bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracazolate: A novel nonsedative anxiolytic
Authors: Malick Jeffrey B. , Patel J. B. , Salama A. I. , Meiners B. A. , Giles R. E. , Goldberg M. E. 
Published: January 2005

AbstractTracazolate (ICI 136,753; 4‐butylamino‐1‐ethyl‐6‐methyl‐1H‐pyrazolo [3,4‐b] pyridine‐5‐carboxylic acid ethyl ester) exhibited dose‐related anticonflict activity in mice, rats, and squirrel monkeys. The potency of tracazolate appears to be one‐quarter to one‐half that of chlordiazepoxide, and their durations of activity are similar in rats. No tolerance to the anticonflict activity of either chlordiazepoxide or tracazolate was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide; thus, it is predicted that tracazolate will not be sedative at anxiolytic doses in man. Furthermore, based upon studies in rodents, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Although tracazolate is an anticonvulsant in rodents, it is considerably less potent in this respect than chlordiazepoxide. In contrast to benzodiazepine anxiolytics, tracazolate enhances the binding of 3H‐benzodiazepines to their binding sites in brain. Consistent with this finding, tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Although the benzodiazepine antagonists (RO 15‐1788 and CGS 8216) clearly antagonize the anticonflict activity of chlordiazepoxide, the activity of tracazolate was not significantly altered by either antagonist. Both chlordiazepoxide and tracazolate significantly enhanced 3H‐γ‐aminobutyric acid (GABA) binding. These results suggest that tracazolate is a novel psychoactive agent that should be a useful anxiolytic drug in man.
Lack of antinociceptive activity of clonidine in two pain models: Comparison with other analgesics and CNS active drugs
Authors: Spaulding Theodore C. , Ma Minh G. , Dunn Robert W. , Fielding Stuart 
Published: January 2005

AbstractThe antinociceptive activity of clonidine was investigated in two models of pain using the modified Haffner tail clip test (MHA) in mice and the formalin test (FT) in rats. Morphine was used as a positive control for comparison. Clonidine at does from 0.5 mg/kg to 8 mg/kg SC was not effective in MHA while morphine administration resulted in a dose‐dependent increase in the latency to bite the clip and an ED50 of 1.2 mg/kg SC. No antinociceptive activity was observed for clonidine using the FT up to a dose of 4 mg/kg SC which causes severe behavioral depression. The ED50 for morphine in FT was 1.7 mg/kg SC. From these studies we conclude that clonidine is not active in all tests used to predict analgesic efficacy in man. Additional analgesic and centrally acting drugs were also included for comparative purposes. Of the compounds tested only the opiates active in FT and MHA and cholinesterase inhibitors (active in MHA only) showed analgesic effects.
κ‐Agonist analogesics: Evidence for μ2 and δ opioid receptor antagonism
Authors: Wood Paul L. 
Published: January 2005

AbstractDespite a unique in vivo pharmacology, K agonists possess moderate to high affinities for μ, δ, and κ binding sites in vitro. By monitoring the antagonist activity of κ agents on morphine‐ and DADLE‐dependent changes in dopamine and acetylcholine metabolism we were able to demonstrate a specific μ2 and δ receptor antagonism for κ analgesics. Furthermore, this antagonism was probably directly at the receptor level and not physiological.
Antidepressants in states of cognitive dysfunction
Authors: Cohen Robert M. , Sunderland Trey , Aulakh Charanjit S. 
Published: January 2005

AbstractSeveral approaches are described for the design of pharmacologic strategies for the manipulation of cognition. By a variety of criteria, it is concluded that antidepressants deserve a trial in some patients with cognitive dysfunction. Depression is an illness with prominent cognitive dysfunction that shares, to some extent, cognitive and biochemical impairments similar to those observed in cognitive dysfunction of organic etiology. Antidepressants appear to produce their beneficial effect on cognition in depression by inducing slow adaptive changes in catecholamine and indoleamine pathways, therein promoting alterations in the individual's central motivational state. Animal data supporting these ideas are reported. As reviewed, few satisfactory studies of antidepressants in cognitive dysfunction of organic etiology appear in the literature, perhaps as the result of the potent anticholinergic properties of the most popular antidepressant drugs.
Inhibition of regional brain acetylcholine biosynthesis by clonidine in spontaneously hypertensive rats
Authors: Buccafusco Jerry J. 
Published: January 2005

AbstractRecent studies in this laboratory have demonstrated that clonidine, a centrally acting antihypertensive drug, can inhibit the function of central cholinergic neurons. We have also provided evidence for enhanced brain cholinergic activity in the spontaneously hypertensive rat (SHR). The purpose of this study was to determine whether the antihypertensive response to clonidine in the SHR could be correlated with a decrease in acetylcholine synthesis in several brain regions. Clonidine (30μg/kg, i.v.) produced a time‐dependent reduction in blood pressure (BP) in unrestrained SHR's of 18/16 and 27/22 mmHg by 10 min and 100 min, respectively. The formation of 3H‐acetylcholine in the brain following pulse injection of 3H‐choline (20 μCi) into the lateral cerebral ventricle was employed as an estimate of the rate of acetylcholine synthesis. Clonidine produced a time‐dependent inhibition of 3H‐acetylcholine formation in several brain areas. For example, in the pons, 3H‐acetylcholine formation was reduced by 21 and 44% at 10 min and 100 min following clonidine, respectively. Other brain regions to exhibit significant inhibition of cholinergic activity included the rostral and the caudal hypothalamus, medulla oblongata, thalamus‐septum, and midbrain. The striatum exhibited the greatest 3H‐acetylcholine formation in control animals; however, this activity was not affected by clonidine. These results are consistent with the ability of clonidine, at a clinically relevant dose, to elicit concomitantly an antihypertensive response and a marked inhibition of brain cholinergic activity in SHRs. This finding in conjunction with the results from several previous studies suggest that central cholinergic neurons participate in mediating the antihypertensive action of clonidine.
Antidepressant activity of alprazolam in a reserpine‐induced model of depression
Authors: Sethy Vimala H. , Hodges Donald H. 
Published: January 2005

AbstractThe effect of chronic (14–21 day) administration of reserpine (0.1 mg/kg/day), imipramine (10 mg/kg/day), alprazolam (5, 10 and 15 mg/kg/day), and diazepam (10 and 30 mg/kg/day) on beta‐adrenergic receptors in the cerebral cortex and body weight has been reported in this study. Chronic treatment with both imipramine and alprazolam significantly blocked reserpine‐induced increases in beta‐adrenergic receptors and loss in body weight. However, diazepam under similar conditions had no significant effect.
Identification of a new cardioprotective agent—6(2‐isopropylaminopropyl)‐3‐pyridinol
Authors: Schaffer Stephen W. , Tan Boen H. , Lampson William G. , Oei Howard H. H. , Glenn Thomas M. 
Published: January 2005

AbstractThe effect of 6(2‐isopropylaminopropyl)‐3‐pyridinol fumarate (CGS 5649B) on mechanical function and tissue energy levels of the isolated rat heart subjected to 35 min of global ischemia and 25 min of reperfusion was examined. Hearts perfused with buffer supplemented with the drug (0.03–0.4 mM) showed an improvement in the recovery of mechanical function and an attenuation in the loss of tissue adenosine triphosphate (ATP) levels following the 25‐min reperfusion period. In nonischemic tissue, the drug mediated a positive inotropic effect, a slight increase in glucose utilization and oxygen consumption, and a significant change in the levels of some key glycolytic intermediates. It also quenched hydroxyl radicals produced by a hypoxanthine‐xanthine oxidase reaction system. These results suggest that CGS 5649B has a beneficial effect on hearts subjected to ischemia by reducing energy demand. This may be related to its ability to scavenge highly reactive oxygen species.
Pharmacokinetics and bioavailability of ciramadol, a new analgesic
Authors: Locniskar Ann , Lasseter Kenneth C. , Freeland George R. , Chiang Soong T. , Greenblatt David J. 
Published: January 2005

AbstractHealthy male volunteers participated in two studies of the pharmacokinetics of ciramadol, an investigational analgesic. For the dose‐proportionality study, subjects received single i.v. doses of 15, 30, or 60 mg of ciramadol on three separate occasions. Serum samples and urine were collected 48 hr after each dose. Overall mean kinetic values for ciramadol were: volume of distribution, 1.5 liters/kg; elimination half‐life, 3.7 hr; total clearance, 4.9 ml/min/kg. Clearance did not change systematically with dose. Mean 48‐hr urinary excretion was 40% of the dose as the intact drug, with another 24% excreted as ciramadol conjugates; these were dose‐independent. For the bioavailability study, subjects received a 30‐mg dose of ciramadol i.v., i.m., or orally on three separate occasions. The mean absolute systemic availability of the i.m. dose was 98%; the absolute availability of the oral dose was 82%. Peak serum concentration of 235 and 155 ng/ml were attained at 0.27 and 1.5 hr after the i.m. and oral doses, respectively.
Effects of the calcium antagonist D 600 on changes in plasma glucose and enzyme levels produced by isoproterenol in the rat
Authors: Baranes J. , Le Hegarat M. , Thiévant P. , Chapelat M. , Chabrier E. , Guilmard C. , Clostre F. , Defeudis F. V. 
Published: January 2005

AbstractA model based on isoproterenol injections in the female rat was used to examine the effects of the Ca2+ antagonist methoxyverapamil (D 600) on plasma glucose and on certain plasma enzymes that are elevated during cardiac dysfunction [glutamate‐oxaloacetate transaminase (GOT), lactate dehydrogenase (LDH), α‐hydroxybutyrate dehydrogenase (α‐HBDH)]. Four hours after administration, D 600 alone (10 mg/kg, i.p.), as well as isoproterenol alone (30 mg/kg, s.c.), increased plasma glucose level. When administered simultaneously with isoproterenol, D 600 produced a synergistic effect in elevating plasma glucose level. Experimental values for plasma glucose (in mg/ml) were: control, 1.56 ± 0.04 (n = 24); isoproterenol alone, 1.84 ± 0.04 (n = 24); D 600 alone, 2.05 ± 0.12 (n = 24); D 600 + isoproterenol, 3.31 ± 0.28 (n = 24). The synergistic effect of D 600 occurred at doses of 5 and 10 mg/kg, doses at which D 600 opposed the increases in GOT, LDH, and α‐HBDH levels induced by isoproterenol. Other experiments showed that elevations in plasma glucose level produced 15 and 30 min after injection of isoproterenol were associated with increases in plasma insulin levels.
Differences in the cardiac effects of isoproterenol between stroke‐prone and control rats
Authors: Malherbe E. , Baranes J. , Le Hegarat M. , Clostre F. , Defeudis F. V. 
Published: January 2005

AbstractPlasma levels of enzymes that reflect cardiac damage [glutamate‐oxaloacetate transaminase (GOT), lactate dehydrogenase (LDH), and α‐hydroxybutyrate dehydrogenase (α‐HBDH)], of insulin, and of glucose were compared in stroke‐prone (SHR‐SP) and control (WKY) rats four hr after injection of isoproterenol (30 mg/kg, s.c.). Heart weights and histology were studied 24 hr after isoproterenol injection. Isoproterenol produced increases in GOT, LDH, and α‐HBDH in both SHR‐SP and WKY rats, but these changes were more pronounced (about twice as great) in SHR‐SP than in WKY. Plasma glucose level was also increased to a greater extent in SHR‐SP (1.54 ± 0.02 to 3.57 ± 0.16 g/liter) than in WKY (1.60 ± 0.04 to 2.37 ± 0.08 g/liter) after injection of isoproterenol. Basal (plasma) insulin level was higher in WKY (2.46 ± 0.3 ng/liter) than in SHR‐SP (1.0 ± 0.1 ng/liter) and injection of isoproterenol increased this value to a greater extent in WKY (to 4.5 ± 1.2 ng/liter) than in SHR‐SP (to 1.2 ± 0.1 ng/liter). Cardiac edema induced by isoproterenol, determined as changes in heart weight and by histology, did not differ between SHR‐SP and WKY. Taken together, these results indicate that marked differences in plasma parameters and in responsiveness to isoproterenol exist beween SHR‐SP and WKY rats, thus providing a useful model for studying agents that might be used to prevent cardiac pathology.
The roles of apolipoproteins B and E in lipid transport and atherosclerosis
Authors: Krause Brain R. 
Published: January 2005

AbstractThe metabolism of various lipoproteins is largely regulated by the protein constituents, the apolipoproteins. Although approximately a dozen apolipoproteins have been identified, apolipoproteins B and E (apoB, apoE) appear to play the major role in the receptormediated clearance of lipoproteins by the liver and other tissues, thereby directly influencing plasma lipid levels. In man, apoB is synthesized by both the intestine (apoB‐48) and the liver (apoB‐100), but it is the hepatogenic peptide that is the sole constituent of plasma low‐density lipoproteins (LDL) recognized by the LDL receptor in liver and other tissues. ApoB‐100 is found in normal and atherosclerotic aorta and taken up by aortic endothelium in vivo, providing further evidence that LDL is the source of arterial foam cell lipids. Evidence is provided suggesting that the clinical measurement of plasma apoB‐100 provides a better index than LDL for determining coronary heart disease risk. ApoE, on the other hand, is clearly the most important binding ligand for the hepatic removal of a variety of lipoproteins. Numerous studies suggest that apoE directs peripheral cell cholesterol to the liver for excretion from the body (reverse cholesterol transport). Human apoE can be separated into three major isoforms, which differ in primary structure. Patients with the genetic disorder type III hyperlipoproteinemia have severe atherosclerosis due to an excess of one apoE isoform that does not bind normally to hepatic receptors. Other alterations of apoE can change its conformation and hence its ability to be recognized. Future directions in the treatment of dyslipidemias should include the discovery of pharmacologic agents that facilitate lipoprotein clearance by altering apoE conformation or recognition of apoB‐containing lipoproteins. The control of apoB and apoE synthesis should also provide insights for drug discovery in light of the undisputed roles of these proteins in lipid transport and atherosclerosis.
Behavioral pharmacological profile of CGS 9895: A novel anxiomodulator with selective benzodiazepine agonist and antagonist properties
Authors: Bennett Debra A. , Amrick Caryl L. , Wilson Douglas E. , Bernard Patrick S. , Yokoyama Naokata , Liebman Jeffrey M. 
Published: January 2005

AbstractCGS 9895 is a pyrazoloquinoline closely related to the benzodiazepine agonist CGS 9896 and the benzodiazepine antagonist CGS 8216. In anxiolytic test procedures, this compound generalizes to CGS 9896 discriminative stimuli, produces an increase in punished responding, and partially antagonizes pentylenetetrazol discriminative stimuli. This anxiolytic activity is not, however, accompanied by any detectable sedation or muscle relaxation. CGS 9895 does not impair rotorod performance or reduce motor activity and does not potentiate ethanol‐induced rotorod impairment or hexobarbital‐induced sleeptime. This compound does not generalize to diazepam discriminative stimuli, suggesting a difference between the internal stimuli produced by this drug and those of diazepam. Only weak anticonvulsant activity is noted with CGS 9895. In addition to the benzodiazepine agonist effects of this compound, CGS 9895 is capable of antagonizing the rotorod deficit produced by diazepam. It also selectively antagonizes the sedative effect of diazepam in the conflict procedure without reducing the anxiolytic effect of diazepam. Overall, CGS 9895 exhibits a novel combination of benzodiazepine agonist and antagonist properties. This unique profile suggests that CGS 9895 may be a clinically useful, novel anxiolytic agent.
Propentofylline and postischemic brain edema: Relation to Na+‐K+‐ATPase activity
Authors: Mršulja B. B. , Mićić D. V. , Stefanovich V. 
Published: January 2005

AbstractFollowing the bilateral occlusion of common carotid arteries in gerbil, an increase in water content and sodium/potassium ratio as well as the inhibition of Na+‐K+‐ATPase was found. The xanthine derivative propentofylline (HWA 285) [3‐methyl‐1‐(5‐oxohexyl)‐7‐propylxanthine] given either before or after cerebral ischemia attenuated the development or postischemic brain swelling and the increase in sodium/potassium ratio and prevented the postischemic reduction of Na+‐K+‐ATPase activity. It is concluded that the action of propentofylline on brain edema during ischemia is mediated aside from other possible mechanism(s), by the influence of the drug on Na+‐K+‐ATPase activity.
Maximal magnitude of effect and potency of putative α‐adrenoceptor agonists in causing CNS depression, in relaxing muscle, and in lowering body temperature in rat
Authors: Colpaert Francis C. 
Published: January 2005

AbstractThis study determined the maximal magnitude of effect and the potency of 20 putative α‐adrenoceptor agonists in causing CNS depression, muscle relaxation, and hypothermia in rat; CNS depression was evaluated by the degree to which the righting reflex was impaired. The compounds being examined were xylazine, UK‐14,304, oxymetazoline, ergotamine, phenylephrine, l‐adrenaline, guanabenz, l‐noradrenaline, B‐HT 920, dopamine, guanfacine, guanoxabenz, isoproterenol, naphazoline, tramazoline, tiamenidine, clonidine, azepexole, St‐587, and methoxamine. Observations were carried out 15, 30, and 60 min after i.p. injection of doses that covered the dynamic range of the compounds' apparent activity. The putative α2‐adrenoceptor agonists xylazine and UK‐14,304 ranked highest in terms of the magnitude of behaviorally depressant activity and also ranked high in relaxing muscle and lowering body temperature. The magnitude of effect of xylazine and UK‐14,304 on the behavioral response, on muscle tone, and on body temperature exceeded that of all putative α1‐adrenoceptor agonists tested, including phenylephrine, St‐587, and methoxamine. Clonidine ranked last in terms of the magnitude of its effects on the behavioral response and on muscle tone and ranked fifth in terms of its maximal hypothermic activity. The data characterize xylazine and UK‐14,304 as full agonists and clonidine as a particu‐larly weak agonist in depressing rat behavior; other compounds exerted intermediate magnitudes of activity.
In vitro and in vivo evaluation of two ultrashort‐acting beta‐adrenoreceptor antagonists: ACC‐9129 and ACC‐9369
Authors: Shaffer J. E. , Vuong A. , Gorczynski R. J. , Matier W. L. 
Published: January 2005

