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1. |
Editorial |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 111-111
Michael Williams,
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ISSN:0272-4391
DOI:10.1002/ddr.430300302
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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2. |
Surviving as a niche player in the pharmaceutical industry: Reflections from the field |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 112-120
Stig Jorgensen,
Ivan Jensen,
Martin Edwards,
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摘要:
AbstractThe pharmaceutical industry can be divided into a top tier of about 30 major league companies and a second tier (minor league) comprising several thousand. This paper focused on the second tier and the particular challenge of minor league companies—especially niche players—to balance operating requirements and strategic ambitions within limited and limiting resources. In the authors' experience, survival as a niche player requires not only that the company stays on the technology frontier but also that risk willingness and innovative behavior be characteristic of managers' mindset. To this end, the authors share 13 “ground rules” to perform appropriately as a niche player. © 1993 wiley
ISSN:0272-4391
DOI:10.1002/ddr.430300303
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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3. |
Acute treatment of mice with high doses of caffeine: An animal model for choreiform movement |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 121-128
Olga Nikodijević,
Kenneth A. Jacobson,
John W. Daly,
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摘要:
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 A2aselective adenosine agonist 2‐[(2‐aminoethylamino)carbonylethylphenylethylamino]‐5'‐N‐ethylcarboxamidoadenosine (APEC), but not the A1selective 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.
ISSN:0272-4391
DOI:10.1002/ddr.430300304
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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4. |
L‐368,899, a potent orally active oxytocin antagonist for potential use in preterm labor |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 129-142
D. J. Pettibone,
B. V. Clineschmidt,
M. T. Guidotti,
E. V. Lis,
D. R. Reiss,
C. J. Woyden,
M. G. Bock,
B. E. Evans,
R. M. Freidinger,
D. W. Hobbs,
D. F. Veber,
P. D. Williams,
S.‐H. L. Chiu,
K. L. Thompson,
T. W. Schorn,
P. K. S. Siegl,
M. J. Kaufman,
M. A. Cukierski,
G. J. Haluska,
M. J. Cook,
M. J. Novy,
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摘要:
AbstractL‐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 toc
ISSN:0272-4391
DOI:10.1002/ddr.430300305
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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5. |
Structure, synthesis, and antitumor activity of the hydrolysis product of the antitumor agent carmethizole |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 143-146
Wayne K. Anderson,
D. Michael Houston,
Mark A. Jarosinski,
Frederick R. Kinder,
Rao N. Kode,
Patrick Van Roey,
Jeffrey M. Salerno,
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摘要:
AbstractThe 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,
ISSN:0272-4391
DOI:10.1002/ddr.430300306
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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6. |
Hypotensive responses to the putative adenosine A3receptor agonist N6‐2‐(4‐aminophenyl)‐ethyladenosine in the rat |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 147-152
Alan M. Carruthers,
John R. Fozard,
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摘要:
AbstractThe hypotensive response to the putative adenosine A3receptor agonist, N6‐2‐(4‐aminophenyl)ethyladenosine (APNEA), has been further investigated. In pithed rats with blood pressures maintained at normal values with angiotensin II, the hypotensive response to APNEA was resistant to blockade by 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) at a dose of 0.5 mg kg (1.7 μmol kg) iv, which abolished the bradycardia to APNEA and that to the prototype A1receptor agonist, N6‐cyclopentyladenosine (CPA). The xanthine‐resistant hypotensive responses to APNEA were broadly similar in pithed animals whose blood pressures were maintained by phenylephrine, clonidine, or the inhibitor of nitric oxide (NO) synthase, NG‐nitro‐L‐arginine methyl ester (L‐NAME). The blocker of ATP‐dependent potassium (KATP) channels, glibenclamide, did not affect the hypotensive response to APNEA in animals infused with angiotensin II. Thus, the xanthine‐resistant hypotensive response to APNEA is not an effect dependent on a particular agonist‐receptor interaction. Neither the release of NO, newly synthesized from L‐arginine, nor activation of glibenclamide‐sensitive KATPchannels can explain the putative A3receptor‐mediated hypotensive respo
ISSN:0272-4391
DOI:10.1002/ddr.430300307
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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7. |
Alcohol‐induced reinforcement: Dopamine and 5‐HT3receptor interactions in animals and humans |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 153-169
Bankole A. Johnson,
Philip J. Cowen,
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摘要:
AbstractAlcohol abuse is a major health problem worldwide. Whatever the treatment goal, be it abstinence or “controlled” drinking, the outcome from both pharmacological and nonbiological treatments remains disappointing. Behavioural experiments in animals have suggested that the reinforcing properties of alcohol, like other drugs of abuse, are critical to drug‐seeking behaviour. Dopaminergic fibres running from the ventral tegmental area to the nucleus accumbens may play a central role in mediating the reinforcing effects of drugs of abuse including alcohol. Thus, alcohol increases extracellular levels of dopamine in the nucleus accumbens and dopamine receptor antagonists decrease alcohol consumption in a number of behavioural paradigms. A recently described subtype of serotonin (5‐HT) receptor, the 5‐HT3receptor, appears to modulate the effects of alcohol on dopamine release in the nucleus accumbens. In rodents, 5‐HT3receptor antagonists inhibit alcohol‐induced dopamine release in the nucleus accumbens. Further, in behavioural studies, 5‐HT3receptor blockade decreases alcohol consumption in a free‐choice paradigm. In humans, reinforcement is difficult to measure directly. Nevertheless, the pleasurable subjective effects of alcohol are important behavioural correlates of the reinforcement process. Our preliminary findings in humans suggest that the 5‐HT3receptor antagonist, ondansetron, can attenuate some of the pleasurable effects of a small dose of alcohol including the subjective desire to drink. We speculate, although we have no direct evidence for this at present, that in humans this effect could also be due to a blockade of alcohol‐induced dopamine release in the nucleus accumbens as has been demonstrated in animals. Further studies with clinical populations are required to assess the effects of 5‐HT3receptor antagonists on drinking behaviour and to explore their potential in the management of alcohol abuse.
