bluuebunny/crossref_metadata_2025 huggingface dataset:
Mescaline‐induced head‐twitches in the rat: An in vivo method to evaluate serotonin S2 antagonists
Authors: Niemegeers C. J. E. , Colpaert F. C. , Leysen J. E. , Awouters F. , Janseen P. A. J.
Published: January 2005

An intravenous dose of 20.0 mg/kg of mescaline induced a reproducible head‐twitch response in rats. Drugs with very different pharmacological activities were tested for potential inhibition of this response. Among these drugs were a large number of serotonin antagonists, including several members of the recently described selective S2 antagonists of which ketanserin (a potent vascular S2 antagonist) and pirenperone (a pure LSD antagonist) are two prototypes. The same compounds were further studied in six in vivo tests in rats; these tests presumably measure antagonism at sites responsive to serotonin, dopamine, norepinephrine, histamine, or acetylcholine. A large number of test compounds inhibited mescaline‐induced head‐twitches. Although it was often associated with it, this activity did not correlate with any of the following effects: antagonism of apomorphine, norepinephrine, compound 48/80, physostigmine, or with mydriatic activity. Antagonism of mescaline did correlate, however, with in vivo antagonism of tryptamine and 5‐hydroxytryptophan, and with inhibition of 3H‐spiperone binding to the rat prefrontal cortex in vitro. It is concluded that inhibition of mescaline‐induced head‐twitches in the rat is a valid measure of serotonin S2 antagonist activity, also for those compounds whose primary activity occurs at dopamine, norepinephrine, histamine, or acetylcholine receptors. Ketanserin, pirenperone, and several chemically related compounds are very potent mescaline antagonists.
Potentiation of yohimbine‐induced lethality in mice: Predictor of antidepressant potential
Authors: Malick Jeffrey B.
Published: January 2005

The ability of antidepressant agents to potentiate the lethal or toxic effects of yohimbine in mice was evaluated. With very few exceptions, the antidepressants were the only agents that significantly enhanced yohimbine‐induced lethality. All of the clinically effective antidepressants, both typical (e.g., amine reuptake inhibitors, monoamine oxidase inhibitors) and atypical (e.g., mianserin, iprindole, bupropion, quipazine) drugs, produced a dose‐related potentiation of yohimbine in mice. Representative anxiolytics and antipsychotics failed to potentiate yohimbine over a wide range of doses. Although several possible “false positives” (e.g., atropine, chlorpheniramine, and d‐amphetamine) would be detected in this procedure, these same agents would be detected in other models (e.g., tetrabenazine antagonism, behavioral despair) considered predictive of antidepressant potential. Thus, the potentiation of yohimbine‐induced lethality test in mice appears to represent a useful screening procedure for discovering potential antidepressant drugs.
Effect of clonidine on responsiveness of venous smooth muscle to sympathetic neurotransmitter
Authors: Wood William B. , Sticht Frank D. , Cardoso Sergio S. , Elko Edward E.
Published: January 2005

The presence of both longitudinal and circular smooth muscle makes the canine accessory cephalic vein a sensitive preparation for the evaluation of venomotor activity. Infusion of clonidine (10 μg/kg) into this intact, peripheral vein results in transient, localized venoconstriction and prolonged arterial hypotension. Bradycardia, paralleling the hypotension in onset and duration, is a consistent concomitant. Exposure of the test vein smooth muscle to clonidine diminishes responsiveness of this vein to subsequent close injections of norepinephrine. This inhibition, though pronounced, is short‐lived and usually abates within an hour.
Effect of prazosin on veins: Inhibition of norepinephrine venoconstriction in dog forelimb
Authors: Sticht Frank D. , Wood William B. , Cardoso Sergio S. , Elko Edward E.
Published: January 2005

A dose–response curve was established based on increases in venous infusion pressure evoked by injection of a series of small doses of norepinephrine, before and after slow infusion of a prazosin solution into the accessory cephalic vein of anesthetized dogs. During the prazosin infusion, there was an increase in venous infusion pressure, which returned to control levels by the end of the infusion period. The reduction in arterial pressure that occurred during the infusion persisted throughout the experiment. Immediately following the prazosin infusion, venous constrictor responses to norepinephrine were greatly inhibited, an effect that was still present 1 hr later. Prazosin has a marked in vivo α‐adrenergic receptor inhibiting action in the accessory cephalic vein of the dog. This effect may be preceded by an agonistic action on these receptors at this site, as suggested by the increase in venous infusion pressure during the period of prazosin administration.
Buspirone as a midbrain modulator: Anxiolysis unrelated to traditional benzodiazepine mechanisms
Authors: Eison Michael S. , Eison Arlene S.
Published: January 2005

