bluuebunny/crossref_metadata_2025_split huggingface dataset:
Receptor specificity of the 5HT2 receptor antagonist, LY53857
Authors: Cohen Marlene L. , Colbert Walter , Wittenauer Laura A. 
Published: January 2005

AbstractLY53857 is a potent antagonist at vascular 5HT2 receptors that lacks prominent α1 or dopamine antagonist activity. The present report investigates the interaction of LY53857 with other receptor mechanisms. LY53857 showed no agonist activity in the guinea pig trachea, guinea pig atria, guinea pig ileum, or rat vas deferens. Furthermore, LY53857 did not antagonize histamine (H1) or β2 receptors in the guinea pig trachea, β1 in the guinea pig atria, muscarinic, or angiotensin I receptors in the guinea pig ileum. However, LY53857 did block α2 receptors (−log KB = 6.51) as determined by antagonism of the inhibitory effects of the selective β2 agonist, UK‐14,304, on the twitch response in the guinea pig ileum. LY53857 antagonized β2 receptors at concentrations approximately 6000‐fold higher than necessary to block 5HT2 receptors (−log KB = 10.3). Taken in concert, these data support the contention that LY53857 is a highly selective antagonist of 5HT2 receptors, and that LY53857 is a useful tool with which to probe 5HT2 receptors and serotonergic mechanisms.
A preliminary investigation of “albert 285” (HWA 285) on psychomotor performance, mood, and memory
Authors: Hindmarch Ian , Subhan Zahed 
Published: January 2005

AbstractEight healthy female volunteers received 150, 300, and 450 mg of HWA 285 and placebo according to a randomized, double‐blind crossover design. The subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS), and a Sternberg memory scanning test (SMST) 1 and 2 hr following treatment. No statistically significant changes from placebo were observed on CFF, CRT, or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was significantly improved with respect to placebo 1 hr following treatment with HWA 285 at 150, 300, and 450 mg dose levels. The action of the drug was found to be specific in its effects on the central serial comparison stage of the information processing model.
Open label evaluation of the novel antipsychotic compound BW234U in chronic schizophrenics
Authors: Schwarcz Glenn , Halaris Angelos , Dren Anthony , Manberg Paul 
Published: January 2005

AbstractIn a 28‐day open label study, 15 inpatients with chronic schizophrenia in relapse were treated with BW234U. Approximately half of the patients showed marked improvement. Four patients showed no change and three dropped out. Thought disturbance improved markedly. The compound was tolerated very well.
Safety and efficacy of bupropion, a novel antidepressant
Authors: Dufresne Robert L. , Becker Robert E. , Bltzer Robert , Wagner Richard L. , Lal Harbans 
Published: January 2005

AbstractBupropion, a pharmacologically unique antidepressant, was found to be both safe and effective in an open clinical trial in 16 depressed inpatients. Subjects were given either bupropion in doses ranging from 300 to 750 mg daily or the positive control amitriptyline in doses ranging from 75–300 mg daily. Patients were dosed following an ascending dosage regimen for a minimum of 2 and up to 10 weeks. Clinical assessment of antidepressant efficay was made prior to, during, and on the last day of drug therapy through the use of the Hamilton depression scale, the Zung self‐rating depression scale, and the clinical global impressions rating scale. Patients were assessed for adverse reactions on relevant observational, medical, and clinical laboratory tests prior to and throughout the study. Patients improved significantly from baseline on the efficacy rating scales in a manner similar to the positive control, though the small size of the positive control group lessened the chance of occurrence of statistically significant differences between groups. The main adverse reactions reported by bupropion‐treated patients were agitation or excitement, insomnia, and a mild tremor. Dry mouth and orthostatic hypotension occurred most often in amitriptyline‐treated patients.
A novel, orally effective hypoglycemic agent, SaRI 59–801, in laboratory animals
Authors: Ho Robert S. , Wiseberg Jack J. , Brand Leonard J. , Nadelson Jeffrey , Boyajy Louis D. 
Published: January 2005

