bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the sedative and congnitive effects of cyclobenzaprine compared with diphenhydramine and placebo using a computerized test battery
Authors: Lines Christopher , Dawson Catherine , Ambrose Judith , Panebianco Deborah , Cheng Kenneth , Traub Michael 
Published: January 2005

AbstractTwo studies were undertaken to investigate the sedative and congnitive effects of cyclobenzaprine (Flexeril®) in volunteers, using a computerized battery of congnitive tests and subjective rating scales. In Study 1 the effect of acute administration of two doses of cyclobenzaprine (2.5, 5 mg orally) were compared with a single dose of diphenhydramine (Benadryl; 50 mg orally) and placebo. On most tests diphenhydramine produced a significant impairment compared to placebo, whereas there were typically no significant differences between cyclobenzaprine and placebo. In Study 2 the effects of repeated dosing with cyclobenzaprine (5 mg three times daily for 10 doses) were compared to placebo. The test battery was administered after the fourth and tenth doses. There was a small but mainly nonsignificant trend for subjects receiving cyclobenzaprine to do worse at the first test session. No differences between treatments were apparent by the second test session. The battery of tests used here would appear to be useful for assessing sedation. © 1992 Wiley‐Liss, Inc.
Profile of cholinomimetic drugs in primates: Status of screens for potential Alzheimer therapies
Authors: Rupniak Nadia M. J. 
Published: January 2005

AbstractCriticism of the validity of preclinical screens for cognitive enhancers and unsuccessful attempts at cholinotherapy for Alzheimer's disease cast doubt on the likely efficacy of such treatment. However, inadequacies of existing cholinergic drugs and inconclusive clinical trials leave unanswered the question of whether symptomatic relief from dementia can be achieved. Preclinical screens using primates may provide valuable information to support selection of appropriate compounds for clinical development. At present it is not possible to routinely screen cholinergic agents in a manner which provides convincing evidence for beneficial cognitive effects of known relevance for Alzheimer's disease. However, direct comparison of the in vivo effects of a range of cholinomimetic agents in primates has assisted selection of a novel cholinesterase inhibitor, eptastigmine (L‐689,487). In rhesus monkeys, the cholinesterase inhibitors physostigmine and eptastigmine, but not tacrine, were able to fully reverse scopolamine‐induced performance deficits in a visuospatial task. The duration of action of eptastigmine was considerably longer following oral administration (around 4.5 hr) than for physostigmine (approximately 30 min). In contrast, the directly acting, nonselective muscarinic agonists pilocarpine and RS86 were able to induce only partial reversal of the central effects of scopolamine, apparently due to dose‐limiting toxicity. Similarly, the selective M1/M3 direct agonists AF1026 and L‐689,660 caused only partial or no reversal of the scopolamine‐induced impairment. The superior in vivo profile of eptastig‐ mine should enable more definitive evaulation of cholinotherapy for Alzheimer's disease. © 1992 Wiley‐Liss, Inc.
In vivo and in vitro effects of the novel antiarrhythmic ipazilide on cardiac and vascular smooth muscle function
Authors: Ezrin Alan M. , Lee King C. , Harris Alex L. , Silver Paul J. 
Published: January 2005

AbstractIpazilide fumarate is a novel antiarrhythmic currently undergoing clinical evaluation. Since most antiarrhythmics have adverse cardiovascular side effects, we examined the potential effects of ipazilide on cardiac muscle and vascular hemodynamic function utilizing in vivo and in vitro models. The cardiovascular effects of ipazilide and selected reference antiarhythmics, disopyramide and sotalol, at relevant antiarrhythmic concentrations were compared. All agents decreased cardiac contractility, as evident by reductions in dP/dt and cardiac output in anesthetized dogs, and by decreases in contractile force in isolated guinea pig papillary muscles. In vivo, ipazilide was approximately 3–10 × less potent than disopyramide or sotalol while in vitro, ipazilide produced a greater decrease in contractility at a relatively high concentration (30 μM). All three agents increased cardiac preload as reflected by increases in left ventricular end diastolic pressure and right atrial pressure, with ipazilide 2–3 × less potent than disopyramide or sotalol. Differential effects on vascular function were also evident with the three agents. Disopyramide and sotalol significantly increased systemic vascular resistance, and either pulmonary vascular resistance (disopyramide) or left coronary arterial vascular resistance (sotalol); ipazilide did not significantly affect any of these parameters. In isolated rat arterial or canine coronary arterial smooth muscle, ipazilide produced concentration‐related vasorelaxation, with EC50 values ranging from 11–300 μM. Efficacy of ipazilide was higher in depolarized vascular tissue. In conclusion, since previous preclinical studies have indicated equal or greater antiarrhythmic activity of ipazilide relative to disopyramide or sotalol, the current data indicate the possibility for lessened in vivo hemodynamic effects of ipazilide at efficacious antiarrhythmic dosages. © 1992 Wiley‐Liss, Inc.
β2‐Adrenoceptors mediate inhibition of carbachol‐induced contraction and cAMP generation in isolated smooth muscle cells from rabbit gastric antrum
Authors: Moummi Chafiq , Magous Richard , Bali Jean‐Pierre 
Published: January 2005

AbstractThe regulation of inhibition of carbachol‐induced contraction by β‐adrenoceptors of rabbit gastric antrum has been investigated. A functional assay using isolated smooth muscle cells (ISMC) was used to study the effect of β‐adrenergic agonists and antagonists on carbacholcontracted ISMC and cAMP generation. The nonselective β‐adrenergic agonist isoproterenol caused concentration‐related inhibition of carbachol‐induced contraction associated with a significant increase in cellular cAMP. The EC50 for the effect of isoproterenol on cell inhibition of carbachol‐induced contraction was closely related to the EC50 for cAMP formation; the two curves were superimposable, indicating a positive correlation between the biological activity (inhibition of carbachol‐induced contraction) and the intracellular event (cAMP formation) caused by the activation of β‐adrenoceptors. The Kinetic studies demonstrate that maximum inhibition of carbachol‐induced contraction and a parallel elevation of intracellular cAMP content were reached at 30 sec of incubation with isoproterenol. The β2‐selective receptor agonist terbutaline induced inhibition of carbachol‐induced contraction of carbachol‐contracted ISMC and cAMP generation. However, the relatively β1‐selective receptor agonist norepinephrine had no significant effect. Propranolol, a nonselective β‐ adrenoceptor antagonist (β1 and β2) caused a significant inhibition of the carbacholβ2 induced contraction and rise in cAMP induced by isoproterenol and terbutaline, while the β1‐selective adrenergic receptorantagonist metoprolol, even at higher concentration, was inactive. These data demonstrate that there is a correlation between inhibition of carbachol‐induced contraction and cAMP generation upon activation of the β2‐adrenoreceptors in the ISMC of rabbit gastric antrum. © 1992 Wiley‐Liss, Inc.
Enhancement of systemic delivery of peptide drugs via ocular route with surfactants
Authors: Chiou George C. Y. , Shen Z. F. , Zheng Y. Q. , Chen Y. J. 
Published: January 2005

AbstractThe enhancement of systemic delivery of peptide drugs by absorption enhancers via ocular route was studied in the rabbits. The systemic absorption of α‐melanocyte stimulating hormone (α‐MSH) was enhanced by 0.5% polyoxyethylene 9‐lauryl ether (BL‐9) and 0.5% polyoxyethylene 20‐stearyl ether (Brij‐78) for 11 fold and 10 fold, respectively. The enhancement of systemic delivery of somatostatin, vasoactive intestinal peptide (VIP) and adrenocorticotropic hormone (ACTH) by BL‐9 (5.1 fold, 4.0 fold, and 5.3 fold, respectively) and Brij‐78 (6.4 fold, 5.2 fold, and 5.8 fold, respectively) was about half of those of α‐MSH. In all cases, the blood concentration of peptides reached the peak faster with BL‐9 (in 5–20 min after drug instillation) than with Brij‐78 (in 10–60 min after drug instillation). It is concluded that peptide drugs can be delivered systemically through the ocular route particularly when permeation enhancers are added to reduce the costs of the peptide drugs. © 1992 Wiley‐Liss, Inc.
Electropharmacology of bidisomide in the normal intact canine heart
Authors: Garthwaite Susan M. , Frederick Leo , Cook Chyung , Hatley Frida 
Published: January 2005

