bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo assessment of class III agents and their antiarrhythmic activity
Authors: Gibson J. K. , Kersten J. A. 
Published: January 2005

AbstractA variety of in vivo models have been used to detect and develop novel antiarrhythmic/antifibrillatory agents. However, most of these models primarily have identified the class I agents that block sodium ion currents during the upstroke of the cardiac action potential. Since we are interested in identifying agents with a class III electrophysiologic action, i.e. delayed repolarization of the cardiac action potential, we have focused our drug discovery process on a specific, somewhat uncommon in vivo canine model. These studies have demonstrated that class I agents such as encainide, disopyramide, or U58797, a novel benzamide, are clearly identified in the ouabain‐toxic dog or the postinfarction (24–48 hr) conscious dog. In contrast, class III agents such as clofilium sotalol are identified in an acute canine model of coronary artery occlusion and reperfusion. This occlusion‐reperfusion model allows us to further identify the antiarrhythmic and antifibrillatroy actions of novel class III agents.
Electrophysiological specificity of antiarrhythmic drugs: Is it necessary?
Authors: Sullivan Mark E. , Argentieri Thomas M. , Sansone Kenneth J. , Michael Doroshuk C. 
Published: January 2005

AbstractMany factors have been identified in the genesis of cardiac arrhythmias. The relative importance of any given factor over another can vary from individual to individual, and may change with time. Successful antiarrhythmic drug therapy, therefore, must be effective against a multifaceted and evolving matrix. Clinically, the more successful antiarrhythmic agents have complex pharmacological profiles. For example, quinidine and amiodarone have several mechanistic actions which contribute to their antiarrhythmic efficacy. Multiple unfocused actions often result in side effects such as proarrhythmia, which has been demonstrated for both the above agents. Another approach to treating arrhythmias is to use different, selective agents in combination. Using programmed electrical stimulation techniques in dogs, we demonstrated that propranolol was ineffective in preventing reentrant tachycardia. However, subtherapeutic doses of the class III agent sematilide when combined with propranolol prevented reentry. A multivalent approach may also be useful in solving the problem of proarrhythmia. Using standard microelectrode techniques in vitro, we demonstrated that clofilium produced early after depolarizations, as well as an increase in triggered activity. In vivo, clofilium increased the number of ectopic events in infarcted dogs. The addition of a class I or a class IV antiarrhythmic agent in these animals was effective in suppressing the increased ectopic activity. These data suggest that combination therapy, by combining either single agents with selective actions or developing agents with multiple, focused actions may be an effective way to increase antiarrhythmic efficacy and decrease side effects.
GM1 ganglioside treatment of central nervous system injury: Clinical evidence for improved recovery
Authors: Samson Jaap C. 
Published: January 2005

AbstractMonosialoganglioside GM1 is a new pharmacological agent used to enhance recovery after central nervous system (CNS) injury. This agent is a natural component of cell membranes, and its clinical use is based on extensive experimental work which demonstrates that many parameters of brain function in CNS‐injured animals are positively influenced by the parenteral administration of monosialoganglioside GM1. The key mechanism through which monosialoganglioside GM1 is able to exert its clinical effects is by enhancing the neuroplasticity of the CNS. The recovery‐promoting effect is mediated through neuroprotective and neuronotrophic activities exerted or enhanced by monosialoganglioside GM1. The neuroprotective activity is based on the prevention of the neuronotoxic consequences of indiscriminate excitatory amino acid receptor activation, particularly of glutamate receptors. In vitro and in vivo evidence indicates that the product enhances the trophic response of neurons to neurotrophic factors induced as a response to the lesion. The neuropharmacological effects of monosialoganglioside GM1 in humans have been confirmed in controlled clinical trials in head and spinal cord injury and stroke. The therapeutic use of monosialoganglioside GM1 is a significant innovation in an area of neuropharmacology that has been neglected until the functional significance of CNS neuroplasticity was recognized.
Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains
Authors: Bickel Warren K. , Hughes John R. , Higgins Stephen T. 
Published: January 2005

AbstractOne scientific concern with benzodiazepine is their effects on learning (acquisition). One procedure that permits a detailed study of learning processes is the repeated acquisition of behavioral chains procedure. The repeated acquisition of behavioral chains allows for the repeated study of learning in individual subjects and also permits a comparison with comparable performance behavior. This paper reviews the effects of acute and chronic benzodiazepines on the repeated acquisition and performance of response chains. With acute administration, diazepam, alprazolam, and triazolam are all found to produce dose‐related increases in percent errors in the acquisitions component, while generally not affecting percent errors in the performance component. Diazepam showed less activity than either alprazolam or triazolam. With chronic administration, acquisition showed tolerance to the errors‐increasing effects of diazepam at a slower rate than did performance. Clinical implications of these findings are discussed.
Marijuana and behavioral contingencies
Authors: Foltin Richard W. , Fischman Marian W. , Brady Joseph V. , Kelly Thomas H. , Bernstein Daniel J. , Nellis Margaret J. 
Published: January 2005

AbstractTwenty‐four adult male research volunteers, in groups of three subjects each, lived in a residential laboratory for up to 18 days. All contact with the experimenters was through a networked computer system, and subject behavior was continuously monitored and recorded. During the first part of each day, subjects remained in private rooms doing planned work activities, and during the remainder of each day they were allowed to socialize. One or two cigarettes containing active marijuana (1.8‐2.7% Δ9‐THC) or placebo were smoked during both the private work period and the period of access to social activities. Following the determination of baseline distributions of activities, contingency conditions requiring subjects to engage in a low‐probability activity (instrumental activity) in order to earn time that could be spent engaging in a high‐probability activity (contingent activity) were then introduced. Baseline and contingency conditions were studied under periods of placebo and active marijuana administration. Under placebo conditions, introduction of the contingency resulted in increases in instrumental activity and decreases in contingent activity under both placebo and active marijuana conditions. The response to combining marijuana administration with contingencies varied across private work and social access conditions. During work periods, active marijuana administration increased instrumental activity to a larger extent than was observed under placebo conditions. The decreases in contingent activity were similar to those seen under placebo conditions. During social periods, active marijuana administration increased instrumental activity to a smaller extent than observed under placebo conditions. The decreases in high‐probability contingent activity were similar across drug conditions. Smoking active marijuana was thus observed to produce increments in instrumental activity under motivational involving contingencies for “work activities” while producing instrumental decrements under motivational conditions involving recreational contingencies.
Neurochemical correlates of behavioral processes
Authors: Barrett James E. , Nader Michael A. 
Published: January 2005

AbstractCumulative developments in the experimental analysis of behavior and behavioral pharmacology, together with relatively recent technical advances in the field of neuroscience, have provided a strong impetus to build on previous research and combine these disciplines into an integrated approach focusing on behavioral neurochemistry. Neither behavioral nor neurochemical changes are static independent processes but interact in dynamic and complex ways. Neurotransmitter activity can be conditioned using both classical Pavlovian and operant conditioning procedures. Neurochemical changes also occur when behavior is brought under the control of its environmental consequences. Behavioral variables such as the schedule‐controlled rate of responding, prior history, and environmental context have been shown repeatedly to determine the effects of drugs and appear to have definable and distinctive neurochemical correlates. These variables may modify neurochemical substrates involved in drug action. Ongoing changes in behavior and neurochemistry are now concurrently accessible for experimental analysis. The synthesis of these two fields permits the exploration of behavioral and neurochemical interactions that were not easily accessible only a short time ago and promises to yield considerable information about both behavioral and neurochemical processes. This article summarizes the development of research in behavioral neurochemistry and attempts to show how a continuation of these endeavors can provide a better understanding of the interrelationships between behavior and neurochemistry as determinants of drug action.
Behavioral contingencies determine changes in drug‐induced neurotransmitter turnover
Authors: Smith James E. , Dworkin Steven I. 
Published: January 2005

AbstractEvidence from several research areas suggests that response‐dependent and independent presentation of environmental events have different neurobiological consequences. Investigations of neurotransmitter turnover rates and cholinergic muscarinic receptor densities in brain regions of rats receiving contingent and noncontingent intravenous morphineresulted in the identification of two neuronal networks that are involved in response dependent morphine presentation. These circuits are concordant with brain regions showing increased glucose utilization in animals receiving response‐dependent electrical stimulation of either the substantia nigra or ventral tegmental area. These data indicate substantial differences between contingent and noncontingent presentation of environmental events and suggest that neurobiological investigations of reinforcement that use response independent delivery of a putative reinforcer must be interpreted with some caution.
Protective role of pentoxifylline and propentofylline against the increase in osmotic fragility of the human red cell induced by protoporphyrin photosensitization
Authors: Cassoly Robert , Deprette Christiane 
Published: January 2005

AbstractPentoxifylline and propentofylline are potent drugs used in impaired blood‐flow pathologies. As an approach to understand their mode of action we studied their influence on protoporphyrin‐photosensitized damage of the human red cell membrane. Both compounds are shown to exert a strong protection against the increase in osmotic fragility of the red cell which follows their irradiation at 390 nm in the presence of protoporphyrin. They do not, however, prevent cross‐linking of the membrane skeleton proteins, which occurs slowly following irradiation. The results emphasize the ability of pentoxifylline and propentofylline to scavenge toxic photoactivated radicals, a property which could explain their mode of action in vivo. We also show that the two methyl xanthine derivatives considered in this study significantly protect red cells from hemolysis and spontaneous microvesiculization of their plasma membrane, which normally occurs when whole blood is stored for several weeks.
How surface‐bound drugs inhibit thrombus formation
Authors: Wilson Joseph E. 
Published: January 2005

AbstractThis article presents the new concept that surface‐bound drugs can remove coagulation promoters from the bloodstream and thus produce much needed improvement in the surface thromboresistance of polymeric devices such as catheters, vascular grafts, and artificial organs. For example, calcium plays a central role in promoting coagulation, which suggests that surface thromboresistance could be improved by bonding a polymer to a calcium chelator which removes calcium from circulation. This technique has been tried and found successful in animal tests using hydroxyproline as the calcium chelator (Wilson and Jones: Biomater. Artif. Organs 17:437–445, 1989. An alternative design for a thromboristance polymer is proposed: Chemically bond a commercial polymer to a suitable drug containing cationic groups capable of complexing blood coagulation factors and rendering them inactive. The feasibility of this approach is based on two lines of evidence: (1) Several blood coagulation factors are routinely isolated by complexation on ion exchange resins containg cationic groups (tertiary amines). (2) A number of polymers containing cationic groups (tertiary amines) have been patented on the basis of their thromboresistance. In this article an ion exchange equilibrium is postulated between each anionic coagulation factor adsorbed on the polymer and dissolved in the liquid phase, with the surface affinity of each anionic factor being greater the more cationic (basic) the polymer surface. Data on the competitive adsorption of proteins on cationic polymers have been analyzed mathematically. The results suggest more attention should be given to cation/anion interactions in studies of polymeric thromboresistance and protein adsorption).
Initial human safety and tolerance study of a GABA uptake inhibitor, Cl‐966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania
Authors: Sedman Allen J. , Gilmet Gregory P. , Sayed Albert J. , Posvar Edward L. 
Published: January 2005

AbstractAn initial double‐blind, placebo‐controlled safety and tolerance study of single doses of a GABA uptake inhibitor (CI‐966) being developed for the treatment of epilepsy was conducted in healthy volunteers. Drug doses of 1 to 10 mg were well tolerated. A volunteer who received 25 mg of CI‐966 developed transient short‐ and long‐term memory deficits. Both volunteers following administration of 50 mg drug doses presented with a constellation of physical and mental disturbances. Physical abnormalities including tremor, myoclonus, increased muscle rigidity, cogwheeling, and short‐ and long‐term memory impairment of 12–24 hr duration were observed. In addition, striking psychiatric symptoms of many days' duration resembling those seen in patients with mania and schizophrenia were evident. These findings suggest that GABA may modulate memory and dopaminergic pathways responsible for posture and muscle control. In addition, GABA may be a potentially important mediator in the pathogenesis of schizophrenia and mania.
Stimulation of myocardial function after brief regional ischemia by glucagon
Authors: Jolly Stanley R. , Jordan Joseph C. , Rose Gregory C. 
Published: January 2005

