bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of selective dopamine receptor agonists as novel cardiovascular drugs
Authors: Hahn Richard A. 
Published: January 2005

AbstractBenzazepine and ergoline derivatives represent two chemical classes from which orally effective dopamine receptor agonists have been developed. The benzazepines SK&F 38393 and SK&F 82526 increase renal and mesenteric blood flow as a consequence of regional vasodilation mediated by vascular (DA1) dopamine receptor stimulation. Renal vasodilation produced by acute administration of SK&F 38393 and SK&F 82526 is associated with variable diuresis and natriuresis, and minimal change in arterial blood pressure and cardiac rate. Pergolide and LY141865 are chemically related to ergoline and inhibit neurogenic release of norepinephrine by stimulating neuronal (DA2) dopamine receptors. As a result of this action, pergolide and LY141865 produce generalized cardiovascular alterations that are characterized by reduced systemic vascular resistance, arterial blood pressure, and cardic rate. SK&F 38393 and pergolide lack beta receptor agonist activity, although each produces alpha receptor mediated vasoconstriction at or slightly above doses activating dopamine receptors. SK&F 82526, LY141865, and LY171555 (the levo enantiomer of LY141865) are more selective DA1 and DA2 dopamine receptor agonists, respectively, since each is devoid of adrenergic effects over an extended dose range. Potential clinical utilities of DA1 dopamine receptor agonists include the treatment of renal insufficiency and arterial hypertension. DA2 dopamine receptor agonists may also be useful in treating arterial hypertension, as well as cardiac conditions where facilitation of stroke volume and reduction of myocardial work would be desirable.
β‐Adrenergic agonists, potent nonspecific inhibitors of circulatory shock in rats
Authors: Niemegeers C. J. E. , Awouters F. , Janssen P. A. J. 
Published: January 2005

AbstractThe activity of a series of nine β‐adrenergic agonists was studied in the potassium cyanide (KCN; 5.00 mg/kg i.v.) and the compound 48/80 (0.50 mg/kg i.v.) lethality tests in rats. All compounds were found active in both tests. The ED50 values in mg/kg for protection against KCN‐induced lethality were as follows: clenbuterol (0.0047), zinterol (0.0055), hexoprenaline (0.0093), fenoterol (0.012), isoproterenol (0.014), colterol (0.019), salbutamol (0.028), terbutaline (0.14), and metaproterenol (0.33). The obtained results illustrate that KCN antagonism in rats is a general property of β‐adrenergic agonists and that their potency is in agreement with previously reported data for β‐adrenergic stimulation. By increasing the dose levels, the protective activity of some of the compounds disappeared and LD50s at which lethality to KCN was restored could be calculated. The protective dose range, which is defined as the ratio of the LD50 and the ED50, greatly varies among the test compounds. Protection from compound 48/80 induced lethality was also obtained with all compounds. This protection occurred at higher dose levels than in the KCN test, but persisted at agonist doses that had lost protective effect against KCN. Protection from KCN‐induced lethality seems to be due to an increased tissue perfusion and to occur as long as myocardial activity is not markedly changed from normal by the test compound.
The pathogenesis and medical management of glaucoma
Authors: Caprioli Joseph 
Published: January 2005

AbstractThe term glaucoma applies to a group of diseases in which an elevated pressure in the eye causes optic nerve damage resulting in visual loss. Current medical and surgical treatment of glaucoma is designed to lower intraocular pressure to a level at which no further optic nerve damage occurs. This review serves to describe the following aspects of glaucoma and its treatment: aqueous humor dynamics and elevation of intraocular pressure; the pathogenesis of glaucomatous optic nerve damage; the nature of visual loss from glaucoma; the modern medical management of glaucoma; and a discussion of a new drug, forskolin, with potential for clinical use in the treatment of glaucoma.
Effect of propentofylline on the GABA system of a rat brain
Authors: Vukadinovića Vidoje , Stefanovich Vladimir , Rakića Ljubiša 
Published: January 2005