AbstractSaRl 59‐801 (59‐801) (α‐[dimethylaminomethyl]‐2‐[3‐ethyl‐5‐methyl‐4‐isoxazolyl]‐1H‐indole‐3‐methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2‐hr hypoglycemic ED25 in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED50 of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59‐801 to fasting rats (ED25 = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59‐801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1‐hr pretreatment with 59‐801 (ED50 = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED25 of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db+/db+) mice, 59‐801 was more potent in producing hypoglycemia (ED25 = 47 mg/kg) than their lean littermates (ED25 = 131 mg/kg). In alloxan‐diabetic rats or streptozotocin‐diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β‐cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59‐801.
The serotonin‐S2 Receptor: A receptor‐transducer coupling model to explain insurmountable antagonist effects
Authors: De Courcelles Didier de Chaffoy , Leysen Josée E. , Roevens Peter , van Belle Herman 
Published: January 2005

AbstractFive serotonin‐S2 antagonists, ketanserin, pipamperone, methysergide, ritanserin, and LSD, were tested for their ability to inhibit signal transduction coupled to the serotonin‐S2 receptor by measuring the serotonin‐induced [32P] phosphatidic acid formation. The five drugs inhibited the response in a non‐competitive manner. Since drugs such as ketanserin and pipamperone were found to dissociate rapidly from serotonin‐S2 receptor sites in binding studies, slowly reversible binding can hardly explain the apparent non‐competitive inhibition of the biochemical effect. The authors, therefore, propose a new model of interaction between the serotonin‐S2 receptor macromolecule and the signal transducing system that is compatible with the present and previous experimental observations.
Non‐antidopaminergic, non‐cholinergic stimulation of gastric emptying with cisapride (R 51 619) in rats
Authors: Megens Anton A. H. P. , Canters Luc L. J. , Artois Kamiel S. K. , Smeyers Frans , Keersmaekers Roger C. A. , Awouters Frans 
Published: January 2005

AbstractThe gastrokinetic activity of cisapride, bethanechol, domperidone, and metoclopramide was tested in rats and compared with the direct cholinergic activity (induction of salivation and lacrimation in rats) and peripheral and central antidopamine activity (antagonism of apomorphine‐induced emesis in dogs and abnormal behaviour in rats, respectively) of the compounds.Cisapride showed a high dissociation between gastrokinetic activity (0.31 mg/kg) on the one hand, and direct cholinergic activity (ED50: ≥ 40 mg/kg) and peripheral and central antidopamine activity (ED50s: 3.3 and 18.6 mg/kg), on the other hand. In contrast, metoclopramide combined antidopamine effects (ED50s: 0.28 and 0.76 mg/kg for peripheral and central activity) and bethanechol direct cholinergic effects (ED50s: 2.7 and 3.6 mg/kg for lacrimation and salivation) with their gastrokinetic activity, which was obtained with bethanechol at 0.63 mg/kg and with metoclopramide at 1.25 mg/kg. Domperidone was found to be a potent and selective antagonist of peripheral dopamine receptors (ED50: 0.0071 mg/kg) but failed to stimulate gastric emptying (ED50: ≥ 10 mg/kg).The present data confirm cisapride as a potent gastrokinetic compound devoid of antidopaminergic or direct cholinergic properties.
A comparative study on the in vitro metabolism of cisapride using subcellular liver fractions of dog, rabbit, and male and female rats
Authors: Lavrijsen Karel L. M. , Meuldermans Willem , Knaeps Fons A. G. , Lauwers William , Heykants Jozef 
Published: January 2005

