a sustained increase of ACh release from the hippocampus (+ 58%, 120 min after the administration), without affecting choline efflux. Doses of 50 and 300 mg/kg, orally, of aniracetam were ineffective. Oxiracetam and aniracetam (50 and 100 mg/kg) neither modified the output of ACh or choline from the parietal cortex nor induced gross behavioral changes. These results indicate that oxiracetam and aniracetam could act on cognitive processes by stimulating the hippocampal cholinergic pathways. © Wiley‐Liss, Inc.
Problems and perspectives in the design of anti‐HIV‐1 agents
Authors: Mohan Prem 
Published: January 2005

AbstractThe human immunodeficiency virus (HIV) that produces the acquired immune deficiency syndrome (AIDS) continues to evade all strategies for potential therapeutic intervention. Global efforts in the search for potential anti‐HIV‐1 agents have mainly centered around the design of enzyme inhibitors and derivatives that inhibit viral binding or gene expression. Both nucleoside and non‐nucleoside reverse transcriptase inhibitors have demonstrated potent anti‐HIV‐1 activity. However, toxicity considerations and the emergence of resistant strains will require further structural manipulations to diminish these undesirable properties. Protease inhibitors also exhibit activities at nanomolar concentrations, but many of these agents may suffer from problems of absorption and biodegradation. These apparent shortcomings have been circumvented by the preparation of peptidomimetic molecules. Similarly, smaller CD4 mimetics have emerged as alternatives to the larger soluble CD4 derivatives as inhibitors of viral binding. Other viral binding inhibitors, the anionic molecules, suffer from an inherent inability to enter cells and potential anticoagulant activity. These properties may be remedied by rational analog design and synthesis. Oligonucleotides can be constructed to inhibit specific segments of selected regulatory genes of the virus. These agents have been critiqued on the basis of stability, cellular uptake, and assurance of hybridization. Once again, structure activity relationship studies have revealed that many of these apparent problems can be overcome. The more recently discovered agents belong to the unique classes oftatantagonists or viral uncoating inhibitors. © 1993 Wiley‐Liss, Inc. © 1993 Wiley‐Liss, Inc.
Psychomotor stimulants versus antidepressants in the learned helplessness model of depression
Authors: Geoffroy Marianne , Christensen Anne V. 
Published: January 2005

AbstractAnimal models of depression which use stress to induce abnormal behavior generally cannot discriminate antidepressants from drugs which are central stimulants and predominantly stimulate dopamine (DA) neurons. Thus these models lack pharmacological specificity. The present study shows that the Learned Helplessness (LH) model, applied to Wistar rats, becomes a more valid pharmacological model if registration of the animals' behavior during the interval between each trial of the LH shuttlebox test is added. The DA drugs amphetamine, methylphenidate, nomifensine, apomorphine, quinpirole (specific D2 agonist), SKF 81297 (specific D1 agonist), and the antidepressants imipramine, amitriptyline, and isocarboxazide were tested. The results show that the DA drugs had an acute effect and increased the number of shuttle box crossings in the intervals between the test trials. The antidepressants had no acute effect and did not increase the number of intertrial crossings in the therapeutic dose range. The LH model thus seems to be advantageous when discrimination between drugs with DA psychomotor stimulating properties and drugs with antidepressant properties is needed. © 1993 Wiley‐Liss, Inc.
Effect of desferrioxamine on the hepatotoxicity of adriamycin in normal mice
Authors: Al‐Bekairi Abdullah M. , Osman Abdel‐Moneim M. , Hafeez Mohamed A. , Al‐Gharably Naji M. , Al‐Shabanah Othman A. , Al‐Harbi Mohamed M. 
Published: January 2005

