bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of regional brain acetylcholine biosynthesis by clonidine in spontaneously hypertensive rats
Authors: Buccafusco Jerry J.
Published: January 2005

Recent 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

The 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

The 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

Healthy 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

A 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

Plasma 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

The 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

CGS 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

Following 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

This 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

ACC‐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

Prostaglandins 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.
Antidiarrheal specificity and safety of the n‐oxide of loperamide (R 58 425) in rats
Authors: Niemegeers Carlos J. E. , Awouters Frans , Lenaerts Fred M. , Artois Kamiel S. K. , Vermeire Jozef
Published: January 2005

The pharmacological and toxicological effects of loperamide and the N‐oxide of loperamide were studied in adult and 19‐day‐old rats and in 1‐day‐old pups. In adult rats both orally administered compounds were equipotent and specific antidiarrheals, but the N‐oxide was slightly less toxic. In these rats, i.v. injected N‐oxide, in contrast to loperamide, did not induce opiate‐like central effects and its intestinal activity developed more gradually. In 19‐day‐old rats high oral doses of both compounds induced opiate‐like behavioral effects, but the i.v. injected N‐oxide was again virtually devoid of these effects and proved 5 times less toxic than i.v. loperamide. The orally administered compounds in 1‐day‐old pups induced lethality at doses slightly higher than the i.v. lethal doses of loperamide in 19‐day‐old and adult rats. The results are in agreement with rapid and efficient conversion of the N‐oxide to loperamide in intestine and in liver, and a much slower and pharmacologically hardly detectable conversion of circulating N‐oxide. The visceral barriers, which limit access of the orally administered compounds to the systemic circulation, appear fully developed in 19‐day‐old rats; the blood‐brain barrier at this age is still more permeable than in adult rats. The more gradual development of antidiarrheal activity and the reduced risk of acute systemic intoxication are the major pharmacological differences between orally administered N‐oxide and loperamide.
Ketoconazole: From an antimycotic to a drug for prostate cancer
Authors: Amery Willem K. , De Coster Roland , Caers Ivo
Published: January 2005

The observation in a few patients that gynecomastia developed during an antifungal therapy with 200 mg ketoconazole daily set the stage for a totally new application for this drug. By administering 400 mg ketoconazole orally, every 8 hr, serum testosterone levels in or close to the castrate range were obtained within 1 day in prostate cancer patients. In addition, the adrenal androgens androstenedione and dihydroepiandrosterone were dramatically reduced. The effect was due to an interaction with cytochrome P450‐dependent enzymes active in the sex steroid‐synthesizing organs. Clinical improvement and a lowering of acid phosphatase were achieved within the first few days in previously untreated patients, and long‐term objective responses were obtained. A remarkable subjective and objective response to ketoconazole high dose was noticed in several patients who no longer responded to previous hormonal manipulations. Tolerance to the therapy was acceptable. Long‐term side effects were mainly related to the mechanism of action. Hepatotoxicity was rare. In some cases, gastric intolerance interfered with the therapy. The observation during antifungal therapy of a very rare side effect, namely, gynecomastia, has thus opened up new perspectives for patients afflicted with one of the main male cancers.
R 62 818, a new analgesic: A comparative study with codeine
Authors: Schellekens Karel H. L. , Awouters Frans , Artois Kamiel S. K. , Frederickx Remi E. J. , Hendrickx Herman M. R. , van Bruggen Willy , Niemegeers Carlos J. E.
Published: January 2005

