bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local anti‐inflammatory activity of steroid‐21‐oate esters in the carrageenan pleurisy model of acute inflammation
Authors: Heiman Ann S. , Taraporewala Irach B. , Lee Henry J. 
Published: January 2005

AbstractLocal anti‐inflammatory activities in the carrageenan (CGN)‐induced pleurisy model are reported for steroid‐21‐oate esters derived from prednisolone. Following administration of equipotent doses (per rat) of prednisolone (P),.5mg; methyl 17,20α‐acetonidodihydroprednisolonate (P4AC), 1 mg; methyl 20β‐dihydroprednisolonate (P4B), 1.3 mg; methyl 20α‐dihydroprednisolonate (P4A), 5.8 mg; and methyl 17,20β‐acetonidodihydroprednisolonate (P4BC), 6 mg, effects of the steroids on exudate volume, leukocyte recruitment, and enzyme levels of cell‐free exudates and washed exudate cells were assessed. All derivatives tested significantly inhibited emigration of neutrophils (PMNs) and monocytes (MNs). Steroid treatment with the β‐isomers reduced exudate volumes by 41% and 56% for P4B and P4BC, respectively. In 5 hr neutrophilic exudates, free β‐glucuronidase levels were reduced by 43% by either P4B or P4AC treatments. Of the derivatives tested P4B and P4AC treatments resulted in the greatest reduction of free lysozyme levels. Activities of membrane‐bound γ‐glutamyl‐transferase (GGTP) in exudate cell pellets were reduced following treatment with P and the 20 alpha‐epimers P4AC and P4A. Systemic effects assessed as decreases in plasma corticosterone or suppression of circulating lymphocytes were noted only following P treatment. These results suggest that 1) the locally active steroid‐21‐oate esters act at the site of inflammation by inhibiting PMN and MN infiltration in a manner congruous with conventional steroids, 2) steroid stereochemical configuration plays a role in effects on exudate volumes and GGTP activities, and 3) due to the absence of systemic effects, the steroid‐21‐oate esters may be safer local anti‐inflammatory agents.
Aspirin plasma monitoring in juvenile chronic arthritis
Authors: Sharma Bhawna , Seth Vimlesh , Seth Shiva D. , Basu Nandita , Beotra Alka 
Published: January 2005

AbstractThirty‐two patients from the Pediatric Rheumatology Clinic of the All India Institute of Medical Sciences, New Delhi, suffering from juvenile chronic arthritis (JCA) in the age group of 5–15 years were investigated for salicylate monitoring. Of these, 15 (46.9%) had polyarthritis and 11 (34.4%) suffered from systemic onset type of JCA while only 6 (18.7%) had the pauciarticular type of disease. Plasma salicylate and albumin levels were estimated on days 1, 7, 14, and 21, after initiation of therapy with aspirin. Serum SGOT and SGPT were also estimated, as well as clinical evidence of hepatotoxicity. The therapeutic plasma levels (15–25 mg/dl) of salicylates were achieved by a mean dose of aspirin of 81.8 mg/kg/day administered in three divided doses. On the surface area basis the mean dose of aspirin was 2.1 g/m2/day. Steady‐state level of aspirin in plasma was achieved by the seventh day, and the values were 2.8 times more than on the first day. In malnourished patients with low albumin levels, there was a proportional decrease in salicylate binding. Although increase in transaminase levels of 1 1/2 to 2 times the normal was observed in the patients on aspirin therapy, none of the children developed clinical evidence of hepatotoxicity during this short‐term study. The studies indicate that dosage of salicylates can be given either on a body weight or surface area basis. A malnourished child with lower levels of serum albumin may be more predisposed to salicylate toxicity, due to higher levels of free salicylates. There was no evidence of hepatotoxicity in the dosage range of 70–110 mg/kg/day or 1.9 to 2.8 g/m2/day.
Preclinical profile of the pyrimidinylpiperazinyl imide compound WY‐47,846: A potential anxiolytic
Authors: Haskins J. Thomas , Moyer John A. , Andree T. H. , Muth E. A. , Abou‐Gharbia M. 
Published: January 2005