AbstractThe effect of the iron chelator, desferrioxamine (DFO) upon the hepatotoxic effects associated with the use of adriamycin as a cytotoxic agent were evaluated in normal albino mice. Hepatocellular toxicity was assessed by measuring serum aspartate transaminase (SGOT), serum alanine transaminase (SGPT) and serum alkaline phosphatase (ALP) activity. In addition, glucose‐6‐phosphatase (G‐6‐PTase) activity, nucleic acids, calcium, magnesium, and iron levels in liver tissue were also measured. Adriamycin treatment (2 mg/kg i.p.), administered every other day for a total of 5 doses produced a 2.5‐fold increase in SGOT and SGPT, while ALP activity showed a 30% increase in comparison to normal, untreated controls. However, hepatic G‐6‐PTase activity showed a significant decrease after the adriamycin treatment regimen. The calcium and iron content of liver showed also a marked decrease, while magnesium levels were increased two‐fold after treatment with adriamycin. In the presence of the iron chelator, DFO (100 mg/kg i.p., administered every other day for 5 doses), adriamycin treatment did not result in any significant changes in SGOT, SGPT, ALP, or hepatic G‐6‐PTase activity. Histopathological examination of mouse liver showed diffuse ballooning degeneration of liver cells with perivascular cellular infiltration after adriamycin treatment. In the presence of DFO, only focal cellular degenerative and minimal fatty changes were observed. The observed hepatocellular damage is believed to be a result of the lipid peroxidation induced by adriamycin. The role of DFO in preventing lipid peroxidation has been discussed. This study provides evidence that DFO may be useful for prevention of the lipid peroxidation and hepatocellular damage induced by adriamycin. © 1993 Wiley‐Liss, Inc.
Site specific variations in rat adipose tisue transforming growth factor‐α: Effects of age
Authors: Crandall David L. , Cervoni Peter , Kral John G. 
Published: January 2005

AbstractTransforming growth factor alpha (TGF‐α) was assayed in subcellular preparations obtained by sequential centrifugation of adipose tissue homogenates from epididymal and perirenal adipose tissue depots in young and aged rats. When expressed per unit wet weight, per mg protein or per fat cell, TGF‐α activity in young rats was greater in the epididymal than in the perirenal depot. In aged rats, absolute quantity of TGF‐α was significantly increased in the larger perirenal depot. This study demonstrates the presence of TGF‐α in adipose tissue homogenates, and implicates this cytokine in the growth of adipose tissue. © 1993 Wiley‐Liss, Inc.
MK‐329: A non‐peptide cholecystokinin a antagonist
Authors: Evans Ben E. 
Published: January 2005

AbstractPeptide receptors represent important targets for a variety of potentially important disease modifying drugs. Over the past 20 years, considerable effort has been spent on modifying the natural ligands for peptide receptors, the peptides themselves, with limited success. Using a targeted screen, namely cholecystokinin (CCK)‐A receptor binding, the Merck group in 1984 discovered asperlicin, a potent non‐peptide cholecystokinin antagonist selective for peripheral tissues, that was isolated from Aspergillus alliaceaus. This compound was used as a lead to develop MK‐329, a CCK‐A receptor antagonist, the evolution of which is discussed within the context of the drug discovery process and receptor modeling strategies. © 1993 Wiley‐Liss, Inc.
Linopirdine (DuP 996) selectively enhances acetylcholine release induced by high potassium, but not electrical stimulation, in rat brain slices and guinea pig ileum
Authors: Smith Craig P. , Brougham Linda R. , Vargas Hugo M. 
Published: January 2005

AbstractThe enhancement of acetylcholine (ACh) release during electrical or potassium depolarization was compared in the presence of either linopirdine or 4‐aminopyridine (4‐AP) using two different functional assays. We measured ACh and choline (Ch) directly from striatal perfusates using high performance liquid chromatography and electrochemical detection or indirectly by measuring ACh‐mediated twitch height changes in the electrically stimulated guinea pig ileum. Potassium‐induced twitch responses were also measured in resting ileal segments. Linopirdine significantly enhanced ACh release in the presence of elevated potassium levels in rat striatal slices and guinea pig ileum, but had no effect during electrical stimulation in either model. In contrast, 4‐AP enhanced ACh release in both electrically stimulated striatal slices and ileal strips. In agreement with other studies, atropine enhanced ACh release during either electrical or potassium stimulation paradigms in the striatal slice. The in vitro observations in this report suggest that linopirdine has limited ability to augment the cholinergic neurotransmission evoked by electrical stimulation. © 1993 Wiley‐Liss, Inc.
Setting the record straight: The office of technology assessment report—pharmaceutical R&D costs, risks, and rewards
Authors: Sapienza Alice M. 
Published: January 2005

AbstractThe U.S. Office of Technology Assessment (OTA) report on pharmaceutical research and development (R&D)—costs, risks, rewards—has generated a range of often heated responses, both for and against the industry. The purpose of this commentary is to clarify two points of confusion that repeatedly appear about the report: First, it is not a new and definitive study of the cost of pharmaceutical R&D (although certain related studies were commissioned by OTA). Second, the report is not unexpected, given the political‐economic context in which drug prices have historically been discussed. © 1993 wiley‐Liss, Inc.
Preventive effect of the thromboxane A2 receptor antagonist S‐1452 (d‐s‐145 Ca) on arachidonate‐induced sudden death and cerebral infarction in rabbits
Authors: Jyoy Hirokuni , Kurosawa Atsushi 
Published: January 2005

AbstractThe thromboxane A2 (TXA2) receptor antagonist S‐1452, d‐S‐145 Ca, calcium 5(Z)‐1R,2S,3S,4S‐7‐[3‐phenylsulfonylaminobicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoate dihydrate, prevented sudden death induced by arachidonate or U46619 in rabbits when given in a dose range between 0.1 mg/kg and 1 mg/kg, p.o. OKY‐046 and aspirin were also effective in this thromboembolism model, but 10 to 30 times larger doses were needed. Orally administered S‐1452 successfully prevented the incidence of cerebral infarction in the rabbit, which was elicited by infusion of 10 mg/ml sodium arachidonate at a rate of 0.1 ml/min for 30 min via a left internal carotid artery. Significant reduction of the infarction grade was observed in dosing above 3 mg/kg of this compound 1 to 4 h before the arachidonate infusion. OKY‐046 was effective similarly, but less active than S‐1452 (the minimum effective dose: 10 mg/kg). Ticlopidine and aspirin were entirely inactive in this model even after much larger doses. S‐1452 is a useful compound for prevention of TXA2‐mediated thrombosis in the brain. © 1993 wiley‐Liss, Inc.
Differential effects of pretreatment with nicotine and lobeline on nicotine‐induced changes in body temperature and locomotor activity in mice
Authors: Decker Michael W. , Buckley Michael J. , Brioni Jorge D. 
Published: January 2005

AbstractAlthough lobeline and nicotine are both potent ligands at neuronal nicotinic cholinergic receptors, chronic lobeline does not produce the upregulation of nicotinic receptors found with chronic nicotine or the less potent agonist anabasine. Since agonist‐induced receptor upregulation is believed to result from receptor desensitization during chronic treatment, this suggests that lobeline may not desensitize neuronal nicotinic receptors. We addressed this question by comparing lobeline‐ and nicotine‐induced desensitization of the actions of nicotine, using body temperature and locomotor activity as dependent variables. Nicotine pretreatment reduced the hypothermia and locomotor suppression produced by a subsequent nicotine challenge, whereas lobeline pretreatment did not. When tested alone, both nicotine and lobeline reduced locomotor activity and body temperature to a similar degree, but lobeline was significantly less potent. The reductions in activity and temperature produced by nicotine were significantly attenuated in chlorisondamine‐treated mice, whereas treatment with this long‐lasting nicotinic cholinergic antagonist did not alter the effects of lobeline. Thus, nicotine and lobeline appear to differ in their ability to produce desensitization. Furthermore, the effects of these two compounds on locomotor activity and body temperature may be mediated via different mechanisma. © 1994 Wiley‐Liss, Inc.
Modeling the nicotinic receptor loss in dementia using the nicotinic antagonist mecamylamine: Effects on human cognitive functioning
Authors: Newhouse Paul A. , Potter Alexandra , Corwin June , Lenox Robert 
Published: January 2005