R 62 818 and codeine were studied in parallel, mainly in mice and rats. Three levels of analgesia were measured in mice using the hot plate test. ED50 values after sc administration were 6.20, 12.4, and 32.5 mg/kg with R 62 818 and 9.38, 18.7 and 32.5 mg/kg with codeine. In rats five levels of analgesic activity were evaluated, three in the acetic acidinduced writhing and two in the tail withdrawal reaction test. The oral ED50 values were: 2.71, 6.20, 12.4, 12.9, and 17.7 mg/kg with R 62 818 and 5.79, 8.17, 13.3, 24.8, and 69.3 mg/kg with codeine. In mice progressively more marked mydriasis was induced with R 62 818 at doses of 15.2, 23.0, and 52.9 mg/kg, with codeine at the much lower doses of 8.76, 11.5, and 26.4 mg/kg. Straub tail occurred with both compounds at 24.7 mg/kg. In contrast to codeine, R 62 818 did not reduce gastrointestinal motility. In rats various morphine‐like effects (exopthalmos, blockade of pinna and cornea reflexes, muscle rigidity) were observed with both compounds, but with R 62 818 at much higher doses relative to the analgesic dose. In contrast to codeine, R 62 818 did not induce constipation. Naloxone reversed the analgesic and behavioral effects of an equipotent dose of both compounds with comparable effectiveness. R 62 818 protected animals from KCN‐induced lethal shock, whereas codeine did not. Like other narcotic analgesics, codeine potentiated tryptamine lethality, whereas R 62 818 did not. The safety margins (LD50: lowest hot plate ED 50) in mice were 96.3 for R 62 818 and 21.9 for codeine, in rats (LD50: lowest tail withdrawal ED50) 81.8 for R 62 818 and 18.3 for codeine. R 62 818 appears to be a relatively more specific, slightly more potent and safer analgesic than codeine, with earlier peak effect and shorter duration of action. Its activity profile is not typical morphine‐like.
Evaluation of protective effects of lidoflazine and mioflazine in cardiac ischemia
Authors: Liu Guo‐Shu , Borgers Marcel , Xhonneux Raymond , van Overloop Patrick , Thoné Fred , Wouters Luc , Leijssen Lambert
Published: January 2005

The protective effects of lidoflazine and mioflazine against normothermic ischemia were evaluated in isolated rabbit hearts used in the working mode. Pretreatment with 0.125 mg\liter of these drugs improved recovery of cardiodynamic function during postischemic reperfusion. Functional recovery was preceded by less severe impairment of sarcolemmal structure and Ca2+ distribution at the end of the ischemic period, allowing the normalization of other substructures and the prevention of cellular Ca2+ overload during postischemic reperfusion. When cardiac output and semi‐quantitative histology are taken as parameters, the protective effects of mioflazine were greater than that of lidoflazine.
Phenomenology of schizophrenia and neuroleptic drugs
Authors: Kendler Kenneth S.
Published: January 2005

This paper reviews the penomenology of schizophrenia to acquaint non‐clinicans (pharmacology researchers) with the characteristic features of this disorder. Schizophrenia is noted to be a disorder with onset usually during early adult life in individuals who often have been at least mildly abnormal prior to the time of onset. The disorder is characterized by both positive symptoms, particularly delusions, hallucinations, thought disorder, and motoric symptoms, as well as negative symptoms, particularly affective flattening, avolition/apathy, and asociality. In most cases, schizophrenia leads to considerable psychosocial disability. Despite important advances in treatment, individuals who fully recover from schizophrenia remain relatively rare. New drugs are needed to treat this illness.
Brain imaging techniques for diagnosis and drugs against schizophrenia
Authors: Buchsbaum Monte S.
Published: January 2005

Positron emission tomography studies in schizophrenia have used two main approaches; metabolic imaging with deoxyglucose or glucose and dopamine receptor imaging with ligands for the dopamine receptor. The metabolic studies have generally shown relatively reduced metabolic rates in the frontal cortex, consistent with most studies of cerebral blood flow. Relatively low metabolic rates in the basal ganglia have also been observed in some studies. With labeled neuroleptics, brain images with the greatest uptake in the basal gangila have been obtained, and clinical studies comparing normals and schizophrenics are still in progress. For both approaches, the problem of biological heterogeneity in schizophrenia must be fully considered so that PET can reach its full potential as a tool to develop new drugs, to select a particular drug for the individual patients, and ultimately to understand the pathophysiology of schizophrenia.
“Regression” of atherosclerosis in cell culture: Effects of stable prostacyclin analogues
Authors: Orekhov Alexander N. , Tertov Vladimir V. , Mazurov Aleksey V. , Andreeva Elena R. , Repin Vadim S. , Smirnov Vladimir N.
Published: January 2005

