bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychopharmacological profile of clenbuterol
Authors: Francès H. , Poncelet M. , Danti S. , Goldschmidt P. , Simon P.
Published: January 2005

Clenbuterol, a β‐adrenergic agonist known to enter the brain, has been studied in mice with a set of psychopharmacological tests. Clenbuterol has an ambiguous sedative effect: it reduces motor activity in a dose‐dependent manner without modifying exploratory behavior in the open field; it does not potentiate the effect of pentobarbital. Clenbuterol decreases the search for food in starved mice. Regarding the tests in animals which are expected to reflect antidepressant activity in man (hypothermias induced by reserpine, oxotremorine or a high dose of apomorphine, potentiation of yohimbine toxicity) clenbuterol acts at doses much lower than those required with two other β‐adrenergic agonists, isoproterenol and salbutamol. Moreover, the active doses of clenbuterol and salbutamol being nearly the same at a peripheral level, the ratio of the centrally and peripherally active doses is highly in favor of clenbuterol. This suggests that the effects of clenbuterol on depressed patients should be studied.
Some neurochemical properties of pramiracetam (CI‐879), a new cognition‐enhancing agent
Authors: Pugsley Thomas A. , Shih Yu‐Hsin , Coughenour Linda , Stewart Sheila F.
Published: January 2005

The present study was initiated to examine the effect of pramiracetam sulfate [N‐[2‐[bis(1‐methylethyl)amino]ethyl]‐2 oxo‐1‐pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition‐activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5‐HT), 5‐hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d‐methamphetamine‐induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC50 > 10 μM), and benzodiazepine receptors (IC50 > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5‐HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium‐dependent high‐affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal‐hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.
Biochemical characterization of the enantiomers of the novel ergoline dopamine agonist 6‐ethyl‐9‐oxaergoline (EOE)
Authors: Williams Michael , Jones James H. , Watling Keith J.
Published: January 2005

The enantiomers of the novel oxaergoline dopamine (DA) agonist, 6‐ethyl‐9‐oxaergoline (EOE) were compared with the parent recemate for their interactions with dopamine and other monoamine receptor systems in mammalian and teleost nervous tissue. The (−)enantiomer of EOE was over 100 times more active in displacing [3H]apomorphine than the (+)isomer, and 70 times more active in displacing [3H]spiperone. The (−)isomer also exhibited greater binding affinity at serotonin‐1 and ‐2 receptors than the (+)isomer. In contrast, however, the α1‐ and α2‐adrenoceptor activity of the compound resided in the (+)isomer, the latter being some 32 times more active at α2 than α1 adrenoceptors. Examination of EOE in the DA‐sensitive adenylate cyclase system of carp retina showed that while the (−)enantiomer was a partial agonist some 30 times less active than dopamine, the (+)enantiomer was devoid of activity in this D‐1 coupled system at concentrations up to 300 μM.
Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress
Authors: Janowsky David S. , Risch Samuel Craig
Published: January 2005

The cholinomimetic agents, physostigmine, neostigmine, and arecoline, and the anticholinergic agents, atropine, scopolamine, and methscopolamine, have been used to explore an acetylcholine hypothesis of affect disorders and stress. Cholinomimetic drugs cause many of the same effects as do naturally occurring stressors. These include increases in negative affect, the induction of affective disorders, increases in stress neuroendocrines including ACThH, cortisol, beta‐endorphin, growth hormone, prolactin, epinephrine, and noprepinephrine, increases in blood pressure and pulse rate, and increases in analgesia. These parallel effects, combined with the effect of stress on central acetylcholine activity, suggest a stress‐acetylcholine linkage.
Biologically active phospholipids as potential cardiovascular drugs
Authors: Blankley C. John , Kaplan Harvey R.
Published: January 2005

Both useful and undesirable cardiovascular properties have been associated with naturally occurring and synthetically derived phospholipids. Certain phospholipids may function physiologically (or pathophysiologically) in such processes as blood pressure regulation, cardiac rhythm, and platelet aggregation. Drugs that can modify the synthesis or degradation of endogenous phospholipid mediators or selectively mimic or block their effects may be of interest as potentially useful cardiovascular agents. This article reviews the current literature in this area and defines in chemical, biochemical, and biological terms the potential of the phospholipid‐type compounds in the development of useful cardiovascular drugs.
Antagonism of bremazocine‐induced urination as a test for kappa‐opioid receptor antagonists within the phenylpiperidine series
Authors: David Leander J. , Zimmerman Dennis M.
Published: January 2005

