bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature
Authors: Verster Joris C. , Volkerts Edmund R. 
Published: August 2010

ABSTRACTAlprazolam is a benzodiazepine derivative that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered.An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated.In addition to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clinical studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car.
A Review of Pharmacology of NCS‐382, a Putative Antagonist of γ‐Hydroxybutyric Acid (GHB) Receptor
Authors: Castelli M. Paola , Pibiri Fabio , Carboni Giovanni , Piras A. Paola 
Published: August 2010

ABSTRACTγ‐Hydroxybutyric acid (GHB), a naturally occurring metabolite of γ‐aminobutyric acid (GABA), has been postulated to act as a specific agonist of GHB receptors and as well as a weak GABABreceptor agonist. To date, 6,7,8,9‐tetrahydro‐5‐hydroxy‐5H‐benzo‐cyclohept‐6‐ylideneacetic acid (NCS‐382), a semirigid compound structurally related to GHB, is the only compound reported to be an antagonist of the GHB receptor sites. In this article we review thein vivoandin vitropharmacological properties of NCS‐382 and its interaction with GHB and GABABreceptors. Binding studies have demonstrated that NCS‐382 is a stereoselective ligand for GHB‐binding sites, with both, the high and the low component of population, showing the same distribution of GHB receptors. Indeed, this compound did not display affinity for GABAA, GABAB, or any other known receptors, while conflicting data have been reported as to its selective antagonist action at GHB receptor. Only a few studies have shown that NCS‐382 antagonizes GHB‐induced effect, but a re‐evaluation of all data reported in the literature suggests that the antagonistic effect of this compound could be due to an indirect action at GABABreceptors. As revealed by several behavioral studies, NCS‐382 fails to antagonize GHB discriminative stimuli, GHB‐induced inhibition of locomotor activity and ataxia or suppression of operant responses. Moreover, it is capable of either eliciting qualitatively similar effects to those of GHB or enhancing some actions of GHB. In addition, the NCS‐382‐sensitive electrophysiological effects of endogenous and exogenous GHB observedin vivohave not been completely replicatedin vitro.The only electrophysiological action of GHB antagonizedin vitroby NCS‐382 required a previous blockade of GABABreceptors. We concluded that NCS‐382 is a good ligand but not a selective antagonist for GHB receptor.
The Use of 4‐Aminopyridine (Fampridine) in Demyelinating Disorders
Authors: Hayes Keith C. 
Published: August 2010

ABSTRACT4‐Aminopyridine (4‐AP or fampridine) is a potassium channel‐blocking agent that has been shown to restore conduction in focally demyelinated axons. A sustained‐release matrix tablet form of 4‐AP (fampridine‐SR) is currently undergoing multicenter clinical trials in patients with multiple sclerosis or chronic spinal cord injury. This review describes the pharmacology and mechanisms of action of 4‐AP, its pharmacokinetics in human subjects, and the outcomes of clinical trials employing either immediate‐release or sustained‐release formulations of the drug. The randomized clinical trials that have been completed to date indicate that K+channel blockade may prove to be a useful strategy for ameliorating central conduction deficits due to demyelination. Diverse neurological gains have been reported for both motor and sensory domains. At the present time, however, the clinical trials have not provided sufficiently robust or definitive evidence of efficacy to gain regulatory approval for the symptomatic management of patients with either multiple sclerosis or spinal cord injury.
Cotinine, a Neuroactive Metabolite of Nicotine: Potential for Treating Disorders of Impaired Cognition
Authors: Terry Alvin V. , Hernandez Caterina M. , Hohnadel Elizabeth J. , Bouchard Kristy P. , Buccafusco Jerry J. 
Published: August 2010