AbstractA preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound Wy‐47,846, is presented. In an effort to achieve an orally active, nonbenzodiazepine anxiolytic agent, the compound Wy‐47,846 was synthesized and examined in various preclinical neurochemical, psychopharmacological and neurophysiological tests. Wy‐47,846 displayed high affinity at the 5‐HT‐1A receptor binding site (Ki = 16.7 nM) and had weak‐to‐modest affinities for D‐2 and 5‐HT‐2 receptors. Wy‐47,846 also was effective in binding to the 5‐HT‐1A site in ex vivo receptor binding studies, but did not alter D‐2 binding under these conditions. Wy‐47,846 was also weak to inactive at displacing adrenergic (alpha‐1, alpha‐2, and beta), cholinergic, histamine H‐1, opiate, and benzodiazepine receptor radioligands from their respective binding sites. Wy‐47,846 reduced 5‐HT‐2 receptor binding following subacute (3 week) treatment. In both shelf‐jump and discrete trial conditioned avoidance tests, Wy‐47,846 reduced avoidance responding while increasing escape responses. No sedative effects were noted at behaviorally active doses. Like other nonbenzodiazepine anxiolytics, Wy‐47,846 also did not release the suppression of punished responding in shock‐suppressed drinking nor in Geller‐Seifter conflict experiments. Wy‐47,846 also potently inhibited serotonergic neuronal activity in the dorsal raphe nucleus, suggesting agonist activity at the 5‐HT‐1A receptor and increased noradrenergic neuronal activity in the locus coeruleus by an unknown mechanism. These findings support the characterization of Wy‐47,846 as a nonbenzodiazepine anxiolytic agent.
Cardiocirculatory dynamics during heart failure in the rat: Effects of prototypic drugs
Authors: Flaim Stephen F. 
Published: January 2005

AbstractThe goal of these studies was to evaluate the effects of congestive heart failure on the peripheral circulations, looking specifically for the regions responsible for the rise in peripheral resistance observed in patients with this disease condition. During the course of these experiments, we evaluated the effects of different modes of exercise on cardiocirculatory dynamics and cardiac output distribution in normal animals in order to determine the most appropriate mode to induce an adequate exercise stess. Based on these studies, we chose treadmill exercise for use in animal models of heart failure. The animal species chosen for these studies was the rat. This choice was based on the availability of novel techniques which allowed for repetitive and accurate hemodynamic and regional blood flow determinations in rodents which provided a cost‐effective approach to the study of heart disease. Once appropriate models for congestive failure and for exercise were adequately characterized and studied, additional experiments designed to evaluate the acute effects of appropriate therapeutic agents such as calcium blockers, nitro‐vasodilators, and angiotensinconverting enzyme inhibitors were conducted. In order to determine the scope of the therapeutic efficacy of some of these compounds, studies were also conducted on models of hypertensive disease.
Anticancer and antiviral activities in indian medicinal plants: A review
Authors: Rastogi Ram Prakash , Dhawan Bhola Nath 
Published: January 2005

AbstractThis paper reviews the screening studies carried out in India to identify Indian medicinal plants bearing anticancer and antiviral activities. The highlights of the active constituents isolated are described and, based on analysis of screening data, some correlation has been derived on the presence of anticancer and antiviral activities in the taxa belonging to different families.
Stereoselective saluretic effect and localization of renal tubular secretion of enantiomers of S‐8666, a novel uricosuric antihypertensive diuretic
Authors: Nakamura Masuhisa , Kawabata Tomoji , Itoh Takako , Miyata Kenji , Harada Hiroshi 
Published: January 2005

AbstractS‐8666, a newly developed antihypertensive uricosuric diuretic, possesses an asymmetric carbon and exists as a racemic mixture. The enantioselectivity of S‐8666 in natriuresis and the renal excretory mechanisms of the S‐8666 enantiomers were examined. Dose‐dependent natriuresis of the S‐(−)‐enantiomer was observed in male Sprague‐Dawley rats (3–100 mg/kg, p.o.), female Slc:ddy mice (3–300 mg/kg, p.o.) and male NIBS Japan white rabbits (1–10 mg/kg, i.v.). The R‐(+)‐enantiomer produced no significant change in sodium excretion within dose ranges of 100–200 mg/kg p.o. for rats, 3–300 mg/kg p.o. for mice, and 10 mg/kg i.v. for rabits. The (−)‐enantiomer and racemic S‐8666 showed a high‐ceiling property like that of furosemide and unlike that of trichlormethiazide. Plasma protein binding of S‐8666 was over 95% in rabbits and 73% in beagle dogs. In rabbits, both enantiomers of S‐8666 were secreted equally from the proximal tubule; however, only the (−)‐enantiomer of S‐8666 showed diuresis in a stop‐flow pattern. In beagle dogs, secretion of racemic S‐8666 occurred from the proximal tubule and could be inhibited by probenecid. The renal excretion of S‐8666 was largely the result of tubular excretion in rabbits whereas in beagle dogs, some glomerular filtration was also involved in urinary excretion. In conclusion, S‐8666 shows enantioselectivity in natriuresis. Both enantiomers of S‐8666 are excreted mostly by the organic acid transport system in the proximal tubule, but only the (−)‐enantiomer of S‐8666 induces natriuresis from the luminal side of the tubule.
Propentofylline improves the postischemic stroke index of sensitive gerbils
Authors: Delbarre G. , Delbarre B. , Ferger A. 
Published: January 2005

