Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00146.X
M. Meyer, David J. Anderson, Jeffrey E. Campbell, Sherry Carroll, K. Marsh, A. D. Rodrigues, M. Decker
ABT-594 [(R)-5-(2-azetedinylmethoxy)-2-chloropyridine mono-tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT-594 at α4β2-containing nAChRs is comparable to that of (±)-epibatidine, ABT-594 has lower affinity than (±)-epibatidine at α3-containing nAChRs. Similarly, ABT-594 is approximately equivalent to (±)-epibatidine in a Ca2+ flux assay in K-177 cells that express 04132 nAChRs but less potent than (±)-epibatidine in the IMR-32 (α3-containing) cell line. ABT-594 is active in a variety of rodent models of acute thermal (mouse hot-plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT-594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT-594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT-594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT-594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT-594 (AUC0–12)
{"title":"Preclinical Pharmacology of ABT-594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain","authors":"M. Meyer, David J. Anderson, Jeffrey E. Campbell, Sherry Carroll, K. Marsh, A. D. Rodrigues, M. Decker","doi":"10.1111/J.1527-3458.2000.TB00146.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00146.X","url":null,"abstract":"ABT-594 [(R)-5-(2-azetedinylmethoxy)-2-chloropyridine mono-tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT-594 at α4β2-containing nAChRs is comparable to that of (±)-epibatidine, ABT-594 has lower affinity than (±)-epibatidine at α3-containing nAChRs. Similarly, ABT-594 is approximately equivalent to (±)-epibatidine in a Ca2+ flux assay in K-177 cells that express 04132 nAChRs but less potent than (±)-epibatidine in the IMR-32 (α3-containing) cell line. ABT-594 is active in a variety of rodent models of acute thermal (mouse hot-plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT-594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT-594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT-594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT-594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT-594 (AUC0–12)","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"6 1","pages":"183-194"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87462289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00135.X
N. Katsube, R. Ishitani
{"title":"A Review of the Neurotrophic and Neuroprotective Properties of ONO-1603: Comparison with Those of Tetrahydroaminoacridine, an Antidementia Drug","authors":"N. Katsube, R. Ishitani","doi":"10.1111/J.1527-3458.2000.TB00135.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00135.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"36 1","pages":"21-34"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72804044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00160.X
J. Disterhoft
{"title":"Drugs that Enhance Learning in Aging Brain","authors":"J. Disterhoft","doi":"10.1111/J.1527-3458.2000.TB00160.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00160.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"12 1","pages":"4-4"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77745446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00161.X
M. Moss
{"title":"Neurobiologic Basis of Cognitive Decline in Normal Aging and Hypertensive Cardiovascular Disease","authors":"M. Moss","doi":"10.1111/J.1527-3458.2000.TB00161.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00161.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"77 1","pages":"5-6"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90398934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2004.TB00017.X
M. O'Neill, K. Whalley, C. Robinson, M. Ward, C. Hicks, T. Murray
Central administration of growth factors or cell transplantation have been utilized in an attempt to find a therapy to halt and potentially reverse degeneration in Parkinson’s disease (PD). However, these techniques are expensive, invasive and further intensive research is required before they can be utilized safely in man. In our previous poster (Murray et al.) we reported that two AMPA receptor potentiators provided protection in rodent models of PD. Our earlier studies indicating that these molecules could increase neurotrophin expression and the large degree of protection after a severe nigral 6-OHDA lesion prompted us to evaluate the neurotrophic effects of LY503430. A series of studies indicated that delayed treatment with LY503430 (0.5 mg kg s.c. initiated 1, 3, 6, or 14 days post infusion of 6-OHDA into the substantia nigra) provided a correction of apomorphine-induced rotations and loss of striatal tyrosine hydroxylase. In a second series of studies an oral dose response with LY503430 (0.05, 0.1, 0.2, or 0.5 mg kg initiated 1 day after 6-OHDA) indicated that 0.1–0.5 mg kg p.o. provided robust functional and histological protection. In an attempt to characterize the mechanism of this protection, adjacent striatal sections from the oral efficacy studies were immunostained with antibodies for neurotrophins and growth associated protein-43 (GAP-43). The data indicated that there was a dose-dependent increase in GAP-43 in the striatum. The data provide strong evidence that LY503430 has neurotrophic actions and that in addition to providing neuroprotection, it may also be able to regenerate damaged dopaminergic terminals in PD patients.