AbstractCisapride‐3H, labeled at the fluorophenyl moiety or at the piperidine ring, was incubated with the supernatant and microsomal fractions of various animal livers and an NADPH‐generating system. The major metabolites were identified by co‐chromatography with high performance liquid chromatography (HPLC) and by mass spectrometry. A mass balance of the major metabolites in incubates was made up by radio‐HPLC. The rate of metabolism of the drug decreased in the following order: rabbit ≥ male rat ≥ dog ≥ female rat. The major in vitro metabolic pathways in the animal species were rather similar. Main biotransformation routes were oxidative N‐dealkylation at the piperidine nitrogen and aromatic hydroxylation occurring either at the fluorophenyl or at the benzamide moiety. Hydroxylation was relatively more abundant in female compared to male rats, whereas oxidative O‐dealkylation was important in incubates with rabbit subcellular fractions only. Furthermore, the formation of at least four sulfate conjugates could be demonstrated. Metabolism experiments with phenobarbital‐induced or 3‐methylcholanthrene‐induced microsomes indicated that phenobarbital inducible cytochrome P‐450 isoenzyme(s) are involved in the in vitro metabolism of cisapride.
An efficient method to evaluate protective drugs against regional ischemia of the heart
Authors: Vandeplassche Godelieve , Wouters Luc , Hermans Carlo , Xhonneux Raymond , Borgers Marcel , Flameng Willem 
Published: January 2005

AbstractThe variables related to infarct size were examined in order to develop an efficient procedure for the assessment of cardioprotective action in the dog. In the open chest model the left anterior descending coronary artery was ligated for 90 or 240 min. Regional myocardial blood flow was measured by tracer microspheres and infarct size was studied using triphenyltetrazoliumchloride. Infarct size was measured in relation to perfusion area, collateral flow, and rate pressure product. Using perfusion area as an independent variable, only 61% of the variance in infarct size could be explained. Including collateral flow also, this percentage increased to 80. Using perfusion area and collateral flow, infarct size could be predicted accurately. The usefulness of this procedure is demonstrated by data obtained with test compound R 51 430.
Rimcazole (BW 234U), a novel antipsychotic agent whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic receptors in brain
Authors: Ferris R.M. , White H.L. , Tang F.L.M. , Russell A. , Harfenist M. 
Published: January 2005

AbstractRimcazole is a novel antipsychotic agent free of extrapyramidal side effects as judged by its profile in animal behavioral models and by results of early clinical trials in acute schizophrenic patients. The present study shows that rimcazole is different biochemically from the typical and atypical neuroleptics. Concentrations of 10−5 to 10−4 M are necessary to achieve even weak effects on dopamine‐stimulated adenylate cyclase activity (D1 receptors), [3H]dopamine binding in mesolimbic and striatal areas of rat brain. Rimcazole's extremely weak potency as a D2 receptor blocker in brain was readily apparent when compared to several other neuroleptics: It was 160 times weaker than sulpiride, the least potent striatal D2 receptor blocker studied, and 10,000 times weaker than haloperidol, the most potent. Rimcazole had no effect on many of the enzymes involved in catecholamine synthesis and metabolism in vitro, did not effect the synthesis of [3H]dopamine from [3H]tyrosine in vivo, and did not alter the effects of a dopaminergic agonist and a dopaminergic antagonist on [3H]dopamine synthesis in vivo. It was moderately potent as an inhibitor of serotonin (5‐HT2) receptors but had only weak effects on muscarinic cholinergic, α1–, α2 –, β –adrenergic, benzodiazepine, GABA, adenosine (A1 and A2), glycine, serotonin (5‐HT1), imipramine, neurotensin, and phencyclidine receptors and calcium channels in binding assays. It was a moderately potent, competitive inhibitor of dopamine uptake in vitro and had no pharmacologically relevant effects on the spontaneous release of biogenic amines from isolated nerve endings. These data suggest that if rimcazole is shown to be a clinically effective antipsychotic agent, it will be the first antipsychotic whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic (D2) receptors in brain.
Double‐blind dose determination study of a new antidepressant—sertraline
Authors: Guy William , Manov Gregory , Wilson William H. 
Published: January 2005

AbstractAs part of a multicenter dose determination study designed to evaluate the safety and therapeutic activity of four fixed dose levels of sertraline—a new antidepressant with biochemical characteristics different from tricyclics—17 patients with diagnoses of major depressive disorder were treated with active medication under double‐blind conditions for 4 weeks following a 1‐week washout period. Patients receiving the two higher dose levels of sertraline exhibited almost no symptomatic improvement and manifested more adverse events that patients receiving the two lower dose levels. No statistically significant differences between the low‐dose groups and the placebo group were found. Thus, the efficacy of sertraline could not be demonstrated under these design constraints, although differential dose level effects were indicated. Dosage levels up to 100 mg/day would appear to be more clinically appropriate than higher dosage levels.
Diuretic effects of a novel uricosuric antihypertensive S‐8666 in rats, mice, monkeys, and dogs: Comparison with furosemide and trichlormethiazide
Authors: Nakamura Masuhisa , Shimizu Toshikatsu , Miyata Kenji , Kawabata Tomoji , Harada Hiroshi 
Published: January 2005

AbstractOral dose‐response relationships of S‐8666 to Na excretion were established in male and female Sprague‐Dawley rats (3–100 mg/kg), male and female ddy mice (3–300 mg/kg), female cynomolgus monkeys (2–50 mg/kg), and female beagle dogs (3–100 mg/kg). The natriuretic potency of S‐8666 was almost comparable to that of furosemide in rats but was lower in mice, monkeys, and dogs. The maximal effects were similar for S‐8666 and furosemide, which had higher ceiling values than trichlormethiazide (TCM) in rats, mice, monkeys, and dogs. Thus, S‐8666 seems to have a “loop diuretic” property like furosemide. After oral administration of S‐8666 to rats (20–100 mg/kg), the onset of natriuresis was rapid, with the peak effect occurring within 1–2 hr. TCM showed a longer lasting pattern of natriuresis than S‐8666 and furosemide. With intravenous administration (1–10 mg/kg) to rats, the t1/2 for natriuresis was 16–20 min for S‐8666 and furosemide in rats. S‐8666 showed enantioselectivity; its (S)‐(–)‐form was natriuretic, whereas the (R)‐(+)‐form was inactive. These results indicate that S‐8666 is a diuretic with a high ceiling property that has a lower potency than TCM and a longer lasting effect than furosemide.
N‐alkyl‐substituted aryl‐piperazine drugs: Relationship between affinity for serotonin receptors and inhibition of aggression
Authors: McMillen Brian A. , Davanzo Elizabeth A. , Scott Sara M. , Song Arleen H. 
Published: January 2005

AbstractBuspirone is the first of several N‐alkyl‐substituted aryl‐piperazine‐containing drugs to be approved for use as an anxiolytic agent. These drugs do not interact with the benzodiazepine‐GABA receptor complex and therefore do not share the sedating and anticonvulsant effects of benzodiazepines. Buspirone and its analogs, gepirone and ipsapirone, act as agonists both pre‐ and postsynaptically at 5HTla receptor sites. A series of piperazine‐containing drugs was tested for their affinity at the 5HTla (postsynaptic) binding sites in hippocampus and compared with their ability to inhibit isolation‐induced aggression by mice. The potent 5HTla agonist, 8‐OH‐DPAT, was the most potent drug in both tests: IC50 = 1 nM, and ED50 = 2.4 μmol/kg for inhibition of [3H]‐5HT binding and aggression, respectively. There was a good correlation between ability to inhibit aggression and ability to inhibit [3H]‐5HT binding to hippocampal membranes. Fluprazine (DU 27716) was the major exception, but results with SKF 525‐A pretreatment to inhibit drug oxidation suggest that both fluprazine and metabolites have antiaggressive activity. Like other aryl‐piperazine drugs, fluprazine is potentiated by coadministration of a postsynaptic 5HT receptor antagonist, methysergide. Since antagonists of postsynaptic 5HT receptors potentiate gepirone and 8‐OH‐DPAT inhibition of aggression, these data suggest that affinity for 5HTla receptors at presynaptic autoreceptor sites is critical for the antiaggressive activity of these drugs and possibly for their anxiolytic effects.
Cognitive functions affected by scopolamine in alzheimer's disease and normal aging
Authors: Jacob Huff F. , Mickel Susan F. , Corkin Suzanne , Growdon John H. 
Published: January 2005

AbstractWe gave scopolamine to patients with Alzheimer's disease (AD) and age‐matched control subjects in order to identify which cognitive functions are affected by blocking muscarinic receptors for acetylcholine (ACh). Both subject groups showed dose‐related impairments in verbal learning, and patients with AD exhibited enhanced vulnerability to effects of scopolamine on attentional vigilance. In the same dose range, scopolamine did not alter retrieval from long‐term lexical‐semantic memory or performance on a test of visual discrimination, suggesting that cholinergic neurotransmission is not critical for these cognitive functions. The importance of cholinergic transmission in learning and attention is confirmed by this study, and the results indicate that both these abilities should be measured in investigations of potential cholinergic treatments for AD.
Clonidine disrupts aged‐monkey delayed response performance
Authors: Davis Robert E. , Callahan Michael J. , Downs David A. 
Published: January 2005

AbstractClonidine (0.03–0.06 mg/kg), in a dose‐ and delay‐dependent manner impaired the ability of aged rhesus monkeys to perform a microcomputer‐controlled delayed response test similar to that used previously by Bartus et al. (J. Gerontol. 33:858–871, 1978). These doses of clonidine produced overt sedation, increased response latencies and decreased the percentage of correct responses. Continued disruption of delayed response performance was seen during 11 days of repeated daily clonidine (0.04 mg/kg) administration. Performance immediately returned to preexisting baseline levels on the day following cessation of this repeated drug regimen. In addition, repeated clonidine administration did not alter responsivity to acutely administered clonidine, suggesting that tolerance did not develop rapidly to the disruptive effects of this agent. These data indicate that clonidine impairs delayed response performance in aged rhesus monkeys under these testing conditions.
Pharmacological effects of MDL 11,939: A selective, centrally acting antagonist of 5‐HT2 receptors
Authors: Dudley Mark W. , Wiech Norbert L. , Miller Francis P. , Carr Albert A. , Cheng Hsien C. , Roebel Lawrence E. , Doherty Niall S. , Yamamura Henry I. , Ursillo Richard C. , Palfreyman Michael G. 
Published: January 2005

AbstractMDL 11,939 (α‐phenyl‐1‐(2‐phenylethyl)‐4‐piperidine methanol) has been shown, through in vitro studies utilizing radioligand binding and isolated tissues as well as through in vivo tests of central and peripheral serotonergic activity, to be a potent, selective antagonist at 5‐hydroxytryptamine receptors of the 5‐HT2 subtype. In particular, MDL 11,939 shows low affinity for the 5‐HT1 and 5‐HT3 subtypes of the serotonin receptor and displays low or negligible affinity for alpha adrenergic, dopaminergic, cholinergic, histamininergic, and opiate receptors. Because the 5‐HT2 subtype of the serotonin receptor has been implicated in the control of both the central nervous and vascular systems of experimental animals, it is likely that a compound with the potency and specificity of MDL 11,939 has interesting therapeutic potential.
Structure and function of the stratum corneum permeability barrier
Authors: Elias Peter M. 
Published: January 2005

AbstractThe main function of the epidermis is to generate an impermeable outer layer, the stratum corneum. The stratum corneum can be considered morphologically and functionally to represent a two‐compartment system composed of: (1) anucleate corneocytes (the bricks), largely composed of fibrous protein networks; and (2) the intercellular matrix (the mortar), predominantly composed of neutral lipid. Whereas much prior and current work on the stratum corneum has focused on the protein biochemistry leading to the formation of the keratinized corneocyte (“keratinization”), this paper is concerned with the formation, composition, and function of the intercellular matrix of the stratum corneum. For those interested in permeability barrier function, percutaneous transport, and the cutaneous reservoir, as well as most inherited disorders of cornification, it is critical to understand the “mortar,” for it is this domain that logically regulates all of these important phenomena.
Placebo‐controlled, double‐blind, crossover study to investigate the hypoxia‐protective effect of vinpocetine by psychophysiological methodology in healthy volunteers
Authors: Schaffler K. 
Published: January 2005

AbstractVinpocetine positively influences cerebral vascular resistance (> CBF), as well as O2‐extraction (> A/V‐O2‐difference) and the brain's glucose and neurotransmitter turnover, as has been shown in other experimental and clincal studies. Therefore, a hypoxia‐protective effect of vinpocetine should be expected in an experimental simulatory approach using hypoxic hypoxidosis.