bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between inotropic activity and drug plasma levels of a new cardiotonic agent, MDL 19205
Authors: Roebel Lawrence E. , Okerholm Richard A. , Weiner Daniel L. , Woodward James K. 
Published: January 2005

AbstractThe correlation between the positive inotropic action of a new cardiotonic agent, MDL 19205 (4‐ethyl‐1,3‐dihydro‐5‐(4‐pyridinyl‐carbonyl)‐2H‐imidazol‐2‐one), and plasma concentrations of the compound after administration to anesthetized dogs was examined. MDL 19205 solution was introduced into either the stomach or the duodenum of the pylorus ligated dog. Duodenal administration (1–10 mg/kg) resulted in dose‐related increases in MDL 19205 plasma levels accompanied by substantial, dose‐related increases in cardiac contractility, while gastric administration (3–30 mg/kg) produced much lower, highly variable plasma levels of MDL 19205 accompanied by minimal levels of cardiotonic activity. Our results indicate that the cardiotonic activity of MDL 19205 in the anesthetized dog is closely correlated with drug plasma concentrations, and that the duodenum is the preferred site of absorption of MDL 19205, with very little of the drug being absorbed through the stomach. Since the dog has previously been shown to be a good predictor of the kinetics of MDL 19205 in man, our results suggest that the cardiotonic activity and plasma conncentrations of MDL 19205 in man will also be closely linked.
Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Analgesic pharmacology
Authors: Spaulding T. , Fielding S. , Ma M. , Ellis D. B. , Novick W. J. , Ong H. H. 
Published: January 2005

AbstractFluradoline, (HP 494), 2‐fluoro‐11‐[β‐(methylamino)ethylthio]dibenz[b, f]oxepin maleate, was assessed in a variety of antinociceptive testing procedures which are used to predict analgesic efficacy in man. The compound, after oral or systemic administration, effectively attenuated chemical‐induced writhing, heat‐induced tail flick, pressure‐induced clip biting and hypersensitivity, and tail shock‐induced lever pressing. When used for comparative purposes, morphine and/or codeine were also active in all tests, while the tricyclic antidepressant, imipramine, was weakly or not active. The pharmacologic profile differs from that of opiates in that the antinociceptive effect is not reversed by naloxone, and there is no cross tolerance to morphine and no interaction in in vitro binding studies using 3H‐naloxone as the ligand. These data show that fluradoline has the potential for clinical effectiveness as an analgesic agent with a unique mechanism of action that differs from those of opiates and imipramine.
Microcomputer use in measuring onset, duration, and recovery from nondepolarizing skeletal muscle relaxants in rabbits
Authors: Thut Paul D. , Pruzansky Elysa , Rudo Frieda G. 
Published: January 2005

AbstractThis report describes a method which has been developed to use an Apple II Plus microcomputer in studies of the time course and dose response of potential skeletal muscle relaxant drugs. Rabbits are anesthetized with pentobarbital, tracheotomized, and the right common carotid artery is cannulated for direct measurement of blood pressure and heart rate. The ulnar nerve is stimulated at the elbow. Twitch, “train‐of‐four” (T4), tetanus, and posttetanic potentiation (PTP) are monitored by a force displacement transducer. These analog physiological signals are led from a polygraph through an lsaac Cyborg analog‐to‐digital converter attached to the microcomputer where they are stored in digital form. Each animal receives the test drug twice. Spontaneous recovery is allowed following the first administration while the second dose is reversed with neostigmine. The rate of onset, time and magnitude of maximal effect, time and rate of recovery, and time and magnitude of cardiovascular changes are all automatically calculated for both the control and the neostigmine reversal experimental phases. The effect of the test dose on each parameter is rated to provide a composite score for each dose of the test compound as the dose‐response series is completed. All parameters are plotted using a dot‐matrix printer and data are stored to disk. When doses, in 0.1‐log intervals, from the dose which produces no measurable effect to those doses producing unacceptably long durations, have been administrated, the computer uses the composite scores to report an optimal dose. Using regression analysis, the dose required to provide a 90% depression of twitch is calculated. This calculated dose is compared to equiefficacious doses of other test compounds. A tabular, graphic, and narrative report of the drug's effects is generated by the computer with comparison to other compounds of pctential interest. These programs and methods provide efficient data collection and data analysis. They provide for standard report generation. Finally, they allow for comparisons to be made among many pharmacologic parameters of many test compounds, thus providing understanding of the mechanisms of action of the test compounds.
A set of behavioural tests predicting antidepressant activity
Authors: de Graaf Joop S. , van Riezen Henk , Berendsen Hemmie H. G. , van Delft Anton M. L. 
Published: January 2005

AbstractPsychotropic drugs from various classes were tested in a set of behavioural test models for antidepressant activity in order to establish the validity of these models for predicting such activity. The drugs included six recently developed antidepressants with proven clinical effectiveness, namely zimelidine, viloxazine, ciclazindol, amoxapine, bupropion, and trazodone. They were tested in the following models: The muricide rat model (with a measure of specificity provided by the shuttle‐box test); the acquired immobility (behavioural despair) test with mice; potentiation of amphetamine‐induced exploratory behaviour of rats; and potentiation of yohimbine lethality in mice. None of the models is in itself sufficient to predict antidepressant activity in the compounds tested. A combination of the muricidal rat/shuttle‐box paradigm and the acquired immobility test with mice would detect all known antidepressant compounds. This combination can be used to detect compounds comparable to those antidepressants possessing clinically established antidepressant activity.
Persistence of central effects of pirlindole, a short‐acting monoamineoxidase inhibitor, in the presence of a monoamineoxidase inhibitor
Authors: Simon Pierre , Poncelet Martine , Chermat Raymond 
Published: January 2005

AbstractPirlindole, a tetracyclic drug, is known to have a reversible and short‐lived monoamineoxidase inhibitory activity. When administered after a supramaximal inhibitory dose of a classic monoamineoxidase inhibitor, pirlindole continues to antagonize reserpine‐induced ptosis and oxotremorine‐induced akinesia in mice. These results indicate that some central effects of pirlindole are partially independent of its monoamineoxidase inhibitor activity.
BW234: A nondopamine receptor‐blocking antipsychotic drug without extrapyramidal side effects?
Authors: Davidson Jonathan , Dren Anthony , Miller Robert , Manberg Paul , Kilts Clinton , Wingfield Martha 
Published: January 2005

AbstractBased on studies in animals and in healthy human volunteers, it was predicted that the carbazole compound BW234U would have antipsychotic effects in patients without producing concomitant extrapyramidal effects. The compound was administered to 22 inpatients with schizophrenia in an open, dose‐ranging pilot study designed to assess antipsychotic effects as well as side effect profile. Clinical changes were observed on the BPRS and global improvement scales over a 4‐week period. No extrapyramidal side effects were noted, and serum prolactin concentrations showed no change in a subsample of nine patients. Two major side effects appeared to be drug‐related: One seizure occurred at 600 mg/day, and elevations of alkaline phosphatase were noted at several doses in six patients.
Role of cholinergic system in modulating gamma‐aminobutyric acid and dopamine functions in rat brain
Authors: Rastogi S. K. , Rastogi R. B. , Singhal R. L. , Lapierre Y. D. 
Published: January 2005

AbstractThe effects of cholinergic and anticholinergic agents on dopamine (DA) and gamma‐aminobutyric acid (GABA) levels in specific rat brain regions were studied. A single injection of physostigmine (2 mg/kg, i.p.) produced no significant effect on the levels of DA and GABA in corpus stritum. Treatment with atropine increased striatal GABA content by 38%, suggesting that decreased cholinergic activity alters the release of GABA. Administration of physostigmine partially antagonized the atropine‐induced rise in GABA level of corpus striatum, indicating that the cholinomimetic agent facilitated GABA release in this region. This increase in GABA content is not associated with any change in DA content in the striatum. To further assess the effect of physostigmine on GABA level, animals were pretreated with amino‐oxyacetic acid (AOAA), an inhibitor of the GABA‐degrading enzyme 4‐aminobutyrate 2‐oxoglutarate transaminase (GAGA‐T). Treatment with AOAA (50 mg/kg) elevated GABA levels in corpus striatum, midbrain, and frontal cortex. In contrast, DA levels were decreased by 25% and 30% in the frontal cortex and corpus striatum, respectively. Administration of physostigmine facilitated GABA release in AOAA‐treated animals resulting in a 16% lowering of GABA levels in striatum. Physostigmine did not change striatal DA in rats pretreated with AOAA. These results suggest that cholinergic interneurons in striatum probably facilitate the functioning of GABAergic neurons, which elicit inhibitory effects on the DA system. The clinical importance of such an interneuronal circuit is discussed.
Calcium antagonists as antiatherosclerotic drugs
Authors: Weiss George B. 
Published: January 2005

AbstractThe effects of calcium antagonists on mobilization of calcium stores critical for induction and development of atherosclerosis are only beginning to be delineated. The idea that these types of agents (by selectively altering either platelet function or smooth muscle proliferation and accumulation of lipids and calcium) can arrest or even reverse the course of atherosclerosis presents an attractive approach. Available experimental information on the actions of calcium antagonists in atherosclerosis is suggestive rather than definitive in this regard. A number of calcium‐sensitive steps in platelet aggregation and secretion as well as in smooth muscle accumulation and deposition of calcium are identified. Related experimental findings in models of arteriosclerosis and hypertension also support the concept that blockade of calcium accumulation in vascular smooth muscle can retard or prevent subsequent interactions leading to enhanced disease states. Thus technical approaches to delineation of the actions of calcium antagonists are available, and, though the therapeutic value of these types of agents is not established, their potential as novel antiatherosclerotic agents is attractive.
Activation of hormone‐sensitive adenylate cyclase by forskolin
Authors: Seamon Kenneth B. 
Published: January 2005

AbstractAn overview of the organization of adenylte cyclase systems and various sites for regulation is presented. These components are discussed with respect to the activation of adenylate cyclase by forskolin. Evidence for direct activation of adenylate cyclase as well as potentiation of hormone‐activated adenylate cyclase by forskolin is reviewed, as these data relate to the possible site(s) of action of forskolin. Studies of the action of forskolin in different systems and interaction studies with different regulators of adenylate cyclase have yielded valuable information about the regulation of adenylate cyclase and the relationship of its various components. A better understanding of these relationships may reveal new therapeutic potential for forskolin.
Inhibition of serotonin uptake by optical isomers of fluoxetine
Authors: Wong David T. , Bymaster Frank P. , Reid Leroy R. , Fuller Ray W. , Perry Kenneth W. 
Published: January 2005

AbstractThe optical isomers of fluoxetine, a selective inhibitor of serotonin (5‐hydroxytryptamine, 5HT) uptake, have been compared pharmacologically. As inhibitors of 3H‐5HT uptake in cortical synaptosomes and of 3H‐fluoxetine binding in cortical membranes, the (+)‐isomer of fluoxetine was slightly more potent than the (−)‐isomer. The potencies to inhibit 3H‐5HT uptake ex vivo in synaptosomal preparations of cerebral cortex and brain stem were about the same, except that the (−)‐isomer had a much shorter duration of action than the (+)‐isomer in rats.
Anticonvulsant profile of flunarizine
Authors: Wauquier Albert , Ashton David , Clincke Gilbert , Fransen Joannes , Gillardin Jean‐Marie , Janssen A. J. Paul 
Published: January 2005

AbstractThe purpose of the study was to examine in a multi‐experimental profile the purported similarity between the anticonvulsant effects of flunarizine, diphenylhydantoin, and carbamazepine. The compounds were injected at different time intervals and by different routes, and their effects were examined in a genetic model of epilepsy (audiogenic seizures in mice), against maximal seizures induced by bicuculline in mice and rats and in a seizurethreshold test (bicuculline infusion) in rats. All three compounds primarily affected tonic seizures. In the bicuculline seizure test, this was an all‐or‐none effect. In this test, flunarizine differed from diphenylhydantoin and carbamazepine in that it increased the threshold for clonic‐hindpaw seizures. Thus, flunarizine, apart from antagonizing tonic seizures, also increased the threshold for generalization. Further, in agreement with previous experiments (maximal metrazol test and kindling), the duration of action of flunarizine is longer than that of diphenylhydantoin and carbamazepine. Finally, the degree of ataxia and neurological deficits caused by a high p.o. dosis of flunarizine was assessed. A slight neurological deficit and ataxia occurred 1 hr after p.o. administration of 160 mg/kg of flunarizine. By way of analogy with diphenylhydantoin, as a working hypothesis, it is suggested that the anticonvulsant actions of flunarizine result from reducing Na+ currents in neurons, although a direct effect on Ca2+ movements cannot be excluded.
The effects of tofisopam, a 3,4‐benzodiazepine, in animal models of anziety, sedation, and convulsions
Authors: Pellow Sharon , File Sandra E. 
Published: January 2005

AbstractTofisopam, a 3, 4‐benzodiazepine classified as a nonsedative anxiolytic in man, had no effect in two animal tests of anxiety (the social interaction test and a punished drinking test; 10‐‐50 mg/kg) and produced a dose‐related reduction in exploratory and locomotor activity in the holeboard (5‐‐100 mg/kg). These reductions were not antagonised by chlordiazepoxide (5 mg/kg), Ro 15‐‐1788 (10‐‐20 mg/kg), or picrotoxin (2 mg/kg); however, the reductions in head‐dipping but not in motor activity or rears were antagonised by CGS 8216 (10 mg/kg). Tofisopam (10‐‐50 mg/kg) had no anticonvulsant activity, but had proconvulsant activity, with picrotoxin and pentylenetetrazole. In contrast, tofisopam (50‐‐100 mg/kg) antagonised the convulsions induced by the 1, 4‐benzodiazepine Ro 5‐‐4864.
Comparison of the effects of pinacidil and its metabolite, pinacidil‐N‐oxide, in isolated smooth and cardiac muscle
Authors: Cohen Marlene L. , Colbert Walter E. 
Published: January 2005

AbstractThe effects of pinacidil and its major metabolite, pinacidil‐N‐oxide, were compared in isolated smooth and cardiac muscle preparations. Wide variation occurred in the sensitivity of different smooth muscle preparations to the relaxant effect of pinacidil. Relaxant sensitivity of pinacidil was greatest in the one vascular preparation examined, the rat aorta, where the ED50 for pinacidil was approximately 0.5 μM. Pinacidil was equally potent in relaxing serotonin‐ or norepinephrine‐contracted aortic preparations. Although pinacidil was also a smooth muscle relaxant in the guinea pig trachea, guinea pig ileum, rat vas deferens, and rat stomach funds, the ED50 ranged from 1‐‐25 μM in these smooth muscle preparations. In the trachea, pinacidil was most effective in relaxing histamine‐induced contractions as compared to contractions induced by carbamylcholine. Thus, bronchodilatory effects of pinacidil might be most apparent when bronchoconstriction is produced by allergic responses that result from histamine release. Pinacidil was least effective in quiescent rat uterine smooth muscle, where approximately 80% of the maximum contractile response to oxytocin was maintained in the presence of 10−4 M pinacidil. Although a direct cardiostimulatory effect of hydralazine has been postulated, no direct stimulatory effect on guinea pig cardiac rate or force occurred with pinacidil. Furthermore, an inhibitory effect on rate and force of atrial responses occurred only in higher doses of pinacidil. The major metabolite of pinacidil, pinacidil‐N‐oxide, also relaxed the rat aorta, although it was approximately eight‐ to tenfold less potent than pinacidil. These data are consistent with the contention that pinacidil‐N‐oxide would contribute to the antihypertensive activity seen after pinacidil only when plasma levels were approximately tenfold greater than the parent compound. Furthermore, because of the relative insensitivity of other smooth and cardiac.
Effect of astemizole on psychomotor performance in healthy thais
Authors: Dhorranintra Boonchua , Limsuvan Supatra , Bunnag Chaweewan 
Published: January 2005

AbstractThe absence of CNS‐related side effects of astemizole, a new long‐acting specific histamine, H1‐antagonist, has been reported by many authors. To investigate the influence of this new antihistamine on psychomotor performance in Thais, oral therapeutic doses of 10 mg once daily were administered for 7 days to 21 healthy Thai volunteers (13 males and eight females). Ages ranged from 22 to 37 years and body weights from 40 to 65 kg. The study used a double‐blind crossover design. Subjective assessments were carried out by means of a visual analogue rating scale and a four‐point alertness rating scale and objective assessments by means of card sorting, glass bead picking, and recording of reaction times for visual stimuli in a choice situation. Compared to placebo, astemizole caused no change in any of the ratings or performances at either 1 or 2 h subsequent to the first and last (i.e., seventh) dose. It might thus be concluded that astemizole is free of CNS‐depressant effects in Thai volunteers.
Progress on the characterization and identification of endothelium‐derived relaxing factor(s)
Authors: Berkowitz Barry A. , Ohlstein Eliot H. 
Published: January 2005

AbstractSubstantial evidence indicates that there are novel factors released from the vascular endothelium that regulate vasodilatation. The weight of the present evidence is that endothelium‐derived relaxing factor(s) (EDRF) is an oxidation product of arachidonic acid. Whether the oxidative enzyme is a lipoxygenase or related to a cytochrome P450 monooxygenase remains under investigation. Future progress requires a reproducible source of EDRF to allow isolation, purification, and structural identification.
Oral antiallergic activity in ascaris hypersensitive dogs: A study of known antihistamines and of the new compounds ramastine (R 57 959) and levocabastine (R 50 547)
Authors: Awouters Frans , Vermeire Jozef , Smeyers Frans , Vermote Patrick , van Beek René , Niemegeers Carlos J. E. 
Published: January 2005