AbstractBidisomide (SC‐40230) is a class I antiarrhythmic agent. The effects of bidisomide on the electrophysiology of the intact heart were studied using an anesthetized dog model. Three cumulative intravenous doses of bidisomide were studied (n = 5)—1.5, 11.5, and 22.1 mg/kg—given as a loading dose followed by a maintenance infusion to produce three plasma concentration ranges—1.9‐–2.3, 17.2–21.2, and 22.7–24.1 μg/ml. A placebo group (n = 5) received the equivalent volume of saline. Heart rate, blood pressure, lead II electrocardiogram (ECG) intervals, as well as conduction, refractoriness, and nodal function were measured. Placebo had no effect on any parameter. With the exception of prolonging the atrial refractory period, bidisomide had no effect on any parameter at the lowest dose studied. Bidisomide caused a dose‐dependent and statistically significant increase in sinus node recovery time, atrial and ventricular conduction time, atrial effective refractory period, A‐H and H‐V intervals, P‐R and QRS intervals, Wenckebach point, and spontaneous cycle length. The effect of bidisomide on atrial refractory period and on A‐H interval was cyclelength dependent. Bidisomide increased or did not change ventricular refractory period in the five dogs studied. Blood pressure decreased less than 15% at plasma bidisomide concentrations up to 20 μg/ml. These experiments demonstrated that bidisomide affects conduction and/or refractoriness in all parts of the heart and has electrophysiologic effects consistent with ventricular and supraventricular antiarrhythmic activity. © 1992 Wiley‐Liss, Inc.
Misoprostol in the treatment of duodenal ulcers in the people's Republic of China: A comparative, double‐blind, multicenter study
Authors: Dajani Esam Z. , Wang Baoen , Pei Ying , Pan Gaozhong , Chen Shoubo , Zheng Zhitian , Li Yinong , Zhu Wunan , Wang Jiyao , Yuan Shizhen , Yu Yongoda , Yao Zhi Jian 
Published: January 2005

AbstractIn recent years, it has become mandatory for many pharmaceutical companies to conduct country‐specific clinical studies which are needed for obtaining regulatory approvals for their drugs. Such studies are important to delineate possible racial or environmental (lifestyle) differences which could not have been predicted from data obtained in other populations. A double‐blind, randomized, double‐dummy, multiclinic, comparative trial examined the tolerance and efficacy of misoprostol (200 μg QID) and cimetidine (200 mg QID) for the treatment of duodenal ulcers in the People's Republic of China. The trial characteristics and monitoring complied with the standards in the United States of America and the People's Republic of China. Two hundred consenting outpatients of either sex, aged 18–75 years, who had duodenal ulcers (not less than 0.3 cm in longest diameter and not more than 2 ulcers) were enrolled. Endoscopy, physical examination, and laboratory assessments wereperformed on entry and after 4 weeks of treatment. The effects of the treatment on ulcer healing, dyspeptic symptoms, tolerance, and adverse drug reactions were determined. Both treatment groups were well matched for demographic characteristics and disease severity at entry to the study. Misoprostol showed equal efficacy to cimetidine in inducing ulcer healing (60.7% vs. 67.9% for misoprostol and cimetidine, respectively, P > 0.05) and resolving dyspeptic pain. The extent of duodenal ulcer healing achieved by misoprostol in this study is essentially similar to the ulcer healing rates noted in many other worldwide studies, indicating the absence of racial differences in response to misoprostol. The adverse effects observed for misoprostol and cimetidine were also very similar. Both drugs were very well tolerated; however, slightly more patients experienced transient diarrhea with misoprostol (6.4%) than with cimetidine (3.8%). In conclusion, this trial supports the world‐ wide efficacy and tolerance of misoprostol for the treatment of duodenal ulcers and indi‐ cates the absence of racial influences on the safety and efficacy of misoprostol. © 1992 Wiley‐Liss, Inc.
Inability of β‐amyloid (25–35) to bind to central nervous system neurokinin 1 receptors
Authors: Lee John M. , Weinstein David A. , Kowall Neil W. , Beal M. Flint 
Published: January 2005

Abstractβ‐Amyloid (1–40) has recently been shown to exhibit both neurotoxic and neurotrophic properties. The putatively active moiety is β‐(25–35), which has a structural homology to the human tachykinin substance P. Substance P, which preferentially binds to neurokinin 1 (NK1) receptors in the central nervous system (CNS), has been shown to block the neurotoxic effects of β‐amyloid (1–40). These data suggest that effects of β‐amyloid may be mediated by an NK1 receptor‐mediated process. However, in the present study, we demonstrate that β‐(25–35) is unable to competitively inhibit the binding of 0.15 nM 125I‐substance P from rat CNS NK1 receptors. Therefore, the mechanisms of action of β‐amyloid neurotoxic effects are probably not to be mediated through a NK1 receptor‐mediated process. © 1992 Wiley‐Liss, Inc.
Protection and reversal by memantine and atropine of carbofuran‐induced changes in biomarkers
Authors: Gupta Ramesh C. , Goad John T. , Kadel Wade L. 
Published: January 2005

AbstractMale Sprague‐Dawley rats injected with a single acute dose of carbofuran (1.5 mg/kg, sc) developed chewing movements and fine tremors within 5–7 min. The signs of maximal severity with hypercholinergic preponderance including muscle fasciculations, convulsions, tracheobronchial secretions, and diarrhea were evident within 15–30 min and lasted for about 2 h. Various antidotal drugs, alone or in combination with atropine sulfate (ATS), were administered as pretreatment or as therapeutic measures to alleviate carbofuran‐induced cholinergic toxicity. In fact, pyridine‐2‐aldoxime methylchloride (2‐PAM) or diazepam alone or in combination with ATS did not provide any beneficial antidotal effects. Combined pretreatment with memantine (MEM, 18 mg/kg, sc) and ATS (16 mg/kg, sc) provided complete protection against carbofuran toxicity and reversal of clinical evidence when given therapeutically. Carbofuran intoxication caused significant alterations in the activities of biomarker enzymes such as creatine kinase (CK) and lactic dehydrogenase (LDH) and their isoenzymes patterns in serum as a result of their leakage from the target organs (brain, muscles, and heart). Significant increases in the levels of transaminases (GOT and GPT) and glucose were also noted, MEM in the aforementioned parameters, in addition to similar protective effects reported on target enzyme acetylcholinesterase (AChE). These results, along with those reported previously, indicate that MEM antagonizes carbamates toxicity by maintaining cell membrane permeability and integrity through multiple mechanisms, in addition to muscarinic receptor blocking effect of ATS. © 1993 Wiley‐Liss, Inc.
Diadenosine polyphosphate (ApxA) as new neurotransmitters
Authors: Pintor Jesúas , Miras‐Portugal M. Teresa 
Published: January 2005

AbstractThe presence of diadenosine polyphosphates (ApxA), diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap6A), and diadenosine hexaphosphate (Ap6A), has been described in secretory granules of chromaffin cells, Torpedo synaptic vesicles, and rat brain synaptosomes. The release of these compounds by the action of secretagogues and depolarizing agents, in the presence of calcium, increases their importance as active neurotransmitters. Two high affinity receptors have been described in the three neural models, with Kd values ranging from 0.08 to 0.40 nM for the first binding site and from 5.6 to 18nM for the second lower affinity binding site. Both binding sites exhibit a P2y‐like profile in chromaffin cells and Torpedo synaptic terminals and a different pattern in rat brain synaptosomes, suggesting the presence of a novel P2‐purinoceptor tentatively named P2d. Studies about the second messenger linked to this receptor, in chromaffin cells, demonstrate the mobilization of calcium from internal stores. ApxA receptors at the extracellular milieu are responsible for the inhibition of catecholamine release stimulated by secretagogues. Finally, all diadenosine polyphosphates are destroyed by the action of an ecto‐phosphodiesterase which, in chromaffin cells, shows Km values ranging from 1 to 4 μM. © 1993 Wiley‐Liss, Inc.
Prevention of ischemic brain injury by adenosine receptor activation
Authors: Phillis John W. , O'Regan Michael H. 
Published: January 2005

