bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of receptors in the trabecular meshwork of the eye as targeted to the development of antiglaucoma therapy
Authors: Tripathi Ramesh C. , Yang Charles , Tripathi Brenda J. , Borisuth Navaneet S. C. 
Published: January 2005

AbstractThe major pathway for the outflow of aqueous humor from the anterior chamber of the eye is the trabecular meshwork/Schlemm's canal system. The meshwork is composed of connective tissue beams that are ensheathed by trabecular cells; these cells derive their nutrition from the aqueous humor and thus are uniquely susceptible to morphologic and biochemical regulation by bioactive substances that are present or released in this fluid and to pharmacologic agents that are targeted to act on the tissue. The receptors that have been detected on trabecular cells include those for growth modulatory peptides (bFGF, TGF‐βI, transferrin, IGF‐1, and EGF), epinephrine, dopamine, glucocorticoids, benzodiazepines, prostanoids, biogenic amines, the Fc portion of IgGs, and probably those for molecules of the extracellular matrix (integrins). Selective up‐ or down‐regulation of the receptors on the trabecular cells would facilitate an effective control of the intraocular pressure in diseased conditions of the eye. We discuss the prospects and hurdles in the utilization of receptor targeting as a therapeutic modality for trabecular cell regeneration in glaucoma as well as for pharmacologic trabeculectomy and as a treatment for hypotony after glaucoma filtration surgery. We believe that regulation of receptor expression is a novel method for the development of new antiglaucoma agents and for minimizing the side effects of drugs that are administered topically and systemically for the control of the intraocular pressure. © 1992 Wiley‐Liss, Inc.
Potential cognition‐enhancing properties of S 9977 in three moenls of amnesia in the mouse
Authors: Porsolt Roger D. , Lenègre Antoine , Rettori Marie‐Claire , Mocaër Elisabeth 
Published: January 2005

AbstractThe effects of S 9977 (1,3,7‐trimethyl 8‐[3‐(4‐diethylaminocarbonyl‐l‐piperazinyl) 1‐propyl]‐3,7‐dihydro(1H)2,6‐purinedione hydrochloride) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg i.p.) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. S 9977 was studied in a dose range of 0.0312–16 mg/kg administered p.o. 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. S 9977 was also investigated after repeated administration (twice daily for 3 days and then 60 min before acquisition on the 4th day) using the scopolamine‐induced amnesia model. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine‐induced hyperactivity (activity meter test), diazepam‐induced release of punished behavior (four plates test), and ECS‐induced convulsion. S 9977 at low doses (0.0312–0.5 mg/kg p.o.) clearly attenuated the memory deficits induced by the three amnesic treatments after acute treatment and no tolerance was observed after repeated treatment in the scopolamine model. S 9977 did not affect either scopolamine‐induced hyperactivity, diazepam‐induced release of punished behavior, or ECS‐induced convulsions. These results point to the specificity of S 9977's antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in humans. © 1992 Wiley‐Liss, Inc.
Myocardial salvage by trolox and ascorbic acid, but not ascorbic acid alone, in anesthetized dogs and rabbits
Authors: Lee King C. , Horan Patrick J. , Canniff Paul C. , Silver Paul J. , Ezrin Alan M. 
Published: January 2005