AbstractThe loss of central nicotinic receptors is a neurochemical hallmark of several degenerative brain disorders, notably Alzheimer's disease (AD) and Parkinson's disease (PD). However, uncertainty has remained about the significance of this loss for the cognitive symptomatology of these disorders. Symptoms of impaired acquisition of information and short‐term storage, impaired memory consolidation, attention, visual perception, and speed may reflect nicotinic lesions. Administration of the nicotinic antagonist mecamylamine in young and elderly humans produces significant dose‐related impairment of new learning, liberalization of response bias, and slowing of reaction time. These results suggest that mecamylamine may in part model the results of nicotinic receptor loss in AD and that nicotinic augmentation of some aspects of cognitive functioning may be a worthwhile strategy to pursue, particularly if agents can be developed that are more selective than nicotine itself. © 1994 Wiley‐Liss, Inc.
Effects of nicotine on levels of acetylcholine and biogenic amines in rat cortex
Authors: Summers Kathleen L. , Cuadra Gabriel , Naritoku Dean , Giacobini Ezio 
Published: January 2005

AbstractTranscortical dialysis was employed to investigate the effects of systemic nicotine (3.6 μmol/kg, sc) administration on cortical extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5‐HT). Systemic administration of [–]‐nicotine produced a 106% increase of cortical ACh release over basal levels that persisted for approximately 2 h. Concurrently, NE levels were increased 86% over basal values for 60 min. The effects appear to be stereoselective, as systemic injections of [+]‐nicotine significantly increased cortical ACh levels only 48% over basal levels for 30 min, and NE levels in the dialysate only 43% over control levels for 60 min. No significant changes of basal dopamine (DA) or serotonin (5‐HT) levels were observed, although DA did appear to increase in response to systemic nicotine. In addition, striatal total endogenous ACh increased significantly over control levels 15 min after [–]‐nicotine administration (3.6 μmol/kg, sc), and then significantly declined after 3 h, suggesting that nicotine may influence synthesis as well as release. Analysis of total ACh levels in cortical tissue revealed a similar trend. At the dose utilized in this study, no changes in the cortical electroencephalogram (EEG) were observed. © 1994 Wiley‐Liss, Inc.
Cytoprotective actions of 2,4‐dimethoxybenzylidene anabaseine in differentiated PC12 cells and septal cholinergic neurons
Authors: Martin Eileen J. , Panickar Kiran S. , King Michael A. , Deyrup Malgorzata , Hunter Bruce E. , Wang Geehuan , Meyer Edwin M. 
Published: January 2005

AbstractThe potential cytoprotective actions of a novel nicotinic agent 2,4‐dimethoxybenzilidene anabaseine (DMXB) were investigated in differentiated PC12 cells and transected rat septal cholinergic neurons in vivo. In NGF‐differentiated PC12 cells, removal of both NGF and serum led to cell loss, a reduced % of cells expressing neurites, the release of lactate dehydrogenase, and a decrease in total cellular protein. Cell loss was apparent within 24 h, and remained constant between 4–8 days post‐NGF removal. NGF alone (100 ng/ml), DMXB (10 μM), but not nicotine (10 μM), prevented these cell and neurite losses. DMXB‐induced cytoprotection was blocked by 1 μM mecamylamine. DMXB (1 mg/kg, ip) injected twice but not once per day protected cholinesterase‐staining septal neurons from retrograde degeneration following unilateral fimbrial transections. The twice per day DMXB injection‐protocol also decreased cell roundness among cholinesterase‐staining cells in the lesioned septal hemisphere compared to saline‐injected animals. These studies suggest that DMXB may exert cytoprotective activity in NGF‐sensitive neuronal populations. © 1994 Wiley‐Liss, Inc.
Effects of an extract ofGinkgo bilobaOn the action potential and associated transmembrane ionic currents in mammalian cardiac myocytes: Inhibition of isoproterenol‐induced chloride current
Authors: Masson Frédéric , Néliat Gervais , Drieu Katy , Defeudis Francis V. , Jean Thierry 
Published: January 2005