AbstractThe new xanthine derivative propentofylline (3‐methyl‐1‐[5′‐oxohexyl]‐7‐propylxanthine), administered intraperitoneally in a dose of 25 mg/kg 10 min before ligation of the left cerebral carotid artery in “sensitive” gerbils, improves the mean stroke index significantly at 4 and 24 hr postadministration. At a dose of 10 mg/kg, propentofylline improves the mean stroke index at all examined times (4, 24, and 72 hr), but at 5 mg/kg, a protective effect was obtained only after 24 hr. The mortality rate was lower in all propentofylline groups than in the control group. These results suggest that propentofylline is worth further study as a possible antistroke agent.
Electrophysiological actions of BRL 34915 in isolated guinea pig ventricular myocytes
Authors: McCullough John R. , Conder Mary L. , Griffel Louis H. 
Published: January 2005

AbstractSpecimens of diseased human ventricle and of infarcted cardiac tissue obtained from animal models contain admixtures of both well‐polarized and partially depolarized cells which may contribute to the development of cardiac arrhythmias. Recently, it has been suggested that the partially depolarized potentials result from low potassium permeability (PK) since some of the partially depolarized cells can be hyperpolarized by measures which increase Pk including increased external potassium (K+o) and rapid pacing (McCullough et al.: Circulation 66:II–198, 1982; Circulation 70:II–889, 1984). In the present study, we examined the electrophysiological actions of BRL 34915 (Cromakalim), a vasorelaxant agent reported to increase Pk of vascular smooth muscle cells, on the resting potential (RP) and the background K current (IK1) of isolated guinea pig ventricular myocytes by using whole‐cell voltage‐clamping techniques. BRL 34915 (5 μM) significantly hyperpolarized RP at all K+o tested, the extent of hyperpolarization decreasing with increasing K+o. The slope of the relationship between RP and K+o increased in the presence of BRL 34915 from −41.4 to −54.8 mV. BRL 34915 inhibited IK1 by decreasing the inward current at potentials negative to RP and the outward current between RP and ∼−20 mV. Outward current positive to −20 mV was unaffected. Higher concentrations (50–100 μM) of BRL 34915 increased this current. These results suggest that the hyperpolarization induced by low concentrations of BRL 34915 resulted from an increase in selectively of the membrane for potassium. Higher concentrations may increase an outward potassium current. Potential therapeutic applications of cardiac selective potassium channel activators are discussed.
Clinical features of arrhythmia aggravation by antiarrhythmic drugs and their implications for basic mechanisms
Authors: Roden Dan M. 
Published: January 2005