AbstractACC‐9129 and ACC‐9369 were evaluated in guinea pig isolated atria and trachea and in anesthetized dogs and conscious rabbits for beta‐blocking potency, duration of action, and intraocular pressure effects. ACC‐9129 showed competitive cardioselective beta‐blocking activity, with a pA2 of 6.8 in guinea pig right atria and a pA2 of 4.8 in guinea pig trachea. ACC‐9369 was also a competitive beta blocker in these tissues, with a pA2 of 8.0 in both atria and trachea (nonselective). Cardiodepression in guinea pig right and left atria occurred at concentrations of 1‐‐3 × 10−5 M and above for either ACC‐9129 and ACC‐9369, indicating a large therapeutic index for beta‐blocking versus cardiotoxic effects of these compounds. Infusion of ACC‐9129 (53 ±7 μg/kg/min for 180 min) into anesthetized dogs inhibited isoproterenol‐induced tachycardia by 52 ± 4% while reducing the hypotensive response by 6 ± 3%. ACC‐9369 infused at 4.3 ± 1.1 μg/kg/min (for 180 min) produced 67 ± 4% inhibition of the heart rate response and 22 ± 9% inhibition of the hypotensive response to isoproterenol. Following termination of a 3‐hr infusion of each of these agents at the dose rates shown above, beta blockade was observed to decline such that there was a 50% recovery of the heart rate response to isoproterenol by 9 ± 3 min for ACC‐9129 and by 20 ± 4 min (in six of nine dogs) for ACC‐9369. ACC‐9369, but not ACC‐9129, showed some potential for intrinsic sympathomimetic activity in guinea pig atria and in anesthetized dogs. In conscious rabbits, periocular administration of ACC‐9129 (3%) or timolol (0.5%), 4 hr prior to an intravenous infusion of 5% glucose, blunted the increase in intraocular pressure that occurred in the absence of drug; ACC‐9369 (3%) was unable to modify the increase in intraocular pressure. These results indicate that both ACC‐9129 and ACC‐9369 possess competitive beta‐blocking properties with a short duration of action systematically. Only ACC‐9129 was effective in attenuating the increase in intraocular pressure caused by glucose infusion.
Prostaglandins, prostacyclin, and thromboxane in cardiovascular diseases
Authors: Chan Peter S. , Cervoni Peter 
Published: January 2005

AbstractProstaglandins appear to play an important role in or to be found therapeutically useful in various cardiovascular diseases, such as hypertension, arrhythmias, ventricular fibrillation, arterial thrombosis, myocardial ischemia, myocardial infarction, certain types of angina pectoris, atherosclerosis, circulatory shock, and peripheral arterial diseases, etc. Prostacyclin and prostaglandins E1, E2, and D2 are considered beneficial, while thromboxane A2 and prostaglandin F2α are considered harmful and their formations should be inhibited. Inhibition of the formation of the vasodepressor prostaglandins, such as prostacyclin and prostaglandin E2, in humans and animals leads to increase in arterial blood pressure and total peripheral resistance as well as to decrease the efficacy of most antihypertensive drugs, which suggests that these vasodepressor prostaglandins play an important role in hypertension. Most prostaglandins exert antiarrhythmic activity. Prostacyclin and thromboxane synthetase inhibitors are particularly effective in myocardial infarction/reperfusioninduced arrhythmias and ventricular fibrillation (sudden cardiac death) where the classical antiarrhythmic agents are not very effective. Prostacyclin and thromboxane synthetase inhibitors are effective in reducing myocardial infarct size, increasing coronary blood flow, and inhibiting arterial thrombosis. Atheroclerosis may result from decrease in prostacyclin formation in the blood vessel wall due to inhibition by the concentration of lipid peroxides in the blood. Prostacyclin stimulates cholesterol ester hydrolase, the enzyme that converts cholesterol ester to free cholesterol for mobilization out of the cells. PGE2 inhibits acyl CoA cholesterol‐O‐acyltransferase (ACAT), the enzyme that catalyzes the reesterification of free cholesterol. Therefore, prostacyclin, PGE2, and their stable analogs may be useful for the prevention and induction of regression of atherosclerosis. Prostacyclin, PGE1, and other stable prostaglandin analogs, such as iloprost and viprostol, have been reported to be beneficial for the treatment of peripheral arterial diseases. It is very likely that new drugs that affect the prostaglandin systems will be introduced for the prevention and treatment of various cardiovascular diseases in the very near future.