bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of antischistosomal agents: Inhibitors of hypoxanthine‐guanine phosphoribosyltransferase
Authors: Jadhav Arun L. , Sirossian Shahrokh 
Published: January 2005

AbstractDerivatives of purines and 5‐phosphoribosyl 1‐pyrophosphate (PRPP), substrates for purine salvage enzymes, were tested for their ability to inhibit hypoxanthine‐guanine phosphoribosyltransferase (HPRT, E. C. 2.4.2.8) isolated from Schistosoma mansoni in vitro. The parasite enzyme exhibited different kinetic characteristics than the human enzyme. The ‐C2 and ‐C6 substituted purine derivatives, as well as PRPP‐polyamine complexes, were found to be active against the enzyme. Intact purine ring appears to be necessary for the activity against the hypoxanthine dependent reactions mediated by the parasite enzyme since benzimidazoles, quinolines, and triazoles were found to be inactive. Additionally, it appears that PRPP‐polyamine complexes which inhibit the PRPP dependent reaction may provide a novel approach to new chemotherapeutics agents for schistosomiasis.
Flumazenil (Ro 15‐1788) enhances learning in both negatively and positively reinforced tasks
Authors: Raffalli‐Sebille Marie J. , Chapouthier Georges 
Published: January 2005

AbstractFlumazenil (Ro 15‐1788) is classically described as a benzodiazepine‐receptor (BZ‐R) antagonist, devoid of any intrinsic effect and thus used to selectively block the effects of others BZ‐R ligands. The present report provides evidence that flumazenil enhances learning in a multiple‐trial brightness discrimination task in mice, whether the reinforcement is negative (electric foot‐shock) or positive (food reward). However, in contrast to the negative reinforcement, we obtained a significant effect with the positive reinforcement only after a delay of a few days. The type of reinforcement might be involved in this delay necessary to observe enhanced learning. These results are discussed.
Effects of nucleotide cyclase activators on the depressor response to selective low Km cyclic AMP phosphodiesterase inhibitors in rats
Authors: Dundoreph Ronald L. , Pratt Phillip F. , Hallenbeck Wendy D. , Silver Paul J. , Buchholz R. Allan 
Published: January 2005

AbstractThe potential interaction between agents which promote vasodilation through cyclic AMP (cAMP)‐ and cyclic GMP (cGMP)‐dependent mechanisms was examined in conscious, spontaneously hypertensive rats (SHR). Selective inhibitors of low Km cAMP phosphodiesterase (PDE), CI‐930 (0.1−10 mg/kg) and milrinone (0.03−3 mg/kg), were administered i.v. to SHR during a steady‐state i.v. infusion of either the guanylate cyclase activator sodium nitroprusside (SNP, 5 or 15 μg/kg/min) or the adenylate cyclase activator fenoldopam (20 μg/kg/min). The depressor responses to Cl‐930 and milrinone were significantly attenuated in the presence of SNP. This attenuation of the depressor response to Cl‐930 was apparently not due to a hemodynamic floor effect since an equihypotensive dose of the calcium channel blocker verapamil (20 μg/kg/min infusion preceeded by a loading dose of 1.2 mg/kg i.v.) did not alter the response to Cl‐930. The depressor response to Cl‐930 was also attenuated during an infusion of fenoldopam, although this interaction was dependent upon the order of administration of these agents since pretreatment with Cl‐930 (0.3 mg/kg, i.v.) potentiated the depressor response to infusions of fenoldopam (10 and 20 μg/kg/min). These data suggest that activation of either adenylate or guanylate cyclase may alter the intrinsic activity of low Km cAMP PDE and functionally impair the ability of inhibitors of this PDE isozyme to lower blood pressure. Furthemore, teh interactive effects of fenoldoparm and Cl‐930 on blood pressure are dependent upon the order of administration.
Effect of repeated administration of centhaquin, a centrally acting hypotensive drug, on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain regions of rat
Authors: Gulati Anil , Hussain Ghazala , Srimal Rikhab Chand 
Published: January 2005