Buspirone is a clinically effective anxiolytic unrelated to the benzodiazepines in structure and pharmacological properties. Recent mechanism of action studies suggest that rather than working through traditional benzodiazepine mechanisms, buspirone affects diverse aspects of the brain's neurochemical circuitry. It acts as a presynaptic dopamine antagonist with little potency at postsynaptic dopamine sites. This action may synergize with a GABA antagonist component to its action to alter activities in diverse brain systems. These actions can be hypothesized to relate to buspirone's behavioral effects: GABA (catalepsy reversal), corticostriatal glutarnate (stereotypy), acetylcholine (EEG activation and enhanced psycho‐motor performance), and mesolimbic, mesocortical dopamine in addition to midbrain norepinephrine and serotonin (anxiolysis). A hypothetical scheme of buspirone's effects on the brain based upon already established elements of its mechanism of action is presented. This scheme suggests that buspirone's unique anxioselective profile is derived from complex polysynaptic actions and their ramifications upon multiple neural substrates that collectively mediate anxiety.
A double‐blind clinical trial of fluvoxamine and imipramine in patients with primary depression
Authors: Guy William , Wilson William H. , Ban Thomas A. , King Douglas L. , Manov Gregory , Fjetland Olaf K.
Published: January 2005

Fluvoxamine, a new serotonin‐reuptake inhibitor, and imipramine were compared under double‐blind conditions in 36 unipolar and bipolar depressed inpatients. Both drugs produced significant reductions in depressive symptomatology over a 4–6‐wk course of treatment, with the greater part of the improvement occurring in the first 2 wk. No statistically significant differences were obtained between the two drugs. Adverse reactions, particularly anticholinergic ones, were much less frequently observed in the fluvoxamine group. No clinically significant laboratory abnormalities were reported for either treatment; but minor ECG irregularities were seen under both treatments. The findings generally correspond to results obtained in previous comparative clinical trials.
The toxicology of the schistosomicidal agent oxamniquine
Authors: Chvédoff M. , Faccini J. M. , Gregory M. H. , Hull R. M. , Monro A. M. , Perraud J. , Quinton R. M. , Reinert H. H.
Published: January 2005

Oxamniquine displayed low acute toxicity in mice, hamsters, and rabbits. In rats, however, oxamniquine was much more toxic, the female being 8–10 times more sensitive than the male; single doses elicited an idiosyncratic sex‐linked hepatic necrosis and bile duct proliferation. Dogs given repeated oral doses of 20 or 30 mg/kg/day for 5 successive days every 4 weeks for 11 months showed neurological disturbances of short duration, which tended gradually to increase in severity from one dosage period to the next; no histopathological correlate could be found. In chronic studies in mice (18 months) and hamsters (19 months) with intermittent dosage regimens relevant to likely usage in man, no evidence of carcinogenicity potential was observed at dose levels up to 150 mg/kg. Oxamniquine displayed no maternal toxicity or teratogenicity in mice and rabbits, and only slight embryotoxicity after high oral doses.
Modulators of intracellular calcium
Authors: Winquist Raymond J.
Published: January 2005

The importance of calcium in excitation‐contraction coupling in both cardiac and vascular smooth muscle has resulted in an intense research interest into the intracellular regulation of this ion. Selective foci for the modulation of intracellular calcium include the interaction of calcium with the contractile protein apparatus, sites of calcium release and sequestration, and pathways for the extrusion of calcium into the extracellular space. Research efforts directed towards elucidating these phenomena have met with varied degrees of success. The presence of different calcium regulatory systems for contractile protein function, i.e., troponin in cardiac and calmodulin‐myosin light chain kinase in vascular, provides an attractive rationale for the design of selective compounds. The inherent difficulty in studying intracellular release and sequestration presently presently precludes examining the physiological implications of specific inhibition of these phenomena. However, the apparent absence of a sodium‐dependent calcium extrusion pathway in vascular tissue may lead to the design of novel cardiotonics. It is anticipated that further clarification of the similarities and differences in the calcium cycle between these tissues will result in the development of tissue‐selective therapeutic agents.
Development of selective dopamine receptor agonists as novel cardiovascular drugs
Authors: Hahn Richard A.
Published: January 2005

