bluuebunny/crossref_metadata_2025_split huggingface dataset:
GV150526: A Neuroprotective Agent
Authors: Bordi Fabio , Mugnaini Manolo , Terron Andrea , Barnaby Robert , Reggiani Angelo 
Published: August 2010

ABSTRACTThromboembolic stroke is a severe, disabling disease characterized by an abrupt reduction of cerebral blood flow, which leads to deprivation of oxygen and nutrients to neuronal tissue, followed by permanent brain damage. Evidence has been accumulated to implicate excitotoxicity in the pathogenesis of ischemic brain injury. Overstimulation of excitatory amino acid receptors becomes deleterious for neuronal cell survival. Glutamate antagonists can ameliorate the ischemic injury by any of several mechanisms. Because blockade of the glycine site of theN‐methyl‐D‐aspartate (NMDA) receptor seems to offer a better side‐effect profile, glycine antagonists are attractive targets for blocking excitotoxicity following stroke.GV150526 is a selective and potent glycine antagonist at the NMDA receptor complex. It binds to the glycine site with both high affinity and high selectivity inin vitrobinding studies.In vivostudies have shown that GV150526 significantly reduces infarct volume in the middle cerebral artery occlusion model of stroke. This effect remained statistically significant, even if treatment was delayed for as long as 6 h post‐occlusion. GV150526 showed no evidence of adverse effects usually associated with NMDA receptor blockers, such as neuronal vacuolization in standard assays or cognitive impairment in behavioral tests. GV150526 had no significant treatment‐related respiratory or cardiovascular effects or effects on behavior, body temperature, or blood pressure in mice or rats. Pharmacokinetic studies indicated that GV150526 has low clearance and volume of distribution in both the rat and the dog. Preclinical toxicology studies have shown that the compound is well tolerated in both species. Phase I/II studies were undertaken to assess the safety, tolerability, and pharmacokinetics of GV150526 in healthy volunteers and acute stroke patients, and from these a dose was selected to be studied in Phase III clinical trials. These efficacy studies have now completed recruitment and data reconciliation is ongoing. GV150526 has the potential to be an effective therapy for acute ischemic stroke.
Paroxetine: A Review
Authors: Bourin Michel , Chue Pierre , Guillon Yannick 
Published: August 2010

ABSTRACTParoxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive‐compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache.Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5‐hydroxytryptamine, 5‐HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5‐HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, has a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5‐HT1A) and terminal (5‐HT1B/1D) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactivein vivo.Steady state levels are achieved after 4–14 days and an elimination half‐life of 21 h is consistent with once‐daily dosing. There is wide inter‐individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment. Serious adverse events are, however, extremely rare even in overdose.In summary, paroxetine is well tolerated and effective in the treatment of both depressive and anxiety disorders across the age range.
HU 210: A Potent Tool for Investigations of the Cannabinoid System
Authors: Ottani Alessandra , Giuliani Daniela 
Published: August 2010

ABSTRACTThe synthetic compound HU 210 displays a multiplicity of biochemical, pharmacological, and behavioral effects, most of which have been demonstrated to be dependent on a selective agonistic activity at CB1and CB2cannabinoid receptors and to involve the main neurotransmitter systems. Results obtained in various studies suggest a potential clinical application of this highly potent drug (e.g., as antipyretic, antiinflammatory, analgesic, antiemetic, and antipsychotic agent) as well as its usefulness in research aimed to develop a better understanding of the involvement of the endogenous cannabinoid system in a number of physiopathological functions.
Donepezil for Alzheimer's Disease: Pharmacodynamic, Pharmacokinetic, and Clinical Profiles
Authors: Shigeta Masahiro , Homma Akira 
Published: August 2010

ABSTRACTDonepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine‐based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable Pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase‐III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long‐term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function.The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders.
CHF2819: Pharmacological Profile of a Novel Acetylcholinesterase Inhibitor
Authors: Trabace Luigia , Cassano Tommaso , Loverre Antonia , Steardo Luca , Cuomo Vincenzo 
Published: August 2010

ABSTRACTCHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE.In vivoCHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose‐dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine‐induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5‐hydroxytryptamine (5‐HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), γ‐aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit).Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose‐dependent manner.The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer‐type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.
Duloxetine Pharmacology: Profile of a Dual Monoamine Modulator
Authors: Karpa Kelly D. , Cavanaugh Jane E. , Lakoski Joan M. 
Published: August 2010

ABSTRACTDysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5‐HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use.In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants.In a six‐week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight‐week multicenter, double‐blind, placebo‐controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half‐life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5‐HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.
Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists
Authors: Mirza Naheed R. , Peters Dan , Sparks Robin G. 
Published: August 2010

ABSTRACTBinding studies initially suggested that the muscarinic agonist, xanomeline, was a subtype selective muscarinicM1receptor agonist, and a potential new treatment for Alzheimer's disease. However, laterin vitroandin vivofunctional studies suggest that this compound is probably better described as a subtype selective M1/M4muscarinic receptor agonist. This subtype selectivity profile has been claimed to explain the limited classical cholinomimetic side effects, particularly gastrointestinal, seen with xanomeline in animals. However, in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for xanomeline and in the patient population this led to a>50% discontinuation rate. Clearly, the preclinical studies have not been able to predict this adverse profile of xanomeline, and this suggests that either xanomeline is not as subtype selective as predicted from preclinical research or that there are differences between humans and animals with regard to muscarinic receptors. Nevertheless, in Alzheimer's patients xanomeline dose‐dependently improves aspects of behavioral disturbance and social behavior including a reduction in hallucinations, agitation, delusions, vocal outbursts and suspiciousness. The effects on cognition are not as robust and mainly seen at the highest doses tested. These effects in Alzheimer's patients have given impetus to the suggestion that muscarinic agonists have potential antipsychotic effects. The current review assesses the antipsychotic profile of xanomeline within the framework of the limited clinical studies with cholinergic agents in man, and the preclinical research on xanomeline using various models commonly used for the assessment of new antipsychotic drugs. In general, xanomeline has an antipsychotic‐like profile in various dopamine models of psychosis and this agrees with the known interactions between the cholinergic and dopaminergic systems in the brain. Moreover, current data suggests that the actions of xanomeline at the M4muscarinic receptor subtype might mediate its antidopaminergic effects. Particularly intriguing are studies showing that xanomeline, even after acute administration, selectively inhibits the firing of mesolimbic dopamine cells relative to dopamine cell bodies projecting to the striatum. This data suggest that xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects. The preclinical data on the whole are promising for an antipsychotic‐like profile. If in a new formulation (i.e., transdermal) xanomeline has less adverse effects, this drug may be valuable in the treatment of patients with psychosis.
The Cellular Biochemistry of Cholesterol and Statins: Insights into the Pathophysiology and Therapy of Alzheimer's Disease
Authors: Wolozin Benjamin , III James Brown , Theisler Catherine , Silberman Simone 
Published: August 2010

ABSTRACTThe causes of late onset Alzheimer disease (AD) are poorly understood. Although β‐amyloid (Aβ) is thought to play a critical role in the pathophysiology of AD, no genetic evidence directly ties Aβ to late onset AD. This suggests that the accumulation of Aβ and neurodegeneration associated with AD might result from an abnormality that indirectly affects Aβ production or accumulation. Increasing evidence suggests that abnormalities in the metabolism of cholesterol and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol might contribute to the pathophysiology of late onset AD by increasing production of Aβ. 24(S) Hydroxycholesterol is a member of a family of oxidized cholesterol catabolites, termed oxysterols, which function to regulate export of cholesterol from the cell and transcription of genes related to cholesterol metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in several different genes important for cholesterol physiology are associated with an increased load or level of Aβ in AD. These genes include apolipoprotein E, cholesterol 24 hydroxylase (Cyp46), acyl‐CoA:choles‐terol acetyltransferase (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of cholesterol, or its precursors, are elevated in subjects early in the course of AD. Finally, studies of the processing of amyloid precursor protein show that cholesterol and its catabolites modulate amyloid precursor protein processing and Aβ production. These lines of evidence raise the possibility that genetic abnormalities in cholesterol metabolism might contribute to the pathophysiology of AD.
ABT‐089: Pharmacological Properties of a Neuronal Nicotinic Acetylcholine Receptor Agonist for the Potential Treatment of Cognitive Disorders
Authors: Rueter Lynne E. , Anderson David J. , Briggs Clark A. , Donnelly‐Roberts Diana L. , Gintant Gary A. , Gopalakrishnan Murali , Lin Nan‐Horng , Osinski Mark A. , Reinhart Glenn A. , Buckley Michael J. , Martin Ruth L. , McDermott Jeffrey S. , Preusser Lee C. , Seifert Terese R. , Su Zhi , Cox Bryan F. , Decker Michael W. , Sullivan James P. 
Published: August 2010

ABSTRACTABT‐089 [2‐methyl‐3‐(2‐(S)‐pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT‐089 shows selectivity for the cytisine binding site on the α4β2receptor subtype as compared to the α‐bungarotoxin (α‐BgT) binding sites on the α7and α1β1δγ receptor subtypes. In functionalin vitroelectrophysiological and cation flux assays, ABT‐089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT‐089 is as potent and efficacious as (–)‐nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT‐089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT‐089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT‐089 shows little propensity to induce adverse
Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology
Authors: Davies Marilyn A , Sheffler Douglas J. , Roth Bryan L. 
Published: August 2010

ABSTRACTAripiprazole (Abilify®) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G‐protein coupled receptors (GPCRs) [especially dopamine (D2) and 5‐HT1A] and antagonistic action at others (especially 5‐HT2A). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short‐term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and Schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long‐term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time‐to‐relapse.Aripiprazole represents the first functionally selective atypical antipsychotic drug.
Cortagine: Behavioral and Autonomic Function of the Selective CRF Receptor Subtype 1 Agonist
Authors: Farrokhi Catherine Borna , Tovote Philip , Blanchard Robert J. , Blanchard D. Caroline , Litvin Yoav , Spiess Joachim 
Published: August 2010

ABSTRACTCorticotropin‐releasing factor (CRF) is a neuropeptide and mediating component of neuroendocrine, autonomic, and behavioral processes associated with the stress response. The two receptor subtypes identified in the mammalian brain, CRF receptor subtype 1 (CRF1) and CRF2, are suggested to differentially modulate these processes. Manipulation of these receptors with selective CRF compounds and transgenic models has revealed, in most studies, a clear potentiation of the stress response through central activation of CRF1. However, pharmacological activation of CRF restricted to CRF1 has been limited by the availability of selective peptidic compounds. Recently, a highly selective CRF1 agonist, cortagine, has been developed. It was synthesized from chimeric intermediate sequences of ovine CRF, sauvagine, and human/rat CRF into a highly soluble peptide with strong affinity for CRF1 (IC50< 5 nM) and a very low binding preference for CRF2 (IC50> 500 nM). Affinity for the CRF binding protein (IC50> 1,000nM) can be abolished by the addition of a glutamate residue on position 21 of the cortagine peptide sequence. Cortagine has recently been tested in a variety of preclinical models of behavior including the elevated‐plus‐maze (EPM), forced swim test (FST), homecage, and rat exposure test (RET). Preliminary characterization in the EPM and FST suggested that this compound elicits anxiogenic and antidepressant‐like effects, respectively. Additional testing in the homecage and RET, which targets various elements of behavior, directs to a more potent anxiogenic profile of cortagine. In this review, we discuss the behavioral findings and the tests used to measure these effects. Finally, we also discuss preliminary findings of autonomic activation obtained by central injection of cortagine that support CRF1 involvement in the modulation of heart rate and heart rate variability.
Making and Remaking “Good Government” in Brazil: Subnational Industrial Policy in Minas Gerais
Authors: Montero Alfred P. 
Published: August 2010

AbstractComparative examples of “good government” at the subnational level may underanalyze the “public goods” problem facing politicians. Delegating authority and resources to policymaking agencies is possible when political conflict is low. The benefits can be maintained only if public agencies establish ties of “horizontal embeddedness” with industrial clients. This case study of innovative industrial policymaking in Minas Gerais, which is compared with one from Rio de Janeiro, finds that horizontal, interagency ties were critical to policy success. The contrast leads to an examination of themineirosystem's efficacy in promoting externalities, attracting foreign investment, and planning infrastructure in the state's automotive industry.
“We Have a Consensus”: Explaining Political Support for Market Reforms in Latin America
Authors: Armijo Leslie Elliott , Faucher Philippe 
Published: August 2010

AbstractBy the 1990s, to the astonishment of many observers, most Latin American countries had reformed their systems of national economic governance along market lines. Many analysts of this shift have assumed that it circumvented normal political processes, presuming that such reforms could not be popular. Explanations emphasizing economic crisis, external assistance, and politically insulated executives illustrate this approach. Through a qualitative investigation of the reform process in the region's four most industrialized countries, Argentina, Brazil, Chile, and Mexico, this study argues, to the contrary, that reforming governments found or created both elite and mass political support for their policies.