bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatoprotective effect of an active constituent isolated from the leaves of Ricinus communis Linn
Authors: Shukla Binduja , Visen P. K. S. , Patnaik G. K. , Kapoor N. K. , Dhawan B. N. 
Published: January 2005

AbstractDose (1.5–12 mg/kg p.o. × 7) dependent choleretic, anticholestatic, and hepatoprotective activity in rat was observed with N‐demethyl ricinine isolated from the leaves of Ricinus communis Linn. The anticholestatic and hepatoprotective activity was seen against paracetamol‐induced hepatic damage. The choleretic and anticholestatic activity was evidenced by an increase in the volume of bile and its contents. The hepatoprotective effect was evaluated by an increase in the percent viability of hepatocytes (ex vivo) and by the reversal of altered enzymatic levels (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], and alkaline phosphatase) towards normal. The compound showed more potent activity than silymarin, a known hepatoprotective agent.
The development of a highly selective 5‐HT1 receptor agonist, sumatriptan, for the treatment of migraine
Authors: Feniuk Wasyl , Humphrey Patrick P. A. 
Published: January 2005

AbstractSumatriptan is a highly selective 5‐HT1 receptor agonist and an effective treatment for migraine. It causes constriction of cranial blood vessels. In anaesthetised animals, it selectively constricts parts of the carotid vasculature and has been shown to inhibit plasma protein extravasation from blood vessels of the dura mater induced by antidromic stimulation of the trigeminal nerve. This effect may result from a localised vasoconstriction of the meningeal vessels and/or a direct inhibitory effect on adventitial nerve endings. Sumatriptan penetrates the blood brain barrier poorly. These findings are consistent with the view that the locus of action of sumatriptan is at the level of the wall of cranial blood vessels that are distended and edematous during a migraine headache. © 1992 Wiley‐Liss, Inc.
Concepts for the design of 5‐HT1A serotonin agonists and antagonists
Authors: Glennon Richard A. 
Published: January 2005

AbstractThe accessibility and use of a standard 5‐HT1A agonist radioligand ([3H]8‐hydroxy‐2‐(dipropylaminotetralin) has resulted in the availability of a large amount of binding data on various serotonergic agents. This, in turn, has permitted the formulation of structure—affinity relationships (SAFIR). By contrast, much less information is available concerning the agonist and antagonist activity of these agents. This is primarily due to a lack of standard evaluation procedures, controversy regarding the presynaptic versus postsynaptic nature of certain models, and the recent realization that many 5‐HT1A agents are partial agonists. Thus, it has been difficult to formulate structure—activity relationships (SAR) for these agents. The present review examines the various classes of 5‐HT1A serotonergic agents and the available data on their 5‐HT1A agonist and antagonist activity with the aim of formulating SAR. These SAR should provide useful information for the subsequent design of 5‐HT1A‐selective agonists and antagonists. © 1992 Wiley‐Liss, Inc.
Effects of new clonidine derivatives on rabbit intraocular pressure
Authors: Li Byron H. P. , Chiou George C. Y. 
Published: January 2005

AbstractEffects of 25 topically applied clonidine derivatives on rabbit IOP recovery model using intravenous hypertonic saline were studied. Among them, 12 compounds were dissolved in aqueous medium, 11 compounds in polyethylene glycol (PEG 200) and 2 compounds in dimethyl sulfoxide (DMSO). Four compounds showed marked delay in IOP recovery and were more active than S‐timolol and clonidine. Five compounds were about equiactive to S‐timolol and more active than clonidine in suppression of IOP recovery and prolongation of the duration of drug action. There were three compounds that were less active than S‐timolol yet they were still as active or were active than clonidine. Thirteen out of 25 compounds were inactive in suppressing IOP recovery curves. Most of these active compounds (9 out of 12) suppressed IOP recovery in the same magnitude for both treated and non‐treated contralateral eyes, indicating that these effects were manifested though central actions. Three out of 12 compounds showed more effect with treated eyes than with nontreated contralateral eyes, indicating that the local effects were predomiant.
ACE inhibitor lacks acute effect on cognition or brain blood flow in alzheimer's disease
Authors: Weiner Myron F. , Bonte Frederick J. , Tintner Ron , Ford Neville , Svetlik Doris , Riall Teresa 
Published: January 2005

AbstractThe effects of the acute administration of the ACE inhibitor ceronapril were studied in 12 Alzheimer's disease (AD) patients and 2 age‐matched controls. A 4‐week open trial was performed with daily doses of 40–80 mg/day. Testing was performed at baseline and at 4 weeks using the Mini‐mental State Exam and the cognitive portion of the Alzheimer's Disease Assessment Scale as cognitive measures, and regional cerebral blood flow (rCBF) as determined by Xe 133 single‐photon emission computerized tomography as an indirect measure of brain metabolism. There was no effect on cognition and blood flow increased significantly only in the left temporal region. It was concluded that the acute administration of the ACE inhibitor ceronapril had no significant acute effect on cognitive function of rCBF in AD. © 1992 Wiley‐Liss, Inc.
Milacemide: Safety assessment in senile dementia of the Alzheimer type
Authors: Dysken Maurice W. , Fakouhi T. Daniel , Skare Stacy S. , Mendels Joseph , LeWitt Peter , Hendrie Hugh C. , Venable Thomas C. , Hantsbarger Gary L. , Herting Robert L. 
Published: January 2005

AbstractMilacemide, both an MAO‐B inhibitor and a prodrug for glycine, has demonstrated cognitive enhancing effects in animal models, in cognitively intact young and elderly, and has been suggested as a potential treatment for senile dementia of the Alzheimer type (SDAT). This multicenter open‐label trial evaluated the safety and potential efficacy of long‐term milacemide treatment in 209 SDAT outpatients (50–87 years of age). Milacemide treatment was intiated at 400 mg/day and was titrated up to a maximum dose of 1,600 mg/day. Laboratory screening tests, adverse effects reports, the Clinical Global Impression Scale, and the Patient Global Improvement Rating Scale were collected to assess patients' physical and cognitive functioning. Only 8 of 209 patients completed 1 year of treatment and the remaining patients were withdrawn due to adverse effects (73), protocol violations (89), treatment failure (34), and failure to follow‐up (5). Liver function tests became elevated in 145 patients and required study withdrawal of 67 of these patients. There was no evidence of cognitive enhancement or reduction in disease progression. It does not appear that milacemide is a viable treatment for SDAT patients. © 1992 Wiley‐Liss, Inc.
Clinical evaluation of bidisomide, a new class I antiarrhythmic: Initial intravenous dose‐finding study
Authors: Li Moreno Fidela , Summers Kaye L. , Menlove Ronald L. , Claypool William D. , Cox James R. , Garthwaite Susan M. , Karagounis Labros , Anderson Jeffrey L. 
Published: January 2005

AbstractTo assess effectiveness and tolerability of intravenous bidisomide, 16 patients (aged 57 ± 15 years) with ≥ 100 premature ventricular complexes (PVCs)/hr received a 10‐min infusion of bidisomide at 0.4 (n = 4), 0.75 (n = 4), 1.0 (n = 4), or 1.35 (n = 4) mg/kg body weight. Mean PVCs and repetitive beats per 3 and 15 min (± SD) from 2 hr pre‐ and 2 hr postdosing were determined and averaged after logarithmic transformation. Results: Group response assessed from 3‐min rhythm strips showed PVC reduction to be apparent at 15 min (48.2%, P = 0.06), significant at 30 min (57.2%, P = 0.02), maximal at 45 min (59.3%, P = 0.005), and declining at 60 min (48.8%, P = 0.06). Individual PVC reduction (> 70%) was observed in 0/4 (0%) at 0.4 mg/kg, 3/4 (75%) at 0.75 mg/kg, 3/4 (75%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 3 min) showed a significant difference between lowest dose (0.4 mg/kg) and the higher doses (0.75 to 1.35 mg/kg) (P = 0.04). Individual reduction assessed on a 48‐hr Holter monitor was observed in 0/4 (0%) at 0.4 mg/kg, 2/4 (50%) at 0.75 mg/kg, 1/4 (25%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 15 min) at various time points also showed a significant difference between the lowest dose (0.4 mg/kg) and the higher doses (P = 0.05). Analysis of log (PVCs/hr) in the succeeding 3 to 48 hr postdosing did not show a significant difference in PVC frequency compared to baseline. PR and QRS intervals increased significantly at 15 min ( + 5.4% for PR, + 6.8% for QRS, P < 0.05), and at 30 min ( + 5.3% for PR, + 4.8% for QRS, P < 0.05), returning to baseline by 90 min. RR and QT intervals did not change. Vital signs were stable and no evidence of any adverse hemodynamic effect was noted. No significant side effects occurred. Peak plasma bidisomide levels showed a dose response (1.7 ± 0.7, 2.8 ± 1.3, 5.4 2 0.3, 5.7 ± 1.7 μg/ml, doses 1 to 4 respectively, P = 0.0007). Similar results were obtained when the area under the curve (AUC) values were analyzed. Thus, bidisomide was well tolerated and effective in reduction of PVCs in single IV doses ≥ 0.75 mg/kg, associated with small increases in PR and QRS intervals. © 1992 Wiley‐Liss, Inc.
A‐75169 HCI: Pharmacological profile and ocular pharmacology studies of a new α‐2 antagonist
Authors: Giardina William J. , Buckner Steven A. , Hancock Arthur A. , Lee Jang‐Yun , Wismer Carol T. , DeBernardis John F. 
Published: January 2005

AbstractA‐75169 HCI (1,2,3,4‐tetrahydro‐6‐hydroxy‐1‐[N‐methylamino)‐methyl‐N‐phenethyl]‐naphthalene HCI, a racemate, is derived from a series of compounds that combine selective α‐2 receptor antagonism and amine uptake inhibition in a single molecule. A‐75169 HCI showed high affinity (pK1 = 8.79) for cerebral cortex‐derived α‐2 adrenoceptors assayed with [3H] rauwolscine. The R‐enantiomer showed a tenfold greater affinity (pk1 = 9.09) for these receptors than the S‐enantiomer (pK1 = 8.10). A‐75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic α‐2 adrenoceptors (pA2 values 7.31–7.49, dog saphenous vein). The racemate and the R‐enantiomer were moderately potent as antagonists for presynaptic α‐2 adrenoceptors (pA2 values 7.06 and 7.09, respectively, rat vas deferens), and they were more potent inhibitors (ID50 = 1.50 mg/kg, i.v., and 0.60 mg/kg, i.v., respectively) of clonidine‐induced mydriasis, an α‐2 mediated effect, than the S‐enantiomer. The S‐enantiomer was a more potent inhibitor of norepinephrine synaptosomal uptake than the R‐enantiomer (pIC50 = 6.00 and 5.79, respectively). When applied topically to the eyes of rabbits (3.0% solution) and monkeys (0.3% solution), the racemate significantly reduced intraocular pressure (IOP). The topical administration of A‐75169 HCI (0.5% solution) to dog cornea did not affect blood pressure or heart rate. A‐75169 HCI, a selective α‐2 antagonist possessing amine uptake blocking properties, is a potentially novel antiglaucoma compound. © 1993 Wiley‐Liss, Inc.
Pharmacological properties of dolasetron, a potent and selective antagonist at 5‐HT3 receptors
Authors: Miller Robert C. , Galvan Martin , Gittos Maurice W. , van Giersbergen Paul L. M. , Moser Paul C. , Fozard John R. 
Published: January 2005

AbstractIn the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA2 = 9.8) antagonist at 5‐hydroxytryptamine3 (5‐HT3) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold‐Jarisch reflex elicited by iv injection of 5‐HT; the iv ED50 was approximately 3 μg/kg and following a dose of 140 μg/kg iv the reflex was abolished for >85 min. The compound displayed no significant affinity for 5‐HT1, 5‐HT2, or a variety of other radioligand binding sites at concentration of 10 μM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti‐cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05–0.5 mg/kg) administered 30 min before and 45 min prior to cisplatin, were clearly anti‐emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin were also effective. Minimal changes in the behaviour of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron is a potent, selective, and reversible antagonist at neuronal 5‐HT3 receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting. © 1993 Wiley‐Liss, Inc.
3‐Nitropropionic acid, obtained from astragalus species, has vasodilator and antihypertensive properties
Authors: Castillo Carlos , Valencia Ignacio , Reyes Gerado , Hong Enrique 
Published: January 2005

Abstract3‐Nitropropionic acid (NPA) elicited a dose‐dependent relaxation of precontracted rabbit aortic rings. Since the NPA effect was independent of the contractile agonist used, it did not appear to act by blocking a specific set of receptors. Aortic rings precontracted with KCl were less sensitive to relaxation by NPA suggesting that at least part of the mechanism of vasodilation is not related to an inhibition of calcium influx through the voltage‐dependent Ca+ + channel. The arterial relaxation induced by NPA is independent of endothelium and it is not mediated by muscarinic, β‐adrenergic, nor histaminergic (H1) receptors. On the other hand, methylene blue clearly inhibited the vasodilation induced by NPA suggesting that it is a consequence of guanylate cyclase stimulation. Finally, a mild but consistent decrease of both systolic and diastolic arterial blood pressure was observed after oral NPA administration during 4 weeks to renal hypertensive dogs. The data in the present study clearly demonstrate that NPA possesses vasodilator and antihypertensive properties. © 1993 Wiley‐Liss, Inc.
Physiological and pathological roles of purines: An update
Authors: Burnstock Geoffrey 
Published: January 2005