Proceeding from the fact that the production of prostacyclin is decreased during atherosclerosis, which likely leads to the development of an atherosclerotic lesion, we assumed that addition of the exogenous prostacyclin would facilitate regression of atherosclerotic manifestations. To test this assumption we added stable prostacyclin analogues (carbacyclin and 6 β‐dihydro prostacyclin) to cells cultured from atherosclerotic lesions of human aorta. In primary culture, such cells retained the major manifestations of atherosclerosis at the cellular level, namely, enhanced proliferative activity and high lipid content. The stable prostacyclin analogues decreased the [3H]thymidine uptake into aortic cells by 1.5–2‐fold. These agents also substantially reduced the triglyceride and cholesteryl ester level in the cells cultured from atheorsclerotic lesions of aorta. In all these respects, carbacyclin was slightly more potent than 6 β‐dihydro prostacyclin. Thus, the stable prostacyclin analogues can inhibit proliferation and decrease the content of lipids in “atherosclerotic” cells, i.e., effect the “regression” of atherosclerosis at the arterial cell level. Apparently, these compounds may be regarded as potential antiatheroscelerotic drugs.
Rabbit tooth pulp compared to 55°C mouse hot plate assay for detection of antinociceptive activity of opiate and nonopiate central analgesics
Authors: Wynn Richard L. , Ford Robert D. , McCourt Patricia J. , Ramkumar Vickram , Bergman Stewart A. , Rudo Frieda G.
Published: January 2005

The rabbit tooth pulp (RTP) assay was compared to the 55°C mouse hot plate (MHP) assay for detecting the antinociceptive actions of carfentanil, sufentanil, fentanyl, alfentanil, meperidine, morphine, ketamine, and nefopam. Except for meperidine, all the the opioid agonists exhibited lower ED50 values (P ≤ 0.01) from RTP. Meperidine exhibited a lower value, significant at P ≤ 0.10. Rank orders of potencies were the same for both assys, with carfentanil the most and morphine the least potent. The durations of action of single equianalgesic doses were significantly longer for all six opioids when determined by the RTP compared to the MHP assay. Rank orders of duration were similar in both assys, with alfentanil the shortest and morphine the longest. Graded dose responses could not be detected for ketamine and nefopam using the MHP, but they were observed and ED50 values were obtained with the RTP assay. The results indicate that the RTP is singnificantly more sensitive than the MHP assay in detecting antinociceptive activity of six oplate and two nonopiate central analgesics.
Antipentylenetetrazol activity of diazepam: A site of action
Authors: Chweh A.Y. , Ulloque R.A. , Swinyard E.A.
Published: January 2005

The site at which pentylenetetrazol (PTZ) and diazepam interact was explored. Neither Ro (15‐1788, a benzodiazepine DZ) receptor antagonist, nor 4,5,6,7‐tetrahydroisoxagolo (5,4‐c) pyridin‐3‐ol, (THIP), a γ‐aminobutyric acid (GABAA) receptor ligand, alone had any effect on the incidence of PTZ‐induced seizures. Ro 15‐1788 inhibited the anti‐PTZ activity of diazepam but not that of pentobarbital. THIP had no effect on the anti‐PTZ activity of diazepam even after toxic doses. Combination studies with diazepam and progabide (GABAA receptor ligand) or diazepam and pentobarbital demonstrate that the anti‐PTZ activity of the individual components interact additively. These results imply that (GABA‐independent BDZ receptors contribute to the anti‐PTZ action of BDZs).
Discriminative stimulus effects of tizanidine hydrochloride: Studies with rats trained to discriminate either tizanidine, clonidine, diazepam, fentanyl, or cocaine
Authors: Shearman Gary T.
Published: January 2005