AbstractAlthough cardiac arrhythmias are major cause of morbidity and mortality, widespread use of antiarrhythmic drugs is not appropriate at this time for two major reasons: (1) There is no evidence that antiarrhythmic drugs alter mortality in the vast majority of patients; further data will be forthcoming from large‐scale multicentered clinical trials which are currently underway. (2) Side effect are a prominent feature of therapy with antiarrhythmic drugs. The most striking of these toxicities is apparently paradoxical provocation of, rather than suppression of, cardiac arrhythmias by these agents. Two common clinical entities have been recognized. Therapy with action‐potential‐prolonging agents, including quinidine, sotalol, and the major active metabolite of procainamide, N‐acetyl procainamide, has been associated with the development of a morphologically distinctive polymorphic ventricular tachycardia, Torsades de Points, in approximately 5% of patients. Bradycardia and hypokalemia are commonly associated clinical features. In vitro studies indicate that triggered automaticity, in the from of early afterdepolarizations, are responsible for the genesis of Torsades de Pointes. The second common form of arrhythmia aggravation by antiarrhythmic drugs is the development of a marked increase in frequency of sustained ventricular tachycardia events in patients being treated for ventricular tachycardia. Therapy with sodium channel blockers of the “class Ic” subtype, including flecainide and encainide, are most commonly implicated. Since the underlying mechanism for sustained ventricular tachycardia in this patient population is thought to be microreentry, it appears likely that slow conduction due to the “class Ic” properties of the drugs may under appropriate conditions enable rather than block reentrant circuits. A variation on this clinical entity is the increasingly recognized phenomenon of drug‐induced impaired ventricular defibrillation. Although this is recognised with agents of the “class Ic” subtype, other sodium channel blockers have also been implicated, while action potential prologation actually appears associated with a decrease in defibrillation energy requirements. These adverse electrophysiologic drug action are not tightly linked to high plasma concentrations; rather, they represent an interplay among drug dose, plasma concentration, and underlying substrate. However, subsets of patients with variant drug metabolism on a genetic on a genetic basis have been identified and, under appropriate circumstances, these may be at increased risk for adverse electrophysiologic drug actions. Thus, intensive study of the clinical features of arrhythmia aggravation by antiarrhythmic drugs and their correlates in the basic laboratory have resulted not only in improved patient care but also in an increased understanding of the fundamental mechanisms responsible, and, potentially, may result in improved method for identifying new and safer antiarrhythmic compounds.
On stability and control of ligand‐receptor interactions according to the mass action law: A theoretical model of chaos
Authors: Tallarida Ronald J. 
Published: January 2005

AbstractThe stability and control of ligand‐receptor interaction obeying the mass action law were analyzed with a control model that is applicable to drugs and endogenous compounds. Whereas the local concentration of drugs, and consequent receptor occupancy, depend on pharmacokinetic parameters and, possibly, intrinsic control, natural substances are almost certainly controlled. The model assumes constant ligand production, with first‐order elimination and a feedback function (ϕ) that modulates these. The feedback signal, which may originate at a site proximal or distal to the receptor, is expressed as a function of the occupied receptor concentration (y). Instantaneous values of free (z) and bound (y) ligand represent a state or a point of the system. Basal values of y and z define a critical point that is stable; that is, perturbations producing states away from it will return in time to this critical point. In contrast, other critical points can be unstable, meaning that movements near such points will result in loss of control and possible chaos. It is shown that any critical point at which the derivative ϕ'(y) < 0 is stable; thus if unstable critical points exist then ϕ'(y) > 0 at such points. The model predicts at least one unstable point or repellor. The distance between these points is crucial to maintenance of control. Loss of control may account for certain abnormalities such as vasospasm and other pathologic conditions. The model, containing four parameters that control the three of the ligand‐receptor interaction, predicts conditions that alter stability. These insights may be useful for drug use and development.
Neuropeptide Y: An overview
Authors: Lehmann John 
Published: January 2005

AbstractNeuropeptide Y (NPY) has a broad distribution and numerous physiological functions in the peripheral and central nervous systems. The gene transcription and fundamentals of peptide processing have been elucidated. NPY levels and release are exquisitely sensitive to pharmacological and physiological manipulation. NPY receptors have been partially characterized pharmacologically. The effects of NPY on target organs and their implications for drugs interacting with the NPY system are described.
Antagonizing bradykinin (BK) obliterates the cardioprotective effects of bradykinin and angiotensin‐converting enzyme (ACE) Inhibitors in ischemic hearts
Authors: Linz Wolfgang , Martorana Piero A. , Grösch Horst , Bei‐Yin Qi , Schölkens Bernward A. 
Published: January 2005