AbstractThe abilities of the xanthine oxidase inhibitor, oxypurinol, and the adenosine deaminase inhibitor, deoxycoformycin, to alleviate cerebral ischemic damage were evaluated in gerbil and rat models. Cerebral ischaemia of 5 min duration was induced in unanesthetized Mongolian gerbils by bilateral occlusion of the carotid arteries. Cerebral damage was assessed behaviorally by the elevation of motor activity and by histological assesment of neuronal degeneration in the CA1 area of the hippocampus. Oxypurinol (40 mg/kg) administered either prior to or 30 min after and ischaemic episode significantly reduced both the hypermotility and hippocampal damage observed in saline‐treated control ischemic gerbils. Deoxycoformycin (500 μg/kg) was effective only when administered prior to ischemia. Rats with a focal ischaemic lesion (unilateral occlusion of a middle cerebral artery combined with tandem occlusion of the ipsilateral common carotid artery) were used to model strokes. The degree of ischaemic damage was evaluated by measuring the contralateral neurological deficits at 24 and 48 h post infarction and by calculating the volume of infarcted tissue after brain slices had been stained with 2,3,5‐triphenyl, 2H‐tetrazolium chloride (TTC) solution. Oxypurinol (40 mg/kg) administered 30 min prior to or 1h after the onset of focal ischaemia significantly reduced the infarct size, brain swelling, and neurological deficits. Deoxycoformycin (500 μg/kg) was effective only when administered preischemia. These findings suggest that oxypurinol and deoxycoformycin may be useful for the prevention and treatment of ischaemic brain injuries. © 1993 Wiley‐Liss, Inc.
Action of a novel potassium channel opener, SR 47063, on human bronchi and on guinea‐pig trachea in vitro: comparison with cromakalim
Authors: Martin Corinne A. E. , Naline Emmanuel , Advenier Charles 
Published: January 2005

AbstractPotassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our study was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field stimulation in guinea‐pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakalim, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea‐pig isolated trachea and the human isolated bronchus in basal tone with pD2 of 7.79 ± 0.01 and 7.83 ± 0.09, respectively, or during precontractions induced by acetylcholine 10−4 M, histamine 10−5 M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (≥30 mM); these effects were antagonized by glibenclamide 10−5 M. This spectrum of action is typical of the compounds known as potassium channel openers. Electrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10−6 M and propranolol 10−6 M) of guinea‐pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakalim. Although we have not studied the effects of KCOs on exogenous neurokinin A‐ or substance P‐induced contractions, it might be suggested as a hypothesis that this inhibition seems to take place presynaptically and to affect the release of neuromediators produced by electrical field stimulation. In conclusion, SR 47063 exerts in vitro on the bronchial smooth muscle an inhibitory effect which seems to be due to the opening of glibenclamide‐sensitive potassium channels. SR 47063 is 3‐ to 10‐fold more potent than cromakalim. © 1993 Wiley‐Liss, Inc.
Effects of linopirdine, HP 749, and glycyl‐prolyl‐glutamate on transmitter release and uptake
Authors: Zaczek Robert , Tinker William J. , Logue Andrew R. , Cain Gary A. , Teleha Christopher A. , Tam S. William 
Published: January 2005

AbstractLinopirdine, HP 749, and glycyl‐prolyl‐glutamate (GPE) are compounds that have been reported to alter the release of neurotransmitters. This study compares the potassium‐stimulated neurotransmitter release enhancing properties maximal release enhancement. HP 749 increased the extracellular concentrations of the catecholamines, [3H]NE and [3H]DA, but not [3H]ACh or [3H]d‐Asp. HP 749 was a potent inhibitor of both [3H]NE and [3H]DA uptake, and this may, in part, be responsible for the apparent release enhancing activity of the drug. GPE was devoid of release enhancing activity under the conditions of these compounds in parallel. While not affecting the apparent release of [3H]norepinephrine ([3H]NE), linopirdine at a concentration of 10 μM enhanced the potassium evoked release of cerebral cortical and hippocampal [3H]acetylcholine ([3H]ACh) release by 143% and 200% over control, respectively, and striatal [3H]dopamine ([3H]DA) and hippocampal [3H]d‐aspartate ([3H]d‐Asp) release by 236% and 65% over control, respectively. The release enhancing effects of linopirdine were not due to inhibition of high‐affinity uptake processes, since the drug did not inhibit neurotransmitter uptake at the concentration (10 μM) which caused used in the present study. © 1993 Wiley‐Liss, Inc.