bluuebunny/crossref_metadata_2025_split huggingface dataset:
[3H]5′‐N‐Ethylcarboxamidoadenosine selectively labels the low affinity adenosine binding protein, adenotin, on intact chinese hamster ovary cells
Authors: Jarvis Michael F. , Saltzman Alan 
Published: January 2005

AbstractThe ability of [3H]5′‐N‐ethylcarboxamidoadenosine (NECA) to specifically bind recognition sites on intact Chinese hamster ovary (CHO) cells was examined in the present study. Saturation experiments indicated that [3H]NECA bound with moderate affinity (Kd = 400 nM) and large capacity (apparent Bmax = 3.2 pmol/105 cells) to intact CHO cells. No specific binding to these cells was observed with the A1‐selective agonist 20 nM [3H]cyclohexyladenosine or with the A2‐selective agonist 20 nM [3H]CGS 21680. Competition studies revealed that close structural analogs of NECA and the xanthine phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX) inhibited 20 nM [3H]NECA binding with moderate affinity (IC50s 0.5–15 μM). Adenosine also showed weak activity (IC50 = 100 μM) for inhibiting [3H]NECA binding. However, a wide variety of prototypic adenosine receptor agonists and antagonists did not significantly interact with these [3H]NECA recognition sites on CHO cells. [3H]NECA binding to CHO cell membranes was not sensitive to guanine nucleotides and NECA did not stimulate cAMP formation. These results are consistent with the previously demonstrated ability of [3H]NECA to bind low affinity adenosine binding proteins (adenotin proteins), as well as, adenosine receptors in a variety of mammalian tissues. The present results further indicate that [3H]NECA selectively labels in adenotin‐like recognition site on intact CHO cells in the absence of detectable binding to high affinity adenosine receptors. © 1993 Wiley‐Liss, Inc.
Long‐term potentiation and the mechanisms of memory
Authors: Izquierdo Ivan 
Published: January 2005

AbstractLong‐term potentiation (LTP) is a cellular model of the memory processes that occurs in many nerve cells, usually at glutamatergic synapses. For this reason, glutamatergic synapses being the most abundant in the brain, LTP has been widely proposed as a mechanism of memory. Recent findings support this proposal and indicate that, indeed, LTP and memory processes share many properties. The initial steps of LTP and of memory involve the activation of glutamatergic NMDA (N‐methyl‐D‐asprtate) receptors, sensitive to AP5 (amino phosphono valerate), and are very sensitive to inhibition by GABAA (gamma amino butyric acid type A) receptor agonists. The phase that follows in the next 2 or 3 h depends on activation of protein kinase c (PKC) and is sensitive to inhibitors of this enzyme family. Like LTP, the underlying mechanism of memories persists for very long periods without the need of expression; and, like LTP, memories are readily expressed upon a reinstatement of the stimuli used in their induction, as is the case in test sessions. The expression of LTP and the expression of memory rely on AMPA (D,L‐alpha‐amino hydroxy methyl isoxazolone propionate) receptors sensitive to CNQX (cyano nitro quinoxaline dione). LTP occurs in many places within the brain, including the hippocampus, amygala, medial septum, and entorhinal cortex. the drug effects on memory mentioned above are seen when the drugs are infused into these brain regions. The region(s) involved depend on the type of memory being processed. These findings support the idea that LTP underlies memory acquisition, retention, and retrieval (the latter, at least for many days after acquisition) and may provide some clues for the development of drugs to alleviate memory disorders. © 1993 wiley‐Liss, Inc.
Some decision in the development of cimetidine
Authors: Duncan W. A. M. 
Published: January 2005

AbstractThe histamine H2 blocker, cimetidine (TagametTM), was one of the first drugs discovered bya mechanism‐based approach under the direction of Sir James black at Smith, Kline & french in the United Kingdom. Cimetidine also holds the distinction of being the first drug ever to achieve more than $1 billion a year in sales. In this case study, the crucial scientific milestones in the discovery and development of cimetidine are recounted from the perspective of the Director of Research and placed within the context of the organizational dynamics ongong in the mid‐1960s as Smith, Kline & french sought to retain its independence as a pharmaceutical company. The impact of the tremendous success of cimetidine as an anti‐ulcer medication on the SK&F organization and the issue of managing success within a multinational drug research are presented to provide younger scientists with a feel for the tactical issues involved and the outcomes. © 1993 wiley‐Liss, Inc.
Antithrombotic action of the orally available thromboxane A2 receptor antagonist S‐1452 (d‐s‐145 Ca) in rodents
Authors: Jyoyama Hirokuni , Hori Yozo , Hatakeyama Hisao , Asanuma Fujio , Kurosawa Atsushi 
Published: January 2005

AbstractThe thromboxane A2 (TXA2) receptor antagonist, S‐1452, calcium salt of a steroselectively synthesized d‐enantiomer of the racemate S‐145, calcium 5(Z)‐1R,2S,3S,4S‐7‐[3‐phenylsulfonylaminobicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoate dihydrate, was examined for its antithrombotic action in vivo, in mice and rats. Orally administered S‐1452 dose‐dependently prolonged the bleeding time which was measured by a tail transection method. The effect was observed at doses above 1 mg/kg in both animals. S‐1452 clearly prevented U46619‐induced sudden death in mice and its ED50 value for the prevention was 0.47 mg/kg at 1 h after oral administration. It was more potent and long‐acting than reference compounds such as ONO‐3708 and SQ‐26548. The preventive effect of S‐1452 was also observed in arachidonate‐induced sudden death, although much larger doses were required in comparison with the case of the U‐46619‐induced response (ED50: 4.6 mg/kg p.o., at 30 min; 3.1 mg/kg p.o., at 60 min after S‐1452). Aspirin, used as a reference compound, was much less active than S‐1452 (ED50: 85.9 mg/kg p.o., at 30 min; 88.2 mg/kg p.o., at 60 min after aspirin). The pharmacologically active moiety of S‐1452, d‐S‐145, was several times more potent than the opposite enantiomer 1‐S‐145 in the prolongation of the bleeding time in rats, and in the prevention of the U46619‐induced sudden death in mice. These stereoselective efficacies suggest that S‐1452 causes its antithrombotic action by blocking TXA2 receptors in vivo. S‐1452 significantly reduced collagen‐induced thrombocytopenia in mice at doses above 0.1 mg/kg p.o. In rats, the compound improved clearly collagen‐induced abnormal electrocardiogram. The minimum effective doses were 1 mg/kg for S‐1452, 15 mg/kg for ONO‐3708, and 10 mg/kg for OKY‐046, 60 min after oral administration. It is concluded that S‐1452 is a very potent and orally available antithrombotic compound. © 1993 wiley‐Liss, Inc.
Pharmacological evaluation of leukotriene biosynthesis and inflammation in an adoptive model of peritoneal anaphylaxis in the mouse
Authors: Griswold Don E. , Hillegass Leonard M. , White John R. 
Published: January 2005

AbstractThe ability of IgE anti‐arsenilate hapten‐sensitized bone marrow‐derived mast cell line (1BD‐8) to generate leukotriene C4 (LTC4) and increase vascular permeability, and neutrophil infiltration in vivo in Balb/c mice challenged with arsenilated BSA (ARS‐BSA) was studied. Sensitized 1BD8 cells (5‐10 × 106) were administered intraperitoneally followed by 0.1 μg ARS‐BSA. Following CO2 asphyxia, the peritoneal contents were harvested and assayed for immunoreactive LTC4 (iLTC4) by radioimmunoassay. Maximal production of iLTC4 (60 ng/mouse) was seen 2.5 min after challenge and then decreased to a nadir at 15 min. Animals which were depleted of resident peritoneal cells by treatment with cyclophosphamide gave an iLTC4 response equivalent to non‐treated controls, indicating that the transferred cells contributed most of the iLTC4 response. The oral administration of the 5‐lipoxygenase (5‐LO) inhibitors, phenidone, SK&F 107649, and the pyridinyl imidazoles SK&F 104493 and SK&F 105809 all reduced the iLTC4 response (61‐96% inhibition); whereas the vasoactive amine antagonist cyproheptadine and the cyclooxygenase inhibitors, meclofenamic acid and naproxen, had no effect. Extravasation of Evans blue dye was also monitored spectrophotometrically and was significant 5 min after challenge and reached a plateau at 45 min. Like iLTC4, despite depletion of resident peritoneal cells, no difference in dye extravasation was seen in cyclophosphamide‐ versus saline‐treated animals. Those compounds which inhibited iLTC4 also inhibited dye extravasation with similar potency. Cyproheptadine, however modestly, inhibited dye extravasation (33%) without altering iLTC4 production. Neutrophil infiltration was also monitored and was significantly inhibited by the oral administration of phenidone (73%) and SK&F 104493 (81%). This model provides a reliable method to evaluate in vivo inhibition of leukotriene biosynthesis and the associated inflammatory response induced by a pathophysiologically relevant stimulus. © 1993 wiley‐Liss, Inc.
Acute treatment of mice with high doses of caffeine: An animal model for choreiform movement
Authors: Nikodijević Olga , Jacobson Kenneth A. , Daly John W. 
Published: January 2005

AbstractInjection of caffeine at a dose of 35 to 70 mg/kg causes choreiform (dance‐like) movements in NIH Swiss mice in a dose‐dependent manner. The effect is less pronounced in mice that had chronically ingested caffeine for 7 days. The A2a selective adenosine agonist 2‐[(2‐aminoethylamino)carbonylethylphenylethylamino]‐5'‐N‐ethylcarboxamidoadenosine (APEC), but not the A1 selective agonist N6‐cyclohexyladenosine (CHA), diminished caffeine‐elicited choreiform movement. The data suggest involvement of A21‐adenosine receptors in the appearance of choreiform movements. The dopamine antagonist haloperidol also reduced the chorea movements elicited by caffeine, but high doses were required. The calcium‐channel blocker nitrendipine reduced the choreiform movements. These animals could provide a model for further investigation of the mechanisms underlying choreiform movements; as well as possible therapeutic appraoches to certain choreas in humans related either to disease states (e.g., Huntington's disease or Tourette's syndrome) or to side effects of drug treatments. © 1993 wiley‐Liss, Inc.
Serotonin involvement in cocaine sensitization: Clues from studies with cocaine analogs
Authors: Elsworth John D. , Taylor Jane R. , Jatlow Peter , Roth Robert H. 
Published: January 2005

AbstractWhile the behavioral effects of cocaine are generally ascribed to its ability to inhibit the uptake of dopamine, there is evidence to indicate that some of the other pharmacological properties of cocaine may play a significant role in its actions. Behavioral, biochemical, and electrophysiological data suggest that the potent inhibition of serotonin uptake elicited by cocaine is a mechanism that may contribute to its overall effects in vivo. Cocaethylene is the ethyl ester of benzoylecognine which is formed in vivo during concurrent ingestion of cocaine and ethanol. Cocaethylene is equipotent with cocaine as an inhibitor of dopamine uptake, but less potent as an inhibitor of serotonin uptake. We have compared the effects of acute and chronic cocaine and cocaethylene on rat locomotor activity in an attempt to determine the serotonin component in this behavior. Acute dose‐response studies revealed that at higher doses (20 mg/kg ip) cocaethylene produced less stimulation of locomotor activity than cocaine. Prior exposure to cocaine resulted in an augmented response to a subsequent challenge dose of either cocaine (sensitization) or cocaethylene (cross‐sensitization). However, previous treatment with cocaethylene did not significantly affect the locomotor activity produced by challenges with cocaethylene or cocaine. The involvement of serotonergic systems in the development of cocaine‐induced sensitization is one intriguing possible explanation of these data. Biochemical studies have shown that other cocaine analogs possess even more selectivity for the dopamine uptake site than cocaethylene. In terms of comparative potency as inhibitors of dopamine, serotonin, and norepinephrine uptake, isopropylcocaine (isopropyl ester of benzoylecognine) is more selective than even cocaethylene. A metabolically resistant analog of cocaine, β‐CIT (2β‐carbomethoxy‐3β‐(4‐iodophenyl)tropane), was shown to be extraordinarily long‐acting, stimulating locomotor activity for 10 h following a dose of 0.1 mg/kg ip. Furthermore, β‐CIT was extremely potent, inhibiting dopamine or serotonin uptake in vitro at a concentration 100 times lower than is required for cocaine. Thus, isopropyl or other substitutions at the carbomethoxy position of the cocaine or β‐CIT structures may provide useful tools for the analysis of the serotonin or norepinephrine components in cocaine's actions and as selective probes of central dopamine systems in imaging studies. © 1993 wiley‐Liss, Inc.
Effect of flumazenil on the memory‐enhancing properties of (−)‐nicotine in rodents
Authors: O'Neill Alyssa B. , Brioni Jorge D. 
Published: January 2005

AbstractThe effect of the benzodiazepine‐receptor antagonist flumazenil on the facilitatory effect of (−)‐nicotine on memory in septal‐lesioned rats in a spatial task and in the inhibitory avoidance test in mice was investigated. In the two‐platform spatial discrimination test, septallesioned rats exhibited a significant number of errors in comparison to sham animals, an effect that can be reversed by the administration of (−)‐nicotine during the training phase. Flumazenil did not affect the performance of septal‐lesioned rats but it blocked the facilitatory effect of (–)‐nicotine on lesioned rats. In the inhibitory avoidance test in mice,(−)‐nicotine as well as flumazenil facilitated retention of the test at 0.62 and 10 μmol/kg, respectively. However, a low‐noneffective dose of flumazenil blocked the memory enhancing effect of (−)‐nicotine. The blockade of the facilitatory effect of (−)‐nicotine by flumazenil in normal and septal‐lesioned animals suggests that the cognitive effect of (−)‐nicotine requires the activation of benzodiazepine receptors. © 1994 Wiley‐Liss, Inc.
Smoking and food intake in a field study: Continuous actometer/heart rate recording and pocket computer assisted dietary reports, subjective self‐assessments, and mental performance
Authors: Bättig Karl , Kos Jiri , Hasenfratz Markus 
Published: January 2005

AbstractFour‐day food intake reports, collected with electronic diaries, and saliva probes for cotinine analysis were obtained from 39 smokers and 43 nonsmokers. The nonsmokers had a higher caloric intake than the smokers, but this was related to more frequent sport activities. The distribution of energy intake across carbohydrates, fat, and protein was identical for both groups, but the smokers consumed bread, sweets and desserts, cheese, fruit juices, muesli (a cereal and yoghurt mixture), and water less frequently, but also more soft drinks, coffee, and alcohol. Only coffee and alcohol drinking were correlated with saliva continine. For two additional days, the recording of food intake was continued together with the continuous recording of activity and heart rate, intermittent measurements of blood pressure, assessments of subjective state, and performing a mental task. On one of these 2 days, the smokers had to abstain from smoking. Abstinence lowered heart rate and increased caloric intake by about 500 kcal, whereas actometer readings, blood pressure, subjective state, and mental performance were unaffected. Also unaffected were the percentage intake of fat, protein, and carbohydrates and the frequency of consuming particular food items. Post hoc correlations between subjective state, cotinine measures, excess intakes of total calories, macronutrients, and specific groups of food items were obtained only occasionally and in an inconsistent fashion. It is suggested that effects of smoking on taste and eating as a hedonic substitute when abstaining might represent important factors for food intake beyond the effects of nicotine. The new methods developed for this study appear to offer a way to obtain detailed information under particularly naturalistic conditions in studies on smoking and related problems. © 1994 Wiley‐Liss, Inc.
Effect produced by acute and chronic administration of the selective 5‐HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat
Authors: Ashby Charles R. , Minabe Yoshio , Toor Alon , Fishkin Lyle D. , Granoff Martin I. , Wang Rex Y. 
Published: January 2005

AbstractThis study examined the effect of acute and chronic administration of the selective 5‐HT3 receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose‐response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01‐0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)‐apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2‐fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose‐response curve of BRL 46470A. © 1994 Wiley‐Liss, Inc.
Optimizing organization and effectiveness of pharmaceutical discovery by molecular target rather than by therapeutic area
Authors: Silver Paul J. 
Published: January 2005

AbstractThe majority of drug discovery units in pharmaceutical companies are currently organized by therapeutic area. In this Commentary, a proposal is offered which focuses discovery organization by molecular target, rather than therapeutic area. Examples of such molecular targets include ion channels, proteases, and tyrosine kinases, to name but a few. In the face of continued rationalization in the pharmaceutical industry, major cutbacks in the world‐wide pharmaceutical R&D workforce, and the changing landscape of health care reform, the drug companies that survive the 90s will be those that gain sustainable competitive advantages in R&D. For this interim, and beyond, classes of numerous, highly validated molecular targets have already been identified in the past few years which have strong links to major disease processes with unmet therapeutic needs. Moreover, it is evident that these disease processes, and molecular targets, play key roles in therapeutically unrelated diseases. For example, tyrosine kinases have roles in endocrine, oncological, and certain cardiovascular disorders. There is little need for therapeutically aligned researchers in industry trying to find new targets. The key factors in gaining a sustainable competitive advantage in research will be to rapidly obtain these human targets, identify, design, and synthesize proprietary modifiers of these targets, and efficiently determine efficacy, biodistribution, and safety so that these modifiers can be rapidly advanced to clinical trials. A focus and organization of molecular target‐oriented drug discovery is proposed to attain this advantage.
Effects of neurotensin on midbrain dopamine neuronal activity
Authors: Litwin Linda C. , Goldstein Jeffrey M. 
Published: January 2005

AbstractThe effects of acute intracerebroventricular administration of the tridecapeptide, neurotensin, and a pseudopeptide analog of neurotensin‐(8‐13) were compared to the effects of haloperidol and clozapine on the spontaneous activity of dopamine cells in both the ventral tegmental area (A10) and the substantia nigra compacta (A9). Unlike the typical antipsychotic haloperidol, which causes a non‐selective increase in both A9 and A10 cell activity, both neurotensin and a neurotensin analog, H‐Lys (CH2NH)Lys‐Pro‐Tyr‐lle‐Leu‐OH, in like manner to clozapine, at low doses selectively increase the number of spontaneously active A10 dopamine cells. These data provide the first in vivo evidence that acute administration of neurotensin can produce changes in spontaneous activity of midbrain dopamine cells similar to the atypical antipsychotic, clozapine.
Effects of imipramine and mirtazapine on operant performance in rats
Authors: Andrews John S. , Jansen Johannes H. M. , Linders Sandra , Princen Anthonius , Drinkenburg Wilhelmus H. I. M. , Coenders Carla J. H. , Vossen Joseph H. M. 
Published: January 2005

AbstractThe effects of the tricyclic antidepressant imipramine and the atypical antidepressant mirtazapine were compared on the performance of rats in three operant procedures: a differential reinforcement of low rates schedule (DRL), a delayed matching to position (DMTP), and simultaneous visual discrimination tasks. Both compounds improved performance in the DRL task in a similar dose‐related manner. Imipramine, but not mirtazapine, disrupted performance in the visual discrimination task. Imipramine reduced accuracy and increased response latencies and missed trials. Neither compound effected accuracy in the DMTP; both compounds caused some slowness of responding and imipramine caused several animals to fail to respond in a manner similar to that observed in the visual discrimination task. These data suggest that although imipramine and mirtazapine are similarly effective in putative tests of antidepressant activity, imipramine has a greater tendency to disrupt other aspects of cognitive performance, as well as exert generally depressive effects on operant responding.
U.S. drug and biologic product approvals during 1993
Authors: Beary John F. , Robert Eaton C. , Copmann Thomas L. , Wierenga Dale E. 
Published: January 2005

AbstractDrugs remain a key element in the effective containment of health care costs. In 1993, 29 new drugs were approved for marketing by the US Food and Drug Administration (FDA). These entities, according to a 1993 Office of Technology Assessment study, each took on average 12 years and $359 million each to discover and develop. The FDA reported that the average review time for these entities was 26.5 months, some 3 months less than reported in 1992. Under the prescription Drug User Fee Act of 1992, which will generate an additional $327 million over the period 1993–1997, the FDA will hire an additional 600 review staff.