AbstractCenthaquin, a hypotensive drug, produced a dose dependent decrease in blood pressure and heart rate in urethane anesthetized rats. The hypotensive and bradycardic effects of centhaquin were absent in cervial sectioned rats. There was no effect on blood pressure or heart rate upon intrathecal injection of centhaquin in normal rats. These results indicate that centhaquin is a centrally acting hypotensive drug with supraspinal site of action. Centhaquin (0.1 mg/kg) or its vehicle was administered orally to rats for 2 months. The blood pressure was recorded indirectly in unanesthetized rats by the plethysmographic tail cuff method. The animals were sacrificed, decapitated, and specific areas of the brain, like corpus striatum, cerebral cortex, hypothalamus, and medulla were dissected out and membranes prepared for binding studies. The mean blood pressure of rats before starting the treatment was comparable in control and treated groups. A significant decrease in mean blood pressure was observed in centhaquin treated rats. Chronic administration of centhaquin in rats produced alterations in central α‐adrenergic, dopaminergic, and serotonergic (5‐hydroxytryptamine1 [5‐HT1]) receptors. In the cerebral cortex corpus striatum of centhaquin treated rats, Bmax and Kd values of 3H‐dihydroergocryptine binding did not change, while in hypothalamus and medulla, centhaquin treatment increased the Bmax value by 52% and 86%, respectively. There was no change in the Kd values. Centhaquin treatment did not affect Bmax and Kd values of 3H‐dihydroalprenolol binding to β‐adrenergic receptors, 3H‐quinuclydinyl benzylate binding to cholinergic (muscarinic), and 3H‐spiperone binding to 5‐hydroxytryptamine2 (5‐HTs) receptors in any of the four brain regions. In the cortex, centhaquin treatment decreased the Bmax value (25%) but did not change the Kd values was produced in corpus striatum, hypothalamus, and medulla of 3H‐spiroperidol binding to dopaminergic receptors. Cerebral cortex, corpus striatum, and hypothalamus of centhaquin treated rats did not show any change in Bmax or Kd values of 3H‐5‐HT binding to 5‐HT1 receptors. In medulla, centhaquin treatment increased the Bmax value (41%) of HT1 receptors but had no effect on Kd values. It can be concluded from the present study that centhaquin, a centrally acting hypotensive drug, acts on several neurotransmitter receptors. The brain regions mainly involved in cardiovascular regulation, hypothalamus and medulla, show up‐regulation of αadrenergic and serotonergic (5‐HT1) receptors and may play a role in the mechanism of hypotensive action of centhaquin.
Characterization of indorenate effects on brain monoamine metabolism
Authors: Benítez‐King Gloria , Antón‐Tay Fernando , Hong Enrique 
Published: January 2005

AbstractThe effect of indorenate, a central antihypertensive agent, on the catecholamine and indolamine metabolism was studied in the rat brain. Acute administration of 10 mg/kg of indorenate causes an increase in 5‐HT concentrations and a decrease on its metabolite 5‐hydroxyindolacetic acid (5‐HIAA) in the brain stem, cerebral cortex, hypothalamus, and striatum. Maximal effects were observed between 1.5 and 3 hr after indorenate administration. Additionally, a significant decrease in homovanilic acid (HVA) and 3,4‐dihydroxyphenylacetic (DOPAC) concentrations was noted after 1.5 hr of a 10 mg/kg indorenate injection. Modification of both catecholamine and indolamine metabolites was dose related. Control values were recovered 24 hr after indorenate administration. Activity of monoamine oxidase present in crude homogenates obtained from the cerebral cortex, brain stem, hypothalamus, and striatum was not affected by indorenate. The present results suggest that indorenate acts as an agonist at serotonin receptors in the central nervous system (CNS).
Labeling in vivo of sigma receptors in mouse brain with [3H]‐(+)‐SKF 10,047: Effects of phencyclidine, (+)‐ and (−)‐N‐allylnormetazocine, and other drugs
Authors: Ferris Robert M. , Russell Anne , Tang Flora L. M. , Topham Phillip A. 
Published: January 2005