Representative compounds from a series of phenylpiperidine‐opioid antagonists were compared in their ability to antagonize the diuretic effect of 0.08 mg/kg of bremazocine, a kappa‐opioid receptor agonist. Three of the compounds produced dose‐related antagonism of bremazocine, whereas four others did not. The four ineffective compounds also did not exhibit any kappa agonist activity. The potency of the three effective antagonists did not correlated with their antagonist activity against morphine or in suppressing deprivation‐induced drinking. These results demonstrate that several kappa receptor antagonists can be found in the phenylpiperidine series of opioid antagonists, and further emphasize the usefulness of kappa‐mediated diuresis as an in vivo test for kappa‐opioid receptor activity.
Psychopathology of cognition
Authors: Hamilton Max
Published: January 2005

Disorders of cognition can be considered in terms of perception, thought, and memory. Disorders of perception can be subdivided into sense deceptions, such as illusions and hallucinations, and sense distortions. The first are of particular interest to psychologists and physiologists. Hallucinations can occur in any of the senses, but in nonorganic conditions the most important are auditory, chiefly in the form of “voices.” The features of these are described in detail. The most important sense distortions are those of the internal senses which form the basis of the body image. Thinking covers disorders of the stream, possession, content, and form of thought. These are described in detail; and it is shown how many of the forms of thought disorder can be regarded as disturbances of association and indirectly of “set.” Disorders of memory occur most frequently in organic disease of the brain but are also found in the functional disorders. The changes seen after severe concussion serve as a model to illustrate the types of disturbance which can occur in the various aspects of the process of learning and memorizing.
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

The 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

Fluradoline, (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

This 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

Psychotropic 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

Pirlindole, 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

Based 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

The 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

The 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

An 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

The 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

The 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

Tofisopam, 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

The 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

The 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

Substantial 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

The 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

Four 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

The 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.
Alfentanil infusions for peroperative and postoperative analgesia
Authors: Noorduin Henk , Waldron Heather , van Peer Achiel , Vanden Bussche Gabriel
Published: January 2005

The theoretical and clinical data available to date on the use of alfentanil by infusion as a supplement to N2O anaesthesia are summarized. These data suggest that alfentanil plasma levels of 200–400 ng/ml are required to provide adequate peroperative analgesia, depending upon the severity of the surgical procedure. Patients may be expected to awaken and breathe spontaneously at plasma levels of less than 200 ng/ml. Infusion regimens that achieve the required plasma levels without prolonging recovery are recommended for both minor and major surgery. Tentative suggestions are also given for the use of alfentanil by infusion in the postoperative period in spontaneously breathing patients.
R 58 735: A new antihypoxic drug with anticonvulsant properties and possible effects on cognitive functions
Authors: Wauquier Albert , Clincke Gilbert , Ashton David , De Ryck Marc , Fransen Joannes , van Clemen Gust
Published: January 2005

R 58 735, a benzthiazole derivative, is a potent antihypoxic agent with anticonvulsant properties. As an antihypoxic drug, it was more potent than any other reference substance in hypobaric hypoxia in mice and in histotoxic dysoxia and nitrogen hypoxia in rats. In the nitrogen hypoxia test, R 58 735 was equipotent in males and females, and the p.o.\i.v. ratio varied from 2.8 to 2.6. The antihypoxic activity of orally administered R 58 735 latested more than 8, but less than 24 hr. The anticonvulsant profile of R 58 735 resembled that of flunarizine, i.e., blockade of the tonic convulsions induced by pentylenetetrazol, allylglycine, or bicuculline, but not of clonic convulsions, except those seen in audiogenic seizureprone mice. In the allylglycine or bicuculline tests, it was more potent than any other reference anticonvulsant. In the bicuculline test, there were no sex‐related differences in activity, and the p.o.\s.c. activity ratio was 2.01 in males and 1.74 in females. Following oral administration, the duration of anticonvulsant activity in the bicuculline test was more than 8, but less than 24 hr. In guinea pigs, R 58 735 completely antagonized hypoxia‐induced amnesia at a dose of 2.5 mg\kg s.c. Furthermore, it enhanced acquisition of a two‐way avoidance task over a broad dose range (0.63–20 mg\kg) in rats.
R 58 735, a novel antihypoxic drug improves memory in rats
Authors: Clincke Gilbert , Sahgal Arjun
Published: January 2005

