bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible role of adenosine receptors in psychiatric diseases
Authors: van Calker Dietrich , Berger Mathias
Published: January 2005

Effective antidepressive treatments like electroconvulsive therapy and sleep deprivation increase adenosine A1‐receptors in the brains of experimental animals. It has therefore been of considerable interest that carbamazepine, which is known to be clinically similarly effective as lithium ions in the prophylaxis of affective illness, interacts with adenosine receptors. We have recently characterized this interaction using cellular model systems, in which adenosine receptor subtypes evoke different second messenger responses. The results show that carbamazepine at therapeutically relevant concentrations, is a selective antagonist of the A1‐ but not of the high affinity A2‐receptor subtype. The increase in the frequency and severity of the episodes that is often observed in the course of affective illness has been interpreted as the result of plastic changes in neuronal sensitivity that lead to the development of pathologically supersensitive neural circuits. The prophylactic properties of lithium ions are thought to be due to a dampening of the inositol‐phospholipid second not directly influence the generation of inositol phosphates. However, adenosine‐agonists, presumably acting via A1‐receptors, can potently modulate the neurotransmitter‐evoked increase of inositol phosphates and cytosolic free calcium ions. This effect could play a role in synaptic plasticity. Indeed, A1‐agonists can block the development of “long term potentiation,” a model of synaptic plasticity. We suggest that the prophylactic properties of carbamazepine in affective psychoses might be related to the inhibition by carbamazepine and the subsequent supersensitization of the A1‐receptors that modulate the neurotransmitter‐induced formation of inositol phosphates and synaptic plasticity. © 1993 Wiley‐Liss, Inc.
Adenosine receptors in rat brain synaptosomes: Receptor characterization and relationships with glutamate release
Authors: Dagani Fiorenzo , Cattabeni Flaminio , Canevari Laura , Ferrari Rosaria , Camisa Manuela , Abbracchio Maria P.
Published: January 2005

The role of adenosine receptor(s) activation in modulating glutamate release in synaptosomes isolated from different rat brain areas was investigated. Receptor binding studies with selective A1 and A2 adenosine receptor ligands were performed in parallel with functional studies on depolarization‐induced increases of intrasynaptosomal calcium concentrations and glutamate release. Specific binding to the selective A1 ligand [3H]‐Cyclohexyladenosine was detected, with highest densities in hippocampal synaptosomes, followed by c. striatum and cortex. In contrast, no specific binding to the selective A2a ligand [3]CGS 21680 was demonstrable in synaptosomes from any of the studied brain areas, suggesting that no adenosine receptors belonging to this receptor subtype are present on rat brain pre‐synaptic terminals. In parallel, the adenosine analogue cyclopentyladenosine (CPA) could partially inhibit the KCl‐induced glutamate release from hippocampal synaptosomes. The agonist‐induced effect was monophasic, dose‐dependent, and already demonstrable at the 10−8 M concentration, which indeed confirms that only A1 receptors inhibitory on calcium‐dependent release are functionally present in synaptosomal preparations. The effect on glutamate release was likely due to the ability of CPA to partially counteract KCl‐induced increases of intrasynaptosomal calcium concentrations. IT is therefore concluded that rat hippocampal synaptosomes represent an adequate in vitro model to study the molecular and functional correlates of pre‐synaptic adenosine receptors, and therefore investigate their role in both physiological and ischemia‐associated pathological neurotransmission. © 1993 Wiley‐Liss, Inc.
Guanine nucleoside diphosphate and triphosphate modulate [3H]CGS 21680 binding to A2 adenosine receptor in rat striatal membranes
Authors: Mazzoni Maria R. , Tacchi Paolo , Martini Claudia , Lucacchini Antonio
Published: January 2005

In striatum and several other tissue, a guanine nucleotide binding protein (Gs) couples A2 adenosine receptor to activation of adenylyl cyclase. We have examined the effect of guanine nucleoside diphosphate and triphosphate on [3H]CGS 21680 binding to A2A adenosine receptors of rat striatum. Both GDP and GTP inhibited specific [3H]CGS 21680 binding to rat striatal membranes by 50% at about 0.1 mM. GMP was inhibitory only at higher concentrations, and the estimated IC50 value was greater than 1mM. The nonhydrolyzable analog of GTP, GPP (NH)p, was as potent as GTP with an IC50 value of approximately 86 μM. These results suggest that the regulation of A2a adenosine receptor binding properties by guanine nucleotides is independent of Gs activation, since inhibition of agonist binding is achieved by addition of agonist binding is achieved by addition of both guanine nucleoside diphosphate and triphosphate © 1993 Wiley‐Liss, Inc.
Antagonistic A2a/D2 receptor interactions in the striatum as a basis for adenosine/dopamine interactions in the central nervous system
Authors: Fuxe Kjell , Ferré Sergi , Snaprud Per , von Euler Gabriel , Johansson Björn , Ferdholm Bertil
Published: January 2005

From behavioural and biochemical experiments, we have found evidence for the existence of a specific adenosine A2a receptor/dopamine D2 receptor interaction in the brain. Behavioural data show that stimulation A2a receptors inhibits and their blockade potentiates a D2‐mediated locomotor activation in mice and that stimulation of D2 receptors counteracts on A2a mediated cataleptic effect in rats. Biochemical data show that, in rat striatal membrane preparations, A2a receptor stimulation decreases the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G‐protein. Based on these findings it is postulated that this A2a/D2 interaction might be the main mechanism responsible for the central effects of adenosine agonists and antagonists, like methylxanthines. The increased behavioural effect of methylxanthines after dopamine denervation could be explained by an increased interaction between adenosine A2a and dopamine D2 receptors. Membrane preparations‐denervated striatum are more sensitive to the effect of adenosine A2a receptor stimulation. Our results underline the potential antiparkinsonian action of adenosine A2a antagonists and the potential antipsychotic of adenosine A2a agonists. © 1993 Wiley‐Liss, Inc.
Extracellular adenosine, formed during low level NMDA receptor activation, provides an inhibitory threshold against further NMDA receptor‐midiated neurotransmission in the cortex
Authors: White Thomas D. , Craig Constance G. , Hoehn Katja
Published: January 2005

In the cortex only a few of the available NMDA receptors must be activated to evoke maximal release of adenosine. In fact, maximal adenosine release occurs at 30 μM NMDA, a concentration at which noradrenaline release is only 20% maximal. NMDA‐evoked noradrenaline release appears to require the generation of propagated action potentials, while adenosine release does not. Noncompetitive block of NMDA‐evoked release of adenosine, but not noradrenaline, can be overcome by increasing NMDA concentrations. The above findings are consistent with the possibility that there are spare receptors for NMDA‐evoked adenosine release, but not for nor‐adrenaline release. These spare receptors are not due to elevated levels of glycine in the vicinity of those NMDA receptors mediating adenosine release. Functionally, it appears that low level NMDA receptor activation provides a purinergic inhibitory threshold against higher level NMDA receptor mediated processes. This could provide inhibitory tone and selectivity for critical functions, such as learning, memory, and synaptic plasticity in the cortex. © 1993 Wiley‐Liss, Inc.
Intracoronary diltiazem limits infarct size during prolonged angioplasty balloon inflation
Authors: Rose Gregory C. , Jordan Joey C. , Jolly Stanley R.
Published: January 2005

An animal model of failed coronary angioplasty was used to evaluate the effect of intracoronary diltiazem on regional ischemia and the degree of myocardial necrosis. Ischemia was produced in closed‐chest, pentobarbital‐anesthetized male mongrel dogs by inflation of 2.5–3.0 mm diameter balloons introduced under fluoroscopy into the left anterior descending or left circumflex coronary arteries. Animals were randomly assigned to control or diltiazem administered at the time of balloon inflation. Diltiazem, 900 μg/kg, was administered in divided doses through the lumen of the angioplasty balloon catheter. Diltiazem reduced the mean arterial pressure by 27 ± 6 mm Hg and blunted tachycardia following occlusion, which was also seen in controls. After 50 min of ischemia, a left thoracotomy was performed, and the left atrium was cannulated for injection of radiolabeled microspheres at 70 min. The animal was then reperfused by deflating the balloon. Regional segment function showed similar dyskinesis in the ischemic area of both groups. At 4 h the animal was sacrificed and the heart was removed for measurement of the area at risk and infarct size using a dual staining technique. Infarct size, when determined as the percent of the area at risk, was significantly reduced in diltiazem treated animals, 9 ± 2%, as compared to control animals, 22 ± 5%. Regional myocardial blood flow did not differ between groups. Therefore, intracoronary diltiazem produced a significant reduction in myocardial injury. This intervention may be useful to delay cell death in the setting of failed coronary angioplasty. © Wiley‐Liss, Inc.
Comparison of the cardiovascular effects of the α2‐adrenoceptor agonist, dexmedetomidine, in rats and rabbits
Authors: MacDonald Ewen , Vartiainen Jaana , Jäsberg Kari , Urtti Arto
Published: January 2005

Dexmedetomidine is a potent, specific, and selective α2‐adrenoceptor agonist undergoing clinical trials as an adjunct to anesthesia. It may also have potential use in the treatment of glaucoma. In anesthetized rats and rabbits, dexmedetomidine induced marked bradycardia, rats being 5 times more sensitive than rabbits. In conscious rabbits, the bradycardia induced by dexmedetomidine was even less apparent; a dose of 40 αg/kg ws needed to consistently slow the pulse. Higher doses of dexmedetomidine induce a direct vasoconstrictor response in the anesthetized animals, in the case rabbits were 9 times less sensitive than rats. In both tests the anesthetized rat better mimicked the sensitivity of humans to dexmedetomidine. Thus, it should be remembered that in ocular pharmacology, where the rabbit is the prevalent experimental animal used, this species is relatively insensitive to the cardiovascular effects of this novel α2‐adrenoceptor agonist. © Wiley‐Liss, Inc.
Effects of S 9977 on learning and memory in the mouse and rat
Authors: File Sandra E. , Mabbutt Peter S. , Bontempi Bruno , Destrade Claude , Jaffard Robert
Published: January 2005

S 9977 (1,3,7‐trimethyl 8‐[3‐(4‐diethylaminocarbonyl‐l‐piperazinyl)1‐propyl]‐3,7‐dihydro(1H)2,6‐purinedione hydrochloride) is a methylxanthine derivative lacking activity at adenosine receptors and having no phosphodiesterase inhibitory action, but which has been reported to enhance cholinergic function. In mice 0.06 mg/kg ip increased, whereas 0.25 and 1 mg/kg ip decreased, spontaneous alternation in a T‐maze. Doses of 0.03 and 0.06 mg/kg ip improved acquisition and retention of a spatial discrimination task when administered on the test days. The dose of 0.06 mg/kg ip was without effect on subsequent retention when given immediately post‐acquisition, suggesting it was without effect on storage processes. When it was administered for 14 days prior to testing 0.06 mg/kg ip retained its effects on acquisition and retention of the discrimination task, but no longer had significant effects on spontaneous alternation. In rats, there was no effect on between‐day habituation of exploration or on acquisition of a working and reference memory task with a 24 h intertrial interval. However, 0.06 mg/kg ip significantly improved retention of this task and 0.12 mg/kg ip significantly improved acquisition when a 48‐h intertrial interval was used, mainly due to a reduction in working memory errors. In a test of reference memory in a helical maze 0.03 mg/kg ip improved acquisition. These results suggest that low, but not high, doses of S 9977 can improve acquisition in tasks relying on both working and reference memory and also can improve performance on retention tasks. The results are discussed with reference to the effects of S 9977 in enhancing cholinergic function. © Wiley‐Liss, Inc.
Paradoxical effects of 2‐amino‐4‐phosphonobutanoic acid and other 2‐amino‐ω‐phosphonoalkanoic acid on the n‐methyl‐d‐aspartate receptor ion channel
Authors: Szabó Géza , Horváth Edit J. , Aráanyi Péter
Published: January 2005

An extensively washed membrane preparation was used to measure the noncompetitive binding site of the N‐methyl‐D‐aspartate (NMDA) receptor complex with [3H]‐1‐[1‐(2‐thienyl) cyclo‐hexyl] piperidine ([3H]‐TCP). Addition of glutamic acid (Glu) or Glu + glycine (Gly) increased the binding of [3H]‐TCP, reflecting that the NMDA receptor ion channel was opened by these compounds. [3H]‐TCP binding was also increased by various 2‐amino‐ω‐phosphonoalkanoic (AP) compounds, of which 2‐amino‐4‐phosphonobutanoic acid (AP4) was the most effective. The effects of AP compounds were also observed in the presence of Gul. However, in the presence of Gly, or in the presence of Glu + Gly, 2‐amino‐5‐phosphonopentanoic acid (AP5) and 2‐amino‐7‐phosphonoheptanoic acid (AP7) inhibited the binding. The enhancing effect of AP4 was also inhibited by these compounds. Our conclusion is that AP compounds exert complex effects: they bind to and effect the NMDA receptor complex ion channel not only via the competitive binding site but may also interact with the potentiating Gly binding site. © Wiley‐Liss, Inc.
Effects of BMY 33462, a selective and potent serotonin type‐3 receptor antagonist, on mesolimbic dopamine‐mediated behavior
Authors: Geissler Marie A. , Torrente John R. , Eison Arlene S. , Gylys Jonas A. , Wright Robert N. , Iben Lawrence G. , Davis Houston H. , Yocca Frank D.
Published: January 2005

The compound BMY 33462 (4‐amino‐N‐(1‐azabicyclo‐[2,2,2]oct‐3‐yl)‐2‐(butan‐2‐one‐3‐yl)oxy‐5‐chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type‐3 (5‐HT3) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5‐HT3 receptor (Ki, 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (Ki > 1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold‐Jarisch reflex in the anesthetized rat (ED50, 0.09 μg/kg, iv), a functional correlate of 5‐HT3 receptor antagonism in vivo. It has been reported that ondansetron and other 5‐HT3 antagonists have the ability to block hyperactivity in rats induced by DiMe‐C7 ([pGlu5, Me‐Phe8, Sar9]SP5–11), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe‐C7‐induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe‐C7‐induced hyperactivity as was haloperiodol and ondansetron. The dopamine‐2 (D2) antagonist haloperidol produced the greatest inhibition of DiMe‐C7‐induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe‐C7‐induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe‐C7‐induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe‐C7‐induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5‐HT3 antagonists to alter a mesolimbic DA‐mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5‐HT3 receptors and 5‐HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5‐HT3 antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side effect liability generally associated with classical neuroleptics. © 1993 Wiley‐Liss, Inc.
Role of serine/threonine kinase casein kinase‐II in vascular smooth muscle cell proliferation and inhibition by heparin
Authors: Singh Jai Pal , Wiernicki Todd R. , Gupta Shalley K.
Published: January 2005

The role of serine/threonine kinase casein kinase‐II (CK‐II) in vascular smooth muscle cell proliferation and inhibition by heparin was investigated. cDNAs for α and β subunits of CK‐II form rabbit vascular smooth muscle cells were cloned and sequenced. A strong evolutionary conservation was found at amino acid and nucleotide levels in CK‐II from rabbit and human. Treatment of smooth muscle cells with a specific antisense oligonucleotide to CK‐II blocked stimulation of DNA synthesis in response to PDGF. Addition of a known inhibitor of CK‐II to cultures of smooth muscle cells also blocked DNA synthesis. Mitogenic stimulation of growth arrested quiescent cultures of smooth muscle cells with PDGF produced a 2–3‐fold increase in CK‐II activity. Heparin was a potent inhibitor of smooth muscle cell derived CK‐II in vitro and attenuated the stimulation of CK‐II activity in response to PDGF in intact cells. Intracellular localization studies showed that heparin and CK‐II were localized in the nucleus. These results suggest a potential role of CK‐II in signal transduction mediating smooth muscle cell growth. Modulation of CK‐II activity by heparin and its co‐localization in the nucleus suggest that heparin may effect CK‐II activity in intact cells. © 1993 Wiley‐Liss, Inc.
Zatosetron, a selective 5‐HT3 receptor antagonist: Pharmacological activities of human and animal metabolites
Authors: Cohen Marlene L. , Bloomquist William , Schmid Christopher R. , Robertson David W. , Wong David T.
Published: January 2005

Zatosetron is a potent, orally active 5‐HT3 receptor antagonist with a long duration of activity in laboratory animals and humans. Several metabolites have been detected in plasma and urine of humans and experimental animals receiving zatosetron. The present study was designed to explore the pharmacological activity of the detected metabolites, 3‐hydroxyzatosetron, 3‐ketozatosetron, and N‐desmethylzatosetron, relative to the parent molecule. These three metabolites had relatively high affinity at 5‐HT3 receptors based on in vitro radioligand binding and inhibited serotonin‐induced bradycardia in urethane‐anesthetized rats after intravenous administration. However, these metabolites had lower affinity and were less potent than zatosetron. Of these metabolites, 3‐hydroxyzatosetron (ED50 = 4.0 μg/kg iv) was approximately 5‐fold less potent than zatosetron (ED50 = 0.8 μg/kg iv) in vivo and had approximately 10‐fold lower affinity at 5‐HT3 receptors in vitro relative to zatosetron. N‐desmethylzatosetron and 3‐ketozatosetron were approximately 15‐fold less potent than zatosetron in vivo as 5‐HT3 receptor antagonists. With regard to duration of activity in vivo, after intravenous administration, 3‐hydroxyzatosetron and 3‐ketozatosetron blocked 5‐HT3 receptors longer than zatosetron, whereas N‐desmethylzatosetron showed a duration of pharmacological activity similar to zatosetron. A fourth metabolite, zatosetron‐N‐oxide can exist in two isomeric forms, with stereoselective N‐oxidation of zatosetron resulting in formation of only one isomer in humans, zatosetron‐β‐N‐oxide. Zatosetron‐β‐N‐oxide had approximately 100‐fold lower 5‐HT3 receptor affinity relative to zatosetron and was approximately 150‐fold less active as an antagonist at 5‐HT3 receptors in vivo (ED50 = 115 μg/kg iv). Thus, although pharmacological activity was observed with all four metabolites, they were all less active in vivo than zatosetron. Therefore, these metabolites would contribute significantly to the activity of zatosetron only if plasma (and tissue) levels greatly exceeded those of zatosetron. © 1993 Wiley‐Liss, Inc.
Chronic theophylline prolongs the refractory period in amygdala‐kindled rats
Authors: Kleinsorge Robert J. , Bowers Lakeisha M. , Jarvis Michael F. , Berman Robert F.
Published: January 2005

The effects of chronic theophylline treatment on brain adenosine A1 receptors and amygdala‐kindled seizures were examined in rats. The repeated administration of theophylline 417 μmoles/kg/day i.p. (75 mg/kg/day) for 14 days resulted in a significant increase in 1 nM [3H]cyclohexyladenosine binding to adenosine A1 receptors in thalamus, hippocampus, and cerebellum. This chronic theophylline treatment was shown to significantly prolong the immediate postseizure refractory period (defined as sensitivity to a subsequent kindling stimulation) while both the severity and duration of an initial kindled seizure was not affected. These findings indicate that the postseizure refractory period can be influenced by the brain adenosine system, and implicate adenosine as an important neuromodulator of the patterning of seizure episodes. © 1993 Wiley‐Liss, Inc.
[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

The 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

Long‐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

The 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

The 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

The 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

Injection 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

While 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

The 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

Four‐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

This 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

The 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

The 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

The 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

Drugs 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.
Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A1‐receptor antagonist
Authors: Barrett Richard J. , Wright Kathryn F. , Droppleman David A.
Published: January 2005

The renal hemodynamic and excretory effects of intravenous N‐0861, a non‐xanthine adenosine A1‐receptor antagonist, were evaluated in conscious and anesthetized male Sprague‐Dawely rats. In conscious rats, N‐0861 (10, 30 μmol/kg, iv) significantly increased the excretion of urine, Na+, and K+; UClV was increased only in the rats treated with 10 μmol/kg, N‐0861. The relative excretion of K+ was similar to that of Na+. Lower doses of N‐0861 (1, 3 μmol/kg, iv) had no effect. During clearance studies in anesthetized rats, N‐0861 (3, 10, 30 μmol/kg, iv) had little effect on systemic or renal hemodynamics, but provoked significant saluresis that was poorly related to dose, and that was characterized by a somewhat greater excretion of Na+ and Cl−− relative to K+. These results indicate that the selective adenosine A1 receptor antagonist N‐0861 has little influence on resting renal hemodynamics and suggest that the natriuretic responses are due to inhibition of tubular Na+ reabsorption.