AbstractThe sigma receptor, so named because of the distinct pharmacolgical profile produced by its prototypic agonist SKF 10,047 (N‐allynormetazocine), is believed to mediate mania and psychotomimetic effects in man. While this sigma receptor has received extensive biochemical and pharmacological characterization in vitro, little information is available on the nature of the sigma site in vivo. In the present study, we examined the binding of [3H]‐(+)‐SKF 10,047 to sigma receptors in mouse brain in vivo and to sigma receptors in mouse and guinea pig brain in vitro and determined the relative potencies of various drugs in displacing this ligand. Mice were injected with 5 μCi of [3H]‐(+)‐SKF 10,047 into the tail vein. After various time intervals, the mice were decapitated; their brains were rapidly removed, weighed, and homogenized in 50 mM Tris‐HCI buffer, pH 7.7; and total and particulate bound radioactivity were determined. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction was defined as the difference in total radioactivity in the particulate fraction obtained from vehicle‐injected mice minus the radioactivity in the particulate fraction from haloperidol (2 mg/kg i.p.)‐injected mice. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction reached peak levels of 30 min after i.v. injection and constituted 90–95% of the total particulate radioactivity. Labeling of the sigma sites could be blocked in vivo by injecting mice i.p. with the drug 30 min before the i.v. injection of the 3H‐ligand. Under these conditions, (+)‐SKF 10,047, (+)‐3‐PPP, cyclazocine, pentazocine, and haloperidol were found to be the most potent compounds in reducing specific [3H]‐(+)‐SKF 10,047 binding. Neuroleptics such as thioridazine and chlorpromazine had good potency, while clozapine, spiperone, and sulpiride were very weak inhibitors in vivo. Specific [3H]‐(+)‐SKF 10,047 binding was also reduced in vivo by imipramine, dl‐propranolol, bupropion, rimcazole, and phenoxybenzamine, but was not reduced by apomorphine and naloxone at doses of 50 mg/kg i.p. Phencyclidine, m‐NH2‐PCP and (−)‐3‐PPP were only weak inhibitors of (+)‐SKF 10,047 binding in vivo. The relative potencies of these agents obtained in vivo correspond well with their relative affinities obtained in vitro in mouse and guinea pig brain for displacing [3H]‐(+)‐SKF 10,047 but not with their relative affinities for displacing TCP in guinea pig brain. Comparison of the dose‐response curves for the drug revealed the presence of perhaps two sites labeled by [3H]‐(+)‐SKF 10,047 in vivo.
Chronic administration of buspirone down‐regulates 5‐HT2 receptor binding sites
Authors: Taylor Duncan P. , Hyslop Deborah K. 
Published: January 2005

AbstractBuspirone (BuSpar®), a clinically effective anxiolytic, has been found in clinical trials to produce effects which suggest antidepressant efficacy. As antidepressants down‐regulate type 2 serotonin (5‐HT2) receptors when given chronically to laboratory animals, we investigated whether buspirone would have similar effects; the possibility that chronic buspirone administration would affect β‐adrenergic, D‐2 dopaminergic, and γ‐aminobutyric acid (GABA) receptor binding was also investigated. When chronically administered in a regimen which reflected activity in an animal model of anxiety, buspirone produced significant decreases in in vitro 5‐HT2 and β‐adrenergic receptor binding but was without effect on D‐2 dopaminergic of GABAergic binding. Ligand saturation experiments revealed that the decrease in 5‐HT2 binding was due to a decrease in the maximal concentration of binding sites. These data demonstrate that chronic administration of buspirone to animals produces effects which suggest the potential for antidepressant efficacy in clinical use.
Effects of p‐chloroamphetamine and a side‐chain monofluorinated analogue on levels of indoles in rat brain
Authors: Owen Michael L. S. , Baker Glen B. , Coutts Ronald T. , Dewhurst William G. 
Published: January 2005

AbstractLevels of tryptophan (Trp), 5‐hydroxytryptamine (5‐HT), and 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) in rat brain were measured at 1, 2, 4, and 24 hr after intraperitoneal administration of p‐chloroamphetamine (pCA) (0.03 mmol/kg) or of p‐cloro‐α‐fluoromethylphenylethylamine (fluoro‐p‐chloroamphetamine; FpCA) (0.05 or 0.10 mmol/kg). FpCA is less potent than pCA at producing depletions of 5‐HT and elevations of Trp, and the effects with FpCA are shorter‐lasting. pCA has been reported to possess good antidepressant properties but was withdrawn from clinical studies because of reported neurotoxicity to 5‐HT systems in rat brain. The less potent effects of FpCA on 5‐HT and 5‐HIAA reduction shown here suggest that further research on this analogue as a potential antidepressant is warranted.
Effects of acrihellin, a new cardiosteroid, compared to digoxin, MDL 17043, and milrinone in the pentobarbital‐compromised dog
Authors: Czyzewski Leo B. , Asaad Mary , De Vine Cindy , Sofia R. Duane , Diamantis William 
Published: January 2005

AbstractAcrihellin, digoxin, MDL 17043, and milrinone were administered intravenously in the anesthetized dog to compare their effects on the cardiovascular parameters following pentobarbital‐induced heart failure. Dogs were instrumented to record left ventricular pressure, the derivative of the left ventricular pressure (dP/dt max), mean arterial pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. Pentobarbital compromise caused significant decreases from baseline in all cardiovascular parameters and slightto‐marked increases in stroke volume and left ventricular end‐diastolic pressure. Following pentobarbital‐induced heart failure, acrihellin reversed the cardiovascular changes with dose‐dependent, positive inotropic effects (dP/dt max), decreases in left ventricular enddiastolic pressure, and increases in stroke volume and cardiac output. Acrihellin caused a significant shift upwards and to the left of the stroke volume index/left ventricular enddiastolic slope at peak inotropy (45 min). Comparable, but nonsignificant, shifts were evident with each of the three standard compounds at peak inotropy: digoxin at 45 min, MDL 17043 at 5 min, and milrinone at 5 min. The intravenous drug doses were 45 μg/kg (1 molar equivalent) for acrihellin, 70.5 μg/kg (1 molar equivalent) for digoxin, 59.75 μg/kg (3 molar equivalents) for MDL 17043, and 38.1 μg/kg (2 molar equivalents) for milrinone. The present findings indicate that acrihellin is a potent cardiotonic drug as demonstrated in the failing heart dog model following pentobarbital.
Ritanserin, a new therapeutic approach for drug abuse. Part 2: Effects on cocaine
Authors: Meert T. F. , Janssen P. A. J. 
Published: January 2005

AbstractAfter a period of forced exposure to cocaine, rats developed a preference for cocaine when given the choice to drink either a cocaine solution or water. The development of cocaine preference was dependent on the cocaine concentration given during choice but appeared to be independent of the presence of an cocaine withdrawal phase. The serotonin antagonist ritanserin reduced cocaine (0.1 mg/ml solution) preference and cocaine intake in a dose‐related manner. The activity of ritanserin started at doses ≥ 0.04 mg/kg when given subcutaneously once daily. Changes in test procedure did not affect the effectivity of ritanserin, although shifts in the lowest active dose were present. In the active dose range (i.e., between 0.04 and 10.00 mg/kg) ritanserin reduced cocaine intake by 29 to 53% and cocaine preference decreased by 19 to 32%. At any time during treatment, the decrease in cocaine consumption was compensated by an increase in water consumption. As a consequence, total fluid intake remained at a constant level. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. In additional experiments it was shown that ritanserin neither directly interacted with the discriminative stimulus properties of cocaine nor induced a cocaine aversion. The activity of ritanserin against chronic exposure to cocaine is discussed in terms of a serotonin 5‐HT2 antagonism.
Autoradiographic localization of dopexamine binding sites and dopexamine‐sensitive cyclic adenosine monophosphate generating system in the rat heart
Authors: Napoleone Paolo , Cavallotti Carlo , Strocchi Paola , Ricci Alberto , Amenta Francesco 
Published: January 2005

AbstractThe present study was designed to analyze the pharmacological characteristics and the anatomical localization of (3H)x‐dopexamine (DPX) in frozen sections of rat right and left ventricles. Moreover, the effect of DPX on 3′‐5′‐cyclic adenosine monophosphate (cAMP) generating system in membrane particles of rat left ventricle was investigated. (3H)‐DPX was specifically bound by sections of rat right and left ventricles. The binding was time‐, concentration‐, and temperature‐dependent and reversible. The pharmacological profile of (3H)‐DPX binding was consistent with the labeling of both β2‐adrenoceptors and DA2 receptors. In fact, the most potent displacer of (3H)‐DPX binding was the β2‐adrenoceptor antagonist ICI 118,551, followed by L‐propranolol, dopamine, noradrenaline, and L‐sulpiride. The β1‐adrenoceptor antagonist metoprolol and the DA1 receptor antagonist SCH 23390, even at high concentrations, were without effect on (3H)‐DPX binding. Autoradiography revealed a rather homogeneous distribution of (3H)‐DPX binding sites within both right and left ventricles. (3H)‐DPX is specifically bound by myocytes. The binding was antagonized primarily by ICI 118,551 and in lesser amounts by L‐sulpiride. ICI 118,551 and L‐sulpiride together reduced the density of silver grains to non‐specific binding. DPX dose‐dependently increased CAMP concentration in membrane particles of rat left ventricle. This effect was antagonized by ICI 11 8,551 but not by SCH 23390. The above data suggest that the cardiac actions of DPX are primarily mediated via an interaction with β2‐adrenoceptors. Moreover, a specific binding to DA2 receptors is also noticeable. The interaction with these different receptors most likely accounts for some of the cardiac effects of DPX.
General pharmacology of CK‐1649C: A new quaternary class III antiarrhythmic agent
Authors: Greenberg Stanley S. , Luisi Alan , Long John P. , Williamson Harry E. 
Published: January 2005

AbstractCK‐1649C is a new quaternary ammonium class III antiarrhythmic agent undergoing clinical trials. The side effect profile of a class III antiarrhythmic agent is generally unknown. This study compared CK‐1649C with quinidine and lidocaine (class I), acecainide (class I/III), and clofilium (class III), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK‐1649C was devoid of neuropharmacologic activity in the mouse and rat. CK.‐1649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenan‐induced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK‐1649C was devoid of activity on transmural nerve stimulation and did not exhibit α1‐muscarinic, nicotinic, or β‐adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK‐1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water‐loaded dogs. CK‐1649C (30mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK‐1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic doses of 1–3 mg/kg in man.
Pharmacology of sematilide, a non‐quaternary class III antiarrhythmic agent
Authors: Greenberg Stanley S. , Luisi Alan , Long John P. , Williamson Harry E. 
Published: January 2005

AbstractSematilide is a new, non‐quaternary class III antiarrhythmic agent currently undergoing clinical trials. We showed that a quaternary ammonium class III antiarrhythmic agent exhibits few extracardiac effects (Greenberg et al., Drug Dev. Res. 25.107–123, 1992). However, the extracardiac effects of a non‐quaternary, pure class III antiarrhythmic agent are unknown. Sematilide, a pure class III antiarrhythmic agent, is effective in a canine model of arrhythmia at 0.3–1.0 mg/kg, intravenously (i.v.). We compared the nervous system and extracardiac effects of sematilide to acecainide (a class I/III) and several class I antiarrhythmic agents to evaluate the potential side effects of this new drug. Sematilide was devoid of neuropharmacologic activity in the mouse and rat, devoid of gastrointestinal activity in the mouse fed a charcoal meal, and without effect in the rat carrageenan‐induced paw edema test. Ten to 30 times the average antiarrhythmic dose or plasma levels of sematilide were devoid of α1, muscarinic, nicotinic, and β‐adrenoceptor blocking activities in a variety of preparations. Moreover, sematilide was devoid of depressant activity on (1) cholinergic, nicotinic, and sympathetic neurotransmission; (2) vascular and non‐vascular smooth muscle reactivity and contractility; (3) aggregation of human platelets; (4) responses of the anesthetized dog to i.v. acetylcholine, isoproterenol, and nicotine; and (5) displacement of quinuclidinyl benzilate (QNB) binding to dog atrial membranes. Sematilide (10–30 mg/kg, i.v.) inhibited vagal nerve stimulation in the dog and slightly enhanced free water clearance in water‐loaded dogs. The data show that effective antiarrhythmic doses and concentrations of sematilide are devoid of significant, injurious neural, hemodynamic, or smooth muscle side effects. © 1992 Wiley‐Liss, Inc.
Effects of epidermal growth factor in the mammalian central nervous system: Its possible implications in brain pathologies and therapeutic applications
Authors: Mazzoni Irene E. , Kenigsberg Rhoda L. 
Published: January 2005

AbstractThe development and maintenance of the normal functional integrity of the mammalian central nervous system is under the influence of a number of growth and trophic factors. One such growth factor, epidermal growth factor, has been detected in the mammalian brain and found to be associated with various brain regions and cell types. This small ubiquitous polypeptide can influence the proliferation, Metabolism, and differentiation of both glia and neurons in the central nervous system. We discuss the effects of epidermal growth factor on glial and neuronal cell function in an attempt to understand its role in development and maintenance of normal brain integrity. In addition, we review its possible implications in several pathological states in the central nervous system and speculate on therapeutic applications for this growth factor. © 1992 Wiley‐Liss, Inc.
Nicotine does not interact with the discriminative stimulus effects of clozapine in rats
Authors: Villanueva Heidi F. , Arezo Shahwali , Rosecrans John A. 
Published: January 2005

AbstractThe purpose of the present study was to assess the potential interaction between clozapine, an atypical antipsychotic recently approved for clinical use in the United States and nicotine. Male Sprague‐Dawley rats were trained to discriminate nicotine or clozapine in a standard two‐lever operant drug discrimination procedure. Rats were tested for generalization to nicotine and clozapine, and the interactions produced by combining various doses of nicotine and clozapine were evaluated. Results suggest that nicotine does not interact with the discriminative stimulus effects of clozapine. Thus, patients who smoke while receiving clozapine therapy may not experience the decreased antipsychotic effectiveness which is common in patients who smoke while receiving treatment with typical antipsychotic compounds. © 1992 Wiley‐Liss, Inc.