bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine transporters in vascular smooth muscle and endothelium: Multiple [3H]Nitrobenzylthioinosine binding sites in human umbilical vein endothelium
Authors: Williams Evan F. , Harris‐Hooker Sandra , Gordon Portia B. 
Published: January 2005

AbstractCultured vascular smooth muscle and endothelial cells may be useful models for studying the cardiovascular adenosine transport system and metabolism. We have quantified the nucleoside transporter elements of cultured primate vascular smooth muscle, bovine aortic endothelial, and human umbilical vein endothelial cells by radioligand binding and by using membrane preparations of these cells and the nucleoside transporter probe nitrobenzylthioinosine ([3H]NBMPR), a potent and tightly bound inhibitor of nucleoside transport. The binding was rapid, reversible, saturable, and site‐specific. Scatchard analysis of the saturation data showed that [3H]NBMPR bound to high and low affinity binding sites in human umbilical vein endothelial cell membranes with apparent binding affinities (KD) of 0.093±0.01 nM 1.92±0.1 nM, and binding site densities (Bmax values) of 13.48±1.2 and 69+5.3 fmol/mg protein, respectively. In contrast, the binding to primate vascular smooth muscle and bovine aortic endothelial cell membranes occurred to an apparently high affinity single class of binding sites at which the KD was 1.4±0.3nM and 0.28±0.05nM, respectively, and which had Bmax values of 1,977±163 and 1,284±267 fmol/mg protein, respectively. Scatchard analysis of the binding inhibition by dipyridamole showed a mixed type inhibition, while NBMPR inhibited the binding competitively. Several recognized nucleoside transport inhibitors and vasodilators inhibited the binding with an order of potency similar to that observed for the inhibition of [3H]NBMPR binding to guinea pig cardiac membranes.
Newer aspects of antiarrhythmic drug development: Introduction
Authors: Steinberg Mitchell I. , Cervoni Peter 
Published: January 2005

AbstractAlthough cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re‐evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.
Fibroblast growth factor in the eye and prospects for its therapeutic use
Authors: Tripathi Ramesh C. , Kolli Susmitha P. , Tripathi Brenda J. 
Published: January 2005

AbstractFibroblast growth factor (FGF) is a monomeric mitogenic protein that exists as an acidic and a basic form and is distributed widely in tissues of the eye. Because FGF interacts with the cells and with the extracellular matrix, it has potential as a therapeutic agent, either alone or in combination with other agents such as epidermal growth factor, in promoting healing of corneal wounds, in restoring corneal endothelial cell loss due to dystrophic, degenerative, and surgical insults, as well as in regenerating lens cells after cataract surgery. Excess FGF probably plays a significant role in the pathogenesis of blinding disorders of the eye such as neovascular glaucoma, age‐related macular degeneration, and proliferative diabetic vitreoretinopathy, as well as failure of surgical filtering procedures for glaucoma. The use of transforming growth factor‐beta, anti‐FGF antibodies, and other blocking agents in the treatment of such diseases seems logical.
Comparison of the effects of secobarbital and diazepam on the repeated acquisition of response sequences in humans
Authors: Higgins Stephen T. , Stitzer Maxine L. 
Published: January 2005

AbstractThe present study was conducted to compare the acute effects of secobarbital (0–300 mg) and diazepam (0–30 mg) on learning in normal volunteers. The repeated acquisition of behavioral chains procedure was used to assess learning. Subjects were exposed to varying doses of secobarbital, diazepam, and placebo under double‐blind conditions. Both compounds increased overall percent errors and decreased overall response rates as an orderly function of dose. No statistically significant differences were observed between these two compounds in onset, magnitude, or duration of effects. As expected, potency differences were observed with diazepam being approximately 10 times more potent than secobarbital. Overall these results indicate that secobarbital and diazepam produce a comparable profile of effects in humans responding under a repeated acquisition of behavioral chains procedure. Thus, with regard to learning impairment, the liability associated with using or abusing secobarbital vs. diazepam appears to be the same.
Titration of duration discrimination in behavioral pharmacology and toxicology
Authors: Daniel Stephen A. , Evans Hugh L. 
Published: January 2005

AbstractThis study investigated a discrete‐trial, titration duration discrimination procedure in behavioral pharmacology. Pentobarbital and d‐amphetamine, measured with this procedure, selectively affected discrimination more than response tendencies. Pentobarbital also tended to affect selectively discrimination of longer durations, whereas d‐amphetamine did not. Further experiments showed that (1) other algorithms for modulating stimulus duration are useful in behavioral pharmacology and toxicology, (2) threshold estimates are similar with the method of constant stimuli and the method of titration, and (3) this titration procedure permits the separate examination of drug effects upon discrimination and upon response tendencies; the fixed‐interval procedure does not. Baseline variability was an important correlate of drug effects in that the endpoints with more variable baselines were also more sensitive to drugs.
Mild ethanol intoxication may enhance pavlovian conditioning
Authors: Hernandez Linda L. , Valentine James D. 
Published: January 2005

AbstractEvidence is reviewed showing that low doses of ethanol (∼200–400 mg/kg), administered prior to training, can facilitate aversive Pavlovian conditioning and delay subsequent extinction of Pavlovian conditioned responses in both rabbits and rats. The effect of ethanol during Pavlovian training occurs during later testing in both intoxicated and sober animals and is stronger for Pavlovian than for comparable instrumental conditioned responses. New data are reported showing that the facilitatory effect of ethanol on Pavlovian conditioned suppression in rats interacts with both the extent of Pavlovian training and the reinforcement schedule used to maintain the operant baseline but also resembles the effect of more extended Pavlovian training in saline‐treated animals. Together, these findings suggest that facilitation of Pavlovian conditioning may be a general effect of mild ethanol intoxication. Possible behavioral mechanisms of this effect are discussed.
Antihypertensive, vasodilating, and sympatholytic activities of ofornine® in spontaneously hypertensive rats
Authors: Defelice Albert , Lape Harlan , Horan Patrick , Frering Richard , Brousseau Armand , O'Connor Bernard , Herrmann John , Bailey Denis 
Published: January 2005

AbstractThis study of spontaneously hypertensive (SH) rats documents oral antihypertensive activity of the vasodilator Ofornine®, an anthranilamide whose effect was sustained, at least in part, by suppression of compensatory renal and neurohumoral responses. Doses of 2.5 to 100 μg/kg p.0. reduced systolic blood pressure (BP) by up to 75 mm Hg. Effect lasted 6‐24 hr and did not diminish during a 16 day (25 μg/kg/day) regimen. Metoclopramide (10.0 μg/kg)and haloperidol (3.0 μg/kg) antagonized the antihypertensive effect. Antihypertensive activity was confirmed by direct (arterial cannula) monitoring where 0.001‐1.O μg/kg i.v. reduced mean BP by 6‐47% without tachycardia. Doses of 1‐10 ag/kg i.a. reduced perfusion pressure of the SH rat hindquarters by 35‐74 mm Hg. A dose of 5.0 μg/kg p.0. reduced BP and urine norepinephrine levels of SH rats by 58 mm Hg and approximately 50% without raising plasma renin activity or causing sodium retention. How‐ ever, Ofornine® (25 μg/kg p.0. daily for 6 days) did not affect reflex bradycardic or tachy‐ cardic effects of phenylephrine and sodium nitroprusside in SH rats. These and other results indicate that Ofornine@ reduces SH rat blood pressure through vasodilating and presynaptic adrenolytic activities, and that a dopaminergic mechanism may be involved.
Effects of chronic torbafylline treatment on energy metabolism of ischemic skeletal muscle
Authors: Comte Jane , Gautheron Danièle C. , Godinot Catherine , Okyayuz‐Baklouti Ismahan 
Published: January 2005

AbstractThis study investigates the effects of chronic oral treatment with Torbafylline, a xanthine derivative, on the energy metabolism of chronically ischemic skeletal muscle of the rat. Blood flow to one hindlimb was reduced by unilateral femoral artery ligation. One group of animals received 5 ml/kg body weight saline while the other group received 25 mg/kg Torbafylline dissolved in the same volume of saline. Treatment was pursued for 5 weeks, 2 times a day, except during the weekends. In NaCI‐treated rats, ischemia leads to muscle atrophy as measured by a decrease in muscle weights and to a concomitant decrease in lactate dehydrogenase and creatine kinase activities, while adenine nucleotide contents remain unchanged. Chronic administration of Torbafyllin almost totally prevented these changes. In isolated mitochondria from ischemic and non‐ischemic muscles, treated or not with Torbafylline, no significant changes were measured in malate dehydrogenase, citrate synthase, creatine kinase, cytochrome oxidase and oligomycin‐sensitive ATPase. However, in mitochondria prepared from NaCI‐treated muscles with limited flow, an increase of substrate oxidation was observed after formation of endogenous ATP (final state 4 of oxidation). This increase can be interpreted as an indication of a deviation from the normal use of ATP, e.g., non‐efficient energy production. Torbafylline treatment prevented this apparent waste of energy.
Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione
Authors: Jones Gary L. 
Published: January 2005