AbstractThe myocardial salvaging properties of Trolox (Trix; a water‐ and lipid‐soluble vitamin E analog with antioxidant properties) and ascorbic acid (Asc; a water‐soluble antioxidant) were evaluated in anesthetized male dogs and rabbits. Myocardial infarction (MI) was induced by occlusion and reperfusion of the left anterior descending coronary artery: a 2‐hr occlusion and 4‐hr reperfusion in dogs, and a 15‐min occlusion and 3‐hr reperfusion in rabbits. This occlusion/reperfusion protocol induced %MI (MI normalized to area at risk) of approximately 20% beyond that induced by occlusion alone in both species. Trlx, Asc (100 and 150 mg/kg/injection, respectively, by injection; or 100 and 150 mg/kg/min, respectively, by continuous infusion), or vehicle (Veh) were administered into the ascending aorta in dogs and into the left atrium in rabbits. In severely ischemic dogs (myocardial collateral blood flow < 0.1 ml/min/g), a single injection of Trlx plus Asc, but not Asc alone, at the onset of reperfusion reduced %MI (Trlx + Asc = 24.3 ± 5.4%, n = 7; Asc = 50.1 ± 9.6%, n = 4; Veh = 45.0 ± 5.0%, n = 5). In rabbits, %MI was reduced (or tended to be reduced) by either 3 hourly injections (Trlx + Asc = 33.3 ± 4.0%, n = 19; Asc = 48.3 ± 6.3%, n = 11; Veh = 43.7 ± 3.3%, n = 8) or an injection followed by continuous infusion (Trlx + Asc = 36.0 ± 4.0%, n = 9; Veh = 49.0 ± 3.0%, n = 8), beginning at the onset of reperfusion. %MI in rabbits was not affected by either hourly injections beginning from 1 hr after, or a single injection at 1–3 × the dosages (i.e., 100–300 and 150–450 mg/kg for Trlx and Asc, respectively), during onset of reperfusion. Hemodynamic variables (arterial pressure, heartrate, rate‐pressure‐product and left ventricular contractility) were similar among all treat‐ ment groups in both species. In conclusion, Trlx/Asc combination, but not Asc alone, re‐ duces %MI in dogs and rabbits. The salvaging effects of Trlx/Asc are unrelated to any changes in hemodynamics. These results are consistent with the hypothesis that lipid peroxidation is involved in myocardial reperfusion injury. © 1992 Wiley‐Liss, Inc.
Chemical and enzymatic modification of the platelet binding site for two antidepressant drugs
Authors: Chudzik Jerzy , Helmeste Daiga M. , Tang Siu Wa 
Published: January 2005

AbstractIsolated human platelet membranes were subjected to chemical and enzymatic modification using a range of protein and lipid‐modifying agents. We studied the binding properties of two antidepressant drugs (imipramine and paroxetine) for the serotonin uptake protein under these conditions, with the premise that if the binding sites had different topographical requirements, then their binding properties may be differentially modulated. The results show differential modulation of binding of these two drugs by thiol/disulfide bond modifying reagents. This suggests the presence of two different mechanisms of recognition and binding for IMI and paroxetine. Additionally, the binding of both drugs to the serotonin transporter was found to be extremely sensitive to lipid‐modifying reagents, but susceptible to proteolytic cleavage only under certain environmental conditions. © 1992 Wiley‐Liss, Inc.
Preclinical toxicology of the GABA uptake inhibitor CI‐966
Authors: Walker Robin M. , Houston Barry J. , Macallum G. Eileen , Clarke David W. , Smith Graham S. , Cox Raymond H. , Hawkins Kathleen L. , Radulovic Louis L. 
Published: January 2005

AbstractCl‐966 (1‐[2‐[bis[4‐(trifluoromethyl)phenyl]methoxy]]‐1,2,5,6‐tetr5ahydro‐3‐pyridinecarboxylic acid, HCl salt) is an anticonvulsant agent that blocks the re‐uptake of gammaaminobutyric acid (GABA) into presynaptic nerve terminals and glial cells. The preclinical toxicology of Cl‐996 was evaluated in male and female B6C3F1 mice, Wistar rats, and beagle dogs. Doses were administered orally and are expressed as free acid equivalents. Acute (gavage) toxicity was characterized principally by CNS signs (hypoactivity, atasia, tremors, convulsions, and prostration); diarrhea and urine scald; and delayed mortality (2–3 days in mice and 2–11 days in rats) with 14 day median lethal doses of 653 and 825 mg/kg in male and female mice and 1,019 and 830 mg/kg in male and female rats, respectively. In a 4‐week rat study in which Cl‐966 was given in the diet, the high dose of 500 mg/kg/day was not tolerated, with marked decreases in body weight and food consumption necessitating sacrifice during the second week. The 150 mg/kg/day dose caused reduced body weight gain, lower food consumption, and hyperactivity, while 50 mg/kg/day was clearly a no‐effect level. In dogs, Cl‐966 was given in gelatin capsules at doses of 2 to 25mg/kg/day in an exploratory study and at 2,6, and 15 mg/kg/day in a 4‐week study. Prostration, ataxia, disorientation, and other mainly CNS‐related clinical signs occurred at 5 to 25mg/kg. Aspartate and/or alanine aminotransferase activities were elevated at 20 and 25 mg/kg in the exploratory dog study. However, there were no histopathologic findings in either species directly attributable to Cl‐966 treatment. Enhanced GABAergic activity was considered to be the cause of most of the clinical signs elicited by Cl‐966 in rodents and dogs. Blood Cl‐966 levels were dose‐dependent, but higher in females than males for both rats and dogs. These results were used to support initial clinical trials of Cl‐966 in humans. © 1993 Wiley‐Liss, Inc.
Identification of multiple nitrobenzylthioinosine binding sites in guinea pig platelets: Comparison with binding in guinea pig erythrocytes
Authors: Williams Evan F. 
Published: January 2005

AbstractThe novel existence of multiple binding sites for the potent nucleoside transporter Probe, [3H]nitrobenzylthioinosine, was identified in guinea pig platelet membranes and the binding characteristics compared to those of guinea pig erythrocyte membranes. Scatchard analysis of the binding in platelets reveled two high affinity binding sites with affinity constant (KD) of 0.94 ± 0.07 nM and 83 ± 13 nM with corresponding maximal binding capacities (Bmax) of 21 ± 7 and 110 ± 25 fmol/mg protein, respectively. In comparison, guinea pig erythrocyte membranes revealed a homogeneous population of the binding sites with KD of 0.17 ± 0.04 nM and a Bmax value of 73 ± 11 fmol/mg protein. Biphasic semi‐log plots of the binding site heterogeneity in erythrocytes not reveled by Scatchard plots. Determination of the potencies of selected drugs in inhibiting the binding showed evidence of differential interacitons with the binding sites by various agents which may be exploited pharmacologically. © 1993 Wiley‐Liss, Inc.
WAY 100289: Pharmacological profile of a novel 5‐HT3 receptor antagonist
Authors: Rhodes Keith F. , Middlefell Vicki C. , Lattimer Norman , Brammer Neil T. , Coleman James , Taylor Anne P. , Saville Valerie L. , Ward Terence J. 
Published: January 2005

AbstractWAY 100289, endo‐N‐[8‐methyl‐8‐azabicyclo [3.2.1.] octan‐3‐yl) aminocarbonyl]‐2‐cyclopropylmethoxybenzamide, was an antagonist of 5‐HT evoked depolarization (5‐HT3 receptor‐mediated) of the rat isolated cervical vagus nerve (pA2 value 8.9). Schild‐plot analysis was consistent with a competitive antagonist mechanism (slope 0.8), though antagonism was not fully surmountable. WAY 100289 was a relatively weak antagonist of 5‐HT3 receptor‐mediated contractions of the guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus preparation (pA2 value 6.2). In 5‐HT3 receptor binding studies in rat entorhinal cortex membranes WAY 100289 displaced [3H]‐zacopride with a pK1 value of 8.4, in good agreement with results in the vagus nerve. In urethane anaesthetised rats the 5‐HT evoked Bezold‐Jarisch reflex was blocked by WAY 100289 with an ED50 of 1.3 μg/kg i.v., consistent with 5‐HT3 receptor antagonism. In the conscious rat WAY 100289 was approximately 30‐fold more potent by the i.v. than by the p.o. route. Following a dose of 1 mg/kg of WAY 100289 the Bezold‐Jarisch reflex was reduced by more than 50% for in excess of 6 h. In a series of in vitro functional and ligand binding assays WAY 100289 showed good selectivity for the 5‐HT3 receptor with the only notable additional activity that of non‐competitive antagonism of nicotinic receptor mediated depolarization of the rat vagus nerve (−log IC50 value 6.7). The compound was without significant effect as an inhibitor of the uptake of 5‐hydroxytryptamine, noradrenaline or dopamine by rat brain synaptasomes. In general, WAY 100289 is a novel, achiral 5‐HT3 receptor antagonist with good in vitro potency and selectivity and good in vivo activity, oral bio‐availability, and duration of action. © 1993 Wiley‐Liss, Inc.
Cardiovascular effects of apraclonidine in the conscious dog
Authors: Jones Carl E. , Sallee Verney , DeSantis Louis , Gayheart Pamela A. , Hamrick Melissa L. , Bravenec J. Stanley , Longlet Nancy A. 
Published: January 2005