Male Sprague Dawley rats were trained in a two‐lever food‐reinforced procedure to discriminate between the effects of saline and either tizanidine hydrochloride, clonidine hydrochloride, diazepam, fentanyl, or cocaine hydrochloride. Tizanidine‐trained rats dose‐dependently generalized the effects of tizanidine and clonidine but not pentobarbital, diazepam, morphine, or cocaine. Clonidine‐trained rats dose‐dependently generalized the effects of clonidine and tizanidine but not pentobarbital, diazepam, or morphine. Diazepam‐trained rats dose‐dependently generalized the effects of diazepam but did not generalize tizanidine. Fentanyl‐trained rats dose‐dependently generalized the effects of fentanyl but did not generalize tizanidine. Cocaine‐trained rats did not generalize the effects of tizanidine to the cocaine discriminative stimulus. Yohimbine hydrochloride but not naloxone hydrochloride dose‐dependently antagonized the discriminative stimuli produced by both tizanidine and clonidine. These data demonstrate that tizanidine shares discriminative stimulus properties with clonidine but not with pentobarbital, diazepam, fentanyl, morphine, or cocaine. The discriminative stimuli produced by tizanidine and clonidine are mediated via an agonistic interaction with alpha2‐adrenergic receptors and not via an agonistic interaction with opioid receptors.
Reduction of food consumption and body weight of normal and obese mice by chronic treatment with fluoxetine: A serotonin reuptake inhibitor
Authors: Yen Terence T. , Wong David T. , Bemis Kerry G.
Published: January 2005

Fluoxetine, a serotonin reuptake inhibitor, reduced the food intake and body weight of both normal mice and viable yellow obese mice fed ad libitum. Fluoxetine was given at 10 mg/kg, i.p., daily for 10 days or fed in the diet at a concentration of 0.04% for 21 days. In both experiments, mice did not develop tolerance to the compound. In the 21‐day experiment, however, the decrease of food intake of normal mice was the same from week to week, and weight reduction was more in the first week than in the third week, suggesting an adjustment of metabolism or feed efficiency that did not occur in the obese mice. Heat treatment reduced the uptake of serotonin in homogenates of various brain regions and the number of 3H‐5HT binding sites but did not alter the dissociation constants. This study demonstrates that fluoxetine is an orally effective antiobesity agent in both normal and obese mice and does not elicit tolerance in these mice for at least 3 weeks.
Probability and nature of misattribution of drug side effects
Authors: Buckalew L. W. , Ross Sherman
Published: January 2005

There are situations in which physicians must rely on drug side effects to identify a preparation, and in drug research, the blind condition is often compromised owing to assumptions based on side effects. This study sought to sensitize practitioners and researchers to the “pharmacologic” action of placebos inclusive of side effects. In a survey of practicing physicians, a cluster of typically reported placebo side effects was presented with the task of identifying the pharmacologic‐therapeutic category to which this unidentified contributing preparation might belong. Only 5% correct identification was evidenced, and a significant bias toward classification of placebo side effects as representative of antihistamine or autonomic preparations was noted. These specific biases were evident both when considering a chance distribution of classification responses and national prescription patterns. Implications for practice and research are discussed.
Comparatice effects of loratadine and selected antihistamines on sleep‐waking patterns in the cat
Authors: Ongini Ennio , Marzanatti Mario , Guzzon Vittorio
Published: January 2005