生长因子或细胞移植的集中管理已被用于试图找到一种治疗来阻止和潜在地逆转帕金森病(PD)的退化。然而，这些技术是昂贵的，侵入性的，需要进一步深入的研究才能安全地用于人类。在我们之前的文章(Murray et al.)中，我们报道了两种AMPA受体增强剂在啮齿动物PD模型中提供保护。我们早期的研究表明，这些分子可以增加神经营养因子的表达，并且在严重的神经6-OHDA损伤后具有很大程度的保护作用，这促使我们评估LY503430的神经营养作用。一系列研究表明，延迟LY503430治疗(在6- ohda输注黑质后1,3,6或14天开始0.5 mg kg s.c.)可以纠正阿吗啡诱导的旋转和纹状体酪氨酸羟化酶的丧失。在第二个系列研究中，LY503430口服剂量反应(6-OHDA后1天开始的0.05,0.1,0.2或0.5 mg kg)表明0.1 - 0.5 mg kg p.o.具有强大的功能和组织学保护作用。为了描述这种保护的机制，我们用神经营养因子和生长相关蛋白43 (GAP-43)抗体对口服疗效研究的邻近纹状体切片进行了免疫染色。数据显示纹状体中GAP-43呈剂量依赖性增加。这些数据提供了强有力的证据，表明LY503430具有神经营养作用，除了提供神经保护外，它还可能能够再生PD患者受损的多巴胺能末梢。
{"title":"Increased Sprouting and Delayed Protection with an AMPA Receptor Potentiator in a Rodent Model of Parkinson's Disease Suggests a Trophic Mechanism of Action","authors":"M. O'Neill, K. Whalley, C. Robinson, M. Ward, C. Hicks, T. Murray","doi":"10.1111/J.1527-3458.2004.TB00017.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2004.TB00017.X","url":null,"abstract":"Central administration of growth factors or cell transplantation have been utilized in an attempt to find a therapy to halt and potentially reverse degeneration in Parkinson’s disease (PD). However, these techniques are expensive, invasive and further intensive research is required before they can be utilized safely in man. In our previous poster (Murray et al.) we reported that two AMPA receptor potentiators provided protection in rodent models of PD. Our earlier studies indicating that these molecules could increase neurotrophin expression and the large degree of protection after a severe nigral 6-OHDA lesion prompted us to evaluate the neurotrophic effects of LY503430. A series of studies indicated that delayed treatment with LY503430 (0.5 mg kg s.c. initiated 1, 3, 6, or 14 days post infusion of 6-OHDA into the substantia nigra) provided a correction of apomorphine-induced rotations and loss of striatal tyrosine hydroxylase. In a second series of studies an oral dose response with LY503430 (0.05, 0.1, 0.2, or 0.5 mg kg initiated 1 day after 6-OHDA) indicated that 0.1–0.5 mg kg p.o. provided robust functional and histological protection. In an attempt to characterize the mechanism of this protection, adjacent striatal sections from the oral efficacy studies were immunostained with antibodies for neurotrophins and growth associated protein-43 (GAP-43). The data indicated that there was a dose-dependent increase in GAP-43 in the striatum. The data provide strong evidence that LY503430 has neurotrophic actions and that in addition to providing neuroprotection, it may also be able to regenerate damaged dopaminergic terminals in PD patients.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"126 1","pages":"195-195"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90277060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00140.X
S. Chaki, A. Nakazato, S. Okuyama
{"title":"Atypical Antipsychotic Profile of NRA0045, a Novel Dopamine D4 receptor, 5-Hydroxytryptamine2A (5-HT2A) Receptor and α1 Adrenoceptor Antagonist","authors":"S. Chaki, A. Nakazato, S. Okuyama","doi":"10.1111/J.1527-3458.2000.TB00140.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00140.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"248 1","pages":"95-110"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77284622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00179.X
A. Breier
{"title":"The Effects of Olanzapine on Cognition","authors":"A. Breier","doi":"10.1111/J.1527-3458.2000.TB00179.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00179.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"10 1","pages":"35-35"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76617460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2004.TB00006.X
U. Bonnet
{"title":"SSRI/Moclobemide‐Combination in the Treatment of Resistant Depression: Response to Dr. Gillman's letter.","authors":"U. Bonnet","doi":"10.1111/J.1527-3458.2004.TB00006.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2004.TB00006.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"59 1","pages":"86-88"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76200279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00150.X
P. Jobe, J. Dailey
