摘要:

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 wil

ISSN:0272-4391    

DOI:10.1002/ddr.430300102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe histamine H2blocker, 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‐L

ISSN:0272-4391    

DOI:10.1002/ddr.430300103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractUrinary 3‐methoxy‐4‐hydroxyphenlglycol (MHPG) levels were measured in 14 normal volunteers during a Phase I study of the novel, reversible monoamine oxidase‐A (MAO‐A) inhibitor BW 1370U87 targeted for the treatment of depression. baseline MHPG excretion (day 0) showed a significant diurnal increase (n = 14,P<0.05) between 1200 and 2000 h. Oral administration of BW 1370U87 produced significant (35‐45% maximal,P<0.05) decreases from these basal levels during the same 1200‐2000 h time interval Twenty‐four hours after the dose (dose was given at 0800 h), urinary MHPG levels returned to baseline, consistent with a reversible mechanism of inhibition by BW 1370U87. Decreases in urinary MHPG did not appear to be dose‐dependent between 200‐800 mg BW 1370U87 per day, suggesting that maximal MAO‐A inhibition was achieved at the 200 mg dose. These effects on MHPG excretion may be helpful in predicting the efficacy of BW 1371370U87 in the treatment of depression.

ISSN:0272-4391    

DOI:10.1002/ddr.430300104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe 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

ISSN:0272-4391    

DOI:10.1002/ddr.430300105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe class II antiarrhythmic agent properties of the novel compound MS‐551 (1,3‐dimethyl‐6‐{(2‐[N‐(2‐hydroxyethyl‐3‐(4‐nitrophenyl)propylamino]ethylamino} ) 2,4 (1H3H)‐pyrimidinedione hydrochloride) have been characterized in vitro and in vivo. Using isolated canine Purkinje fibers, the effect of MS551 on the action potentials was studied. MS‐551 (0.1‐10μg/ml) caused a uniform and concentration‐dependent increase in action potential duration without changing parameters of action potential depolarization. IN anesthetized open‐chested dogs. MS‐551 (0.1‐10 mg/kg i,v.) produced a dose‐dependent increase in both atrial and ventricular effective refractory periods 9ERP) with QTcprolongation. At 0.3 mg/kg i.v., atrial and ventricular ERP were significantly increased 28 ± 4 mec and 12 ± 2 msec, respectively, and the minimum e4ffective plasma concentration of MS‐551 for atrial ERP prolongation was approximately 0.1 μg/ml. However, MS‐551 did not slow intracardiac conduction time (A‐H, H‐V) even at the highest dose studied (30 mg/kg i.v.). These data suggest that MS‐551 has a “pure” class III electrophysioloigcal property in dogs. Furthermore, we compared the effects of MS‐551 on the hemodynamics in anesthetized dogs with those ofd‐sotalol. MS‐551 (0.1‐3 mg/kg) produced dose‐dependent decrease in heart rate with QTcprolongation and slight increase in LVdP/dtmax. In contrastd‐sotalol (0.1‐10 mg/kg i.v.) depcreased heart rate, mean arterial pressure, LVdP/dtmax and aortic flow in a dose‐dependent manner. Moreover, we reassessed in anesthetized dogs the cardiovascular toxicity of continuously infused MS‐551 (2 mg/kg/min for 50 min). Ath the end of the infusion (total dose: MS‐551 100 mg/kg), LVdP/dtmax was decreased 23%, but QTcprolongation never exceeded 30%. Thus, arrhythmias, such astorsade de pointes, were not seen. In conclusion, MS‐551 appears to be a pure and potent class III antiarrh

ISSN:0272-4391    

DOI:10.1002/ddr.430300106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe effect of intravenous mannitol on soman‐induced neuropathology and cardio‐myopathy was studied in rats. Soman, an organophosphorus agent, irreversibly inhibits total body acetylcholinesterase and induces a cholinototoxic syndrome in rats which results in the development of sezures, brain damage, and degenerative cardiomyopathy. The severity of the cardiomyopathy parallels the severity of the neuropathology. When mannitol at a dose of 1.5 g/kg was administered at the onset of sezures and followed by a second dose 5 h later, there was a significant increase in 24 h survival. Moreover, the severity of brain lesions was reduced in the piriform cortex, thalamus, amygdala, and the caudate putamen. The same treatment schedule also provided almost complete protection against the concomitant development of degenerative cardiomyopathy. The finding that the mannitol treatments reduced both the severity of the neuropathology and the degenerative cardiomyopathy reinforces the concept of a possible central neurogenic mechanism for the development of the cardiomyopathy. These results suggest that mannitol may be useful to reduce the severity of sezure‐related neuropathology and to provide additional protection to other vital organs which may be secondarily susceptible to neurogenically mediatd pathologic change, such as the heart in rats which develop cardiomyopathy following soman‐induced seizures. © 1993 wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430300107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430300108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430300101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY