bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of vinpocetine in scopolamine‐induced learning and memory impairments
Authors: Groó Dóra , Pálosi Éva , Szporny László
Published: January 2005

Scopolamine‐induced memory dysfunctions are related to reduced cholinergic transmission. In our experiments scopolamine (3.0 mg/kg i.p.) inhibited acquisition and induced retrograde amnesia in a one‐trial step‐ through passive avoidance task in mice. We have studied the effect of vinpocetine (CavintonR), in the amnesic states mentioned above compared to that of vincamine, nicergoline (SermionR), and papaverine, to assess its activity on learning and memory processes impaired by scopolamine. Vinpocetine decreased the disrupting effect of scopolamine on acquisition and prevented and restituted the memory loss with 21.0 and 7.0 mg/kg i.p. peak effect dose, respectively. It facilitated the recall of memory traces damaged by scopolamine. Vincamine (3.5–63.7 mg/kg i.p.) showed a favorable effect in two of the four tests (reversal of amnesia and recall). Nicergoline (5–40 mg/kg i.p.) exerted moderate activity, and papaverine (10–40 mg/kg i.p.) was ineffective in the situations tested. Our findings indicate that vinpocetine directly or indirectly influences the cholinergic system, which may explain its previously reported beneficial effect in electroconvulsive shock‐ and hypoxia‐induced experimental amnesic states, and its therapeutic activity in human mental and cognitive disorders.
Buspirone antagonizes the expression of conditioned taste aversion in rats
Authors: Ervin Gregory N. , Soroko Frank S. , Cooper Barrett R.
Published: January 2005

When the parameters of taste aversion conditioning and testing have been appropriately adjusted, benzodiazepines and barbiturates will markedly antagonize the expression of moderate taste aversions in rats. We call this the taste aversion conflict model of anxiety. In the present study, we investigate whether buspirone HCl (buspirone; p.o. and i.p.) is active in the taste aversion conflict model and whether buspirone will also increase unsuppressed saccharin (SACC) intake. We also investigated the effects of imipramine, desipramine, phenelzine sulfate, chlorpromazine, scopolamine and d‐amphetamine sulfate in the taste aversion conflict model. To assess the possible effects of buspirone on the GABA‐benzodiazepine supramolecular receptor complex, we compared buspirone with certain benzodiazepines, meprobamate and sodium phenobarbital on the antagonism of pentylenetetrazol‐induced lethality in mice. Unlike benzodiazepines, meprobamate and phenobarbital, buspirone did not antagonize pentylenetetrazol‐induced lethality. However, like those other anxiolytics, buspirone markedly antagonized the expression of conditioned taste aversion. All nonanxiolytic drugs tested had either no effect or very slight effects on the expression of conditioned taste aversion. These results suggest that the taste aversion conflict model is sensitive to novel anxiolytics and that it is selective for drugs clinically effective in the treatment of generalized anxiety disorders in man.
Pharmacological profiles in vivo of benzodiazepine receptor ligands
Authors: Gardner Colin R.
Published: January 2005

Since the discovery of specific binding sites for benzodiazepines in the brain, a range of compounds have been discovered that do not have the benzodiazepine structure but that do interact with the benzodiazepine receptors. Classical benzodiazepines were considered to be agonists at these receptors. Some compounds only possess part of the profile of classical benzodiazepines and antagonise benzodiazepines in those test procedures in which they are totally inactive. Such compounds are regarded as partial agonists. The discovery of methyl and ethyl β‐carboline‐3‐carboxylate opened a new vista in the pharmacology of benzodiazepine receptors. These agents and now several other compounds act on the benzodiazepine receptors to induce effects functionally opposite to those of classical benzodiazepines (proconvulsant and convulsant) and have been called inverse agonists. Both agonists and inverse agonists can be blocked by compounds with affinity for the receptors but little intrinsic activity (antagonists). A recent increase in the number of benzodiazepine receptor ligands with in vivo activities allows comparison of a range of compounds from several different structral groups. Their pharmacological profiles suggest that these compounds all fit onto a continuum of behavioural effects related to activation of benzodiazepine receptors.
Cyclic AMP and cyclic GMP phosphodiesterases: Target for drug development
Authors: Pang David C.
Published: January 2005

Cyclic nucleotide phosphodiesterases catalyze the hydrolysis of 3′,5′ cyclic nucleotides to the corresponding nucleoside 5′ monophosphates. Multiple forms of cyclic nucleotide phosphodiesterase have been identified in both the cardiac muscle and vascular smooth muscle from various species. These isozymes differ in apparent molecular mass, chromatographic properties, substrate specificity, immunologic reactivity, sensitivity to inhibitors, and mode of regulation. The phosphodiesterases play important roles in the regulation of cyclic nucleotide concentrations, which in turn mediate cellular responses to a variety of biological stimuli. The development of phosphodiesterase inhibitors to increase intracellular cyclic nucleotide levels represents an important pharmacological approach to the treatment of various cardiovascular diseases.
Platelet‐activating factor‐induced cellular and pathophysiological responses in the cardiovascular system
Authors: Doebber Thomas W. , Wu Margaret S.
Published: January 2005

Recent findings in several laboratories have demonstrated the important interactions of platelet‐activating factor (PAF) with vascular endothelial cells, and thus the potential role of this lipid mediator in the pathophysiology of the cardiovascular system. PAF potently and specifically stimulates the in situ and in vivo release of tissue‐type plasminogen activator from the vascular endothelium [Emeis and Kluft, 1985]. Several lines of evidence indicate that PAF may play a critical role in the neutrophil adhesion to endothelial cells stimulated with thrombin or leukotrienes [Zimmerman et al., 1985]. PAF is a potent stimulator of Ca+2 efflux from endothelial cells, which thus might be an early step in the suspected involvement of the endothelium in in vivo responses to PAF, such as hypotension and increased vascular permeability [Brock and Gimbrone, 1986]. In our own laboratory, we have developed a specific and potent PAF receptor antagonist, L‐652,731, in order to determine the role of PAF in different animal models of disease. Utilizing this receptor antagonist as well as other criteria, PAF is indicated to be a major mediator of the endotoxin‐induced hypotension in rats and soluble immune complex‐induced hypotension and extravasation, also in rats. The immune complex‐induced increased plasma glucosaminidase is partially mediated by PAF, whereas the immediate and complete neutropenia is not indicated to involve PAF.
HP 663: A novel compound for the treatment of glaucoma
Authors: Hartman Harold B. , Roehr Joachim E. , Kotyuk Bernard L. , Kosley Raymond W. , Cherill Robert J. , Petko Wayne W. , Conway Paul G.
Published: January 2005

Various studies suggest that the 7‐dihydroxypropionyl derivative of forskolin, HP 663, effectively lowers intraocular pressure (IOP) by a novel mechanism. Biochemically, HP 663 stimulates rat striatal adenylate cyclase and displays an affinity for forskolin binding sites similar to that of forskolin. Following topical administration this compound lowers IOP in both New Zealand White (NZW) and Dutch Belt (DB) rabbits. In NZW rabbits, concentrations from 0.05 to 2.0% in a buffered hydroxypropylmethylcellulose (HPMC) vehicle produce significant reductions in outflow pressures of 35–45% for 5–6 hr. Additionally, HP 663 is soluble in this vehicle up to a concentration of 0.25%. As mentioned, HP 663 also reduces IOP in DB rabbits; however, this response is not significant until a concentration of 1% is attained. The effect on aqueous humor inflow was indirectly determined by studying the rate of IOP recovery following rapid i.v. infusion of 20% NaCl. In NZW rabbits, HP 663 significantly reduced aqueous humor inflow as shown by a 40% decrease in the IOP recovery rate compared to control. Tolerance also does not appear to develop to the IOP lowering effects of HP 663 in NZW rabbits. This compound is still capable of significantly lowering IOP following twice daily treatment for 21 consecutive days. Following topical administration of concentrations which effectively lower IOP, HP 663 exhibits no significant effects on heart rate or blood pressure of NZW rabbits. Therefore, this compound does not appear to exhibit a potential for peripheral side effects after topical application. Based on the results of the present study, HP 663 appears to be a potent activator of adenylate cylase and may provide a novel and effective treatment for glaucoma.
Gastric mucosal protective effects of the synthetic prostanoid Ro 22‐1327 in rats
Authors: Gaginella Timothy S. , Will Peter C. , Witt Constance G.
Published: January 2005

Nonsteroidal antiinflammatory drugs (NSAID) and ethanol can produce gastritis and mucosal hemorrhages in man. We report the potent protective effects of a synthetic prostanoid, Ro 22‐1327, on experimental models of NSAID and ethanol‐induced gastric mucosal injury. Rats were orally administered aspirin (200 mg/kg in 150 mM HCl), indomethacin (80 mg/kg), or absolute ethanol (1 ml) after pretreatment with vehicle or Ro 22‐1327. Oral administration of 10 μg/kg and 100 μg/kg of Ro 22‐1327 significantly (P ≤ ·05) protected the gastric mucosa from the corrosive effects of aspirin and ethanol; Ro 22‐1327 protected against indomethacin at a dose of 100 μg/kg. The duration of the protective effect was 90 and 180 min for aspirin and ethanol, respectively. Topical (dermal) application of 100 μg/kg and intraperitoneal injection of 1 μg/kg and 100 μg/kg of Ro 22‐1327 produced significant (P ≤ ·01) inhibition of the formation of ethanol‐induced lesions. Orally administered Ro 22‐1327 produced a significant (P ≤ ·001) dose‐related (25 μg/kg–225 μg/kg) increase (40–90%) in mean thickness of mucus covering the gastric mucosa. PGE2 was less effective than Ro 22‐1327. Ro 22‐1327 produced diarrhea only when administered orally at doses that were 100‐fold greater than the dose required for mucosal protection. The results suggest that this new prostanoid may be useful as adjunctive therapy in rheumatoid arthritic patients susceptible to gastritis and mucosal injury caused by large doses of aspirin or other NSAID.
Characterization of cAMP‐phosphodiesterase as a possible laboratory marker of atopic dermatitis
Authors: Hanifin Jon M. , Chan Sai C.
Published: January 2005

Atopic dermatitis (AD) is a chronically recurrent cutaneous inflammatory disease which may affect up to 10% of the population. The condition is part of the atopic triad which also includes asthma and allergic rhinitis. These diseases have strong hereditary patterns but the genetics is unclear. AD is characterized by a variety of immunologic and pharmacologic abnormalities, and evidence from transplant studies indicates that the basic abnormality is expressed in bone marrow cells. Defects such as increased basophil histamine release and high spontaneous IgE production by B lymphocytes imply defective cellular regulation. Abnormalities of cyclic nucleotide metabolism have been demonstrated in AD, and elevated cAMP‐phosphodiesterase (PDE) with resultant low intracellular cAMP levels may have a net permissive effect on immune and inflammatory responses. Biochemical characterization studies of abnormal PDE in mononuclear leukocytes from patients with AD have demonstrated two distinctly abnormal cytosolic fractions of PDE activity. These probably represent different enzyme forms in monocytes and lymphocytes; the consequent dysregulation of these immunologically important cells may explain many of the immune abnormalities associated with AD, and may provide a much needed biochemical marker for epidemiologic, genetic and clinical studies.
Evidence that reversal of mouse aggression is not related to beta blockade
Authors: DaVanzo John P. , McConnaughey M. M. , Brooks Richard , Cooke Lisa
Published: January 2005