AbstractThe anticonvulsant ED50 of 5,5‐diphenyl‐2,4‐oxazolidinedione (DPO) was determined in male CF#1 mice by a standard maximal electroshock method, and compared with that for phenytoin (PHT) and phenobarbital (PB). Acute neurotoxicity (TD50) and acute lethality (LD50) were also determined. These parameters are reported with respect to i.p. dosage, and blood and brain concentrations. The anticonvulsant ED50 (308 mg/kg) of DPO was significantly less than that of either PHT (7.1 mg/kg) or PB (19.0 mg/kg). The same order of potency was observed when expressed in terms of blood or brain concentrations, although important quantitative differences were noted. Neurotoxicity was observed with doses of DPO required for anticonvulsant action (TD50 = 335 mg/kg). Furthermore, acute lethality (LD 50 = 373 mg/kg) was observed at doses not significantly different (P≥.05) than the ED50. Doses between the ED50 and LD50 produced profound motor incoordination, seizures, and coma. Because of its extremely narrow margin of safety, DPO would not be considered a likely candidate for evaluation as a therapeutic agent in man. However, a greater understanding of its pharmacology is desirable because, in spite of its structural similarity to PHT, it contrasts sharply in certain properties.
Preclinical profile of Wy‐49,051: A new H1‐antagonist
Authors: Abou‐Gharbia Magid , Nielsen Susan T. , Andree Terrance H. , Tasse Rene , Leventer Steven 
Published: January 2005

AbstractIn an effort to develop an orally active, non‐sedating H1‐antagonist, compound Wy‐49,051 was synthesized and examined in various in vivo and in vitro assays. In vitro, the compound possessed high affinity for H1 receptors (IC50 = 44 nM) and was found to competitively antagonize histamine‐induced guinea pig ileum contraction. At a concentration of 1 × 10−10 M, Wy‐49,051 shifted the histamine dose‐response curve to the right in a parallel fashion. Wy‐49,051 demonstrated H1 antagonism in a variety of in vivo tests. Wy‐49,051 (s.c.) protected against histamine‐induced death (guinea pig) in a dose‐dependent manner and with a longer duration of action than terfenadine. In addition, Wy‐49,051 effectively antagonized histamine‐induced wheal formation (administered up to 18 hr prior to challenge) and was more potent than astemizole and chlorpheniramine. At a dose of 5 mg/kg (p.o.), Wy‐49,051 produced less inhibition of in vivo brain [3H]pyrilamine binding than ebastine (5 mg/kg, p.o.), terfenadine (20 mg/kg, p.o.), and chlorpheniramine (100 mg/kg, p.o.). Importantly, Wy‐49,051 did not exhibit H2‐antagonist activity (as indicated by a lack of effect on gastric acid secretion in the pylorus‐ligated rat) and did not affect histamine‐induced changes in blood pressure and heart rate in the anesthetized guinea pig. Although Wy‐49,051 displayed significant alpha1‐receptor affinity in vitro (IC50 =8 nM), it did not alter blood pressure or heart rate in SHR rats at doses examined above its projected therapeutic dose for H1‐receptor antagonism. Wy‐49,051 did not affect carbachol‐induced guinea pig ileum contraction and possessed little affinity for M2 muscarinic receptors (IC50 = 7.3 μ). Taken together with the previously mentioned in vivo [3H]pyrilamine binding data, these data indicate that Wy‐49,051 is a long‐acting, potent H1‐antagonist with less potential for sedative and anticholinergic side effects than many common antihistamines including chlorpheniramine.
Cardiovascular effects of medorinone in β‐adrenoreceptor‐blocked and non‐blocked anesthetized dogs
Authors: Lee King C. , Ezrin Alan M. , Pagani Edward D. , Canniff Paul C. , Hamel Douglas W. , Fort Dorothy J. , Silver Paul J. 
Published: January 2005

AbstractThe hemodynamic effects of the low Km cAMP peak III PDE inhibitor medorinone (0.01–0.3 mg/kg, i. v. ) were evaluated in anesthetized dogs in the presence and absence of β‐adrenoreceptor blocked. Medorinone increased the peak derivative of left ventricular pressure (+ dP/dt) in non‐blocked (all doses) and β‐blocked dogs (≥0.03 mg/kg) (2,766±259 and 1,403±262 mm Hg/sec, respectice max. changes). Heart rate (HR) was increased by medorinone in non‐blocked (≥0.1 mg/kg) and β‐blocked dogs (≥0.03 mg/kg) (77.4±8.9 and 25.5±4.3 beats/min, respective max. changes). In non‐blocked dogs only, medorinone (all doses) decreased left ventricular end‐diastolic pressure (LVEDP) (7.7±1.7 mm Hg, max. change). Mean arterial pressure (MAP) was similarly decreased by medorinone (<0.03 mg/kg) in β‐blocked and non‐blocked dogs (max. approx. −27 mm Hg). Medorinone did not affect cardiac output or renal blood flow. The hemodynamics of medorinone and milrinone (another peak III PDE inhibitor) in non‐blocked dogs were similar, except meddorinone was less potent in increasing +dP/dt (2,766±259 vs. 3,747±388, max. changes) and more potent in reducing LVEDP (−7.7±1.7 vs. −1.8±1.2 mm Hg, max. changes). In conclusion, medorinone similarly reduced MAP, but more effectively decreased preload, increased inotropy and chronotropy in non‐blocked than β‐blocked anesthetized dogs. Medorinone is more potent in reducing preload, but less potent in enhancing inotropy when compared to milrinone in anesthetized dogs.
Synthesis and metabolic profile of Cl‐966: A potent, orally‐active inhibitor of GABA uptake
Authors: Bjorge Susan , Black Ann , Bockbrader Howard , Chang Tsun , Gregor Vlad E. , Lobbestael Sandra J. , Nugiel David , Pavia Michael R. , Radulovic Louis , Woolf Thomas 
Published: January 2005

AbstractA lipophilic derivative of the known GABA uptake inhibitor guvacine has been prepared. The synthesis of this compound, [1‐]2‐bis 4‐(trifluoromethyl)]phenyl[‐methoxy]ethyl[‐ 1,2,5,6‐tet‐rahydro‐3‐pyridine carboxylic acid, monohydrochloride, Cl‐966, is described. Studies were carried out to determine the metabolic profile of Cl‐966, in rats. Two metabolites, one less polar and the other more polar than Cl‐966, were identified and their structures assigned by spectroscopic methods and confirmed by comparison to synthetic material.
Assessment of zolpidem and Cl‐966 for anxiolytic and anxiogenic properties by using the discrimination of pentylenetetrazole by rats
Authors: Emmett‐Oglesby M. W. , Abdel‐Malek S. L. 
Published: January 2005

AbstractThis experiment determined if two novel compounds, zolpidem and CI‐966, would show anxiogenic or anxiolytic activity in an animal model of anxiety based upon the discrimination of pentylentetrazole (PTZ). Rats were trained to detect the anxiogenic drug PTZ, 20 mg/kg, and tested with zolpidem (an agonist at omega [benzodiazepine] receptors) and CI‐966 (a GABA‐uptake inhibitor). Zolpidem did not substitute for PTZ. This drug blocked the PTZ stimulus in a dose‐related manner (0.32–5.0 mg/kg), although only partial blockade was obtained even at the highest dose that could be tested. These data suggest that zolpidem may have weak efficacy as an anxiolytic drug. CI‐966 partially substituted for PTZ at 3 to 6 hr post injection of doses of 16.0 and 32.0 mg/kg. Lower doses of CI‐966 produced a slight, but non‐significant, blockade of the PTZ stimulus, which appeared to be additive with the blocking effects of diazepam upon this discrimination. Because CI‐966 has been shown to block PTZ seizures in mice, the present data suggest that the discriminative stimulus produced by PTZ is not related to its ability to produce convulsions. The partial substitution of CI‐966 given in high doses is consistent with clinical reports that this compound may produce anxiogenic effects.
General pharmacology of CK‐2130: A new selective positive inotrope
Authors: Greenberg Stanley S. , Paul Jeff , Luisi Alan 
Published: January 2005

AbstractCK‐2130 is a new imidazolone developed to treat congestive heart failure. We compared CK‐2130 to four inodilators and ouabain in several pharmacologic models. Intravenous (i.v.) administration of CK‐2130 to pentobarbital‐anesthetized dogs (0.03 to 1 mg/kg) relatively selectively increased myocardial dP/dT when compared to the dual positive inotropic and vasodilator activity of milrinone, enoximone, imazodan, and piroximone. Milrinone and piroximone (600 mg/kg, p.o., and 30‐300 mg/kg, i.p.) were central nervous system depressants in mice. CK‐2130 (100 mg/kg, i.v. and 600 mg/kg, i.p. and p.o.) was not depressant. Gastric acid secretion in the guinea pig was not affected by CK‐2130 (1 mg/kg, i.v.) and was inhibited by milrinone (1 mg/kg, i.v.) and enhanced by enoximone (1 mg/kg, i.v.). CK‐2130 and milrinone (0.03‐1 mg/kg, i.v.) did not affect rabbit sciatic nerve‐gastrocnemius muscle function. CK‐2130, piroximone, imazodan, and milrinone (100 μM) did not affect sympathetic neurotransmission, postsynaptic receptors, or guinea‐pig nonvascular smooth muscles but relaxed canine arteries and veins. Ouabain (1‐100 μM) initially facilitated, then inhibited, sympathetic neurotransmission, contracted vascular and non‐vascular smooth muscles, enhanced the vas deferens contraction to norepinephrine, and inhibited uterine contractions to bradykinin (10 μM). CK‐2130, milrinone, piroximone, and imazodan (0.1 to 100 μM) inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. Thus, CK‐2130, a relatively selective positive inotrope, should be devoid of adverse central nervous system; neural, smooth, and skeletal muscle; and gastrointestinal side effects associated with digitalis and enoximone therapy.
Antihypertensive effect of metoprolol in diuretic‐treated, mild primary hypertension
Authors: Mahapatra Rajat , Hunter Kenneth W. , Mahapatra Dipta , Yaden Senka , Lal Harbans 
Published: January 2005

AbstractMetoprolol tartrate was administered to 41 patients with mild essential hypertension already treated with a diuretic for a period of 2 weeks. In the majority of those patients, other step 2 antihypertensive agents either failed to control high blood pressure or caused adverse reactions. All other antihypertensive agents except diuretics were discontinued during the 2‐week wash‐out period. Patients with a diastolic blood pressure of 95 to 104 mmHg (inclusive) received oral metoprolol at a dose of 50mg twice daily for 2 weeks. Subsequently, metoprolol titration was individualized on a bi‐weekly basis until either the diastolic blood pressure was = 90 mmHg and/or a maximal daily dose of 300mg of metroprolol was reached. The analysis of efficacy and safety was done for a total period of 14 weeks. Diastolic blood pressure and heart rates were significantly reduced (P≤0.05) in all treatment groups. Minor adverse reactions such as mild fatigue in 11 patients, nervousness in 2, and leg cramps in 2 patients were reported. Transient skin rash, dizziness, headache, chest pain, insomnia, and cold extremities were also reported in one patient each. It is concluded from the present study that metropolol (in twice daily dose) in combination with a diuretic is safe, effective, and well tolerated in the treatment of mild hypertension.
Use of the hydrated rat to assay diuretic and antidiuretic activity of drugs
Authors: DeFelice Albert , Harris Alex , Brousseau Armand 
Published: January 2005

AbstractThis study compared oral renal excretory effects of several agents in three rat strains with that reported in man to assess predictive value of this species in cardiorenal drug development. Sprague‐Dawley (SD), Wistar‐Kyoto (WK), and spontaneously hypertensive rats (SHR) were hydrated and 3 hr urine volume, Na+, and K+ were measured, Normotensive SD and WK rats responded similarly, i.e., hydrochlorothiazide (HCTZ) and aminophylline were diuretic, while hydralazine and milrinone caused Na+ retention. Accordingly the more economical SD rat was then compared with SHR. Aminophylline (3–30 mg/kg) and the more effective HCTZ (1–30 mg/kg) achieved dose‐related diuresis and kaliuresis in both strains, increasing Na+ excretion by a maximum of 5–14‐fold, whereas the vasodilators hydralazine (3–30 mg/kg) and milrinone (1–10 mg/kg) reduced Na+, K+ and volume dose‐relatedly with Na+ output being 5–50% of control values. Verapamil promoted Na+ excretion in both strains by 1.5‐ to 4‐fold at 30 mg/kg, but was antinatriuretic at 80 mg/kg. Conversely, nifedipine had qualitatively differents effects in SHR and SD rats. That is, it elicited diuresis in the SHR at 10mg/kg (Δ Na+ = +155%) and no change in urine volume or Na+ and K+ cutput at 30 mg/kg, where as the Ca++‐antagonist provoked dose‐related volume, Na+, and K+ retention in the normotensive rat with 3 hr output being ca. 15–22% of that of vehicle‐treated controls. Accordingly the SD rat predicted the renal effects typically seen clinically for all agents except milrinone (Cody et al.: Clinical Pharmacology and Therapeutics 39: 128–135, 1986), supporting use of the economical SD rat as a primary assay for effects on renal excretion with the SHR strain reserved for assessing Ca++‐channel blockers in the hypertensive state.