Rats weren given free choice to enter either a black or a white compartment when placed on an illuminated runway. On the fourth day a mild shock was given upon entry. Animals were subsequently injected with either solvent or a dose of R 58 735. Drug treatment dose‐relatedly increased entry latency on retention test (day 5) and doubled choice reversal at the highest dose (25 mg\kg s.c.) given. The results suggest that R 58 735 has a direct, memory enhancing action.
Interactions of haloperidol with discriminative responding controlled by 10 mg/kg of cocaine in rats
Authors: Colpaert Francis C.
Published: January 2005

Nine rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two‐lever food‐reinforced drug discrimination procedure. Saline and 0.31–10 mg/kg doses of cocaine were tested for generalization after pretreatment with either vehicle or 0.04 and 0.16 mg/kg of haloperidol. The 0.04 and 0.16 mg/kg doses of haloperidol produced a 2.3 and 5.0‐fold shift to the right, respectively, of the cocaine generalization gradient. Extrapolation of the generalization data suggests that about 3 mg/kg of haloperidol is required to antagonize completely the discriminative effects of the 10 mg/kg training dose of cocaine. Cocaine (0.63 mg/kg) reversed the rate‐depressant effects of 0.04 mg/kg of haloperidol, but even 10 mg/kg only partially attenuated the behavioral depression produced by 0.16 mg/kg of haloperidol. Also, up to 10 mg/kg doses of cocaine exerted no reliable effect on the alternative lever responding produced by 0.04 or 0.16 mg/kg of haloperidol. The data suggest that 2.3–5.0‐fold shift of the cocaine gradient, but not a complete blockade of the discriminative effects of the 10 mg/kg training dose of cocaine, can be achieved with doses of haloperidol at which the drug presumably interacts in a specific manner with dopamine receptors in the brain.
Short‐term and chronic effects of transdermal nitroglycerin in stable angina pectoris
Authors: Hunter Kenneth W. , Mahapatra Rajat
Published: January 2005

Thirty‐five patients with stable angina pectoris (AHA functional class II or III) entered a 5‐week short‐term study to determine the efficacy and safety of a transdermal therapeutic system of nitroglycerin (TDN; 5 to 20 mg/day). Nineteen of these patients were available for a final reassessment in a long‐term follow‐up after at least 1 year of continuous therapy; hence, total treatment time exceeded 8,400 patient‐days. The therapeutic efficacy of TDN was determined from weekly patient diaries of angina frequency, as well as the clinical assessment of functional class according to the criteria of the American Heart Association. Frequency of angina was reduced from ten to less than three attacks per week in all treatment groups, irrespective of angina severity at the outset, and reduction in anginal frequency was statistically significant (P <0.05) in the 10‐, 15‐, and 20‐mg dosage groups. Sixteen of the 19 patients (84%) who entered the long‐term follow‐up required no change in dosage, and all 19 patients showed improvement in AHA function class at the final reassessment. Our study showed that TDN exerted a sustained, clinically significant therapeutic benefit during both a short‐term study and long‐term follow‐up in patients with stable angina pectoris.
Pinacidil monohydrate—a novel vasodilator: Review of preclinical pharmacology and mechanism of action
Authors: Cohen Marlene L.
Published: January 2005