AbstractIn this review article, the early history of studies of purinergic neurotransmission and of purinoceptor subclassification is described. This is followed by a survey of current knowledge of the distribution of purinoceptors and of the physiological roles of purines in the nervous system, muscle, secretory, endocrine and immune cells, as well as in spermatocytes, osteoblasts, fibroblasts, and tumour cells. Recent studies of transduction mechanisms for different purinoceptor subtypes, as well as reports of the molecular properties of encoding genes for purinoceptors, are reviewed. The evolution of purinergic mechanisms and the long‐term ‘trophic’ actions of purines are discussed. Finally, the clinical potential of purines and related compounds for various cardiovascular and behavioural disorders. As well as for inflammation and cancer are considered. © 1993 Wiley‐Liss, Inc.
Storage, release, uptake, and inactivation of purines
Authors: Meghji Parviz 
Published: January 2005

AbstractAdenine nucleotides are released into the interstitial space during platelet thrombus formation and neurotransmission. ATP has also been reported to be released from the heart and endothelial cells in some studies. Ecto ATPase, ADPase, and 5′‐nucleotidase activities capable of hydrolyzing ATP sequentially to adenosine are present in many cell types and may serve to terminate the actions of the nucleotides. The opposing effects of adenosine and ATP on the same cell types have suggested a modulatory role for adenosine of the actions of extracellular ATP and that the rates of hydrolysis of nucleotides might be regulated. Consistent with this it has been found that the balance between feedforward inhibition of 5′‐nucleotidase by ADP and/or ATP and preferential delivery of AMP from ADPase to 5′‐nucleotidase determines the rate of adenosine production and that this differs in different cell types. Alternatively, adenosine may be produced intracellularly as a result of an imbalance between energy demand and supply. There are at least two different cytosolic forms of 5′‐nucleotidase. Degradation of ATP during increased metabolic activity results in an increase in intracellular AMP concentration. Either cytosolic enzyme has a high KM (2–5 mM) and would thus respond to this increase with a proportional rise in the rate of adenosine production. The nucleoside transporter is essential to allow the diffusion of adenosine to extracellular receptor sites. In general, adenosine must be taken up via the nucleoside transporter before it is inactivated either by phosphorylation by adenosine kinase in the micromolar range or by deamination by adenosine deaminase at higher concentrations. © 1993 Wiley‐Liss, Inc.
Adenosine deaminase inhibitors: Structure‐activity relationships in 1‐deazaadenosine and erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine analogues
Authors: Cristalli Gloria , Eleuteri Alessandra , Vittori Sauro , Volpini Rosaria , Camaioni Emidio , Lupidi Giulio 
Published: January 2005

AbstractAdenosine deaminase (ADA) is the enzyme which catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. It is widely distributed in vertebrate tissues and is thought to be essential for proper functioning of mammalian cells. ADA inhibitors may have several clinical applications (i.e., in the chemotherapy of lymphoproliferative disorders, in the immunosuppresive therapy, in adenosine level modulation). Modification of the purine moiety of adenosine led to ADA inhibitors. In particular, 1‐deazaadenosine (1, Ki = 0.66 μM) and its 2′‐deoxy derivative (21, Ki = 0.19 μM) are the most potent in the series. Substitutions on the N6amino group did not produce a decrease in activity only when small groups, as hydroxyl or methyl, were introduced. The presence of a chlorine atom in position 2 produced a decrease in ADA inhibitory activity. All these findings are in agreement with a direct interaction of the 1‐deazapurine moiety with the catalytic site of ADA. Erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine (12, EHNA) and 3‐deazaEHNA (14) are potent ADA inhibitors with Ki in the nanomolar range. Opening the pyrimidine ring of EHNA led to a series of erythro‐1‐(2‐hydroxy‐3‐nonyl)imidazole derivatives which are still ADA inhibitors. In order to introduce additional simplification and to investigate the role of nitrogen atoms in the azole structure, a series of di‐, tri‐, and tetrazoles bearing the 2‐hydroxy‐3‐nonyl chain have been synthesized and tested. The results indicated that the presence of N‐3 in the azole ring is critical for the inhibitory activity and that the introduction of additional nitrogens led to compounds whose potency range accounts for a direct interaction with an inhibitory site of ADA. © 1993 Wiley‐Liss, Inc.
Multiple effects of extracellular ATP in cardiac tissues
Authors: Vassort Guy , Scamps Frédérique , Pucéat Michel , Clément‐Chomienne Odile , Alvarez Julio 
Published: January 2005