The ED50s for reversal of mouse aggression were determined for nine beta adrenergic receptor blockers: metoprolol, nadolol, pindolol, propranolol, acebutolol, penbutolol, labetalol, timolol, and atenolol. Propranolol and penbutolol generated linear doseresponse curves, suggesting easy access to brain. To determine if beta blockade was actually occurring at the receptor level, upregulation of beta receptors after 10 days of chronic treatment with the ED50s was determined in the limbic system as well as other areas of brain. These areas included: olfactory bulbs, hypothalamus, septum, amygdala, cortex, midbrain, cerebellum, pons, and medulla. Upregulation occurred in all areas of the brain in animals treated with propranolol and penbutolol, suggesting that at the dose required to block aggressing in fighting mice, beta receptors were also effectively blocked. With other drugs (timolol, atenolol, pindolol, metoprolol, nadolol, and acebutolol) the ED50s produced localized upregulation of beta receptors, but nothing consistent in the limbic areas. The beta blocker labetalol at the ED50 for reversal of mouse aggression produced virtually no upregulation of brain receptors, suggesting no correlation between antiaggression and beta blockade.
Double‐blind placebo‐controlled study of the autonomic effects of clovoxamine, imipramine, and amitriptyline in normal volunteers
Authors: Wilson William H. , Rasmussen Jill , Vause Beth , Manov Gregory
Published: January 2005

The autonomic effects of clovoxamine, a possible new antidepressant, were compared with placebo, imipramine, and amitriptyline in a double‐blind, repeated‐measures, latin‐square study design, using 16 healthy volunteers. Salivary flow, pupillary response, near‐point accommodation, and pilocarpine‐evoked miosis were assessed before and 1, 2, and 3 hours after each treatment condition. Dose‐related autonomic effects were seen with all three active drugs. Clovoxamine at a 50‐mg dose was not distinguishable from placebo. For salivary flow, perhaps the most reliable index of anticholinergic activity, the effects of 100‐mg and 150‐mg doses of clovoxamine were comparable to those of 50‐mg and 75‐mg doses of imipramine but were less than those of 50‐ and 75‐mg doses of amitriptyline at 3 hours postdosing.
Effect of denbufylline in passive avoidance trials in gerbils, following transiet forebrain ischaemia, and in mice
Authors: Nicholson C. D. , Jukna J. J. , Wilke R. , Angersbach D.
Published: January 2005

Denbufylline (1,3‐di‐n‐butyl‐7‐[2‐oxopropyl]‐xanthine) has been examined in passive avoidance trials in gerbils, following transient forebrain ischaemia, and in mice. Animals were conditioned to avoid a darkened compartment by means of a foot shock received upon entering. Learning and memory were tested 24 hr later by replacing the animals in the box and measuring the latency to enter the dark compartment. In gerbils, transient (5 min) forebrain ischaemia was induced 24 hr prior to training by bilateral closure of the carotid arteries. Controls were sham‐ligated. All gerbils received seven subcutaneous injections of saline or denbufylline, the first during forebrain ischaemia or immediately following sham‐ligation, and the rest 3, 6, 24, 27, 30, and 48 hr later. Mice received one subcutaneous injection of saline or denbufylline immeediately after training. The results show that denbufylline enhances memory formation in mice after a mild learning stimulus and recollection in gerbils following forebrain ischaemia.
Pharmacological profile of ritanserin: A very specific central serotonin S2‐antagonist
Authors: Awouters Frans , Niemegeers Carlos J. E. , Megens Anton A. H. P. , Meert Theo F. , Janssen Paul A. J.
Published: January 2005

Ritanserin, a novel methylenepiperidine derivative, was studied in a wide range of common pharmacological tests mainly in rats. The lowest ED50, 0.0070 mg/kg, was obtained against tryptamine‐induced cyanosis. At 0.037 mg/kg, tryptamine‐induced bilateral clonic seizures were inhibited. Slightly higher doses, up to 0.11 mg/kg, inhibited mescaline and 5‐hydroxytryptophan (5‐HTP)‐induced head twitches and antagonized tryptamine‐induced coarse body tremors. Ritanserin did not generalize with LSD but was a weak antagonist of the LSD‐discriminative stimulus. Potent serotonin S2‐antagonism was confirmed by the inhibition of reactions mediated by endogenous serotonin, such as reversal of mast cell serotonin (5‐HT) cyanosis (0.012 mg/kg) and inhibition of gastric lesions (0.028 mg/kg). The lowest dose reducing the intensity of serotonin‐induced skin reactions was 0.04 mg/kg. Reduction of histamine‐induced skin reactions required a dose of at least 10 mg/kg. Time‐course studies in several tests indicated a relatively long duration of serotonin S2‐antagonism. Ritanserin doses up to 40 mg/kg were devoid of central dopamine antagonism and did not interfere with the neurotransmitters norepinephrine and acetylcholine. In an additional series of interactions and functional tests, ritanserin was virtually devoid of effect. In the wide range of tests, peripheral histamine antagonism was the first activity component unrelated to serotonin and it was observed at 270 times the dose for central S2‐antagonism. It is concluded that ritanserin is a very effective central serotonin S2‐antagonist which is at the same time relatively long acting and very specific.
Autoantibodies, immune complexes, and behavioral disorders: Neuropsychiatric involvement in systemic lupus erythematosus
Authors: Hoffman Steven A. , Narendran Anthony , Shucard David W. , Harbeck Ronald J.
Published: January 2005

There is a great deal of interest in immune mediation of neurobehavioral disorders. In this paper we emphasize the role that immune complexes and autoantibodies are likely to play in interfering with normal central nervous system functioning. The evidence indicates that immune complexes can affect behavior, probably via C3a and C5a, and alter blood–brain barrier permeability. The evidence also indicates that brain‐reactive autoantibodies are likely to affect behavior. There is, however, a diversity of these autoantibodies which will have to be better characterized in order to truly understand their role in autoimmunemediated central nervous system disease.
Exercise‐induced myocardial ischemia in pigs: Cardiovascular actions of nisoldipine with or without β‐adrenoceptor blockade
Authors: Duncker Dirk J. , Heiligers Jan P. C. , Verdouw Pieter D. , Saxena Pramod R.
Published: January 2005

We evaluated the effects of oral nisoldipine with or without propranolol on exercise‐induced myocardial ischemia in conscious pigs with a coronary artery stenosis. Treadmill‐running up to 4 km/hr increased cardiac output (90%), heart rate (90%), maxLVdP/dt (80%), left ventricular systolic (15%) and end‐diastolic (13±3 mmHg) blood pressures, while systolic wall thickening (SWT) of the poststenotic left ventricular myocardium was reduced from 29%±8% to 19%±6%. Nisoldipine neither affected the systemic hemodynamic profile during exercise nor the exercise‐induced reductions in SWT. Propranolol attenuated both the positive chronotropic and inotropic effects and the deterioration of wall function caused by the treadmill exercise. Combined treatment with the two drugs resulted in a cardiovascular profile similar to propranolol during exercise, but the loss of wall function was now completely prevented. We conclude that, unlike propranolol, nisoldipine alone was not effective against the exercise‐induced myocardial ischemia but, in combination with β‐adrenoceptor antagonists, nisoldipine may further decrease the exercise‐induced reductions in SWT of the poststenotic myocardium.
Pentylenetetrazole‐like stimulus is produced in rats during withdrawal from ingested chlordiazepoxide
Authors: Idemudia Smart O. , Lal Harbans
Published: January 2005

The present study was undertaken to determine whether withdrawal from chlordiazepoxide administered via a liquid diet would produce a pentylenetetrazole (PTZ)‐like stimulus. Rats were trained with food reward in a two‐lever operant task. Presses on one lever were reinforced after injections of PTZ (20 mg/kg, i.p.) and on the other lever after saline (1 ml/kg, i.p.). After rats had acquired the PTZ discrimination, training was halted, and chlordiazepoxide (240 mg/kg/day) was administered via a nutritionally balanced liquid diet to three groups of rats for 3, 4, or 6 days. Upon termination of chronic administration, withdrawal was precipitated with the benzodiazepine receptor blocker flumazenil (Ro 15‐1788) given intraperitoneally. During precipitated withdrawal, the rats selected the PTZ‐appropriate lever, indicating the presence of a PTZ‐like stimulus, and this stimulus was blocked by phenobarbital (80 mg/kg, i.p.). The percentage of rats selecting the PTZ‐appropriate lever depended on the duration of chlordiazepoxide treatment and dose of flumazenil. At 10 days after the last chlordiazepoxide dose, the rats had recovered baseline discrimination, as indicated by their selection of the saline appropriate lever following saline injections and the PTZ‐appropriate lever following PTZ. These data indicate that a subjective effect of withdrawal similar to that produced by the anxiogenic drug PTZ is present during withdrawal from oral chlordiazepoxide.
Pharmacological properties of MDL 19,301: A novel, nonsteroidal, anti‐inflammatory agent
Authors: Doherty Niall S. , Beaver Thomas H. , Westrich Gerald L. , Miller Francis P. , Roebel Lawrence E.
Published: January 2005

Oral administration of MDL 19,301 (N‐(1,3‐dithiolan‐2‐ylidene)‐4‐hexyl‐benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mg/kg p.o.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mg/kg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti‐inflammatory agents. Its major metabolite ((MDL16,861, 4[1,3‐dithiolan‐2‐yliden)amino]‐benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mg/kg p.o.), although it was more ulcerogenic (UD50 52 mg/kg p.o.). The anti‐inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co‐administration of an inhibitor of drug metabolism (SK&F525A 30 mg/kg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti‐inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic‐acid‐induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic‐acid‐induced, but not prostaglandin‐E2‐induced, diarrhea in mice; and inhibition of ex vivo arachidonic‐acid‐induced, but not adenosine‐diphosphate‐induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti‐inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.
Human neutrophilic polymorphonuclear leukocytes and hamster adipocytes as cellular model systems for the study of β‐adrenergic effects
Authors: Piot Etienne , Verheyen Willy , van Belle Herman , Janssen Paul A. J.
Published: January 2005

Two cellular model systems for the in vitro study of biochemical and pharmacological effects of new β‐adrenergic compounds were compared: the human neutrophilic polymorphonuclear leukocyte and the hamster white fat tissue adipocyte. The adipocyte β‐adrenoceptor governing the physiological response is atypical in nature, whereas neutrophils seem to have a homogeneous β2‐adrenoceptor population. Both model systems have their own advantages, but as far as pharmacological characterisation is concerned, the β2‐adrenoceptor of neutrophils is far more sensitive and this model system is an obvious choice for the comparison of, for example, isomers. The differentiation between R 67 138 and R 67 145, optical isomers of the β‐adrenoceptor antagonist nebivolol (R 67 555), is 20 times larger on neutrophils than on adipocytes. Some broader applications of both systems are discussed.
In vivo pharmacology of irindalone, a 5‐HT2 receptor antagonist with predominant peripheral effects
Authors: Arnt Jørn , Bøgesø Klaus P. , Boeck Vita , Christensen Anne V. , Dragsted Nils , Hyttel John , Skarsfeldt Torben
Published: January 2005

The in vivo effects of irindalone, a newly developed serotonin2 (5‐HT2) antagonist, have been investigated in comparison with a series of reference compounds. Irindalone potently antagonizes the pressor response induced by 5‐HT in pithed rats, but has a 173 times weaker effect against the α1‐adrenoceptor agonist phenylephrine. Irindalone is relatively weak in rat models detecting central 5‐HT2 antagonism, that is, inhibition of quipazine‐ or I‐5‐HTP plus citalopram‐induced head twitches, inhibition of I‐5‐HTP plus citalopram‐induced increases of flexor reflexes, and inhibition of the discriminative stimulus properties induced by d‐LSD. Furthermore, it displaces in vivo 3H‐ketanserin binding in frontal cortex. Irindalone weakly antagonizes the flexor reflex stimulated by the α1‐adrenoceptor agonist St 587. No dopamine receptor inhibition is detected in the methylphenidate gnawing test in mice. High bioavailability is indicated by the identical ED50 values obtained in the head twitch model after s.c. and p.o. administration. The activity profile of irindalone resembles that of ketanserin except in two characteristics: ketanserin has greater potency than irindalone as an antagonist in the 5‐HTP‐induced flexor reflex, but has a shorter duration of action. The effect of irindalone is stereoselective, since its opposite enantiomer Lu 21‐099 is almost inactive in the models for central and peripheral 5‐HT2 receptor antagonism. Finally, the effect of repeated treatment with irindalone (18 μmol/kg, p.o., twice daily for 2 weeks) on inhibition of quipazine‐induced head twitches was studied. Two days after the last dose, the potency for inhibiting quipazine was unchanged, indicating that no tolerance to 5‐HT2 receptor antagonism develops using this dose regimen. It is concluded that irindalone is a potent 5‐HT2 antagonist with preferential effects at peripheral sites.
Stimulus properties of arylpiperazines: NAN‐190, a potential 5‐HT1A serotonin antagonist
Authors: Glennon R. A. , Naiman N. A. , Pierson M. E. , Misenheimer B. , Herndon J. L. , Titeler M. , Lyon R. A.
Published: January 2005

Arylpiperazines have been demonstrated to bind both at 5‐HT1A and 5‐HT1B serotonin receptors. In an attempt to design novel 5‐HT1A agonists and antagonists, based on an arylpiperazine nucleus, we investigated the stimulus properties of a series of such agents (in rats trained to discriminate 0.5 mg/kg of the 5‐HT1B agent TFMPP from saline) to determine what structural features were important for 5‐HT1B activity. This done, we modified these agents to eliminate those features and, at the same time, incorporated structural features that appeared important for 5‐HT1A affinity. The resulting agents displayed high affinity for 5‐HT1A sites. One agent in particular, NAN‐190, neither mimicked nor antagonized the TFMPP stimulus, but was capable of antagonizing the stimulus produced by the 5‐HT1A agonist 8‐OH DPAT (0.2 mg/kg). These preliminary results suggest that NAN‐190 may be a potential 5‐HT1A antagonist.
Antiatherogenic and antiatherosclerotic effects of mushroom extracts revealed in human aortic intima cell culture
Authors: Ryong Li Hwa , Tertov Vladimir V. , Vasil'ev Andrew V. , Tutel'yan Victor A. , Orekhov Alexander N.
Published: January 2005

Alcohol and water extracts from 20 edible fungi species belonging to the following genera— Agaricum, Armillaria, Boletus, Collybia, Coriolus, Cortinfrius, Flammulina, Ganoderma, Hirneola, Lentinus, Lyophyilum, Pleurotus, Sarcodon, Tremella, and Tricholoma— were added to primary culture of cells isolated from atherosclerotic lesions of human aorta to ascertain their influence on the major cellular manifestations of atherosclerosis. Thirteen of the 20 tested extracts were antiatherosclerotic in culture, that is, they caused the decrease in the cellular cholesterol level and/or the inhibition of cellular proliferation ([3H]thymidine incorporation). The antiatherogenic (prophylactic) action of mushroom extracts was also tested using cell culture. The extracts were added to the primary culture of normal intimal cells, which had been stimulated by atherogenic serum from coronary heart disease (CHD) patients to undergo atherogenic transformation (increase in total cholesterol and stimulation of proliferation). Ten of the 20 tested extracts displayed antiatherogenic as well as antiatherosclerotic effects. Four mushroom species were chosen for the study of antiatherosclerotic effects in vivo. Cultivation of “atherosclerotic” cells during 24 hr in the presence of serum from healthy subjects who had had mushroom meals resulted in a 21–30% decrease in the cellular cholesterol level. The atherogenic serum obtained from CHD patients after dietary mushroom consumption partly (30–41%) lost its ability to increase the cellular cholesterol content. The current study presents data suggesting that some mushroom species may be useful as dietary supplements in the prevention and therapy of atherosclerosis.
Effect of SC‐40230, a new class I antiarrhythmic agent, on canine ventricular tachycardias
Authors: Garthwaite S. , Hatley Frida , Frederick Leo , Ruby Jeanette , Cook Chyung
Published: January 2005

SC‐40230, α‐[2‐[acetyl(1‐methylethyl)amino]ethyl]‐α‐(2‐chlorophenyl)‐1‐piperidinebutanamide, a new class I antiarrhythmic agent, was tested for efficacy against coronary ligation‐induced arrhythmias and ouabain toxicity arrhythmias in dogs. Doses of 9mg/kg i.v. and 15, 25, and 35 mg/kg p.o. significantly reduced ectopic rate in conscious dogs that had undergone ligation of the left anterior descending coronary artery 24 hr prior to testing. Plasma concentrations of SC‐40230 ranging from 3 to 9 μg/ml corresponded with ectopic rate reductions of 10–82% in the coronary ligation model. SC‐40230 was well tolerated at all doses tested in the conscious dogs. A 5 mg/kg i.v. dose of SC‐40230 converted ouabain‐induced ventricular tachycardias to normal sinus rhythm in anesthetized dogs. The antiarrhythmic effect of SC‐40230 in the ouabain toxicity model was reversed by large (⪇ 240 U) doses of insulin. The experiments described in this study demonstrated that SC‐40230 is a well‐tolerated new class I antiarrhythmic agent with intravenous and oral effectiveness against ventricular arrhythmias.
Local anti‐inflammatory activity of steroid‐21‐oate esters in the carrageenan pleurisy model of acute inflammation
Authors: Heiman Ann S. , Taraporewala Irach B. , Lee Henry J.
Published: January 2005

Local anti‐inflammatory activities in the carrageenan (CGN)‐induced pleurisy model are reported for steroid‐21‐oate esters derived from prednisolone. Following administration of equipotent doses (per rat) of prednisolone (P),.5mg; methyl 17,20α‐acetonidodihydroprednisolonate (P4AC), 1 mg; methyl 20β‐dihydroprednisolonate (P4B), 1.3 mg; methyl 20α‐dihydroprednisolonate (P4A), 5.8 mg; and methyl 17,20β‐acetonidodihydroprednisolonate (P4BC), 6 mg, effects of the steroids on exudate volume, leukocyte recruitment, and enzyme levels of cell‐free exudates and washed exudate cells were assessed. All derivatives tested significantly inhibited emigration of neutrophils (PMNs) and monocytes (MNs). Steroid treatment with the β‐isomers reduced exudate volumes by 41% and 56% for P4B and P4BC, respectively. In 5 hr neutrophilic exudates, free β‐glucuronidase levels were reduced by 43% by either P4B or P4AC treatments. Of the derivatives tested P4B and P4AC treatments resulted in the greatest reduction of free lysozyme levels. Activities of membrane‐bound γ‐glutamyl‐transferase (GGTP) in exudate cell pellets were reduced following treatment with P and the 20 alpha‐epimers P4AC and P4A. Systemic effects assessed as decreases in plasma corticosterone or suppression of circulating lymphocytes were noted only following P treatment. These results suggest that 1) the locally active steroid‐21‐oate esters act at the site of inflammation by inhibiting PMN and MN infiltration in a manner congruous with conventional steroids, 2) steroid stereochemical configuration plays a role in effects on exudate volumes and GGTP activities, and 3) due to the absence of systemic effects, the steroid‐21‐oate esters may be safer local anti‐inflammatory agents.
Aspirin plasma monitoring in juvenile chronic arthritis
Authors: Sharma Bhawna , Seth Vimlesh , Seth Shiva D. , Basu Nandita , Beotra Alka
Published: January 2005

Thirty‐two patients from the Pediatric Rheumatology Clinic of the All India Institute of Medical Sciences, New Delhi, suffering from juvenile chronic arthritis (JCA) in the age group of 5–15 years were investigated for salicylate monitoring. Of these, 15 (46.9%) had polyarthritis and 11 (34.4%) suffered from systemic onset type of JCA while only 6 (18.7%) had the pauciarticular type of disease. Plasma salicylate and albumin levels were estimated on days 1, 7, 14, and 21, after initiation of therapy with aspirin. Serum SGOT and SGPT were also estimated, as well as clinical evidence of hepatotoxicity. The therapeutic plasma levels (15–25 mg/dl) of salicylates were achieved by a mean dose of aspirin of 81.8 mg/kg/day administered in three divided doses. On the surface area basis the mean dose of aspirin was 2.1 g/m2/day. Steady‐state level of aspirin in plasma was achieved by the seventh day, and the values were 2.8 times more than on the first day. In malnourished patients with low albumin levels, there was a proportional decrease in salicylate binding. Although increase in transaminase levels of 1 1/2 to 2 times the normal was observed in the patients on aspirin therapy, none of the children developed clinical evidence of hepatotoxicity during this short‐term study. The studies indicate that dosage of salicylates can be given either on a body weight or surface area basis. A malnourished child with lower levels of serum albumin may be more predisposed to salicylate toxicity, due to higher levels of free salicylates. There was no evidence of hepatotoxicity in the dosage range of 70–110 mg/kg/day or 1.9 to 2.8 g/m2/day.
Preclinical profile of the pyrimidinylpiperazinyl imide compound WY‐47,846: A potential anxiolytic
Authors: Haskins J. Thomas , Moyer John A. , Andree T. H. , Muth E. A. , Abou‐Gharbia M.
Published: January 2005

A preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound Wy‐47,846, is presented. In an effort to achieve an orally active, nonbenzodiazepine anxiolytic agent, the compound Wy‐47,846 was synthesized and examined in various preclinical neurochemical, psychopharmacological and neurophysiological tests. Wy‐47,846 displayed high affinity at the 5‐HT‐1A receptor binding site (Ki = 16.7 nM) and had weak‐to‐modest affinities for D‐2 and 5‐HT‐2 receptors. Wy‐47,846 also was effective in binding to the 5‐HT‐1A site in ex vivo receptor binding studies, but did not alter D‐2 binding under these conditions. Wy‐47,846 was also weak to inactive at displacing adrenergic (alpha‐1, alpha‐2, and beta), cholinergic, histamine H‐1, opiate, and benzodiazepine receptor radioligands from their respective binding sites. Wy‐47,846 reduced 5‐HT‐2 receptor binding following subacute (3 week) treatment. In both shelf‐jump and discrete trial conditioned avoidance tests, Wy‐47,846 reduced avoidance responding while increasing escape responses. No sedative effects were noted at behaviorally active doses. Like other nonbenzodiazepine anxiolytics, Wy‐47,846 also did not release the suppression of punished responding in shock‐suppressed drinking nor in Geller‐Seifter conflict experiments. Wy‐47,846 also potently inhibited serotonergic neuronal activity in the dorsal raphe nucleus, suggesting agonist activity at the 5‐HT‐1A receptor and increased noradrenergic neuronal activity in the locus coeruleus by an unknown mechanism. These findings support the characterization of Wy‐47,846 as a nonbenzodiazepine anxiolytic agent.
Cardiocirculatory dynamics during heart failure in the rat: Effects of prototypic drugs
Authors: Flaim Stephen F.
Published: January 2005

The goal of these studies was to evaluate the effects of congestive heart failure on the peripheral circulations, looking specifically for the regions responsible for the rise in peripheral resistance observed in patients with this disease condition. During the course of these experiments, we evaluated the effects of different modes of exercise on cardiocirculatory dynamics and cardiac output distribution in normal animals in order to determine the most appropriate mode to induce an adequate exercise stess. Based on these studies, we chose treadmill exercise for use in animal models of heart failure. The animal species chosen for these studies was the rat. This choice was based on the availability of novel techniques which allowed for repetitive and accurate hemodynamic and regional blood flow determinations in rodents which provided a cost‐effective approach to the study of heart disease. Once appropriate models for congestive failure and for exercise were adequately characterized and studied, additional experiments designed to evaluate the acute effects of appropriate therapeutic agents such as calcium blockers, nitro‐vasodilators, and angiotensinconverting enzyme inhibitors were conducted. In order to determine the scope of the therapeutic efficacy of some of these compounds, studies were also conducted on models of hypertensive disease.
Anticancer and antiviral activities in indian medicinal plants: A review
Authors: Rastogi Ram Prakash , Dhawan Bhola Nath
Published: January 2005

This paper reviews the screening studies carried out in India to identify Indian medicinal plants bearing anticancer and antiviral activities. The highlights of the active constituents isolated are described and, based on analysis of screening data, some correlation has been derived on the presence of anticancer and antiviral activities in the taxa belonging to different families.
Stereoselective saluretic effect and localization of renal tubular secretion of enantiomers of S‐8666, a novel uricosuric antihypertensive diuretic
Authors: Nakamura Masuhisa , Kawabata Tomoji , Itoh Takako , Miyata Kenji , Harada Hiroshi
Published: January 2005

S‐8666, a newly developed antihypertensive uricosuric diuretic, possesses an asymmetric carbon and exists as a racemic mixture. The enantioselectivity of S‐8666 in natriuresis and the renal excretory mechanisms of the S‐8666 enantiomers were examined. Dose‐dependent natriuresis of the S‐(−)‐enantiomer was observed in male Sprague‐Dawley rats (3–100 mg/kg, p.o.), female Slc:ddy mice (3–300 mg/kg, p.o.) and male NIBS Japan white rabbits (1–10 mg/kg, i.v.). The R‐(+)‐enantiomer produced no significant change in sodium excretion within dose ranges of 100–200 mg/kg p.o. for rats, 3–300 mg/kg p.o. for mice, and 10 mg/kg i.v. for rabits. The (−)‐enantiomer and racemic S‐8666 showed a high‐ceiling property like that of furosemide and unlike that of trichlormethiazide. Plasma protein binding of S‐8666 was over 95% in rabbits and 73% in beagle dogs. In rabbits, both enantiomers of S‐8666 were secreted equally from the proximal tubule; however, only the (−)‐enantiomer of S‐8666 showed diuresis in a stop‐flow pattern. In beagle dogs, secretion of racemic S‐8666 occurred from the proximal tubule and could be inhibited by probenecid. The renal excretion of S‐8666 was largely the result of tubular excretion in rabbits whereas in beagle dogs, some glomerular filtration was also involved in urinary excretion. In conclusion, S‐8666 shows enantioselectivity in natriuresis. Both enantiomers of S‐8666 are excreted mostly by the organic acid transport system in the proximal tubule, but only the (−)‐enantiomer of S‐8666 induces natriuresis from the luminal side of the tubule.
Propentofylline improves the postischemic stroke index of sensitive gerbils
Authors: Delbarre G. , Delbarre B. , Ferger A.
Published: January 2005

The new xanthine derivative propentofylline (3‐methyl‐1‐[5′‐oxohexyl]‐7‐propylxanthine), administered intraperitoneally in a dose of 25 mg/kg 10 min before ligation of the left cerebral carotid artery in “sensitive” gerbils, improves the mean stroke index significantly at 4 and 24 hr postadministration. At a dose of 10 mg/kg, propentofylline improves the mean stroke index at all examined times (4, 24, and 72 hr), but at 5 mg/kg, a protective effect was obtained only after 24 hr. The mortality rate was lower in all propentofylline groups than in the control group. These results suggest that propentofylline is worth further study as a possible antistroke agent.
Electrophysiological actions of BRL 34915 in isolated guinea pig ventricular myocytes
Authors: McCullough John R. , Conder Mary L. , Griffel Louis H.
Published: January 2005