Pinacidil dose‐dependently decreased blood pressure in normotensive, renal hypertensive, spontaneously hypertensive, and neurogenic hypertensive rats; in anesthetized cats; and in normotensive and renal hypertensive dogs by a mechanism associated with decreased total peripheral resistance and reflex tachycardia. Pinacidil was 2–4‐fold more potent as an antihypertensive than hydralazine. Antihypertensive activity of pinacidil was not modified by α, β, cholinergic, or histaminergic receptor antagonists and was not associated with calcium channel blockade, activation of cyclooxygenase, or formation of the vasodilator, adenosine. In vitro, pinacidil relaxed blood vessels contracted with several agonists by a mechanism that was independent of an intact endothelium, did not increase either CAMP or cGMP, and was approximately 700 times more potent than minoxidil or hydralazine. Thus, pinacidil is a direct‐acting vasodilator, whereas minoxidil and hydralazine must be metabolized to a vasoactive species or exert some indirect effect for anithypertensive activity in vivo. Pinacidil lowered blood pressure in decerebrated cats, and only trace amounts of radiolabeled pinacidil distributed to the brain, suggesting minimal central effects. Pinacidil was rapidly absorbed after oral administration in rats, dogs, and man, showing a plasma half‐life of approximately 30 min in all three species with peak plasma levels within 30 to 60 min. The major biotransformation product of pinacidil in rats, dogs, and man was pinacidil‐N‐oxide; and renal excretion was the main elimination pathway for both agents. Pinacidil‐N‐oxide was less potent than pinacidil as an antihypertensive agent and showed approximately 10–100‐fold less vasodilation than pinacidil in vitro. In summary, pinacidil is a clinically effective novel antihypertensive agent that nonselectively inhibits contractile responses of arterial and other smooth muscle.
The effects of clovoxamine on sleep of normal volunteers: A double‐blind placebo‐controlled study
Authors: Wilson William H. , Ban Thomas , Coleman Bernard , Vause Beth , Papadatos John
Published: January 2005

In a double‐blind placebo‐controlled study the effects of clovoxamine on sleep were evaluated. Each of 12 healthy male volunteers was given clovoxamine (50 and 150 mg) and placebo according to a repeated‐measures randomized Latin square design. All night sleep EEGs and subjective evaluations of sleep were recorded on each night. Clovoxamine was found to have effects on sleep EEG and subjective evaluation that were consistent with findings reported for other antidepressants such as imipramine.
Dimaprit stimulation of gastric acid secretion in rhesus monkeys and dogs
Authors: Russell James , Becci Michels , Mir G. Nabi
Published: January 2005

Tests were performed to characterize the gastric secretory effect of the H2 agonist, dimaprit, in rhesus monkeys. Dose‐response studies were performed. The monkeys were chaired, and increasing doses of dimaprit (0.03 to 3.0 mg/kg hr) were infused intravenously. Gastric secretions were collected continuously through a nasogastric tube and were measured at 15‐min intervals. The completeness of collection was confirmed based on the recovery of an intragastric marker. Dimaprit dose dependently increased the total acid output (ED50 = 0.198 mg/kg hr) and the volume of gastric secretion. Ranitidine (1 mg/kg hr, i.v.) shifted the dimaprit dose‐response curve to the right in a parallel fashion causing a 13‐fold increase in the ED50 for acid output (2.54 mg/kg hr). Similarly, ranitidine competitively inhibited the secretory effect of dimaprit in the gastric fistula dog. In addition, when a single dose of dimaprit was infused over a 4‐hr period, both the monkey and dog exhibited a secretory plateau followed by a secretory “fade.” We conclude that the secretory effects of dimaprit are qualitatively similiar for rhesus monkeys and dogs.
Effects of flunarizine on rat cerebral cortex
Authors: Reid Kennet H. , Marrannes Roger , Wauquier Albert
Published: January 2005

Flunarizine was tested using a single dose (40 mg/kg IP) and multiple doses (30 mg/kg PO presurgery) in 200–250 g male Wistar rats, using physiological measures related to the rapid ionic shift seen in cerebral cortex following a sudden insult. The threshold for initiation of a spreading depression was increased by flunarizine treatment only in rats in which the cortex had previously been injured. The time to rapid ionic shift after cardiac arrest (global ischemia) was increased by both flunarizine and phenytoin. Other measures tested showed no difference in normal cortex under flunarizine treatment. Flunarizine appears to have little or no effect on normal cortical tissure, but rather seems to exert a therapeutic effect on injured cortical tissue. Flunarizine may be a useful agent in the management of cerebral trauma.
Proof of antihypoxidotic properties of tenilsetam in man by EEG and psychometric analyses under an experimental hypoxic hypoxidosis
Authors: Saletu B. , Grünberger J. , Anderer P.
Published: January 2005