AbstractBefore its degradation to adenosine, extracellular ATP released by nerves, or by cardiac cells during ischemia, induces a positive inotropy related to stimulation of the calcium conductance by P2‐purinoceptors. This stimulation is additive with the β‐adrenergic one and seems to occur via the activation of an isoform of a Gs‐protein sensitive to cholera toxin, although with no increase in cAMP. No Phosphorylation of the CA Channel is required since the P2‐purinergic stimulation is rapidly reversible even in the presence of the poorly hydrolysable compounds ATPγS or GTPγS intracellularly. Transiently, ATP may also depolarize the cells and trigger arrhythmias by binding to a new P3‐purinoceptor type which requires Mg ions. Such a receptor induced a tyrosine phosphorylation of CI/HCO3 Exchanger, a band 3‐like protein which under such activation induces a large, transient acidosis. © 1993 Wiley‐Liss, Inc.
Adenosine and cerebral microcirculation
Authors: Kuschinsky Wolfgang 
Published: January 2005

AbstractAdenosine participates in the coupling of function to blood flow in the brain. With regard to the 2 mechanisms of coupling, the feedforward and feedback mechanisms, adenosine plays an important role in feedback regulation. Whereas the feedforward mechanism is based on the fast release of K+ form the cell, which induces an immediate vasodilatory response of cerebral vessels, feedback regulation appears to yield a long‐term adjustment of blood flow to the metabolic demands of the brain tissue. This holds for physiological conditions and even more for pathophysiological conditions, such as hypoxia and ischemia. © 1993 Wiley‐Liss, Inc.
Adenosine A2a receptor expression in striatal neurons: Implications for basal ganglia pathophysiology
Authors: Schiffmann Serge N. , Halleux Pascale , Menu Roberte , Vanderhaeghen Jean‐Jacques 
Published: January 2005

AbstractTwo dog adenosine receptors have been recently cloned. They were pharmacologically characterized as an A1 and the A2a receptor, respectively. The adenosine A2a receptor is exclusively expressed in medium‐sized neurons of the striatum as demonstrated by in situ hybridization. The relationships of this A2a receptor with three major components of the striatum, enkephalin, substance P, and choline acetyltransferase, were studied in the rat. This demonstrates that the adenosine A2a receptor is exclusively expressed by the enkephalinergic striatal neuronal subpopulation that also selectively expresses the dopamine D2 receptor. Conversely, The A2a receptor is never detected in the substance P containing neurons or in the cholinergic neurons. This observation most probably constitutes the anatomical substratum for the preciously described A2a‐D2 receptors interactions. It also indicates that A2a receptor is selectively express in the indirect pathway of the basal ganglia system which is hypoactive in hyperkinetic disorders such as Huntington's disease and hyperactive in hypokinetic disorders such as Parkinson's disease. The development of highly A2a selective ligands could be therefore useful in the therapy useful in the therapy of basal ganglia degenerative diseases. © 1993 Wiley‐Liss, Inc.
Electrophysiological analysis of exogenous and endogenous adenosine actions in the rat and human hippocampus in vitro
Authors: Haas Helmut L. , Gerber Urs , Greene Robert W. , Stevens David R. 
Published: January 2005

AbstractAdenosine acts in at least three different ways at A1 receptors in order to reduce excitability and signal transfer. In the hippocampus, it causes in a steady state outward (potassium) current which is blocked by barium ions and not sensitive to voltage; (ii) an increase in the calcium and cyclic AMP‐dependent current 1AHP which is responsible for a long lasting afterhyperpolarization and the accommodation of action potential firing; (iii) a presynaptic reduction of excitatory but not inhibitory transmitter release. The mechanism of this effect is unclear. It is, in contrast to the former, not sensitive to pertussis toxin. When the adenosine elicited potassium currents at the postsynaptic site are blocked, slow inward currents, normally carried by calcium, are unaffected by adenosine. A2 receptor mediated actions have not been found in the hippocampus. While the precise analysis of these effects has been done largely on rats they were all found in human hippocampal slices as well. © 1993 Wiley‐Liss, Inc.