Two independently derived, inbred strains of genetically epilepsy-prone rats (GEPRs) have been developed, the moderately epileptic GEPR-3 and the more severely epileptic GEPR-9. Seizures expressed by GEPRs model human generalized tonic/clonic seizures (GTCSs) and partial seizures secondarily generalized to tonic/clonic seizures. Several types of existing antiepileptic drugs have been tested in the GEPR model. Without exception, the seizure suppressing properties of these drugs occur both in GEPR-3 s and GEPR-9s. The differential responses of the two GEPR strains separate the antiepileptic drugs into three categories: (1) those effective in GTCSs and partial seizures; (2) those that are additionally effective in absence seizures; and (3) those effective in absence seizures but not in convulsive seizures. No known false positives have yet been detected in GEPR tests. In addition to the utility of the seizures expressed by GEPRs in drug development paradigms, these animals also have potential in the search for drugs that are specifically “antiseizure predisposition” rather than merely anticonvulsant. Heretofore, worldwide drug development efforts have emphasized the discovery of drugs that are anticonvulsant in nonepileptic animals. As might have been anticipated, these same drugs have proven to be anticonvulsant in epileptic subjects. Paradigms that would detect drugs with the capacity to correct the biological determinants of predisposition are in early stages of application. Kindling seizures provide a means to identify drugs that might be useful in correcting stimulus-induced seizure predisposition. The GEPR and other genetic models of the epilepsies provide models for developing treatments to correct genetically determined seizure predisposition. Emerging evidence supports the hypothesis that GEPRs model comorbidity between the epilepsies and affective disorders. Understanding the basis of this comorbidity has the potential to enable the development of treatments that reverse the underlying abnormalities of the coexisting disorders. Because human epilepsies and affective disorders are environmentally and genetically complex, the abnormalities of the GEPR probably will not account for all predispositions leading to this comorbidity.
{"title":"Genetically Epilepsy‐Prone Rats (GEPRs) in Drug Research","authors":"P. Jobe, J. Dailey","doi":"10.1111/J.1527-3458.2000.TB00150.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00150.X","url":null,"abstract":"Two independently derived, inbred strains of genetically epilepsy-prone rats (GEPRs) have been developed, the moderately epileptic GEPR-3 and the more severely epileptic GEPR-9. Seizures expressed by GEPRs model human generalized tonic/clonic seizures (GTCSs) and partial seizures secondarily generalized to tonic/clonic seizures. Several types of existing antiepileptic drugs have been tested in the GEPR model. Without exception, the seizure suppressing properties of these drugs occur both in GEPR-3 s and GEPR-9s. The differential responses of the two GEPR strains separate the antiepileptic drugs into three categories: (1) those effective in GTCSs and partial seizures; (2) those that are additionally effective in absence seizures; and (3) those effective in absence seizures but not in convulsive seizures. No known false positives have yet been detected in GEPR tests. In addition to the utility of the seizures expressed by GEPRs in drug development paradigms, these animals also have potential in the search for drugs that are specifically “antiseizure predisposition” rather than merely anticonvulsant. Heretofore, worldwide drug development efforts have emphasized the discovery of drugs that are anticonvulsant in nonepileptic animals. As might have been anticipated, these same drugs have proven to be anticonvulsant in epileptic subjects. Paradigms that would detect drugs with the capacity to correct the biological determinants of predisposition are in early stages of application. Kindling seizures provide a means to identify drugs that might be useful in correcting stimulus-induced seizure predisposition. The GEPR and other genetic models of the epilepsies provide models for developing treatments to correct genetically determined seizure predisposition. Emerging evidence supports the hypothesis that GEPRs model comorbidity between the epilepsies and affective disorders. Understanding the basis of this comorbidity has the potential to enable the development of treatments that reverse the underlying abnormalities of the coexisting disorders. Because human epilepsies and affective disorders are environmentally and genetically complex, the abnormalities of the GEPR probably will not account for all predispositions leading to this comorbidity.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"147 3 1","pages":"241-260"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75584936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00171.X
S. Petanceska, K. Duff, D. Frail, V. Nagy, L. Refolo, S. Gandy
{"title":"Control of β-amyloid Brain Levels by Estrogens","authors":"S. Petanceska, K. Duff, D. Frail, V. Nagy, L. Refolo, S. Gandy","doi":"10.1111/J.1527-3458.2000.TB00171.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00171.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"2 1","pages":"24-25"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80670276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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