AbstractThe effect of propentofylline (HWA 285) [1‐(5′‐oxohexyl)‐3‐methyl‐7‐propylxanthine] on γ‐aminobutyric acid (GABA) levels and activities of 1‐glutamate decarboxylase (GAD), GABA transaminase (GABA‐T), and succinyl‐semialdehyde dehydrogenase (SSADH) in various rat brain regions (cortex, nucleus caudate, thalamus, hypothalamus, hippocampus, cerebellum, and brain stem) has been examined. Propentofylline (25 mg/kg body weight) 30 min after intraperitoneal injection induced a decrease of GAD and GABA‐T activity in all brain regions examined (significantly for GAD in cortex, caudate, thalamus, hypothalamus, and brain stem and for GABA‐T in cortex, caudate, thalamus, cerebellum, and brain stem). Under the same treatment, the GABA levels and SSADH activity were elevated in the regions examined (significantly for GABA in cortex, caudate, and thalamus and for SSADH in all brain regions). The results obtained indicate the existence of a multiple modulation of the GABA system functioning under propentofylline treatment.
Effects of putative α‐adrenoceptor antagonists and of other compounds on the loss of the righting reflex and on exophthalmia induced by xylazine in the rat
Authors: Colpaert F. C. 
Published: January 2005

AbstractIntraperitoneal injection of 20 mg/kg of xylazine causes loss of the righting reflex (LRR) and exophthalmia in the rat. The experiments determined some of the pharmacological characteristics of these responses to xylazine. The putative α2‐adrenoceptor antagonists yohimbine, piperoxan, CGS 7525 A, and idazoxan blocked the LRR response; tolazoline, phentolamine, and salbutamol attenuated the response to some extent, whereas prazosin, aceperone, and phenoxybenzamine exerted no apparent effect. The putative α2‐agonists clonidine, guanabenz, guanfacine, guanoxabenz, tiamenidine, and naphazoline were identified in an earlier study as acting only as partial agonists in depressing rat behavior and were found here to antagonize partially the LRR response. Other compounds that attenuated but did not block the response either have some affinity for and perhaps act as partial antagonists at α2‐receptors (e.g., phentolamine, LSD, lisuride) or exert some arousing or behaviorally stimulating action (e.g., cocaine, nomifensine, tranylcypromine, apomorphine). Arousing sensory stimulation also produced a partial attenuation of the LRR response. The xylazine‐induced exophthalmia appeared responsive to the putative α1‐antagonists prazosin and aceperone, and other drugs exerting α1‐antagonist activity also antagonized the exophthalmia. The doses at which compounds antagonize xylazine‐induced LRR and exophthalmia in rat might offer an estimate of the compounds' in vivo potency in acting as antagonists at a2‐ and a,‐adrenoceptors, respectively.
Enhancement of benzodiazepine binding by methaqualone and related quinazolinones
Authors: Koe B. Kenneth , Minor Katherine W. , Kondratas Elena , Lebel Lorraine A. , Koch Susan W. 
Published: January 2005

AbstractMethaqualone and mecloqualone were found to inhibit [3H]diazepam binding to rat cortical membranes, whereas a related quinazolinone, piriqualone (3‐(2‐methylphenyl)‐2‐[2‐(2‐pyridinyl)ethenyl]‐4(3H)‐quinazolinone), elicited an increase in the binding. Irrespective of their in vitro effects on benzodiazepine binding, all three quinazolinones enhanced the amount of intravenously administered [3H]flunitrazepam bound to mouse brain in vivo. Ex vivo experiments indicated that the enhanced binding induced by methaqualone and piriqualone, as well as that elicited by the pyrazolopyridine binding enhancers cartazolate and tracazolate, involved an increase in receptor density. This ex vivo effect differed from the in vitro enhancement of [3H]diazepam binding by piriqualone, cartazolate, and tracazolate, which was caused by an increase in binding affinity, and the in vitro inhibition of binding by methaqualone. The quinazolinones did not appear to affect [3H]GABA binding, but GABA‐like activity was suggested by their potent reversal of the cerebellar cyclic GMP accumulation induced by isoniazid. The benzodiazepinelike actions (anticonvulsant, hypnotic, anxiolytic) exerted by methaqualone and related quinazolinones may be mediated via GABA/benzodiazepine/barbiturte receptor complexes.
Effect of hot plate temperature on the antinociceptive activity of mixed opioid agonist‐antagonist compounds
Authors: Zimet Phillippe O. , Wynn Richard L. , Ford Robert D. , Rudo Frieda G. 
Published: January 2005

AbstractThe effects of four different hot plate temperatures (49.5, 53, 55, and 60°C) on the antinociceptive activity of butorphanol, nalbuphine, pentazocine, and morphine were determined. Antinociception, as measured by an increase in percent maximum possible effect (%MPE) derived from time to paw lick in mice increased with dose for all compounds except nalbuphine at all temperatures. Nalbuphine elicited activity (50% MPE) at one dose (3 mg/kg) at 49.5°C. Butorphanol, 10 mg/kg, and pentazocine, 10 mg/kg, produced 100% MPE and 80% MPE at 49.5°C and 53°C, respectively. Only morphine (20 mg/kg) produced 100% MPE at all temperatures. Since every compound exhibited antinociceptive activity at 49.5°C at some dose below toxicity, it is suggested that this is the preferred temperature to screen for mixed opioid compounds.
Platelet activating factor and inflammation in atherogenesis: Targets for drug development
Authors: Handley Dean A. , Saunders Robert N. 
Published: January 2005

AbstractThere is substantial evidence that the pathogenesis of atherosclerosis has one or more inflammatory components. As arterial injury is a primary event in the disease initiation and progression, inflammatory agents which injure and thus increase permeability of the arterial endothelium may lead to the development of atherosclerosis. The actions of circulatory mediators of inflammation to increase endothelial permeability may consequently accelerate entry or infiltration of lipid and other plasma macromolecules into the vessel wall. Reviewed are the biological properties of platelet activating factor (PAF), a potent lipid mediator believed to play a role in such disease states as allergic asthma, inflammation, systemic shock, myocardial ischemia, and allograph rejection. Emphasized are the actions of PAF related to increased endothelial permeability, cardiovascular actions and pathological profiles which indicate a role in the development of atherosclerosis and heart disease.
Impact of Janssen drugs for the identification of brain receptors
Authors: Laduron Pierre M. , Leysen Josée E. , Gommeren Walter , Janssen Paul F. M. , Schotte Alain , van Dun Jacky , van Gompel Paul , Verwimp Mady , Wouters Walter 
Published: January 2005

AbstractChemical compounds synthesized at Janssen Pharmaceutica are commonly used to identify and characterize neurotransmitter receptors in the brain and in the peripheral system through in vitro or in vivo binding techniques. In this regard, they have played a prominent role in advancing our knowledge about dopamine and serotonin receptors; indeed the identification in vitro or in vivo of these receptors, their solubilization, and their purification were made possible by the availability of3H‐haloperidol,3H‐spiperone, and3H‐ketanserin. Other ligands such as3H‐dexetimide and3H‐lofentanil were used to demonstrate, for the first time, axonal transport of muscarinic and opiate receptors. Finally some of these ligands (spiperone, carfentanil, ketanserin) allowed human brain receptors to be visualized through PET scanner.
Dose‐proportionality, bioavailability, and steady‐state kinetics of astemizole in man
Authors: Heykants Jozef , van Peer Achiel , Woestenborghs Robert , Jageneau Anton , Vanden Bussche Gabriel 
Published: January 2005

AbstractThe pharmacokinetics and dose‐proportionality of astemizole (AST) (10, 20, and 30 mg given orally) were studied in 12 healthy male subjects by radioimmunoassay after selective extraction, enabling the determination of the plasma levels of AST and its major metabolite desmethylastemizole (DES‐AST). Peak levels of AST were reached within 1 hr. Plasma levels decayed biphasically with terminal half‐lives of about 1 day for AST and about 10 days for DES‐AST. Areas under the curve of parent drug accounted for 5% of those of DES‐AST. The bioavailability/bioequivalence of AST was studied in 21 healthy subjects according to a three‐way cross‐over design. Subjects received orally 30‐mg doses as a tablet, suspension, or solution. The study demonstrated an equal bioavailability of the drug from the three formulations since rate and extent of absorption were not significantly different. In patients with perennial allergic rhinitis, treated for 20 weeks with AST 10 mg/day, steady‐state was reached within 1 week for AST and within 4 weeks for DES‐AST. Elimination half‐lives after chronic treatment were similar to those after single dosing. Steady‐state plasma levels were in close agreement with predicted levels, indicative of linear pharmacokinetics of AST in man.
Haemodynamic effects in man during exercise of a single oral dose of narbivolol (R 67555), a new beta‐1‐adrenoceptor blocking agent: A comparative study with atenolol, pindolol, and propranolol
Authors: De Crée Jean , Geukens Hedwig , Leempoels Jos , Verhaegen Herman 
Published: January 2005

AbstractIn eight normal volunteers R 67555 at 5 mg and 10 mg significantly lowered the exercise‐induced increase of systolic blood pressure by 20 and 25%, and the exercise‐induced increase of heart rate by 20 and 21% respectively. The blood pressure lowering effect of R 67555 6 hr after intake was comparable to that observed after atenolol, pindolol, and propranolol. In contrast, the lowering of exercise‐induced increase of heart rate was significantly less with R 67555 than with the other beta‐blockers tested. The ratio of PEPc/LVETc, a measure of left ventricular performance, significantly increased 3 hr after intake aof atenolol, propranolol, and 10 mg of R 67555 but not after pindolol and 5 mg of R 67555. Six hr after administration of pindolol and of 5 mg of R 67555, the ratio PEPC/LVETc was significantly lowered as compared with control values. The post‐exercise left ventricular ejection time (LVETc) significantly shortened 3 hr and 6 hr after intake of 5 mg and 10 mg of R 67555, whereas a trend to prolongation was observed after administration of atenolol, pindolol, and propranolol.
Ketanserin: A novel cardiovascular drug
Authors: Symoens Jan , Janssens Monique 
Published: January 2005

AbstractExtensive clinical investigation has shown that ketanserin is an effective first‐line antihypertensive agent with particular advantages in older patients. It has a favorable hemodynamic profile and seems devoid of serious side‐effects. Clinical studies in various diseases indicate a gradual improvement of the microcirculation, which is compatible with selective serotonin S2‐antagonism. Ketanserin has a favorable influence on several cardiovascular risk factors. Preliminary data suggest that it has vascular protective effects in patients with atherosclerosis.
A comparative study of the effects of ritanserin (R 55 667) and chlordiazepoxide on rat open field behavior
Authors: Meert Theo F. 
Published: January 2005

AbstractA rat open field test is described in which the inherent tendency of rats to explore an environment is titrated against their inherent tendency to avoid an open field that is large, brightly illuminated, ceilingless, and novel. The procedure appeared responsive to the effects of benzodiazepines, barbiturates, and some related compounds. Particularly pronounced activity was obtained with ritanserin; the compound disinhibited rat exploratory behavior at doses ranging from 0.04 to 10 mg/kg. Ritanserin, but not chlordiazepoxide, significantly increased the number of animals entering the open field. Chlordiazepoxide, but not ritanserin, significantly increased the number of animals making at least nine transits. The observations suggest that chlordiazepoxide and ritanserin differ in their mode of disinhibitory action on rat open field behavior.
Thymosthenic effects of ritanserin (R 55667), a centrally acting serotonin‐S2 receptor blocker
Authors: Reyntjens André , Gelders Yves G. , Hoppenbrouwers Marie‐Lise J. A. , Vanden Bussche GabriëL 
Published: January 2005

AbstractRitanserin, characterized as a long‐acting serotonin‐S2 antagonist and as a pure and selective antagonist of LSD discrimination in rats, was found to be effective in the treatment of anxiety states. In these studies the observation that the patients felt less tired and more energetic with improved mood has led to study the effects of ritanserin 10 mg b.i.d. in dysthymic disorder and chronic schizophrenia, two conditions with a predominant symptomatology of anergy. The results obtained from two separate placebo‐controlled studies showed significant improvement of depressive mood, early insomnia, agitation, and psychic anxiety in the dysthymic group, whereas negative and affective symptoms showed the best improvement in the schizophrenic group under concurrent decrease of extrapyramidal symptomatology. In both diagnostic groups the drug treatment was very well tolerated. Based on the results that ritanserin showed predominant improvement of anergy and depressed mood, the drug was ascribed thymosthenic properties, which are further supported by the specific property of ritanserin to increase human slow wave sleep.
Stimulation of gastroduodenal motor activity: Dopaminergic and cholinergic modulation
Authors: Schuurkes Jan A. J. , Helsen Ludo F. M. , Ghoos Etienne C. R. , Eelen Jan G. M. G. , van Nueten Jan M. 
Published: January 2005

AbstractThe effects of domperidone, cisapride, metoclopramide and bethanechol were determined on antroduodenal coordination, in vitro in the gastroduodenal preparation of the guinea pig and in vivo in conscious Beagle dogs implanted with strain gauge force transducers. In vitro dopamine inhibited and the dopamine antagonist domperidone stimulated antroduodenal coordination. The effect of domperidone was blocked by atropine or tetrodotoxin, but not by hexamethonium. Propranolol, prazosin, and yohimbine did not enhance antroduodenal coordination. Only at one of the concentrations tested did bethanechol moderately enhance antroduodenal coordination. Cisapride stimulated antroduodenal coordination in a dose‐dependent manner. This effect could also be blocked by atropine or tetrodotoxin. Metoclopramide (at higher concentrations) also enhanced antroduodenal coordination. The order of potency (expressed in terms of EC50‐values) was domperidone (1.4 × 10−7 M) = cisapride (1.9 × 10−7 M) ≥ ≥ metoclopramide (2.2 × 10−5 M). In vivo in conscious Beagle dogs, similar results were obtained. Bethanechol did not enhance antroduodenal coordination. In this case, the order of potency (expressed in terms of the percentage increase in antroduodenal coordination at 0.31 mg/kg, i.v.) was cisapride (208%) ≥ domperidone (152%) = metoclopramide (138%). Thus, domperidone, cisapride and, to a lesser extent, metoclopramide, but not bethanechol, can effectively improve antroduodenal coordination. The stimulatory effects of domperidone are mediated via specific dopamine receptors (i.e., different from α1‐, α2‐ or ß‐adrenergic receptors), located on postganglionic nerves in the myenteric plexus. The stimulatory effects of cisapride are mediated via cholinergic nerves in the myenteric plexus and the moderate effects of metoclopramide may be mediated via both mechanisms.
Quantitative aspects of the antisporulant activity of imazalil, an agricultural fungicide
Authors: van Gestel Jef , Van Leemput Leo , Marichal Patrick 
Published: January 2005

AbstractA new technique for collecting aerial conidiating parts of Penicillium italicum was used to study the action of imazalil as an antisporulant. In spite of its very low vapor pressure, imazalil reached the target site–‐the aerial hyphae–‐via the vapor phase. Using 14C‐labelled imazalil it was found that uptake proceeded very rapidly, reaching concentrations of 2 to 3.8 μg imazalil per g fresh weight of aerial mycelium within 24 hr. This amount caused alterations, both in the morphology of the hyphae and in ergosterol biosynthesis.
Post‐harvest treatment of apples with imazalil: Fate of the fungicide during fruit storage and juice production
Authors: van Leemput Leo , Meuldermans Willem , Woestenborghs Robert , Hendrickx Jan , Hendriks Rik , Heykants Jozef 
Published: January 2005

AbstractGolden Delicious apples were dip‐treated with 14C‐labeled or unlabeled imazalil (500 mg/liter) and subsequently kept in controlled‐atmosphere storage for up to 7 months. Virtually all the residue was restricted to the peel of the fruit. Although the extraction recovery declined with storage time due to formation of “bound‐residue,” more than 80% of the total imazalil‐derived residue was recovered at the end of storage. The levels of imazalil on the 14C‐treated apples decreased with a first‐order rate constant of 3.45 × 10−2/month. The presence of an O‐dealkylation product (R 14 821) and the formation of “boundresidue” was prominent from the 4‐month sampling on. Apples that had undergone imazalil treatment (375 mg/liter) on a commercial scale were processed to single‐strength juice after 5.5 months of cold storage. The wet pomace contained 66–71% (3.7–4.2 μg/g) of the whole‐fruit residue, and the single‐strenth juice 1.3–3.5% (0.07–0.12 μg/ml). In the filtration cake 6.0–8.3% (5.4–5.8 μg/g) of the original residue was found. Detectable (≥ 0.05 μg/g) levels of R 14 821 were found in the filtration cake only.
Alfentanil and sufentanil: Towards a more specific use of narcotics in anesthesia
Authors: Vanden Bussche Gabriël , Noorduin Henk 
Published: January 2005

AbstractMolecular redesign of existing compounds has led to the development of narcotic agents such as alfentanil and sufentanil, which may allow a greater and more specific use of narcotics in clinical anesthesia. The rapid onset and short duration of action makes alfentanil very suitable in those situations where rapid suppression of reflex responses is required (e.g., peroperative supplementation during stressful moments) or where longer acting compounds are less appropriate (e.g., short surgical procedures). The high specificity and potency of sufentanil provide deeper analgesia and a more complete stress protection than existing narcotics, without increasing postoperative depression. These characteristics make sufentanil especially beneficial in those situations where high doses are required (e.g., major surgical procedures such as cardiac surgery).
In vivo pharmacological activity of r 47 243 in rat: A comparison with putative α2‐adrenoceptor antagonists
Authors: Colpaert Francis C. , Raeymaekers Leen 
Published: January 2005

AbstractThe study examined the effects of R 47 243 and its (‐)‐ and (+)‐isomers as well as those of the putative α2‐antagonists yohimbine, piperoxan, CGS 7225 A, and idazoxan at 1‐ to 24‐hr time intervals after oral administration in rats. The experiments determined the antagonism produced by these compounds of the loss of the righting reflex (LRR) and of the exophthalmia (EXO) induced by intraperitoneal injection of 20 mg/kg of xylazine. Antagonism of LRR constitutes an in vivo measure of drug antagonist effects at CNS receptors that mediate behavioral depression produced by putative α2‐agonists; antagonism of EXO offers an in vivo measure of α1‐antagonist activity. More so than idazoxan or any of the other putative α2‐antagonists tested, R 47 243 appeared to be a potent, long acting, and specific antagonist; it also acted as a full antagonist rather than as a partial agonist and showed excellent oral absorption.