ISSN:0272-4391
DOI:10.1002/ddr.430300308
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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8. |
Serotonin mechanisms in alcohol drinking behavior |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 170-177
William J. McBride,
James M. Murphy,
Kanji Yoshimoto,
Lawrence Lumeng,
Ting‐Kai Li,
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摘要:
AbstractRat lines selectively bred for disparate alcohol‐drinking behaviors exhibit innate differences in the contents of serotonin (5‐HT) in several CNS limbic regions, e.g., nucleus accumbens (ACB), frontal cortex, hypothalamus, and olfactory tubercles. In these regions, the selectively bred alcohol‐preferring (P) line has levels approximately 20% (P>0.05) lower than values obtained for the alcohol‐nonpreferring (NP) line. In addition, in some limbic regions, the densities of (1) 5‐HT1Areceptors are higher by approximately 30% and (2) 5‐HT1Band 5‐HT2receptors are lower (by 25‐40%) in the P than in the NP line. systemic administration of agents that increase synaptic levels of 5‐HT, such as fluoxetine (a 5‐HT uptake inhibitor), d‐fenfluramine (a 5‐HT releaser) and D, L‐5‐hydroxytryptophan (an immediate precursor of 5‐HT), significantly decreased alcohol consumption of the P line of rats. Systemic (1.0 and 2.0 g/kg ip) administration or local perfusion (100 mM) of ethanol significantly increased the extracellular levels of 5‐HT in the ACB of unselected Wistar rats. An interaction of the dorsal raphe nucleus (DRN) 5‐HT system with the ventral tegmental area (VTA) dopamine (DA) pathway projecting to the ACB was indicated by the findings that DA release in the ACB increased and decreased following stimulation and inhibition, respectively, of DRN 5‐HT neurons. Moreover, an involvement of 5‐HT in mediating alcohol‐stimulated DA release in the ACB is indicated by the observation that local application of a 5‐HT3antagonist can attenuate this stimulated release. Overall, the data suggest that an innate 5‐HT deficiency in certain limbic structures of the P rat may be a major neurobiological factor underlying their high alcohol drink
ISSN:0272-4391
DOI:10.1002/ddr.430300309
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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9. |
Role of serotonin in ethanol abuse |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 178-188
Cleatus J. Wallis,
S. Mehdi Rezazadeh,
Harbans Lal,
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摘要:
AbstractSeveral subclasses of serotonin receptors (5‐HT1a, 5‐HT1b, 5‐HT1c, 5‐HT2, and 5‐HT3) have been implicated in the control of ethanol (EtOH) related behaviors, such as: (1) voluntary EtOH consumption, (2) anxiety occurring during EtOH withdrawal (EW), (3) interoceptive stimuli produced by EtOH, and (4) modulation of EtOH intoxication. Serotonin modulation of neuronal excitability and modulation of hormone release may be important mechanisms contributing to the development and/or maintenance of ethanol tolerance/dependence by modulating emotional behavior (anxiety), homeostasis, and adaptive processes. This review examines our current understanding of serotonin's contribution to ethanol abuse. © 1993 wiley
ISSN:0272-4391
DOI:10.1002/ddr.430300310
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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10. |
Serotonin involvement in cocaine sensitization: Clues from studies with cocaine analogs |
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Drug Development Research,
Volume 30,
Issue 3,
1993,
Page 189-200
John D. Elsworth,
Jane R. Taylor,
Peter Jatlow,
Robert H. Roth,
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摘要:
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 studi
ISSN:0272-4391
DOI:10.1002/ddr.430300311
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1993
数据来源: WILEY
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