AbstractGlucagon (1.5 to 45 μg/kg, i.v.) has been examined in open‐chest anesthetized dogs subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCCA) and reperfusion. Regional segment lengths in myocardium supplied by the LCCA and left anterior descending (LAD) coronary arteries were measured by sonomicrometry. Occlusion of the LCCA produced paradoxical bulging. At 2.5 hours after reperfusion, segmental shortening in the LCCA area remained significantly reduced at 33 ± 11% of baseline. Regional shortening in the LAD area increased upon LCCA occlusion but was not significantly different from baseline at 2.5 hours. Glucagon increased heart rate and peak positive dP/dt while decreasing systemic pressure. After glucagon 15 μg/kg i. v., LCCA regional shortening was 71 ± 10% of baseline, a significant increase compared with the 2.5 hours reperfusion value. For comparison, isoproterenol 0.3 mg/kg increased segment shortening to 119 ± 19% of baseline. Glucagon reduced end‐diastolic segment length in both LCCA and LAD regions. In conclusion, glucagon significantly improved regional function in myocardium recovering from an episode of regional ischemia.
Uricosuric property of a new diuretic compound, S‐8666‐S‐(‐)‐enantiomer in rats
Authors: Shinosaki Toshihiro , Harada Hiroshi , Yonetani Yukio 
Published: January 2005

AbstractThe uricosuric property of S‐8666‐S‐(‐)‐enantiomer (S), which is the diuretic component of the uricosuric diuretic agent S‐8666, was studied using rats. S markedly increased the tubular fractional excretion of uric acid in a stop‐flow analysis using rats treated with pyrazinoic acid (PZO), an inhibitor of tubular urate secretion, but did not affect the tubular urate transport in animals not treated with PZO. On the other hand, S was hypouricosuric and hyperuricemic in a clearance study using rats treated with oxonate, a uricase inhibitor, and also in an experiment using eviscerated rats with functional hepatectomy. The diuretic property of S was comparable to that of furosemide in rats. However, furosemide under an equivalent diuretic response was more potently hypouricosuric in oxonate‐treated rats and eviscerated rats with functional hepatectomy and even in the stop‐flow experiments, and more hyperuricemic in eviscerated rats with functional hepatectomy. The hypouricosuric effect of S in oxonate‐treated rats could be canceled by administration together with the R‐(+)‐enantiomer. These results led to the conclusion that S is less hypouricosuric and hyperuricemic than furosemide at an equivalent diuretic dose owing to its dual effects on tubular urate transport, and the hypouricosuric property can be canceled by administration together with the R‐(+)‐enantiomer.
Evaluation of the morphine reversal actions and antinociceptive activity of a new class of opiate antagonists structurally related to fentanyl
Authors: Wynn Richard L. , Bagley Jerome R. , Spencer H. Kenneth , Spaulding Theodore C. 
Published: January 2005

AbstractStructural changes to the fentanyl molecule based on heterocyclic modifications at the sector distal to the piperidine nitrogen results in morphine reversal activity. A series of such compounds known as 4‐(heteroanilido) piperidines were tested for reversal of morphine antinociception and depressed respiration rate per minute (RPM) using a rabbit tooth pulp model. Nine compounds were tested and all reversed morphine depressed RPM with doses ranging from 0.007 mg/kg to 1.55 mg/kg. Four of the nine compounds also significantly reversed antinociception at doses ranging from 0.005 mg/kg to 0.6 mg/kg. All but one compound elicited significant antinociception in non‐morphine rabbits. Maximum possible effect (MPE) ranged from 21% to 57% and cumulative doses to achieve antinociception ranged from 0.16 mg/kg to 7.7 mg/kg. These compounds increased RPM in non‐morphine rabbits with a range from 9% to 49% over control values. A furan ring at the distal site was found to be important in selective reversal of RPM. When a methylated 2‐pyridine was combined with a 2‐furan, reversal of both morphine antinociception and depressed RPM was achieved. One compound in this series compared favorably to the mixed agonist‐antagonist nalbuphine and a second compared favorably to the pure antagonist naloxone.
General approach leading to the development of imidazoquinoline and imidazopyrimidine benzodiazepine receptor ligands
Authors: Tully W. Roger , Gardner Colin R. , Westwood Robert 
Published: January 2005

AbstractThe observation that the imidazoquinoxaline ethyl ester RU32180 possessed an affinity of 175 nM for benzodiazepine (BDZ) receptors led to the discovery of several series of potent receptor ligands such as esters ofimidazoquinolines and imidazobenzothiazoles. The lack of oral activity shown by these esters was rectified in the benzoyl imidazoquinolne RU31719, which possessed nearly all the properties of a classical BDZ agonist but with reduced muscle relaxant activity. Structure‐activity studies led to the benzoyl imidazoquinazoline RU32514 and from there to the imidazopyrimidine RU32698, which has robust anxiolytic activity, but induces little sedation and no muscle relaxation in a range of animal models. Further studies yielded the oxadiazolyl imidazopyrimidines such as RU33203, a potent partial agonist, and the thiazolyl imidazopyrimidine RU33356, the first member of the series to possess antagonist/inverse agonist properties.
Effects of selected imidazopyrimidine ligands for benzodiazepine receptors in rodent models of anxiety and behavioural impairment
Authors: Deacon Robert M. J. , Guy Andrew P. , Gardner Colin R. 
Published: January 2005

AbstractA group of imidazopyrimidine ligands of benzodiazepine receptors has been shown to produce anti‐conflict effects in a punished rat operant task, at comparable doses to classical benzodiazepine agonists such as diazepam. Most were able to attenuate the convulsant effects of pentylenetetrazole and electroshock in the mouse, although with reduced potency compared with the reference classical benzodiazepines. Their activity in tests of functional central nervous system impairment (rotating drum and potentiation of phenobarbitone in the mouse, potentiation of chloral hydrate and pull‐up test in the rat) was also markedly less than the classical agonists. These data are consistent with these imidazopyrimidines being partial agonists at the benzodiazepine receptor.
Hemodynamic profile of the new cardiotonic agent CK‐2289 compared to milrinone and enoximone in the anesthetized dog
Authors: Greenberg Stanley S. , Paul Jeff , Touhey Beatrix 
Published: January 2005

AbstractWe examined the hemodynamic profile of CK‐2289, a new imidazolone developed for the treatment of congestive heart failure, in the normal pentobarbital‐anesthetized dog. Mongrel dogs (10–18 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, intravenously [i.v.]) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. Intravenous administration of CK‐2289 (3, 10, 30, and 100 μ/kg) to pentobarbital‐anesthetized dogs increased left ventricular (LV) dP/dTmax by 9, 26, 73, and 80%, respectively, and decreased mean arterial pressure (MAP) by 2, 6, 18, and 34%. CK‐2289 was 2.7 times more potent as a positive inotropic agent than as a vasodilator. Heart rate (HR) increased by 2, 10, 18, and 28% after these doses of CK‐2289, while left ventricular end diastolic pressure (LVEDP) decreased by 4.5 mmHg after the highest dose of compound. CK‐2289 increased coronary blood flow (CBF) after each dose of compound. However, the increased CBF was less than that produced by milrinone for equivalent increases in LV dP/dTmax. Renal blood flow increased while vertebral blood flow was reduced after administration of the two highest doses of CK‐2289. However, vertebral vascular resistance decreased slightly from control values. Milrinone and enoximone behaved qualitatively similar to, but were 6 and 27 times less potent than CK‐2289 as cardiotonic agents. Thus, CK‐2289 is a mixed positive inotrope and vasodilator with a hemodynamic profile similar to milrinone and enoximone, which sugests it may have utility in the treatment of heart failure.