ABSTRACTThe pharmacological effects of the tobacco‐derived alkaloid nicotine have been widely studied in humans and animals for decades. However, relatively little attention has been given to the potential actions of its major metabolite, cotinine. After nicotine consumption the duration of cotinine's presence in blood and brain greatly exceeds that of nicotine. Therefore, cotinine could mediate the more protracted pharmacological effects of nicotine. The studies described in this report were thus designed to further investigate certain neuropharmacological actions of cotinine. Behavioral tests (e.g., delayed matching‐to‐sample) were conducted in aged rhesus monkeys to assess the effects of cotinine on working memory and attention. In rats a prepulse inhibition (PPI) procedure was used to assess the effects of the compound on auditory gating — a method for predicting the potential antipsychotic properties of drugs. Cotinine exhibited significant effectiveness in these tasks. The drug was also cytoprotective in differentiated PC‐12 cells with a potency equivalent to that of nicotine. The effects of chronic cotinine treatment on the expression of nicotinic and muscarinic acetylcholine receptors in rat brain were measured by [125I]epibatidine, [125I]α‐bungarotoxin ([125I]BTX), [3H]pirenzepine ([3H]PRZ), and [3H]AFDX‐384 ([3H]AFX) autoradiography. Unlike nicotine, cotinine failed to upregulate the expression of brain nicotinic receptors. Based on its relative safety in man, cotinine should prove useful in the treatment of diseases of impaired cognition and behavior without exhibiting the toxicity usually attributed to nicotine.
Pharmacological Properties, Central Nervous System Effects, and Potential Therapeutic Applications of Atipamezole, a Selective α2‐Adrenoceptor Antagonist
Authors: Pertovaara Antti , Haapalinna Antti , Sirviö Jouni , Virtanen Raimo 
Published: August 2010

ABSTRACTAtipamezole is an α2‐adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for α2‐adrenoceptors and its α2/α1selectivity ratio are considerably higher than those of yohimbine, the prototype α2‐adrenoceptor antagonist. Atipamezole is not selective for subtypes of α2‐adrenoceptors. Unlike many other α2‐adrenoceptor antagonists, it has negligible affinity for 5‐HT1Aand I2bindings sites. Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by α2‐adrenoceptor agonists. Due to this property, atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by α2‐adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, atipamezole increased pain‐related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short‐term working memory. At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti‐Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.
KTX 0101: A Potential Metabolic Approach to Cytoprotection in Major Surgery and Neurological Disorders
Authors: Smith Sharon L. , Heal David J. , Martin Keith F. 
Published: August 2010

ABSTRACTKTX 0101 is the sodium salt of the physiological ketone, D‐β‐hydroxybutyrate (βOHB). This neuroprotectant, which has recently successfully completed clinical Phase IA evaluation, is being developed as an intravenous infusion fluid to prevent the cognitive deficits caused by ischemic foci in the brain during cardiopulmonary bypass (CPB) surgery. KTX 0101 maintains cellular viability under conditions of physiological stress by acting as a “superfuel” for efficient ATP production in the brain and peripheral tissues. Unlike glucose, this ketone does not require phosphorylation before entering the TCA cycle, thereby sparing vital ATP stores. Although no reliable models of CPB‐induced ischemia exist, KTX 0101 is powerfully cytoprotectant under the more severe ischemic conditions of global and focal cerebral ischemia, cardiac ischemia and lung hemorrhage. Neuroprotection has been demonstrated by reductions in infarct volume, edema, markers of apoptosis and functional impairment. One significant difference between KTX 0101 and other potential neuroprotectants in development is that βOHB is a component of human metabolic physiology which exploits the body's own neuroprotective mechanisms. KTX 0101 also protects hippocampal organotypic cultures against early and delayed cell death in anin vitromodel ofstatus epilepticus, indicating that acute KTX 0101 intervention in this condition could help prevent the development of epileptiform foci, a key mechanism in the etiology of intractable epilepsy. In models of chronic neurodegenerative disorders, KTX 0101 protects neurons against damage caused by dopaminergic neurotoxins and by the fragment of β‐amyloid, Aβ1–42, implying possible therapeutic applications for ketogenic strategies in treating Parkinson's and Alzheimer's diseases. Major obstacles to the use of KTX 0101 for long term therapy in chronic disorders, e.g., Parkinson's and Alzheimer's diseases, are the sodium loading problem and the need to administer it in relatively large amounts because of its rapid mitochondrial metabolism. These issues are being addressed by designing and synthesizing orally bioavailable multimers of βOHB with improved pharmacokinetics.
Mildronate: An Antiischemic Drug for Neurological Indications
Authors: Sjakste Nikolajs , Gutcaits Aleksandrs , Kalvinsh Ivars 
Published: August 2010

ABSTRACTMildronate (3‐(2,2,2‐trimethylhydrazinium)propionate; MET‐88; meldonium, quaterine) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. Mildronate was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid β‐oxidation in ischemic tissues and to block this highly oxygen‐consuming process. Mildronate is efficient in the treatment of heart ischemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non‐carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the γ‐butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the γ‐butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via acetylcholine receptors or specific γ‐butyrobetaine ester receptors. This article summarizes known pharmacological effects of mildronate, its pharmacokinetics, toxicology, as well as the proposed mechanisms of action.
Molecular genetic analysis of the BRCA2 tumor suppressor gene region in cutaneous squamous cell carcinomas
Authors: Gray Sarah E. , Kay Elaine , Leader Mary , Mabruk Mohamed 
Published: August 2010