AbstractVentricular myocytes of guinea pig heart were used to examine the effects of an extract ofGinkgo biolba(EGb 761) on the action potential and individual transmembrane ionic currents. Elecrophysiological events were recorded using the “whole‐cell” configuration of the patch‐clamp technique. A systematic analysis of the data revealed that EGb 761 (5‐50 μg/ml) did not affect the normal action potential or the various ionic currents involved in its generation; i.e., fast inward sodium current (INa), inward calcium currents (ICaTand ICaL), delayed outward potassium current (IK), inward rectifying potassium current (IK1), and ATP‐senstive potassium current (IK‐ATP) evoked by 2,4‐dinitrophenol (2,4‐DNP). However, EGb 761 (≥5 μg/ml) elicited a pronouced concentration‐dependent and reversible inhibiton of isoproternol‐induced Cl−current (ICl), the maximal effect being observed at 50 μg/ml. This current may be significantly involved in sympathetic hyperactivity, hypoxia, and ischemia, pathophysiological conditions for which EGb 761 offers therapeutic benefit. The basic mechanism(s) underlying the inhibitory effect of EGb 761 on ICland the constituent(s) of EGb 761 responsible for this action remain to be identified, but it seems clear, from results which showed that neither ginkgolide B (50–500 ng/ml) nor biolobalide (150–1,500 ng/ml) influenced this current, that a terpenoid constituent of EGb 761 is probably not involved.
Advanced glycosylation endproducts: Role in diabetic and non‐diabetic vascular disease
Authors: Bucala Richard , Vlassara Helen , Cerami Anthony 
Published: January 2005

AbstractReducing sugars such as glucose react non‐enzymatically with the amino groups of macromolecules to initiate a chemical modification process known as advanced glycosylation. This pathway proceeds from reversible Schiff base adducts to a heterogenous group of irreversibly‐bound, cross‐linking moieties called advanced glycosylation endproducts or AGEs. Recent progress in our understanding of this process in vivo has affirmed the hypothesis that AGEs play an intimate role in the evolution of both diabetic and non‐diabetic vascular disease. Utilizing newly developed AGE‐specific ELISA techniques, AGEs have been identified to be present on a variety of vascular wall, lipoprotein, and lipid constituents. Protein‐bound AGEs, for example, contribute to a variety of pathological effects in vivo by acting to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, and exert direct toxic effects on endothelial cells. Lipid‐AGEs promote oxidative modification and may contribute to atherogenesis by initiating the formation of oxidized low density lipoprotein (ox‐LDL). Aminoguanidine, a recently developed pharmacological inhibitor of advanced glycosylation, is presently undergoing phase II clinical trials and may offer a specific therapeutic modality for the treatment of pathological conditions that result from excessive advanced glycosylation.
Ecto‐enzymes and metabolism of extracellular ATP
Authors: Ziganshin Airat U. , Hoyle Charles H. V. , Burnstock Geoffrey 
Published: January 2005

AbstractExtracellular ATP can produce various effects acting via P2‐purinoceptors. ATP is rapidly broken down by ecto‐ATPase and other ecto‐enzymes that limit its effect. Further, adenosine, a metabolite of ATP breakdown, can produce its own effect acting via P1‐purinoceptors, sometimes masking the effects of ATP. An inhibitor of ATP degradation would be a useful pharmacological tool to discriminate between effects of ATP and its metabolites, as well as to potentiate its actions. Diverse compounds that have been claimed to be inhibitors of ATP‐metabolising ectoenzymes are evaluated, but specific and selective Ca2+ /Mg2+ ‐dependent ecto‐ATPase inhibitors still appear to be lacking.