bluuebunny/crossref_metadata_2025 huggingface dataset:
General pharmacology of CK‐1649C: A new quaternary class III antiarrhythmic agent
Authors: Greenberg Stanley S. , Luisi Alan , Long John P. , Williamson Harry E.
Published: January 2005

CK‐1649C is a new quaternary ammonium class III antiarrhythmic agent undergoing clinical trials. The side effect profile of a class III antiarrhythmic agent is generally unknown. This study compared CK‐1649C with quinidine and lidocaine (class I), acecainide (class I/III), and clofilium (class III), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK‐1649C was devoid of neuropharmacologic activity in the mouse and rat. CK.‐1649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenan‐induced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK‐1649C was devoid of activity on transmural nerve stimulation and did not exhibit α1‐muscarinic, nicotinic, or β‐adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK‐1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water‐loaded dogs. CK‐1649C (30mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK‐1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic doses of 1–3 mg/kg in man.
Pharmacology of sematilide, a non‐quaternary class III antiarrhythmic agent
Authors: Greenberg Stanley S. , Luisi Alan , Long John P. , Williamson Harry E.
Published: January 2005

Sematilide is a new, non‐quaternary class III antiarrhythmic agent currently undergoing clinical trials. We showed that a quaternary ammonium class III antiarrhythmic agent exhibits few extracardiac effects (Greenberg et al., Drug Dev. Res. 25.107–123, 1992). However, the extracardiac effects of a non‐quaternary, pure class III antiarrhythmic agent are unknown. Sematilide, a pure class III antiarrhythmic agent, is effective in a canine model of arrhythmia at 0.3–1.0 mg/kg, intravenously (i.v.). We compared the nervous system and extracardiac effects of sematilide to acecainide (a class I/III) and several class I antiarrhythmic agents to evaluate the potential side effects of this new drug. Sematilide was devoid of neuropharmacologic activity in the mouse and rat, devoid of gastrointestinal activity in the mouse fed a charcoal meal, and without effect in the rat carrageenan‐induced paw edema test. Ten to 30 times the average antiarrhythmic dose or plasma levels of sematilide were devoid of α1, muscarinic, nicotinic, and β‐adrenoceptor blocking activities in a variety of preparations. Moreover, sematilide was devoid of depressant activity on (1) cholinergic, nicotinic, and sympathetic neurotransmission; (2) vascular and non‐vascular smooth muscle reactivity and contractility; (3) aggregation of human platelets; (4) responses of the anesthetized dog to i.v. acetylcholine, isoproterenol, and nicotine; and (5) displacement of quinuclidinyl benzilate (QNB) binding to dog atrial membranes. Sematilide (10–30 mg/kg, i.v.) inhibited vagal nerve stimulation in the dog and slightly enhanced free water clearance in water‐loaded dogs. The data show that effective antiarrhythmic doses and concentrations of sematilide are devoid of significant, injurious neural, hemodynamic, or smooth muscle side effects. © 1992 Wiley‐Liss, Inc.
Effects of epidermal growth factor in the mammalian central nervous system: Its possible implications in brain pathologies and therapeutic applications
Authors: Mazzoni Irene E. , Kenigsberg Rhoda L.
Published: January 2005

The development and maintenance of the normal functional integrity of the mammalian central nervous system is under the influence of a number of growth and trophic factors. One such growth factor, epidermal growth factor, has been detected in the mammalian brain and found to be associated with various brain regions and cell types. This small ubiquitous polypeptide can influence the proliferation, Metabolism, and differentiation of both glia and neurons in the central nervous system. We discuss the effects of epidermal growth factor on glial and neuronal cell function in an attempt to understand its role in development and maintenance of normal brain integrity. In addition, we review its possible implications in several pathological states in the central nervous system and speculate on therapeutic applications for this growth factor. © 1992 Wiley‐Liss, Inc.
Nicotine does not interact with the discriminative stimulus effects of clozapine in rats
Authors: Villanueva Heidi F. , Arezo Shahwali , Rosecrans John A.
Published: January 2005

The purpose of the present study was to assess the potential interaction between clozapine, an atypical antipsychotic recently approved for clinical use in the United States and nicotine. Male Sprague‐Dawley rats were trained to discriminate nicotine or clozapine in a standard two‐lever operant drug discrimination procedure. Rats were tested for generalization to nicotine and clozapine, and the interactions produced by combining various doses of nicotine and clozapine were evaluated. Results suggest that nicotine does not interact with the discriminative stimulus effects of clozapine. Thus, patients who smoke while receiving clozapine therapy may not experience the decreased antipsychotic effectiveness which is common in patients who smoke while receiving treatment with typical antipsychotic compounds. © 1992 Wiley‐Liss, Inc.
Chronic treatment with an acetylcholine synthesis precursor, alpha‐glycerylphosphorylcholine, alters brain parameters linked to cholinergic transmission and passive avoidance behavior
Authors: Govoni Stefano , Lopez Clara M. , Battaini Fiorenzo , Trabucchi Marco
Published: January 2005

The present study extends previous observations on the acuta treatment with alpha‐glycerylphosphorylcholine (GPC), a putative acetylcholine (ACh) precursor, and investigates the effect of chronic treatment with this drug on scopolamine‐induced amnesia and on ACh release in the rat. The drug acutely administered antagonizes the amnesic effect of scopolamine (0.75 mg/kg s.c.) in passive avoidance experiments. The effect peaked at 600 mg/kg i.g. and lasted up to 30 hr. Potassium‐stimulated release of ACh from slices of hippocampus and cerebral cortex was measured after various doses of GPC. The dose curve study indicated that GPC was able to increase ACh release in the hippocampus already at the dose of 75 mg/kg i.g. The maximum effect was obtained with 300 mg/kg i.g. (147% of the control values). The increase of the ACh release reached a maximum 3 hrfollowing the administration, then declined toward control values. In the cortex, the effect was much less pronounced and shorter than in the hippocampus. The repeated (100 and 300 mg/kg i.g.; 22 days) GPC administration effectively antagonized scopolamine‐induced amnesia, indicating that there was no tolerance to this effect of GPC. While both doses were behaviorally active only 300 mg/kg was able to increase ACh release from hippocampus ( + 271 %) and cortex ( + 57%). The data support the hypothesis that GPC improves behavioral performance in passive avoidance through an action on cholinergic transmission. On the other hand, it should be stressed that the action on ACh release is observed in a narrow time window in contrast to the long lasting effect on behavior. It is tempting to speculate that the effect on ACh may be related to cortical activation and important but not sufficient to explain the antagonism of scopolamine‐induced amnesia. Along this line other mechanisms, possibly triggered by the action on ACh, may contribute to mediate the behavioral effect of GPC. © 1992 Wiley‐Liss, Inc.
Long‐term choline alfoscerate treatment counteracts age‐dependent structural changes in the rat hippocampus
Authors: Bronzetti Elena , Collier Wade L. , Felici Laura , Zaccheo Damiano , Amenta Francesco
Published: January 2005

Long‐term choline alfoscerate (αGFC) treatment counteracts age‐dependent structural changes in the hippocampus of Sprague‐Dawley rats. Animals treated with a daily dose of 100 mg/kg αGFC from 18 to 24 months of age had more cells in the CA‐1 to CA‐3 fields and in the dentate gyrus compared to age‐matched cohorts. The density of silver‐gold stained fibers within the stratum oriens of the CA‐1 to CA‐2 fields was greater in rats treated with αGFC than in age‐matched controls. The ramifications of these findings are discussed. © 1992 Wiley‐Liss, Inc.
Vascular effects of class III antiarrhythmic agents
Authors: Baskin Elizabeth , Serik Carolann , Wallace Audrey , Jurkiewicz Nancy , Winquist Raymond , Lynch Joseph J.
Published: January 2005

Methanesulfonanilide Class III antiarrhythmic agents have been shown to block a specific outward delayed rectifier K+ current, Ikr in cardiac cells. K+ conductance also is recognized to be an important regular of contractile tone in vascular smooth muscle. The purpose of the present investigation was to assess the effects of the new and potent methanesulfoanilide Class III agents E‐4031, UK‐68,798, UK‐66,914 and the Class III standard d‐sotalol in vitro in phasically active and electrically quiescent vascular smooth muscle preparations. All four Class III agents augmented phasic contractile tension in spontaneously active rat portal veins at concentrations similar to those effecting significant Class III electrophysiologic activity in cardiac muscle, but failed to contract electrically quiescent rabbit aortic rings. At concentrations exceeding effective cardiac Class III electrophysiologic concentrations, E‐4031 relaxed methoxamine‐ and histamine‐contracted rabbit aortic rings, and d‐sotalol relaxed methoxamine‐contracted aortic rings. UK‐68,798 and UK‐66,914 failed to relax spasmogen‐contracted aortic rings. The similarity in effective concentrations required for the four Class III agents to augment phasic contractile tension in the rat portal vein and increase myocardial refractoriness in cardiac muscle is consistent with the presence of similar K+ channel subtypes in the two tissues. Alternatively, the observed activities in the two tissues may be due to actions of these four Class III agents on another, non‐Ikr ion channel present in rat portal vein, with an order of potency for blockade similar to block of Ikr in cardiac tissue. © 1992 wiley‐Liss, Inc.
Binding studies with the 5‐HT1B receptor agonist [3H]CP‐96,501 in brain tissues
Authors: Lebel Lorraine A. , Koe B. Kenneth
Published: January 2005

Binding studies in rat brain membranes have shown that [3H]CP‐96,501 is a selective, high affinity radioligand for 5‐HT1B receptors. Additional studies with [3H]CP‐96,501 in brain tissues of several other species were undertaken to investigate its utility in detecting this receptor subtype. The presence of 5‐HT1B receptors in brain membranes of the hamster and gerbil was demonstrated with [3H]CP‐96,501. This finding was confirmed by [3H]5‐HT binding experiments that also indicated the presence of other 5‐HT1 subtypes (possibly 5‐HT1D, 5‐HT1E) in these species as well as the rat. Negligible specific binding of [3H]CP‐96,501 was found in membranes of guinea pig brain, dog hypothalamus, bovine caudate, pig choroid plexus, and several human brain tissues, consistent with the reported absence of the 5‐HT1B receptor subtype in these species. Autoradiographic examination of rat brain sections labeled by [3H]CP‐96,501 showed a dense localization in areas known to be enriched in 5‐HT1B receptors (e.g., globus pallidus, substantia nigra, superior colliculus, subiculum). On the other hand, brain sections of dog and guinea pig appeared to show no specific binding of [3H]CP‐96,501 by autoradiography, in agreement with the lack of brain 5‐HT1B receptors in these tissues. © 1992 Wiley‐Liss, Inc.
Cortical focal stroke model to evaluate neuroprotective action of drugs
Authors: Mahadik Sahebarao P. , Wakade Chandramohan G.
Published: January 2005

The experimental central nervous system (CNS) stroke model of cerebral cortical focal isch‐ emia in the rat is detailed to produce consistent and reproducible ischemic injuries, and is discussed for its adequacy to investigate the molecular mechanisms of ischemic injuries and to evaluate the neuroprotective efficacy of drugs. The model involves the permanent occlusion of ipsilateral (left) common carotid artery (CCAo) and middle cerebral artery (MCAod), and 1 hr occlusion of contralateral (right) CCAo. It is relatively easy to perform, highly reproducible, and does not result in mortality, and therefore is most suitable to delineate the time‐dependent changes in biochemical processes associated with various CNS injuries to anatomically distinct regions of the brain initiated after ischemia. These injuries include primary and peri‐ischemic injuries due to direct interruption of blood supply, and secondary non‐ischemic injuries in brain areas with intact blood circulation. The consistency, reproducibility, and reliability are based on the analyses of several physiological (tissue levels of edema, Na+, K+, and Ca++) and biochemical (membrane levels of fatty acids, [Na+ + K+]‐ATPases, Ca++‐ATPase, and levels of enzymes of oxy‐radical metabolism) indices of plasma membrane dysfunction which paralleled the functional deficits. These characteristics of the model make it possible for us to investigate the temporal relationship of a cascade of these acute physiological and biochemical processes in addition to loss of energy and nutrition, alterations in membrane lipid metabolism, increased lipid peroxidation, and alterations in receptor‐mediated transfer of information. These processes, if not attenuated in time, can lead to cellular death. Since the ischemic injury affects several neurotransmitter systems simultaneously in anatomically distinct areas of the brain, probably through generalized alterations of cellular plasma membrane physicochemical properties, the MCAo model is also well suited to compare efficacy of drugs with a wide range of physiological actions using a large number of the same biochemical and behavioral param‐ eters. In summary, a highly reproducible and consistent MCAo model of ischemia is adequate, if not identical to human ischemic stroke, to study several relevant variables of human stroke which include transient ischemia, reperfusion, different degree of ischemia due to varying lengths of occlusion or site of occlusion, hemorrhage, hypoglycemia, and hypothermia, and to evaluate the efficacy of a drug to stop the most acute injury process(es) before injury reaches the “point of no return.” © 1992 Wiley‐Liss, Inc.
Psychopharmacological profile of a new chroman derivative with 5‐hydroxytryptamine1A agonist properties: S 20499 (+)
Authors: Porsolt Roger D. , Lenègre Antoine , Caignard Daniel H. , Pfeiffer Bruno , Mocaër Elisabeth , Guardiola‐Lemaître Beatrice
Published: January 2005

S 20499 is the (+) enantiomer of the racemic compound S 20244 (4‐N‐(methoxychromane‐3‐yl) N‐propylamino butyl‐8‐azaspiro 4,5 decane‐7,9 dione), a novel 5‐hydroxytryptamine1A (5‐HT1A) agonist. The present experiments examined the potential anxiolytic and 5‐HT1A agonist activity of S 20499 (+) in behavioral experiments in rodents. Tests used were the lrwin, activity meter, and tail suspension tests in mice and the Vogel conflict, forepaw treading, and lower lip retraction tests in rats. Further tests examined its duration of activity and the effects of chronic treatment. In most experiments, its effects were compared with the (−) enantiomer (S 20500). Neither S 20499 (+) nor S 20500 (−) was lethal in mice up to 256 mg/kg. S 20499 (+) induced signs of sedation (hypoactivity, decreased traction and muscle tone, ptosis, and hypothermia) in the lrwin test in the dose range 4–64 mg/kg i.p. and a dose‐dependent decrease in locomotion (activity meter) from 2 mg/kg. At high doses (128–256 mg/kg) S 20500 (−) had qualitatively different effects, inducing signs of excitation and stereotyped behavior. At lower doses (16–64 mg/kg), its effects were similar to those of S 20499 (+) but it was between two‐ and fourfold less potent. S 20499 (+) increased the duration of immobility in the tail suspension test (anxiolytic/tranquilizing activity) from 16 mg/kg, whereas S 20500 (−) had no effects up to 32 mg/kg. BothS 20499 (+) and S 20500 (−) increased the number of shocks taken in the Vogel conflict test (anxiolytic activity) at 4 and 16 mgikg, respectively. The duration of activity of S 20499 (+) was between 2 and 4 hr and its effects were maintained after chronic administration over 5 days. Finally, both enantiomers induced forepaw treading and lower lip retraction in rats (signs of 5‐HT, agonist activity), with S 20499 (+) being at least four times as potent as S 20500 (−). Taken together, the results are consistent with other available data suggesting potential anxiolytic activity for S 20499 (+), probably arising through its agonist activity at central 5‐HT1A, receptors. © 1992 Wiley‐Liss, Inc.
Effects of the complexation of various fentanyl analogs in hydroxypropyl‐β‐cyclodextrin after epidural and intrathecal administration in rats
Authors: Meert Theo F. , Putteman Peter , Peeters Jef
Published: January 2005

Complexation of various equipotent doses of fentanyl‐like opioids in hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) results in a potentiation of the spinal activity of these opioids after both epidural and intrathecal administration in a fixed diluent volume of 10 μl. The first active and mot optimal concentrations of HP‐β‐CD after epidural administration differed between the opioids and varied from 1 to 20% HP‐β‐CD. The duration of deep surgical analgesia increased at optimal concentrations of HP‐β‐CD with a factor 3 for fentanyl (15% HP‐β‐CD), 3.6 for sufentanil (5–10% HP‐β‐CD), respectively. Increasing the concentrations of HP‐β‐CD above these optimal concentrations did not further potentiate the analgesic activity of the opioids. The complexation of the opioids in HP‐β‐CD also increased the duration of supraspinal side‐effects. However, except for lofentanil, the potentiations of the analgesic activity were always longer lasting than those for the secondary side‐effects. As a consequence, there was a gain in the total time of analgesia without side‐effects. After intrathecal administration, there was no gain in the duration of deep surgical analgesia after complexation of fentanyl, carfentanil and alfentanil in HP‐β‐CD. For both sufentanil and lofentanil, maximal potentiation of analgesia was measured at 10% HP‐β‐CD with, respectively, 2.8‐ and 1.7‐fold increases in the duration of analgesia. Also intrathecally, there was some gain in the duration of duration of analgesia without supraspinal side‐effects. These results on the potentiation of the opoids with HP‐β‐CD are discussed in relation to the lipophilicity of the tested opioids. © 1993 Wiley‐Liss, Inc.
Potent 5‐hydroxytryptamine3 receptor antagonist activity of RG 12915
Authors: Martin Gregory E. , Chase Billee J. , Davis Marjorie A. , Pendley Charles E.
Published: January 2005

RG 12915, N‐(1‐azabicyclo[2.2.2.]octan‐3(S)‐yl)‐2‐chloro‐(5aS, 9aS)‐5a,6,7,8,9,9a‐hexahydrodibenzofuran‐4‐carboxamide, a potent antiemetic agent active in reducing emesis produced by antieoplastic agents, was examined in tests of 5‐hydroxytryptamine3 (5‐HT3) receptor blockade. RG 12915 was found to be a potent antagonist of 5‐HT3 receptor activation both in blocking 5‐HT‐induced contractions of guinea‐pig ileum and in blocking the Bezold‐Jarisch effect in the rat. Compared to several other 5‐HT3 antagonists, RG 12915 had a greater pA2 value (11.2) for blocking 5‐HT‐induced contractions of guinea pig ileum than zacopride (8.3); BRL 43694 (granisetron) (9.1); and GR 38032F (ondansetron) (7.4). Falls in heart rate due to 5‐HT3 receptor activation following intravenous (i.v.) administration of 5‐HT (the Bezold‐Jarisch effect) were also potently reduced by RG 12915. Minimum effective dose (MED) levels (in parentheses), defined as the lowest dose at which each compound produced a significant reduction in the Bezold‐Jarisch effect, were determined for RG 12915 (1.0μg/kg, i.v.); zacopride (3.0); granisetron (9.0); and ondansetron (27.0). The order of potency in blocking 5‐HT3 receptor activation was generally the same as the order of potency in 5‐HT3 receptor binding. RG 12915 had a lower Ki value (0.17±0.02 nM, mean ± SEM) in binding studies using 3H‐GR‐65630 as the ligand in rat entorhinal cortex tissue than either zacopride (1.5±0.4); granisetron (1.7±0.3); or ondansetron (6.2±2.1). RG 12915 was also found active in blocking contractions of guinea pig ileum and the Bezold‐Jarisch effect induced by the somewhat selective 5‐HT3 receptor agonist 2‐methyl‐secrotonin. The results support the idea that this orally active antiemetic agent is a potent antagonist of 5HT3 receptor activation. © 1993 Wiley‐Liss, Inc.
Effects of intracerebroventricular administration of ethylcholine aziridinium ion on hippocampal cholinergic system, assayed in vivo by a brain dialysis technique, and on spatial memory of rats
Authors: Tajima Toshihisa , Yoshimine Noboru , Goto Tsutomu , Ikari Hiroyuki , Kuzuya Fumio , Endo Hidetoshi
Published: January 2005

We attempted to clarify the effect of hippocampal function on the spatial memory of rats by creating a lesion in the hippocampus with ethylcholine aziridinium ion (AF64A). The hippocampus was damaged by injecting AF64A into the lateral ventricles, 3 nmol/3 μl per side. At 1 or 4 weeks after the injection, acetylcholine (ACh) was measured in perfusion samples collected via brain dialysis of the hippocampus of freely moving rats. The release of ACh stimulated by scopolamine was reduced at 1 week but not at 4 weeks post‐injection. A behavioral change on the eight‐arm radial maze test was also observed in the acquisition or retention trials to determine the deficit in spatial memory, whether acquisition or retention. In the acquisition trial, the initial correct response was decreased and the total error count was increased at 1.5 to 2.5 weeks, but not at 3 weeks, after the AF64A injection. However, those indices remained unchanged in the retention trial. These observations suggest that the hippocampus may be required for the acquisition of spatial memory, but that the stored memory, but the stored memory is located outside the hippocampus, the hippocampus is not concerned with the retrieval process, or the retrieval process may be hippocampal but not cholinergic. The hippocampal cholinergic system would be concerned with the acquisition of spatial memory. Thus, AF64A‐treated rats may serve a model for hippocampal cholinergic dysfunction and the recovery from hippocampal cholinergic damage. © 1993 Wiley‐Liss, Inc.
Adenosine A1 receptor and ligand molecular modeling
Authors: Dudley Mark W. , Peet Norton P. , Demeter David A. , Weintraub Herschel J. R. , Ijzerman Ad P. , Nordvall Gunnar , van Galen Philip J. M. , Jacobson Kenneth A.
Published: January 2005

This symposium provided a forum for presentations by the relevant groups on ligand design and ligand binding on the adenosine A1 receptor. Agreement appears to exist that the “N6C8” model of ligand binding to the receptor is the preferred mode. A consensus has not yet been reached on the actual placement of the ligand in the receptor and the exact amino acids which interact in its binding. Two viable models exist at present. Both can be tested with selective site‐directed mutagenic studies on the A1 receptor as well as with additional designed ligands. © 1993 Wiley‐Liss, Inc.
P2 receptor: Subclassification and structure‐activity relationships
Authors: Cusack Noel J.
Published: January 2005

Structure‐activity relationships (SAR) at P2 receptors that support their subclassification into at least five nucleotide receptor subtypes, P2Z, P2T, P2Y, P2U, and P2X, are reviewed. The P2Z receptor is the most sensitive to alterations to ATP. The adenine base, D‐ribose sugar, and 5′‐triphosphate chain are absolute requirements, but substitutions are tolerated at the C‐2 position and replacement by sulphur of an ionized phosphate oxygen leads to enhanced potency. The P2T receptor, where ADP is the only endogenous agonist, has an absolute requirement for the adenine base, D‐ribose sugar, and a 5′‐diphosphate chain. C‐2 substitution and replacement by sulphur of an ionized oxygen is tolerated. Many analogs of AMP and of ATP are antagonists. The P2Y receptor requires an adenine base, D‐ribose, and a 5′‐polyphosphate for maximal potency only. C‐2 substitution, and replacement of an ionized oxygen by sulphur, can enhance potency. Methylenephosphonate potencies depend on the position of the methylene group. ADP‐β‐F is a specific agonist. The P2X receptor is least sensitive to alterations to ATP. There is no requirement for and adenine base, D‐ribose sugar, or triphosphate chain. Methylenephosphonates and some phosphorothioates have enhanced potencies. L‐AMP‐PCP is a specific agonist. Evidence from SAR for a P2U subtype is reviewed. SAR studies are complicated by the presence of ectonucleotidases. The overall subclassification of P2 receptors is inadequate and awaits the availability of selective competitive antagonists. © 1993 Wiley‐Liss, Inc.
Anticancer activities of adenine nucleotides in tumor bearing hosts
Authors: Rapaport Eliezer
Published: January 2005

The utilization of adenosine 5′‐triphosphate (ATP) infusions against solid refractory cancers is based on the preclinical findings that low levels of extracellular ATP significantly inhibit the growth of a variety of human and murine tumor cells. The mechanisms of tumor cell killing by extracellular ATP are attributed to effects mediated by its interaction with P2 purine receptors as well as non‐receptor‐mediated pore formation in the tumor cell membrane. The achievement of elevated extracellular blood plasma pools of ATP is accomplished by the administration of adenine nucleotides which yield elevated liver, red blood cell, and plasma compartment pools of ATP. Administration of AMP or ATP to tumor‐bearing murine hosts produced, in addition to the cytotoxic effects against the tumor, a variety of host mediated anticancer activities, including significant inhibition of host weight loss in cachectic tumor models. The inhibition of several adverse events Which are among the hallmarks of cancer cachexia is the result of prevention of the significant depletion of visceral energy stores in cachectic animals after the administration of adenine nucleotides, leading to the successful maintenance of hepatic functions, the resumption of normal protein synthesis in the liver, and inhibition of the synthesis of hepatic acute‐phase proteins. Thus, the administration of ATP as an anticancer agent in humans at levels (below 0.1 mg/kg min) which do not adversely affect systemic and cardiovascular functions is expected to lead to the following activities resulting from the generation of elevated hepatic, red blood cell, and blood plasma ATP pools: cytolytic effects against the tumor, inhibition of host weight loss, and other adverse effects of cachexia, anti‐pain effects, modulation of blood flow to the tumor, positive effects on motor functions and performance status due to increases in several other parameters which are also known to be affected by elevated red blood cell and blood plasma (extracellular) ATP levels. © 1993 Wiley‐Liss, Inc.
Cardiovascular effects of adenosine and the adenosine A1 Receptor antagonist NPC 205 are altered with age in guinea pigs
Authors: de Garavilla Lawrence , Valentine Heather L. , Schenden Jan S. , Kinnier William J. , Hanson Robert C.
Published: January 2005

Responsiveness of the cardiovascular system to the effects of vasoactive agents can vary with age. The endogenous metabolite adenosine has negative chronotropic, inotropic, and hypotensive effects. The purpose of this study was to determine if the effects of exogenously administered adenosine and the adenosine A1 receptor antagonist 1,3‐di‐n‐propyl‐8‐(hydroxyphenyl) xanthine (NPC 205) vary with age. The effects of adenosine on mean arterial blood pressure (MABP), heart rate, and cardiac contractility (LV dP/dt) were investigated in two groups of guinea pigs: a young group (3–4 weeks) and an older group (72–75 weeks). In vivo, the older animals were shown to be significantly more sensitive to the negative inotropic, chronotropic, and hypotensive effects of adenosine, whereas the responses to R‐N6‐phenylisopropyladenosine (R‐PIA), a metabolically stable analog of adenosine, were similar in both age groups. In vitro, right atria from young (3–4 weeks) and old (72–75 weeks) guinea pigs exhibited no age‐related differences in the sensitivity to the negative chronotropic effects of adenosine or R‐PIA. Younger animals were more sensitive to the positive inotropic effects of the adenosine A1 receptor antagonist, NPC 205. In addition, basal heart rates were significantly lower in the older group of animals. It may therefore be concluded that there age‐related effects of adenosine. Furthermore, comparison of the effects of adenosine to the effects of the stable analog R‐PIA and the adenosine antagonist NPC 205 suggests that these differences may be due to changes in adenosine metabolism with age. © Wiley‐Liss, Inc.
Cardiovascular pharmacology of FK664, a novel venodilator with cardiotonic properties
Authors: Sudo Yuji , Maeda Kazuhiro , Ozaki Tohru , Takai Masaki , Sakata Yoshihiko , Nishida Keiko , Matsuo Noriko , Nakajima Hiromi , Enda Emiko , Esumi Kimio
Published: January 2005

The cardiovascular effects of FK664, [6‐(3, 4‐dimethoxyphenyl)‐1‐ethyl‐4‐mesitylimino‐3‐methyl‐3, 4‐dihydro‐2 (1H)‐pyrimidinone], were examined in both in vitro and in vivo preparations. FK664 is an orally effective noncatechol and nonglycoside cardiotonic agent. FK664 has vasodilating activity not only in resistance vessels but also in capacitance vessels in both in vitro and in vivo studies (venodilation). This venodilating effect of FK664 has been observed at much lower concentrations than those required to produce an inotropic response. FK664 is effective in the conscious dog at 1 mg/kg (2.5 μmol/kg) orally and in a dog model of congestive heart failure at 3.2 μg/kg/min (7.8 nmol/kg/min), intravenously. The vasodilating and positive‐inotropic activities of FK664 are mainly due to an increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels due to inhibition of cyclic AMP phosphodiesterase. Moreover, FK664 does not affect the balance between myocardial oxygen supply and demand due to a significant increase in coronary blood flow, though the agent does increase myocardial oxygen consumption. In conclusion, the agent produces potent preload reduction and mild cardiac stimulation. This unique pharmacological profile may be beneficial in the management of congestive heart failure. © 1993 Wiley‐Liss, Inc.
Effect of silymarin and silybinin on oxygen radicals
Authors: Pascual Carlos , Gonz Ricardo , Armesto Julio , Muriel Pablo
Published: January 2005

The aim of this work was to study the scavenging action of the flavonoids, silymarin and silybinin (two well known hepatoprotective agents) against different types of oxygen radicals which were generated by specific chemical reactions and detected by luminol‐sensitized chemiluminescence. A well known scavenger for each radical was used as control for the paradigm and for comparing its effect with those of the flavonoids. It was found that 0.8 μg/ml of silymarin and 5.5 mg/ml of silybinin produced the same effect as 3.2 ng/ml superoxide dismutase (SOD). An alkoxy radical scavenging effect similar to the one produced by 0.35 ng/ml of vitamin E was caused by 2 μ/ml silymarin and 1.6 ng/ml silybinin. Silybinin was evaluated as a scavenger of hydroxyl radicals by determining the inhibition of the chemiluminescence produced by the Fenton reaction with luminol; this was compared with the results obtained from a more conventional method which determines the inhibition of the damage to 2‐deoxyribose by the Fenton reaction. In both methods, inhibition was observed at a relatively high concentration of the flavonoid as compared with ethanol. The action of silymarin and silybinin as scavengers of oxygen radicals may explain the protective effect of these flavonoids in certain forms of liver disease where free radicals are involved. However, other properties of these compounds cannot be discarded for their hepatoprotective actions. © 1993 Wiley‐Liss, Inc.
PDGF‐receptor protein tyrosine kinase activity in carotid artery is enhanced by injury and inhibited in vivo by tyrphostin RG 13291
Authors: Bilder Glenda E. , Kasiewski Charles J. , Walczak Edward M. , Perrone Mark H.
Published: January 2005

Tyrphostins (TKI) are synthetic low molecular weight compounds which inhibit in vitro platelet‐derived growth factor (PDGF) mitogenesis by blocking PDGF receptor protein tyrosine kinase activity (PDGF R‐PTK). To determine whether TKIs act by this mechanism in vivo, a rat model of vascular injury was used. Rat carotid arteries were injured by implantation of a tygon cuff machined so that 1 mm of each end touched the artery. PDGF R‐PTK was measured ex vivo by incubation of the excised denuded artery with porcine PDGF followed by homogenization and Western blotting with antiphosphotyrosine/antiPDGF‐R antisera. In arteries from control rats, PDGF produced a maximal 2‐fold increase in R‐PTK at 120 ng/ml. In cuffed arteries, PDGF stimulated R‐PTK in a dose‐related manner after one day of injury; R‐PTK remained elevated for 4–5 days post injury (6‐fold increase in R‐PTK activity at 180 ng/ml). A similar response to PDGF was also evident in contralateral uncuffed arteries. Intraperitoneal injection (+ 2 h) of TKI RG 13291 inhibited PDGF R‐PTK of cuffed artery with an IC50 value of ∽ 2 mg/kg and of the uncuffed artery with IC50 value of ∽ 30 mg/kg. It is concluded that TKIs are potential in vivo inhibitors of injury‐induced PDGF R‐PTK activity and may be useful as inhibitors of PDGF‐dependent effects such as proliferation. © 1993 Wiley‐Liss, Inc.
Inhibition of synovial LTB4 production by a specific leukotriene biosynthesis inhibitor, MK‐0591, in a rabbit model of joint inflammation
Authors: Brideau Christine , Chan Chi‐Chung , Guevremont Diane , Hutchinson John H. , McDonnell Joseph , Moore Vernon
Published: January 2005

The effect of a leukotriene biosynthesis inhibitor (MK‐0591) on LTB4 synthesis was examined in a rabbit model of joint inflammation. Intra‐articular (ia) injection of human recombinant interleukin‐1β (rlL‐1β, 50–400 ng/joint) resulted in dose‐dependent infiltration of leukocytes into the synovium but produced only background levels of LTB4 over a time course of 14–16 h, suggesting that the leukocytes were not activated with respect to LTB4 metabolism. The influx of leukocytes in the synovial space was not inhibited by MK‐0591. Injection of A23187 (100 nmol/joint, ia) in addition to rlL‐1β elicited significant LTB4 release in the synovial fluid. MK‐0591 given iv 30 min before A23187 significantly inhibited the release of LTB4 (ED50 = 0.3 mg/kg), without affecting the number of leukocytes in the synovium. In rabbit whole blood challenged with A23187 in vitro, MK‐0591 also potently inhibited LTB4 synthesis (IC50 = 126 ± 29 nM). The in vivo inhibitory action of MK‐0591 was in good agreement with the plasma levels of the compound (0.62 μM in the group treated with MK‐0591 at 3 mg/kg) and its biochemical efficacy in vitro (100% inhibition of LTB4 synthesis). The effect of MK‐0591 was comparable to that of another leukotriene biosynthesis inhibitor, MK‐886. Indomethacin at dose up to 3 mg/kg iv did not affect the production of LTB4 in the joint. The present study demonstrates that MK‐0591 inhibits LTB4 biosynthesis with high potency in the rabbit synovium, a microenvironment rich in protein and leukocytes. It would be of interest to determine whether such an action would be beneficial in the management of rheumatoid arthritis or other inflammatory conditions in humans. ©1993 Wiley‐Liss, Inc.
Use of neuroendocrine effects in discrimination between CNS‐active drugs in the rat
Authors: Albinsson Agneta , Lundstedt Torbjörn , Andersson Gunnar
Published: January 2005

Different psychotropic drugs were investigated in order to determine their effect on the release of prolactin and corticosterone and their influence on the tuberoinfundibular dopamine (TIDA) neuron activity. The results were used in a principal component analysis, which grouped the psychotropic drugs into different clusters. In the plot showing these clusters the anxiolytic drugs were found to be grouped together and differ from the antidepressant drugs by their potent ability to increase plasma corticosterone. The antipsychotic drugs formed a separate group being clustered together. Typical neuroleptic and atypical antipsychotic drugs could be separated within the cluster by their different effects on plasma prolactin and corticosterone and on TIDA neuron activity. The results indicate that the neuroendocrine profiles of antidepressant and anxiolytic drugs are different from those of antipsychotic drugs and that the neuroendocrine measurements could be a useful tool in the early classification of psychotropic drugs. © 1993 Wiley‐Liss, Inc.
Effects of antiglaucoma drugs on ocular blood flow in ocular hypertensive rabbits
Authors: Hong Show‐Jen , Chiou George C. Y.
Published: January 2005

In search of antiglaucoma agents which can increase the ocular blood flow and effectively lower the intraocular pressure (IOP), numerous antiglaucoma drugs were investigated to determine their ability to increase the ocular pulsatile blood flow in ocular hypertensive rabbits with the intraocular pressure artificially raised to 40 mmHg. It was found that various antiglaucoma drugs increased ocular pulsatile flow; these included (with percent increase) ethoxzolamine (36–56%), pilocarpine (65%), physostigmine (43–83%), echothiophate (23–62%), timolol (28–42%), levobunolol (37–55%), betaxolol (35%), and epinephrine (61%). Metipranolol, metoprolol, and clonidine had no effect on pulsatile blood flow. These results indicate that most antiglaucoma drugs, with the exception of a few, can enhance the ocular pulsatile blood flow in ocular hypertensive rabbits. © 1993 Wiley‐Liss, Inc.
Effects of artilide on spontaneous and induced ventricular arrhythmias in 24‐hour canine myocardial infarction
Authors: Buchanan Lewis V. , Kabell Glenn , Turcotte Uta M. , Brunden Marshall N. , Gibson John K.
Published: January 2005

The electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti‐arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley‐Liss, Inc.
Effects of combinations of methylxanthines and adenosine analogs on locomotor activity in control and chronic caffeine‐treated mice
Authors: Nikodijević Olga , Jacobson Kenneth A. , Daly John W.
Published: January 2005

Chronic caffeine ingestion (CCI) by male NIH Swiss strain mice results in a prolonged reduction in locomotor activity and alterations in response to caffeine, other xanthines, and adenosine analogs. Caffeine, the A1 selective 8‐cyclopentyltheophylline (CPT), and the A2‐selective 3,7‐dimethyl‐1‐propargylxanthine (DMPX) remain stimulatory and the bell‐shaped locomotor dose‐response curves are left‐shifted after CCI. The depressant effects of methylxanthines that are potent phosphodiesterase inhibitors remain after CCI. After CCI, mice became more sensitive to depressant effects of A1, mixed A1/A2, and A2 agonists. In the presence of caffeine the A1‐selective agonist N6‐cyclohexyladenosine (CHA), the mixed A1/A2 agonist 5′‐N‐ethylcarboxamidoadenosine and the A2‐selective agonist 2‐[(2‐aminoethylamino)‐carbonylethylphenylethylamino]‐5′‐N‐ethylcarboxamidoadenosine (APEC) all have dose‐response curves, appearing to consist of initial depressant effects, then stimulatory effects, and finally pronounced depressant effects. The phasic character is reduced or absent after CCI. Synergistic depressant effects of combinations of CHA and APEC also appear reduced after CCI. © 1993 wiley‐Liss, Inc.
L‐368,899, a potent orally active oxytocin antagonist for potential use in preterm labor
Authors: Pettibone D. J. , Clineschmidt B. V. , Guidotti M. T. , Lis E. V. , Reiss D. R. , Woyden C. J. , Bock M. G. , Evans B. E. , Freidinger R. M. , Hobbs D. W. , Veber D. F. , Williams P. D. , Chiu S.‐H. L. , Thompson K. L. , Schorn T. W. , Siegl P. K. S. , Kaufman M. J. , Cukierski M. A. , Haluska G. J. , Cook M. J. , Novy M. J.
Published: January 2005

L‐368,899 [1S‐(‐7,7‐dimethyl‐2‐endo‐(2S‐amino‐4‐(methylsulfonyl)butyramido)‐bicyclo(2.2.1)‐heptan‐1‐yl)methanesulfonyl)‐4‐(2‐methylphenyl)piperazine] was characterized in vitro and in vivo as a potent and selective, orally bioavailable oxytocin (OT) antagonist. L‐368,899 exhibits high affinity for rat (Ki, 3.6 nM) and human (Ki, 13 nM) uterine OT receptors with selectivity versus liver arginine‐vasopressin (AVP)‐V1 and kidney AVP‐V2 receptors in both species. In vitro, L‐368,899 is a potent and competitive OT antagonist in the rat isolated uterus (pA2, 8.9) and mouse anococcygeus muscle (pA2, 8.3) and is inactive against a number of different contractile agents in these preparations. L‐368,899 also inhibits OT‐stimulated phosphatidylinositol turnover in rat uterine slices and exhibits no agonist‐like activity in any of the in vitro assays. In vivo, L‐368,899 selectively antagonizes the uterine contractile effects of OT in the anesthetized rat given both i.v. and intraduodenally (i.d.) (AD50; 350 μg/kg i.v., 7 mg/kg i.d.) with a moderate duration of action. In near‐term pregnant rhesus macaques, L‐368,899 is a potent inhibitor of OT‐stimulated uterine activity (AD50, 27 μg/kg i.v.) and OT‐mediated spontaneous, nocturnal uterine contractions. L‐368,899 is orally bioavailable in several species and, combined with adequate aqueous solubility, represents a potential new tocolytic agent for both oral and i.v. use. © 1993 wiley‐Liss, Inc.
Structure, synthesis, and antitumor activity of the hydrolysis product of the antitumor agent carmethizole
Authors: Anderson Wayne K. , Houston D. Michael , Jarosinski Mark A. , Kinder Frederick R. , Kode Rao N. , Van Roey Patrick , Salerno Jeffrey M.
Published: January 2005

The two isomeric monocarbamates, 2b and 2c, related to the antitumor drug carmethizole (1) were synthesized and the structure of the carmethizole hydrolysis product, 2b, was established by X‐ray crystallography. The chemical reactivity, toxicity, and antitumor activity of the two monocarbamates, 2b and 2c, were compared with 1. © 1993 wiley‐Liss, Inc.
Nicotine and tetrahydroaminoacradine: Evidence for improved attention in patients with dementia of the Alzheimer type
Authors: Sahakian Barbara J. , Coull Jennifer T.
Published: January 2005

A placebo‐controlled, single‐blind study investigated the effects of administering three acute doses of nicotine (0.4, 0.6, and 0.8 mg) to a group of patients suffering from dementia of the Alzheimer type (DAT), and to young and aged normal controls. Performance on objective computerised tests provided evidence for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Despite the lack of drug effect on mnemonic ability, these results demonstrate that DAT patients have significant attentional deficits which can be remediated by nicotine administration. They add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes; and are substantiated by the findings of a second study examining the use of a chronic dose of the cholinesterase inhibitor THA, as a treatment for DAT. In this study, effects on both subjective clinical rating scales and objective computerised tests were assessed. In regard to the former, analysis of the three main clinical outcome measures showed statistically significant effects of the drug on the Mini‐Mental State Examination (MMSE) and the Abbreviated Mental Test Score (AMTS), but not on the Activities of Daily Living scale (ADL). Using objective computerised CANTAB tests, sensitive to specific aspects of memory and attention, evidence was found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. These data will clearly provide important comparative data for future investigations of putative cognitive enhancing drugs in DAT sufferers. © 1994 Wiley‐Liss, Inc.
Comparison of the ability of direct‐ and indirect‐acting nicotinic agonists to induce nicotinic receptor up‐regulation in rat cerebral cortex
Authors: Yang Xiao‐Hong , Buccafusco Jerry J.
Published: January 2005

Chronic twice daily systemic administration of nicotine (1 mg [2 μmol]/kg, sc) over 10 days to rats produced a significant increase in the apparent Bmax for cortical nicotinic receptors. Similar results were obtained whether the labeled ligand employed was [3H]methylcarbamylcholine ([3H]MCC) or [3H]cytisine: Rats were treated twice daily for 10 days with the cholinesterase inhibitor physostigmine (25 μg [64 nmol]/kg, sc) to indirectly activate nicotinic receptors. This regimen inhibited cortical cholinesterase activity by about 51%. Binding analysis of physostigmine‐treated rat cortical tissue indicated that while the Bmax for muscarinic receptors was significantly reduced, there was no change in the binding parameters for neuronal nicotinic receptors. In the next series of experiments, chronic twice daily intracerebroventricular (icv) injection of 30 μg [108 nmol] of MCC, like nicotine, also produced a significant increase in the Bmax for cortical nicotinic receptors. MCC treatment also produced a small but significant increase in the apparent Kd. Twice daily icv injection of 6 μg [23 nmol] of the competitive nicotinic antagonist dihydro‐β‐erythroidine hydrobromide (DHBE) for 10 days did not itself alter the apparent Bmax for cortical nicotinic receptors. In a separate group of rats 6 μg [23 nmol] icv of DHBE preceded by 15 min the icv injection of 30 μg [108 nmol] of MCC. This regimen was administered twice daily for 10 days. Under these conditions the DHBE produced a significant 44% inhibition of the MCC‐induced increase in Bmax. Antagonist pretreatment also blocked the small MCC‐induced increase in Kd. Thus, direct activation of the agonist binding site of the neuronal nicotinic receptor following chronic administration of nicotine or the acetycholine‐like MCC leads to receptor up‐regulation. Indirect activation through cholinesterase inhibition was not effective in this regard. © 1994 Wiley‐Liss, Inc.