The central effects of the new antihistamine loratadine and three reference antihistamine agents were studied in the cat. As a sensitive measure of drug action on the central nervous system (CNS) we evaluated changes in sleep‐waking patterns. For comparison, diphenhydramine was studied as an example of an antihistamine having potent central effects; astemizole and terfennadine were used as examples of new agents claimed to be free of CNS effects. Diphenhydramine, given at 3 mg/kg p.o., increased spindle sleep, i.e., the electrophysiological correlate of drowsiness, and suppressed rapid eye movement (REM) sleep. In addition, cats displayed unusual sleep postures during the various sleep stages. Loratadine had little or no effect on the various features of sleep‐waking patterns over a broad dose range (3 and 30 mg/kg p.o.). Astemizole, at 30 mg/kg p.p., significantly increased wakefulness and reduced both slow‐wave sleep and REM. No significant changes of the sleep patterns occurred after the low dose of 3 mg/kg. Terfenadine reduced REM duration at 30 mg/kg p.o. but had no effects on sleep patterns at 3 mg/kg. The cat appeared to be a sensitive animal model to the central action of antihistamines since the reference drug diphenhydramine affected sleep‐waking patterns at a dose that closely approximates the dose requirements for adverse CNS effects in man. Under the same conditions, loratadine was free of central actions at a dose range far above that effective either therapeutically or in standard tests in other animal species. Astemizole and terfenadine seemed to be devoid of CNS effects at doses similar to those effective as antihistamines in man, but they produced some central actions at higher doses. Comparing the clinically effective doses of the antihistamines examined, loratadine appears to be the least liable to produce adverse effects on the CNS function.
Lack of interaction of MDL 257 and isoproterenol: Comparison with aminophylline
Authors: Abdallah Abdulmuniem H. , Burnell Jim , Cerimale Ben
Published: January 2005

MDL 257 [8‐methyl‐6‐piperidino‐s‐triazolo(4,3‐b)pyridazine], a potential bronchodilator, was evaluated for potential interactions with isoproterenol on isolated tracheal smooth muscle taken from either prednisone‐ or methocel HG‐treated guinea pigs. Its effects were compared to those of aminophylline. In tracheas taken from methocel HG‐injected animals, aminophylline lowered the height of isoproterenol concentrations‐effect curve more than the vehicle (P < .001) and shifted the curve to the left (P < .05). MDL 257, on the other hand, had no effect. In tracheas taken from prednisone‐treated animals, aminophylline and MDL 257 had no significant effect on the maximum relaxation caused by isoproterenol. However, both drugs shifted isoproterenol concentrations‐effect curve to the left. Their effects were significantly different (P < .05) from that of the vehicle. These data suggest that, if given together, MDL 257 would not attenuate the bronchodilator effects of betasympathomimetic amines.
Anxiolytic efficacy and safety evaluation of high dosage oxazepam in patients with severe anxiety
Authors: Karkalas John , Lal Harbans
Published: January 2005

Therapeutic efficacy of high doses of oxazepam was evaluated in highly anxious psychoneurotic, psychotic depressive and schizophrenic patients. Evaluation through Hamilton Anxiety Scale, Serax‐Isosorbide Dinitrate Self Rating Scale, and Brief Psychiatric Rating Scale showed significant reduction of anxiety states and improvement in the mental health of the patients. Doses up to 300 mg per day, often necessary in highly anxious patients, did not produce any serious side effect. Only a few of the 30 patients showed transient drowsiness and/or nausea. Unlike other benzodiazepines, central nervous system depression was not a limiting factor in the use of high doses of oxazepam in psychiatric conditions associated with high anxiety states. One patient continued to receive oxazepam 120 mg daily along with amitriptyline, 30 mg four times a day, and benztropine 2 mg thrice a day after the trial period. She developed an acute confusional state with disorientation and slurred speech. When oxazepam was discontinued, she developed an epileptiform seizure, which was controlled by reinstating oxazepam. Subsquently, oxazepam was gradually withdrawn.
Phospholipase A2 mechanism: Inhibition and role in arachidonic acid release
Authors: Dennis Edward A.
Published: January 2005

The role of phospholipases in cellular activation and arachidonic acid production for prostaglandin and leukotriene biosynthesis is reviewed. Particular emphasis is placed on the function of phospholipase A2 in the processes. The experimental basis of our current state of knowledge of the mechanism of action of the pure, extracellular phospholipase A2 is considered in detail. Experimental approaches dealing with lipid activation, surface dilution kinetics, and enzyme aggregation are considered, and the “dual phospholipid model” for phospholipase A2 action at the lipid/water interface is described in detail. The kinetic analysis of phospholipase A2 inhibitors, including p‐bromophenacylbromide, manoalide, and an alkylether amide analogue of phosphatidylcholine, is considered in light of this model.
Enzyme inhibitiors: Ground‐state/transition‐state analogs
Authors: Abeles Robert H.
Published: January 2005

Compactin and related compounds are highly effective inhibitors of HMG‐CoA (Hydroxymethylglutaryl‐CoA) reductase. These compounds consist of two major structural components: (1) a component resembling hydroxymethyl glutarate and (2) a hydrophobic region. It is concluded that the hydroxymethyl glutarate moiety of these inhibitors interacts with the hydroxymethyl glutarate‐binding domain of the active site. It is postulated that the hydrophobic moiety of these inhibitors interacts with a hydrophobic area of the enzyme that is not part of the active site. Strong binding is the consequence of this two‐point interation. Peptidyl tri‐fluoroketones are effective inhibitors of chymotrypsin and elastase and are probably transition‐state analogs. These inhibitors form an adduct with the activesite serine as determined by X‐ray crystallography and nuclear magnetic resonance spectroscopy. Maximum inhibition is obtained if inhibitors interact with the S and S′ binding domains. The structure of ovomucoids, protein inhibitors of serine proteases, serves as a good model for the determination of the amino acid sequence to be used in that portion of the inhibitor which interacts with the S′ domain. The best amino‐acid sequence to be used in that area of the inhibitor which interacts with the S‐binding domain corresponds to the amino‐acid sequence found in substrates with the highest V/K.
Effect of famotidine and ranitidine on gastric secretion and emptying in the rat
Authors: Scarpignato Carmelo , Tramacere Roberto , Pezzetta Antonella
Published: January 2005

The antisecretory and gastric motor effects of the new H2‐receptor antagonist famotidine (MK‐208) were compared with those of ranitidine in the rat. The Shay rat preparation (5 hr) was used for studying gastric secretion. Gastric motility was assessed by measuring gastric emptying of a liquid meal. Both compounds inhibited acid secretion in a dose‐dependent fashion. Calculated ED50 values were 0.80 and 6.84 mg·kg−1 for famotidine and ranitidine, respectively. Therefore, in this animal model, famotidine was about 9 times more potent than ranitidine. The duration of antisecretory action however, was virtually the same for both drugs. The effect of the two drugs ‐ administered at equiactive antisecretory doses ‐ on gastric emptying was different. Indeed, ranitidine significantly accelerated emptying rate, whereas famotidine was ineffective. The results of the present investigation demonstrate that famotidine is a potent and selective antisecretory compound.
Memory for discriminated escape learning: Pharmacologic enhancement and disruption
Authors: Forster Michael J. , Popper Mark D. , Paul Subir K. , Lal Harbans , Retz Konrad C.
Published: January 2005

Discriminated escape behavior of mice in a T‐maze was evaluated as a model for investigation of drug effects upon memory. All studies involved discriminated escape training trials on which footshock offset occurred following a correct goal‐arm choice. Memory was assessed in retention tests that involved either reversal or relearning of the previously trained goal choice. Analyses of discriminated escape acquisition and training‐retention interval were performed to identify parameters yielding either optimal or poor retention. Parameters yielding poor retention in untreated mice were used in studies involving drugs expected to improve retention. Pretraining treatment of mice with either physostigmine (0.08 mg/kg) or HydergineTM (0.64 mg/kg) yielded improved retention scores when training was minimal (a criterion of two consecutive correct choices) and the retention interval was long (168 hr). The effects of scopolamine (0.64 mg/kg) upon memory were assessed in the context of a short retention interval (24 hr) and more complete training (three consecutive correct choices), parameters yielding optimal retention in saline‐treated mice. Scopolamine yielded poorer 24‐hr retention performance when present during training, retention, or at both times. Overall, the results indicate that the discriminated escape procedures described are potentially useful for detection and analysis of pharmacologic modifications of memory processes.
Diazepam tolerance and withdrawal assessed in an animal model of subjective drug effects
Authors: Emmett‐Oglesby Michael W. , Mathis Dian A. , Lal Harbans
Published: January 2005

Tolerance to and withdrawal from drugs of dependence involves subjective symptoms and physical signs. Until recently, only physical signs associated with these phenomena could be assessed in animals. Recently, however, drug discrimination methodology has been used to bioassay for the occurrence of subjective events in animals; the work reviewed in this paper describes extensions of this general technique to test for subjective aspects of withdrawal from and tolerance to benzodiazepine drugs in rats. The durg dicrimination procedure reinforces differential responding where the controlling stimulus is the presence or absence of a drug‐produced internal stimulus. Although it is impossible to determine the quality (subjective nature) of such stimuli in animals, it is possible to operationally define relationships between classes of stimuli. With regard to the discriminative stimulus produced by pentylenetetrazol (PTZ), data to date show that anxiogenic drugs substitute
for PTZ and anxiolytic drugs block the PTZ stimulus. Because in humans severe anxiety is a frequently seen component of withdrawal from dependence on benzodiazepine drugs, this laboratory initiated experiments to determine if animals trained to detect PTZ and then given chronic treatment with benzodiazepines would substitute a withdrawal state for the
PTZ stimulus. Data reviewed in this paper show that following diazepam administration, treatment with the benzodiazepine antagonist Ro 15‐1788 (RO) produced a dose‐related PTZ‐like stimulus. When given to nondependent animals, RO neither substituted for nor blocked nor enhanced the PTZ stimulus. In additional studies, RO produced a PTZ‐like stimulus when administered once every 3 d in rats maintained chronically on diazepam. Further, rats given a 2‐d regimen of diazepam, 80 mglkgl8 hr, were subsequently tolerant to the PTZ‐blocking action of diazepam. These data demonstrate that the discrimination of PTZ is a useful procedure for assessing subjective aspects of tolerance to and withdrawal from benzodiazepines in animals.
Pharmacological evaluation of HP 370, a potential atypical antipsychotic agent: 2. In vitro profile
Authors: Huger Francis P. , Smith Craig P. , Chiang Yulin , Glamkowski Edward J. , Ellis Daniel B.
Published: January 2005

HP 370, 4,9‐dibromo‐6‐(4‐methyl‐1‐piperazinyl)benzo[b]pyrrolo[3,2,1‐jk][1,4] benzodiazepine, a compound that has an atypical antipsychotic profile in vivo, was tested for activity in a number of neurotransmitter receptor binding and uptake assays and compared with serveral typical and atypical antipsychotic compounds. The in vitro profile of HP 370 was most similar to that of clozapine, with the notable exception that HP 370 was inactive as an inhibitor of quinuclidinyl benzilate (QNB) binding (IC50 10−5). HP 370, like clozapine, was a relatively weak and nonselective inhibitor of dopamine (DA) receptor subtypes, whereas sulpiride, another compound reported to be atypical, is a very selective but weak inhibitor of dopamine‐2(D2) receptors. HP 370 and clozapine inhihited WB4101 binding with high affinity, indicating α1‐adrenergic receptor blockade. Neither HP 370 nor the standard neuroleptic compounds inhibited flunitrazepam or gamma‐aminobutyric acid (GABA) binding. HP 370, Clozapine, and sulpiride were inactive as inhibitors of norepinephrine (NE), DA, and 5HT uptake, whereas HP 370 AND clozapine were weark inhibitors of GABA uptake. Based on this in vitro data, the mesolimbic site‐selectivity of HP 370 seen in vivo cannot be explained by anticholinergic GABA‐mimetic activity in the DA‐parative results point to a distinct advantage of an atypical neuroleptic, without the antocholinergic side effects of clozapine.