Background:  Germ line mutations of the BRCA2 tumor suppressor gene with subsequent loss of the remaining wild‐type BRCA2 allele have been identified in up to 35% of familial breast cancer cases. A high frequency of allelic loss at the BRCA2 gene locus has also been reported in a variety of sporadic epithelial tumors including oesophageal squamous cell carcinomas (SCC), and sporadic head and neck SCC.Aim:  The present study aimed to examine the integrity of the BRCA2 gene in cutaneous SCC.Materials and methods:  Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in 22 histologically confirmed cutaneous SCC at two microsatellite markers, D13S260 (centromeric to the BRCA2 gene) and D13S267 (telomeric to the BRCA2 gene). Immunohistochemical analysis of BRCA2 protein expression was also examined in the cutaneous SCC.Results:  AI/LOH at the D13S260 locus was found in eight of the 19 informative SCC, and AI/LOH at the D13S267 locus was found in 12 of the 18 informative SCC. Seven SCC showed allelic loss at both markers, and six SCC showed retention of heterozygosity at both markers. Expression of BRCA2 protein was only detected in six of the normal epidermises and three of the 21 SCC examined.Conclusion:  AI/LOH of the BRCA2 gene region was found to be common in the cutaneous SCC.
Staphylococcus aureus elongation factor G – structure and analysis of a target for fusidic acid
Authors: Chen Yang , Koripella Ravi Kiran , Sanyal Suparna , Selmer Maria 
Published: August 2010

Fusidic acid (FA) is a bacteriostatic antibiotic that locks elongation factor G (EF‐G) on the ribosome in a post‐translocational state. It is used clinically against Gram‐positive bacteria such as pathogenic strains of Staphylococcus aureus, but no structural information has been available for EF‐G from these species. We have solved the apo crystal structure of EF‐G from S. aureus to 1.9 Å resolution. This structure shows a dramatically different overall conformation from previous structures of EF‐G, although the individual domains are highly similar. Between the different structures of free or ribosome‐bound EF‐G, domains III–V move relative to domains I–II, resulting in a displacement of the tip of domain IV relative to domain G. In S. aureus EF‐G, this displacement is about 25 Å relative to structures of Thermus thermophilus EF‐G in a direction perpendicular to that in previous observations. Part of the switch I region (residues 46–56) is ordered in a helix, and has a distinct conformation as compared with structures of EF‐Tu in the GDP and GTP states. Also, the switch II region shows a new conformation, which, as in other structures of free EF‐G, is incompatible with FA binding. We have analysed and discussed all known fusA‐based fusidic acid resistance mutations in the light of the new structure of EF‐G from S. aureus, and a recent structure of T. thermophilus EF‐G in complex with the 70S ribosome with fusidic acid [Gao YG et al. (2009) Science326, 694–699]. The mutations can be classified as affecting FA binding, EF‐G–ribosome interactions, EF‐G conformation, and EF‐G stability.
Mouse cytosolic sulfotransferase SULT2B1b interacts with cytoskeletal proteins via a proline/serine‐rich C‐terminus
Authors: Kurogi Katsuhisa , Sakakibara Yoichi , Kamemoto Yosuke , Takahashi Saki , Yasuda Shin , Liu Ming‐Cheh , Suiko Masahito 
Published: August 2010

Cytosolic sulfotransferase (SULT) SULT2B1b had previously been characterized as a cholesterol sulfotransferase. Like human SULT2B1, mouse SULT2B1b contains a unique, 31 amino acid C‐terminal sequence with a proline/serine‐rich region, which is not found in members of other SULT families. To gain insight into the functional relevance of this proline/serine‐rich region, we constructed a truncated mouse SULT2B1b lacking the 31 C‐terminal amino acids, and compared it with the wild‐type enzyme. Enzymatic characterization indicated that the catalytic activity was not significantly affected by the absence of those C‐terminal residues. GlutathioneS‐transferase pulldown assays showed that several proteins interacted with mouse SULT2B1b specifically through this C‐terminal proline/serine‐rich region. Peptide mass fingerprinting revealed that of the five SULT2B1b‐binding proteins analyzed, three were cytoskeletal proteins and two were cytoskeleton‐binding molecular chaperones. Furthermore, wild‐type mouse SULT2B1b, but not the truncated enzyme, was associated with the cytoskeleton in experiments with a cytoskeleton‐stabilizing buffer. Collectively, these results suggested that the unique, extended proline/serine‐rich C‐terminus of mouse SULT2B1b is important for its interaction with cytoskeletal proteins. Such an interaction may allow the enzyme to move along microfilaments such as actin filaments, and catalyze the sulfation of hydroxysteroids, such as cholesterol and pregnenolone, at specific intracellular locations.Structured digital abstract MINT‐7975854:Sult2B1b(uniprotkb:O35400)physically interacts(MI:0914) withMyosin‐Ic(uniprotkb:Q9WTI7),Alpha‐actinin‐1(uniprotkb:Q7TPR4),Alpha‐actinin‐4(uniprotkb:P57780),HSP 90‐beta(uniprotkb:P11499),Hsc70,(uniprotkb:P63017),Beta‐actin(uniprotkb:P60710) andGamma‐actin(uniprotkb:P63260) bypull down(MI:0096)
The Significance of the September 11, 2001 Terrorist Attacks for United States-Bound Migration in the Western Hemisphere
Authors: Mitchell Christopher 
Published: August 2010

The economic and political effects of the September 11 terrorist attacks weakened Latin American and Caribbean economies, reduced employment among Western Hemisphere immigrants living in the United States, and hindered new migrants' access to U.S. territory. Thus, the 9/11 events probably increased long-term motivations for northward migration in the hemisphere, while discouraging and postponing international population movement in the short run. In addition, the terrorist assaults dealt a sharp setback to a promising dialogue on immigration policies between the United States and Mexico. Those discussions had appeared to herald constructive new policies towards migration into the U.S. from Mexico and possibly other nations in the hemisphere. A series of significant international migrant flows in South and Central America and in the Caribbean, not involving the United States, are unfortunately beyond the scope of this brief essay. I will first describe the consequences of the September 11 assaults for U.S.-bound migration in the hemisphere, before turning to consider future social, economic and policy paths.
A TWO‐STAGE INFORMATION‐THEORETIC APPROACH TO MODELING LANDSCAPE‐LEVEL ATTRIBUTES AND MAXIMUM RECRUITMENT OF CHINOOK SALMON IN THE COLUMBIA RIVER BASIN
Authors: THOMPSON WILLIAM L. , LEE DANNY C. 
Published: August 2010

ABSTRACT. Many anadromous salmonid stocks in the Pacific Northwest are at their lowest recorded levels, which has raised questions regarding their long‐term persistence under current conditions. There are a number of factors, such as freshwater spawning and rearing habitat, that could potentially influence their numbers. Therefore, we used the latest advances in information‐theoretic methods in a two‐stage modeling process to investigate relationships between landscape‐level habitat attributes and maximum recruitment of 25 index stocks of chinook salmon (Onocorhynchus tshawy‐tscha) in the Columbia River basin. Our first‐stage model selection results indicated that the Ricker‐type, stock recruitment model with a constant Ricker a, i.e., recruits‐per‐spawner at low numbers of fish) across stocks was the only plausible one given these data, which contrasted with previous unpublished findings. Our second‐stage results revealed that maximum recruitment of chinook salmon had a strongly negative relationship with percentage of surrounding subwatersheds categorized as predominantly containing U.S.Forest Service and private moderate‐high impact managed forest. That is, our model predicted that average maximum recruitment of chinook salmon would decrease by at least 247 fish for every increase of 33% in surrounding subwatersheds categorized as predominantly containing U.S. Forest Service and privately managed forest. Conversely, mean annual air temperature had a positive relationship with salmon maximum recruitment, with an average increase of at least 179 fish for every increase in 2°C mean annual air temperature.
OPTIMAL DISCOUNTING OF BENEFITS FROM CLEANUP AT WASTE SITES
Authors: LYON KENNETH S. , CALIENDO FRANK 
Published: August 2010

AbstractThis paper uses a general equilibrium optimal growth model to discuss the role of optimal discounting of future benefits from cleanup at high‐level toxic waste sites. Cleanup simultaneously generates two streams of benefits. One of these is directly from utility and the other is indirectly from the added productivity of workers. We note that the optimal discount rate is different for these two types of benefits. Along the optimal path, the former are discounted at the rate of time preference and the latter at the market rate of interest. We achieve this by identifying four components of the shadow value of the stock of toxic waste. These are the utility, productivity, cost, and abundance effects.The distinction between discount rates appears to have been overlooked in the literature but has significant implications for environmental cost‐benefit analysis due to the growing interest in applying zero time preference to environmental problems, (like waste cleanup) whose consequences extend many generations into the future. A numerical example is included to illustrate these concepts.