Proof of the protective properties against cerebral hypoxic hypoxidosis of a new potentially nootropic drug, tenilsetam (TEN), were studied as compared with 5 mg co‐dergocrine mesylate (CDM) in a double‐blnd, placebo‐controlled trial. Hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% N2, equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. They received randomized after an adapation session placebo, 150 mg, 300 mg, and 900 mg TEN and 5 mg CDM. Blood gases, quantitative EEG, and psychometric measures were obtained under normoxic (21% O2) and hypoxic (9.8% O2) conditions before as well as 2,4,6, and 8 hr after oral drug administration. Blood gas analysis demonstrated under hypoxia a drop in PO2 from 91 to 37 mm Hg and in PCO2 from 38 to 33 mm Hg, while pH increased from 7.41 to 7.47. Under these hypoxic conditions, computer‐assisted spectral analysis of the EEG showed an increase of delta/theta, decrease of alpha, and increase of superimposed fast beta activity indicative of deterioration in vigilance. The latter was documented at the behavioral level by deterioration of intellectual and mnestic functions, psychomotor activity, performance in a reaction time task, mood, and wakefulness. Both TEN and CDM attenuated this brain dysfunction, although in a different manner. Whereas TEN induced an increase in alpha and decrease of fast beta activity as compared with placebo, 5 mg CDM attenuated delta/theta and increased alpha‐adjacent beta activity. Multivariate analysis based on changes in all EEG‐variables exhibited the highest dosage TEN and the reference substance significantly different from placebo. Psychometric data added—despite high variance—further evidence for antihypoxidotic/nootropic properties of both drugs, as psychometric performance under hypoxia deteriorated by 45% after placebo, while after 5 mg CDM, 150 mg, 300 mg, and 900 mg TEN only by 25, 27, 39, and 22%, respectively. Based on changes in all 12 psychometric variables obtained at all times, 900 mg, but also 150 mg TEN as well as 5 mg CDM, were significantly different from placebo. Under normoxic conditions, multivariate analyses did not show any significant differences to placebo, and only singular neurophysiological and behavioral changes were observed.
Role of GTP‐binding proteins in hormone and drug action: Adenylate cyclase and other transduction processes
Authors: Rodbell Martin
Published: January 2005

A large number of surface membrane receptors are coupled to proteins (N or G) that bind GTP. The N proteins generally consist of three distinct subunits, designated α, β, and γ, of which only the α‐subunit binds and degrades GTP to GDP. The α subunits are homologous in structure at the GTP‐binding domains but vary in function. When activated by GTP‐γ‐S and Mg ions or by homones and GTP, α‐subunits are released from the complexes with the β/γ‐subunits remain membrane‐bound during the activation of the α‐subunits. The α‐subunits regulate adenylate cyclase; activate phospholipases that break down phosphoinositides to inositol‐trisphosphate and diacylglycerides; regulate potassium channels and voltage‐activated calcium channels; and may regulate Mg ion channels and glucose transport. Based on the varied actions of the same α‐subunit and evidence that the α‐subunits are modified by kinases and possibly other protein‐modifying enzymes, it is proposed that these GTP‐binding proteins are the primary messengers of hormone action; when released from their moorings with β/γ‐complexes (and receptors) into the cytosol the α‐proteins are suggested to regulate several signal‐amplifying processes (enzymes, channels, transporters) and are subject to alterations in structure and function. In this sense the α‐GTP‐binding programs can be considered as “programmable messengers.”
The usefulness of social behavior in behavioral pharmacology
Authors: Niesink Raymond J. M. , van Ree Jan M.
Published: January 2005

This paper surveys the possibility and importance of studying social behavior of rats in pharmacology. Social behavior of rats tested in dyadic encounters can be used for studying experimentally induced changes in this behavior. Different exogenous factors like administering psychopharmacological agents or changes in the test environment can easily and reproducibly affect social behavior of rats. The involvement of endogenous factors in social behavior is discussed. In this respect, especially the hormones β‐endorphin and γ‐MSH seem to act as intrinsic factors involved in the regulation of social behavior. The models described are useful tools for studying the interaction between psychopharmaca and social behavior and may be of importance for studying mechanisms underlying psychopathological disturbances in humans.