bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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

AbstractThe 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

AbstractR 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

AbstractThe 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

AbstractThis 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

AbstractPositron 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

AbstractProceeding 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

AbstractThe 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

AbstractThe 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

AbstractMale 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

AbstractFluoxetine, 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

AbstractThere 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

AbstractThe 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

AbstractMDL 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

AbstractTherapeutic 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

AbstractThe 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

AbstractCompactin 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

AbstractThe 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.