AbstractApraclonidine (p‐aminoclonidine) a recognized α2‐adrenergic agonist, has been approved for use with ocular laser surgery and is under consideration for use as a chronic treatment for glaucoma. The potential cardiovascular actions of apraclonidine in conscious animals has yet to be fully explored. The present studies were performed in conscious, chronically instrumented dogs to evaluate these possible cardiovascular effects. In a first study, apraclonidine was administered iv in dosages ranging from 5 to 200 μg. When administered by this route, apraclonidine elicited profound, but transient, cardiovascular actions. Mean arterial pressure (MAP) and left ventricular systolic pressure (LVSP) showed significant increases at dosages of 50–100 μg or higher, while heart rate (HR) showed a significant reduction. No variables had values significantly different from control values 60 min after administration. In a second study, apraclonidine was applied topically to either one or both eyes in total dosages of 125–1,000 μg. In contrast to iv administration, even with doses of up to 1,000 μg, topical apraclonidine administered in the eye elicited no significant change in cardiovascular variables. In the third set of studies, the neurotransmitters acetylcholine (1–10 μg/kg) and norepinephrine (0.2–2 μg/kg) were administered iv both before and 45 min after 500 μg apraclonidine was applied to the eye. Topical apraclonidine enhanced the mean AP response to norepinephrine by as much as 18% and the LVSP response to norepinephrine by as much as 17% No effect on the response to acetylcholine was seen. We conclude that all cardiovascular changes following iv apraclonidine can be attributed to its vasoconstrictor action with the consequent rise in MAP. The absence of measurable effects after topical application was likely due to a much slower entry into the circulation, although the vasoconstrictor action of apraclonidine after topical applications seemed to be additive to that of iv norepinephrine. © 1993 Wiley‐Liss, Inc.
Self‐Medication: A survey of nonprescription drug use
Authors: Buckalew Louis W. , Buckalew Nancy M. 
Published: January 2005

AbstractA sample of adults (n = 148) which reflected age, gender, and race characteristics of the 1980 U.S. Census was surveyed on the incidence of obtaining over the counter (OTC) drugs during the previous year and the nature of the drugs used. Most (78%) reported obtaining OTC drugs, and of 15 categories, headache or pain remedies, cold or flu remedies, and vitamins were most frequently (>50%) reported as used. No gender or race effects were found for obtaining OTC drugs or for the nature of OTC drugs used. Identified patterns of OTC drug use were related to previous research and have implications for drug development, health care, and marketing concerns. © 1993 Wiley‐Liss, Inc.
Molecular characterization of A1 and A2a adenosine receptors
Authors: Jacobson Kenneth A. , van Galen Philip J. M. , Ji Xiao‐Duo , Ramkumar Vickram , Olah Mark E. , Stiles Gary L. 
Published: January 2005

AbstractDetailed amino acid sequence analyses of A1 and A2a adenosine receptors were assembled by analogy to other G‐protein‐coupled receptors and correlated with pharmacological observations. Sites for phosphorylation, palmitoylation, and sodium binding have been proposed. Striatal A2a receptors from human and other species were photoaffinity‐labeled using the selective, radioiodinated agonist PAPA‐APEC. Selective chemical affinity labels for A1 and A2a receptors have been introduced. For example, an isothiocyanate, ρ‐DITC‐APEC (100 nM), irreversibly diminished the Bmax for [3H]CGS 21680 (2‐[4‐[(2‐carboxyethyl) phenyl] ethylamino]‐5′‐N‐ethylcarboxamido‐adenosine) binding in rabbit striatal membranes by 71% (Kd unaffected), suggesting a direct modification of the ligand binding site. Novel trifunctional affinity labels have been designed. Rabbit and human A2a receptors were characterized using [3H]XAC binding in the presence of 50 or 25 nM CPX (8‐cyclopentyl‐1,3‐dipropylxanthine), respectively. The inhibition of A2 radioligand binding by the histidyl‐modifying reagent diethylpyrocarbonate suggested the involvement of His residues in interactions with adenosine agonists and antagonists. Properties of transiently expressed mutants of bovine A1 receptors in which either His251 or His278 residues have been substituted with Leu suggest that both histidines are important in binding. © 1993 Wiley‐Liss, Inc.
Inotropic actions of adenosine derivatives in the mammalian heart
Authors: Scholz H. , Kohl C. , Neumann J. , Schmitz W. , Seeland C. , Stein B. 
Published: January 2005

AbstractThe effects of adenosine receptor (AR) stimulation on contractile parameters as well as inositol phosphates, cAMP content, and phospholamban‐phosphorylation was studied in cardiac preparations. In guinea‐pig papillary muscles adenosine increased inositol trisphosphate formation and also slightly elevated force of contraction. In the presence of isoprenaline, however, adenosine still enhanced inositol trisphosphate formation but reduced force of contraction. In isolated electrically driven guinea‐pig ventricular cardiomyocytes the A1‐AR agonist R‐PIA and the A1/A2‐AR agonist NECA reduced isoprenaline‐stimulated contractility but only R‐PIA decreased isoprenaline‐enhanced cAMP content. The selective A2‐AR agonist CGS 21680 increased isoprenaline‐stimulated cAMP content. This effect of CGS 21680 was antagonized by the A2‐AR antagonist CGS 15943A and was increased after pertussis toxin‐pretreatment. Furthermore, R‐PIA and NECA decreased via A1‐ARs the isoprenaline‐stimulated phospholamban‐phosphorylation in guinea‐pig ventricular cardiomyocytes. © 1993 Wiley‐Liss, Inc.
Clinical cardiac electrophysiologic effects of adenosine
Authors: Griffith Michael J. 
Published: January 2005