Specimens of diseased human ventricle and of infarcted cardiac tissue obtained from animal models contain admixtures of both well‐polarized and partially depolarized cells which may contribute to the development of cardiac arrhythmias. Recently, it has been suggested that the partially depolarized potentials result from low potassium permeability (PK) since some of the partially depolarized cells can be hyperpolarized by measures which increase Pk including increased external potassium (K+o) and rapid pacing (McCullough et al.: Circulation 66:II–198, 1982; Circulation 70:II–889, 1984). In the present study, we examined the electrophysiological actions of BRL 34915 (Cromakalim), a vasorelaxant agent reported to increase Pk of vascular smooth muscle cells, on the resting potential (RP) and the background K current (IK1) of isolated guinea pig ventricular myocytes by using whole‐cell voltage‐clamping techniques. BRL 34915 (5 μM) significantly hyperpolarized RP at all K+o tested, the extent of hyperpolarization decreasing with increasing K+o. The slope of the relationship between RP and K+o increased in the presence of BRL 34915 from −41.4 to −54.8 mV. BRL 34915 inhibited IK1 by decreasing the inward current at potentials negative to RP and the outward current between RP and ∼−20 mV. Outward current positive to −20 mV was unaffected. Higher concentrations (50–100 μM) of BRL 34915 increased this current. These results suggest that the hyperpolarization induced by low concentrations of BRL 34915 resulted from an increase in selectively of the membrane for potassium. Higher concentrations may increase an outward potassium current. Potential therapeutic applications of cardiac selective potassium channel activators are discussed.
Clinical features of arrhythmia aggravation by antiarrhythmic drugs and their implications for basic mechanisms
Authors: Roden Dan M.
Published: January 2005

Although cardiac arrhythmias are major cause of morbidity and mortality, widespread use of antiarrhythmic drugs is not appropriate at this time for two major reasons: (1) There is no evidence that antiarrhythmic drugs alter mortality in the vast majority of patients; further data will be forthcoming from large‐scale multicentered clinical trials which are currently underway. (2) Side effect are a prominent feature of therapy with antiarrhythmic drugs. The most striking of these toxicities is apparently paradoxical provocation of, rather than suppression of, cardiac arrhythmias by these agents. Two common clinical entities have been recognized. Therapy with action‐potential‐prolonging agents, including quinidine, sotalol, and the major active metabolite of procainamide, N‐acetyl procainamide, has been associated with the development of a morphologically distinctive polymorphic ventricular tachycardia, Torsades de Points, in approximately 5% of patients. Bradycardia and hypokalemia are commonly associated clinical features. In vitro studies indicate that triggered automaticity, in the from of early afterdepolarizations, are responsible for the genesis of Torsades de Pointes. The second common form of arrhythmia aggravation by antiarrhythmic drugs is the development of a marked increase in frequency of sustained ventricular tachycardia events in patients being treated for ventricular tachycardia. Therapy with sodium channel blockers of the “class Ic” subtype, including flecainide and encainide, are most commonly implicated. Since the underlying mechanism for sustained ventricular tachycardia in this patient population is thought to be microreentry, it appears likely that slow conduction due to the “class Ic” properties of the drugs may under appropriate conditions enable rather than block reentrant circuits. A variation on this clinical entity is the increasingly recognized phenomenon of drug‐induced impaired ventricular defibrillation. Although this is recognised with agents of the “class Ic” subtype, other sodium channel blockers have also been implicated, while action potential prologation actually appears associated with a decrease in defibrillation energy requirements. These adverse electrophysiologic drug action are not tightly linked to high plasma concentrations; rather, they represent an interplay among drug dose, plasma concentration, and underlying substrate. However, subsets of patients with variant drug metabolism on a genetic on a genetic basis have been identified and, under appropriate circumstances, these may be at increased risk for adverse electrophysiologic drug actions. Thus, intensive study of the clinical features of arrhythmia aggravation by antiarrhythmic drugs and their correlates in the basic laboratory have resulted not only in improved patient care but also in an increased understanding of the fundamental mechanisms responsible, and, potentially, may result in improved method for identifying new and safer antiarrhythmic compounds.
On stability and control of ligand‐receptor interactions according to the mass action law: A theoretical model of chaos
Authors: Tallarida Ronald J.
Published: January 2005

The stability and control of ligand‐receptor interaction obeying the mass action law were analyzed with a control model that is applicable to drugs and endogenous compounds. Whereas the local concentration of drugs, and consequent receptor occupancy, depend on pharmacokinetic parameters and, possibly, intrinsic control, natural substances are almost certainly controlled. The model assumes constant ligand production, with first‐order elimination and a feedback function (ϕ) that modulates these. The feedback signal, which may originate at a site proximal or distal to the receptor, is expressed as a function of the occupied receptor concentration (y). Instantaneous values of free (z) and bound (y) ligand represent a state or a point of the system. Basal values of y and z define a critical point that is stable; that is, perturbations producing states away from it will return in time to this critical point. In contrast, other critical points can be unstable, meaning that movements near such points will result in loss of control and possible chaos. It is shown that any critical point at which the derivative ϕ'(y) < 0 is stable; thus if unstable critical points exist then ϕ'(y) > 0 at such points. The model predicts at least one unstable point or repellor. The distance between these points is crucial to maintenance of control. Loss of control may account for certain abnormalities such as vasospasm and other pathologic conditions. The model, containing four parameters that control the three of the ligand‐receptor interaction, predicts conditions that alter stability. These insights may be useful for drug use and development.