Benzazepine 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

The 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

The 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

The 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

Intraperitoneal 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

Methaqualone 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

The 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

There 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

Chemical 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

The 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

In 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

Extensive 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

A 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

Ritanserin, 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

The 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

A 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

Golden 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

Molecular 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

The 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.
Adenosine A1 receptors in mammalian brain: Species differences in their interactions with agonists and antagonists
Authors: Ferkany John W. , Valentine Heather L. , Stone George A. , Williams Michael
Published: January 2005

The binding of the selective ligand [3H]cyclohexyladenosine (CHA) to adenosine A1 receptors was studied in brain membrane from six species; cow, rabbit, rat mouse, human, and guinea pig. Saturation analysis gave evidence for a single binding site in each species. The number of binding sites (2.6–4.7 pmol/mg protein), based on saturation analysis, was virtually identical in each species. The Kd values were, however, different; whereas rat, rabbit, and mouse A1 receptors had similar affinities (Kd=1–2 nM), the binding site in bovine tissue had three to four times greater affinity (Kd=0.59 nM). Adenosine binding sites in human and guinea pig brain had two to three times less affinity, with Kd values 3.7 and 6.6 nM, respectively, than those in rat, rabbit, and mouse brain. Examination of the binding of five agonists, the R and S diastereomers of N6‐phenylisopropropyladenosine (PIA), CHA, 5′N‐ethylcarboxamido adenosine (NECA), and 2‐chloroadenosine, and of five xanthine antagonists, PACPX [1,3,dipropyl‐8‐(2‐amino‐4‐chloro)phenylxanthine], 1,3 diethyl‐8‐phenylxanthine (DPX), 8‐phenyltheophylline (8PT), 8‐parasulfophenyl‐theophylline (8PST), and theophylline, showed that across the species N6‐substituted adenosine analogs showed consistent differences in rank order activity. R‐PIA ≥ CHA >S‐PIA, with the compounds being most active in bovine tissue and least active in guinea pig, showing an 18‐fold difference. In contrast, the 2‐substituted analog, 2‐chloroadenosine was most active in guinea pig and human brain membranes, and least active in rat and bovine brain. The 5′‐substituted analog NECA had similar activity in all species studied. PACPX was the most potent of the xanthines studied, being most active in bovine brain tissue and least active in guinea pig; the difference in activities was 393‐fold. The interaction of the remainder of the xanthines studied was complex. In general, the rank order of potency was PACPX > DPX=8 phenyltheophylline > 8PST >> theophylline. However, in human and rabbit brain 8PT was more active than DPX, and in guinea pig 8PT was twofold less active than DPX. In addition, in human and guinea pig brain, 8PST had comparable activities. These differences in pharmacological profiles may be attributable to differences in the adenosine systems studied as previously noted by Murphy and Snyder [Mol. Pharmacol. 22:250–257, 1982], which may in turn reflect distinct differences in A1 receptors or the presence of different subtypes of adenosine receptor in the various species. While these interspecies studies need to be extended to both A2 receptors and to coupled, i.e., adenylate cyclase, systems, they underline the need for care in choosing the mammalian species in which structure activity relationships are generated. Some caution is necessary in the use of bovine brain tissue in development programs targeted towards therapeutic entities in the adenosine A1 antagonist area.
Cardiovascular pharmacology of the cardiotonic, imazodan (Cl‐914)
Authors: Evans D.B. , Potoczak R.E. , Steffen R.P. , Burmeister W.E. , McNish R.W. , Schenden J.A. , Kaplan H.R.
Published: January 2005