AbstractBradykinin (BK) (1 × 10 −12−1 × 10−8 mol/l) and the ACE inhibitor ramiprilat (2.58 × 10 −9−2.58 × 10−5 mol/l) markedly reduced the incidence and duration of reperfusion arrhythmias in the isolated ischemic rat heart. Pretreatment with ramipril (1 mg/kg p.o.), enalapril (10 mg/kg p.o.), but not captopril (50 mg/kg p.o.) had similar effects. Active compounds also improved cardiodynamics and reduced lactate dehydrogenase (LDH) and creatine kinase (CK) activities, as lactate formation in coronary venous effluent. Cardiac tissue levels of glycogen, adenosine triphosphate (ATP), and creatine phosphate (CP) were preserved. The BK antagonist D‐Arg‐[Hyp2, Thi5,8, D‐Phe7]BK abolished the beneficial effects of BK, ramipril, and ramiprilat in a competitive way. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. In anesthetized dogs an infusion of BK, at the dose of 1 ng/kg/min during coronary occlusion and reperfusion was devoid of cardiovascular effects but reduced mortality and the decrease of LDH activity and lactate concentration in coronary sinus blood and preserved tissue levels of glycogen and energy‐rich phosphates in the ischemic myocardium.
Cocaine tolerance: Interactions among random‐ratio and random‐interval reinforcement‐schedule parameters and repeated exposure to cocaine
Authors: Branch Marc N. 
Published: January 2005

AbstractFood‐deprived pigeons were trained to peck a key under either a three‐component multiple random‐ratio 5, random‐ratio 25, random‐ratio 125 schedule or a three‐component multiple random‐interval 10‐sec, random‐interval 30‐sec, random‐interval 125‐sec schedule of food presentation. Following determination of acute effects of cocaine (1.0‐13.0 mg/kg), are‐sponse‐rate‐reducing dose was given before each daily session. Once performance under conditions of daily administration had become stable, other doses occasionally were substituted for the usual daily dose so that dose effects could be assessed. Tolerance, i.e., a rightward shift in the dose‐effect curve was observed in all subjects. For subjects studied under the random‐ratio schedules, however, the robustness of the tolerance usually was related to the schedule‐parameter value; tolerance was great at lower random values. By contrast, subjects whose responding was maintained by random‐interval schedules were less likely to show tolerance that was schedule‐parameter dependent. The results also provide suggestive evidence that dose may be an important factor in determining effects of repeated cocaine exposure; repeated administration of larger doses may be less likely to result in tolerance than similar exposure to smaller doses.
Elevation of blood pressure as the basis for discriminative stimuli produced by methoxamine
Authors: Lal Harbans , Yaden Senka , Forster Michael J. 
Published: January 2005

AbstractMale, hooded rats were trained to detect methoxamine using a discrimination paradigm in which responding under an FR10 schedule was reinforced on one lever following an injection of methoxamine (1.25 mg/kg) and on an alternate lever following an injection of saline. The rats learned the methoxamine‐saline discrimination to a criterion of correct lever selection on 10 consecutive days in an average of 35 training sessions. In subsequent tests, selection of the methoxamine‐appropriate lever was found to be both time dependent and dose dependent, and these effects closely paralleled time‐ and dose‐related increases in systolic blood pressure. In addition, the ability to increase blood pressure was a common property of those drugs that substituted for methoxamine in the discrimination test. These findings suggest that interoceptive stimuli related to elevated blood pressure provide the basis for methoxamine discrimination. Drug discrimination paradigms may, therefore, be useful within programs for management of hypertension, as a method for enhancing conscious awareness of blood pressure changes.
Use of classical conditioning procedures in behavioral pharmacology
Authors: Schindler Charles W. , Harvey John A. 
Published: January 2005

AbstractWhile operant conditioning clearly dominates the field of behavioral pharmacology, over the past 10 years, classical conditioning has been used more frequently to study the effect of drugs on behavior. In particular, the rabbit nictitating membrane response (NMR) has been used to study the effects of drugs on learning. This procedure offers a number of advantages over other assessments of learning in mammals to the study of drug effects on learning. First, because the rabbit NMR is well characterized behaviorally, it is possible to relate a drug effect to a particular behavioral process (e.g., to an effect directly on learning vs. an effect on the psychological processing of the unconditioned stimulus). In addition, with recent advances in determining the neuroanatomical basis of the conditioned NMR, it may also be possible to relate a drug effect on learning to an effect at a particular anatomical locus. Finally, because the conditioned response is acquired rapidly, the effect of a drug on learning can be assessed rapidly within a large group of animals. The current paper details the behavioral techniques which have been developed to study the effects of drugs, in particular the opioids, on classical conditioning. A number of studies which have used classical conditioning procedures in the rabbit to study drug effects on acquisition, maintenance, and differentiation of conditioned responses are reviewed.