AbstractAdenosine is very useful for the acute diagnosis and treatment of tachycardias in humans. Adenosine's major cardiac effect, when given as a bolus, is to produce transient atrioventricular block. It can be used either to terminate tachycardias that involve the atrioventricular node or to transiently reveal an atrial tachycardia by slowing the ventricular response, and so to allow the diagnosis to be made. Adenosine is effective in the diagnosis of broad complex tachycardias, revealing and terminating supraventricular tachycardias, with usually no effect on ventricular tachycardia. Adenosine's great advantages over verapamil are its safety, especially in haemodynamically unstable patients, and its short half‐life. Is major disadvantage is the somatic side effects it produces: chest pain, deep breathing, flushing, and a variety of other sensations. Adenosine's effects on other tachycardias also gives an insight into their mechanisms. Right ventricular outflow tachycardia is terminated by adenosine, which supports the thesis that it is due to triggered afterdepolarizations. This may be the explanation for the termination of some atrial tachycardias by adenosine. Sinus node reentry tachycardia is slowed and terminated by adenosine, suggesting that at least part of the tachycardia circuit is in the sinus node. To conclude, the ability of adenosine to selectively block atrioventricular conduction, combined with its very short half‐life, make it a very useful drug both clinically and in the electrophysiology laboratory. © 1993 Wiley‐Liss, Inc.
Adenosine and the vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Favilla Stefania , Salvetti Antonio 
Published: January 2005

AbstractThe present study was designed to evaluate whether adenosine can activate a vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients. In a group of 6 patients, we infused adenosine at cumulative increasing doses into the brachial artery and collected simultaneous arterovenous samples for angiotensin II determinations (by radioimmunoassay). Forearm blood flow was evaluated by strain‐gauge plethysmography. Adenosine caused a dose‐dependent increment in forearm blood flow and in venous angiotensin II, whereas it did not affect arterial angiotensin II. When repeated in the presence of the antagonist, theophylline, the adenosine effect was blunted. Moreover, in the forearm of another group of 6 hypertensives ischemia was applied for 7 min to induce the production of endogenous adenosine while active renin (by radioimmunometric assay) and angiotensin II were measured. During the reactive hyperemia, venous active renin and angiotensin II increased, while arterial values did not change. This effect was also blunted by theophylline. Taken together these data indicate that either exogenous or endogenous adenosine can activate a vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients. © 1993 Wiley‐Liss, Inc.
Adenosine myocardial perfusion imaging in the noninvasive diagnosis and prognosis of coronary artery disease
Authors: Verani Mario S. 
Published: January 2005

AbstractAdenosine is a purine base compound which is of fundamental importance in many physiologic processes in the body, including vasodilation in most arterial vascular beds. Adenosine produces maximal or near‐maximal coronary vasodilation by interacting with the adenosine A2 receptors in the cell wall, on a dose dependent fashion. The mechanism of thallium‐201 myocardial perfusion defects induced by adenosine scintigraphy is a heterogeneity of myocardial blood flow due to a greater coronary flow increase in the normal arteries and a lesser increase in the stenotic arteries. The ultra‐short half‐life of adenosine (< 10 sec) necessitates continuous intravenous administration at a dose of 140 μg/kg/min for six min. The excellent safety record of this regimen has been demonstrated in several thousand patients in the United States. Side effects occur in most patients during adenosine infusion. Chest pain occurs often and in some cases may be due to a true coronary steal phenomenon. In the author's experience, first degree AV block occurs in approximately 10% and second or third degree AV block in approximately 4% of the patients, and are due to the negative dromotropic effect of adenosine on the AV node. On the positive side, these untoward effects are very short‐lived and typically disappear within one or two minutes after discontinuing the adenosine infusion. No serious complications or fatalities have been observed to date with this test. The cumulative experience with adenosine thallium‐201 scintigraphy indicates high sensitivity and specificity in the diagnosis of coronary artery disease. Recent data also suggest it may be an excellent technique to assess a patient's prognosis early after a myocardial infarction. Adenosine‐induced coronary vasodilation, in combination with thallium‐201 or the new technetium‐99m perfusion agents, holds great promise in the assessment of patients with coronary artery disease. © 1993 Wiley‐Liss, Inc.