Imazodan is a novel pyridazinone derivative. It was evaluated in excised cardiac tissue, anesthetized dogs and monkeys, and conscious dogs. Imazodan, 10−5–10−3M, produced dose‐dependent increases in guinea pig atrial and rabbit papillary muscle contractility. In ansthetized dogs and rhesus monkeys, imazodan, 0.001–1.0 mg/kg IV, produced dosedependent increases of 10–150% in myocardial contractility (dP/dt max of left ventricular pressure), and decreases of 1–31% in aortic blood pressure. Heart rate increases were minimal (0–34%) in comparison to the changes in contractility and they occurred only at the higher doses. The positive inotropic action of imazodan was not blocked by β‐adrenoceptor blockade with propranolol. Forelimb perfusion studies in the anesthetized dog demonstrated that imazodan produces a dose‐dependent direct peripheral vasodilator action. This agent was also demonstrated to be a highly effective cardiotonic when administered orally (0.1–1.0 mg/kg) to conscious dogs. The results of these studies indicate that imazodan is an orally effective cariotonic that possesses balanced positive inotrophic and peripheral vasodilator activities and possesses a wide margin of cardiac safety.
Buspirone attenuates learned helplessness behavior in rats
Authors: Drugan Robert C. , Crawley Jacqueline N. , Paul Steven M. , Skolnick Phil
Published: January 2005

Rats pretreated with either chlordiazepoxide (5 mg/kg) or buspirone (5 mg/kg) did not develop the shuttlebox escape deficit typically observed 24 hours after a session of inescapable tailshock. In contrast, the buspirone analog gepirone (MJ 13805) (2 or 5 mg/kg) did not block this shock‐induced learning deficit. These results demonstrate that the nonbenzodiazepine anxiolytic buspirone, like chlordiazepoxide, attenuates the learned helplessness syndrome.
Prevention of postsurgical peritoneal adhesion formation by intraperitoneal administration of ibuprofen
Authors: Orita Hiroyuku , Girgis Wefki , diZerega Gere S.
Published: January 2005

Previously, we reported a reduction in the formation of post‐surgical peritoneal adhesions accompanying the use of systemically administered ibuprofen in validated animal models. Since the use of systemic ibuprofen requires high doses, we evaluated intraperitoneal drug delivery to assess the effects of locally administered low doses of ibuprofen on adhesion formation. Adhesion formation was evaluated after (a) parietal peritoneal excision, (b) abrasion of large bowel serosal, and (c) both (a + b) performed together. Adhesions formed in 2/15 rabbits with parietal peritoneal excision only, 3/15 with serosal abrasion only, and 11/15 with both procedures performed in the same rabbit. To further validate the parietal peritoneal excision + adjacent serosal abrasion technique for adhesion induction, a second group of 23 rabbits was similarly treated; 20/23 were found to have adhesions. The minimum dose of ibuprofen delivered into the intraperitoneal cavity via Alzet pump which reduced adhesions was 5 μg/10 μl/5 cm2 test site/hr. No more than 4–5 days of postoperative treatment were required to achieve a significant reduction in adhesion formation. In the 2‐kg rabbits used here that would provide a total daily dose of 60 μg/kg/day. The minimum effective dose reported by this laboratory via systemic administration of ibuprofen for reduction of postsurgical peritoneal adhesions using a similar model was 35,000 μg/kg/day. The potential utility of these findings is enhanced by the ongoing development of biodegradable drug delivery systems which can administer ibuprofen within the peritoneal cavity.
Preclinical and clinical studies on the cardiovascular and renal effects of fenoldopam: A DA‐1 receptor agonist
Authors: Lokhandwala Mustafa F.
Published: January 2005