AbstractThe antiallergic effectiveness of twelve compounds was studied in ascaris hypersensitive dogs by measuring allergen‐induced skin reactions before and 1, 4, 20, and 72 hr after oral treatment. The specific serotonin S2‐antagonist ritanserin at 2.5 mg/kg and the selective histamine H2‐antagonist cimetidine at 10 mg/kg did not reduce the allergic wheals. Chlorpheniramine and clemastine were inactive at 2.5 mg/kg. The remaining eight compounds studied over a wide dose range produced peak activity at markedly different doses and time intervals (hr). The lowest oral ED50‐values in mg/kg were: levocabastine: 0.0035 (4); R 57 959: 0.048 (20); astemizole: 0.13 (20); ketotifen: 0.20 (4); cyproheptadine: 0.21 (4); azatadine: 0.32 (4); oxatomide: 1.26 (20); terfenadine: 1.26 (1). The lowest oral ED50‐values in dogs and in rats (compound 48/80 lethality test) were similar, the largest difference being a fourfold potency gain of oxatomide in dogs. The short‐acting compounds in rats (azatadine, cyproheptadine, ketotifen, and terfenadine) had also a duration of action of less than 12 hr in dogs. Levocabastine, R 57 959, astemizole, and oxatomide acted more than 16 hr. Maximal inhibition of the allergic wheal volumes was highest with levocabastine (90%); it reached 80% with R 57 959 and ranged from 67 to 78% with the remaining compounds. On the basis of their activity characteristics in dogs, levocabastine and R 57 959 are potentially very effective antiallergic drugs.
The chemical development of selective and specific serotonin S2‐antagonists
Authors: Kennis Ludo E. J. , Vandenberk Jan , Boey Jozef M. , Mertens Jos C. , van Heertum Albert H. M. , Janssen Marcel , Awouters Frans 
Published: January 2005

AbstractFour types of chemical intermediates were prepared to synthesize novel piperidine derivatives inspired by the butyrophenones benperidol and lenperone and by the diphenylbutyl neuroleptic pimozide. The fist type, comprising benzimidazolone alkyl intermediates, yielded declenperone and milenperone and also the “symmetrical” compound domperidone, which was pharmacologically unusual by its specific peripheral dopamine antagonism. Declenperone was the most potent serotonin antagonist of that series, and replacement of the benzimidazolinonepropyl by the quinazolinedioneethyl moiety led to ketanserin, which was devoid of residual dopamine antagonism. Very potent serotonin S2‐antagonists were also obtained by using intermediates prepared from 2‐aminoaza‐heterocycles. Pirenperone and setoperone had a complex pharmacological profile, including significant dopamine and norepinephrine antagonism. These activity components were absent from the profile of R 56413 and ritanserin, which were obtained by using the fourth intermediate, benzhydrylenepiperidine. R 56413 and ritanserin are the most specific of the presently known serotonin S2‐antagonists.
Cytochrome p‐450: Target for itraconazole
Authors: Vanden Bossche Hugo , Bellens Dany , Cools Willy , Gorrens Jos , Marichal Patrick , Verhoeven Hugo , Willemsens Gustaaf , De Coster Roland , Beerens Dominiek , Haelterman Christian , Coene Marie‐Claire , Lauwers William , le Jeune Ludo 
Published: January 2005

AbstractThe N‐substituted triazole, itraconazole, has high affinity for the cytochrome P‐450 (cyt. P‐450) isozyme involved in the 14α‐demethylation of lanosterol in Candida albicans microsomes. Fifty per cent inhibition was already observed at itraconazole concentrations ≤ 5 × 10−9 M. Higher concentrations (≥ 10−7 M) of this antifungal are needed to interfere with the 14 α‐demethylation in mammalian cells. Unlike ketoconazole, itraconazole does not significantly affect in vitro androgen, gluco‐ and mineralocorticoid steroidogenesis. Itraconazole also does not affect the cyt. P‐450‐dependent 19‐hydroxylation of testosterone, a step in the conversion of androgens to estrogens. The 1‐hydroxylation of testosterone by pig testes microscomes is only slightly inhibited. It is hypothesized that itraconazole's selective activity on ergosterol bisosynthesis is due to its high affinity for the apoprotein of the C. albicans cyt. P‐450 involved in the 14α‐ demethylation of lanosterol.