bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractVarious 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

AbstractNonsteroidal 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

AbstractAtopic 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

AbstractThe 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

AbstractThe 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

AbstractDenbufylline (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

AbstractRitanserin, 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

AbstractThere 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

AbstractWe 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

AbstractThe 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

AbstractOral 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

AbstractTwo 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

AbstractThe 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

AbstractArylpiperazines 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

AbstractAlcohol 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

AbstractSC‐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.