Recent research in the area of peripheral dopamine (DA) receptors has led to the identification of two distinct subtypes of DA receptors, activation of which results in marked changes in the cardiovascular and renal function consisting of hypotension, bradycardia, diuresis, and natriluresis. Peripheral DA receptors mediating these effects are subdivided into DA‐1 and DA‐2 subtypes. The development of selective DA‐1 and DA‐2 receptor agonists and antagonists has made it possible to furhter characterize DA receptors located at various sites within the cardiovascular system. It is now established that activation of DA‐1 receptors located on blood vessel produces vasodilation, whereas stimulation of DA‐2 receptors on postganglionic sympathetic nerves results in the inhibition of norepinephrine release. The renal effects of DA receptor agonists either involve activation of specific DA receptors at various sites in the kidney and/or result from renal hemodynamic changes produced by these compounds. The concept of developing selective DA receptor agonists as therapeutic agents in the treatment of cardiovascular disorders has been proposed by several investigators. Fenoldopam (SK&F 82526) represents one of these new orally active DA receptor agonists developed for potential use in the treatment of hypertension and ischemic renal disease. In animal experiments fenoldopam was shown to produce hypotension and increase renal blood flow. It produced natriuresis and diuresis, and these effects were due to the activation of DA‐1 receptors. Recent clinical studies show that fenoldopam decreases blood pressure and renal vascular resistance and causes diuresis and natriuresis in hypertensive patients. The antihypertensive action of fenoldopam is mediated by a decrease in total peripheral resistance. There are increases in heart rate and plasma renin activity in hypertensive patients. Fenoldopam also improves left ventricular performance in patients suffering from congestive heart failure. These initial studies with fenoldopam show that peripheral DA‐1 receptor stimulation may represent an effective approach in the treatment of cardiovascular diseases. Future research in this area should be aimed toward developing DA‐1 receptor agonists that have longer duration of action and do not evoke renin release, while maintaining the beneficial effects on the kidney.
On the central effects of the GABA agonist fengabine: Psychometric and pharmaco‐EEG studies utilizing imaging methods
Authors: Saletu B. , Anderer P. , Kinsperger K. , Grünberger J. , Musch B.
Published: January 2005

In a double‐blind, placebo‐controlled study the pharmacokinetic, encephalotropic, and psychotropic properties of fengabine (FEN)‐a novel GABA receptor agonist–were studied in 15 normal subjects utilizing gas chromatography, quantitative pharmaco‐EEG, and topographical analysis methods as well as psychomeric and psychophysiological techniques. The subjects received randomized and, in weekly intervals, single oral doses of placebo; 200, 400, and 800 mg FEN: as well as 75 mg imipramine (IMI) as reference compound. Blood sampling, EEG recordings, and evaluation of pulse, blood pressure, and side effects were carried out at 0, 1, 2, 4, 6, and 8 hr, with psychometric tests at the same times except the first hour.

Pharmacokinetic analyses demonstrated rapid absorption of FEN, with plasma peaks in the second hour, dose‐dependent Cmax, and areas under the plasma concentration time curves. Computer‐assisted spectral analysis of the EEG detected from 17 scalp regions and topographical mapping of the drug‐induced Q‐EEG changes demonstrated significant but subtle central effects of FEN, which resembled in certain aspects the marked CNS effects of 75 mg IMI, such as the increase of theta and concomitant beta‐1 activity in the frontocentral and frontotemporal regions, as well as a decrease of fast alpha activity in the frontocentral and frontotemporal regions, as well as a decrease of fast alpha activity and the centroid over the frontotemporal and centroparietal to occipital regions, respectively, specifically after 800 mg FEN. On the other hand, there was a lack of delt augmentation seen after IMI in the occipitotemporoparietal region, lack of theta increase after the two lower doses of FEN, increase of slow alpha rather than a decrease after IMI, and an augmentation of total power (which declined with increasing doses) rather than an attenuation after IMI.

Regional differences were obtained also in regard to dose/treatment‐efficacy and time‐efficacy relations. Both compounds exhibited the peak encephalotropic effect in the second hour and a gentle decline thereafter. Behavioral dose‐ and time‐efficacy relations were only observed in the thymopsyche after FEN. These were characterized by an improvement in mood and affectivity after 400 and 800 mg FEN, respectively, as compared to placebo, while a deterioration occurred after the reference compound. On the other hand, 800 mg FEN also induced sedation, reflected by an increase of drowsiness and decrease of drive, which was observed to a much greater extent after 75 mg IMI. Noopsychic changes occurred only in singular variables. Evaluation of pulse, blood pressure, and side effects demonstrated good tolerability of FEN quite in contrast to IMI. Our findings suggest that the GABAergic compound should be studied in affective disorders.
Role of cyclic AMP in regulating cardiac muscle contractility: Novel pharmacological approaches to modulating cyclic AMP degradation by phosphodiesterase
Authors: Weishaar Ronald E. , Kobylarz‐Singer Dianne C. , Quade Mary M. , Kaplan Harvey R.
Published: January 2005

The role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP‐dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvement.