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Pharmacologic Properties (pharmacologic + property)
Selected AbstractsNicotinic acetylcholine receptor structure and function in the efferent auditory systemTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2006Lawrence R. Lustig Abstract This article reviews and presents new data regarding the nicotinic acetylcholine receptor subunits ,9 and ,10. Although phylogentically ancient, these subunits have only recently been identified as critical components of the efferent auditory system and medial olivocochlear pathway. This pathway is important in auditory processing by modulating outer hair cell function to broadly tune the cochlea and improve signal detection in noise. Pharmacologic properties of the functionally expressed ,9,10 receptor closely resemble the cholinergic response of outer hair cells. Molecular, immunohistochemical, and knockout mice studies have added further weight to the role this receptor plays in mediating the efferent auditory response. Alternate and complementary mechanisms of outer hair cell efferent activity might also be mediated through the nAChR ,9,10, either through secondary calcium stores, second messengers, or direct protein-protein interactions. We investigated protein-protein interactions using a yeast-two-hybrid screen of the nAChR ,10 intracellular loop against a rat cochlear cDNA library. Among the identified proteins was prosaposin, a precursor of saposins, which have been shown to act as neurotrophic factors in culture, can bind to a putative G0-coupled cell surface receptor, and may be involved in the prevention of cell death. This study and review suggest that nAChR ,9,10 may represent a potential therapeutic target for a variety of ear disorders, including preventing or treating noise-induced hearing loss, or such debilitating disorders as vertigo or tinnitus. Anat Rec Part A, 2006. © 2006 Wiley-Liss, Inc. [source] New concepts in antimalarial use and mode of action in dermatologyDERMATOLOGIC THERAPY, Issue 4 2007Sunil Kalia ABSTRACT: Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed. [source] The impact of diazepam's discovery on the treatment and understanding of status epilepticusEPILEPSIA, Issue 9 2009Howard P. Goodkin Summary The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of ,-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a ,2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive , subunit,containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA-mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABAA receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity-dependent, subunit-specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine-sensitive ,2 subunit,containing receptors and the preserved surface expression of the benzodiazepine-insensitive , subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE. [source] A New Chrna4 Mutation with Low Penetrance in Nocturnal Frontal Lobe EpilepsyEPILEPSIA, Issue 7 2003Tobias Leniger Summary: Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. Methods: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. Results: We report a new CHRNA4 mutation, causing a ,4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of ,4-T265I revealed an increased ACh sensitivity of the mutated receptors. ,4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation. Conclusions: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. ,4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both. [source] Olanzapine in the Treatment of Refractory Migraine and Chronic Daily HeadacheHEADACHE, Issue 6 2002Stephen D. Silberstein MD Background.,Olanzapine, a thienobenzodiazepine, is a new "atypical" antipsychotic drug. Olanzapine's pharmacologic properties suggest it would be effective for headaches, and its propensity for inducing acute extrapyramidal reactions or tardive dyskinesia is relatively low. We thus decided to assess the value of olanzapine in the treatment of chronic refractory headache. Methods.,We reviewed the records of 50 patients with refractory headache who were treated with olanzapine for at least 3 months. All previously had failed treatment with at least four preventative medications. The daily dose of olanzapine varied from 2.5 to 35 mg; most patients (n = 19) received 5 mg or 10 mg (n = 17) a day. Results.,Treatment resulted in a statistically significant decrease in headache days relative to baseline, from 27.5 ± 4.9 before treatment to 21.1±10.7 after treatment (P < .001, Student t test). The difference in headache severity (0 to 10 scale) before treatment (8.7±1.6) and after treatment (2.2 ± 2.1) was also statistically significant (P < .001). Conclusion.,Olanzapine may be effective for patients with refractory headache, including those who have failed a number of other prophylactic agents. Olanzapine should receive particular consideration for patients with refractory headache who have mania, bipolar disorder, or psychotic depression or whose headaches previously responded to other neuroleptic medications. [source] An Overview of the TAXUS® Express®, Paclitaxel-Eluting Stent Clinical Trial ProgramJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 5 2006JOHN M. LASALA M.D., Ph.D. Restenosis remains a problem following percutaneous coronary intervention in patients with coronary artery disease. Drug-eluting stents (DES), which combine mechanical and pharmacologic properties, have been shown to prevent or reduce neointimal growth after deployment. This review describes the TAXUS paclitaxel-eluting stent clinical trial expansion program (TAXUS® Express®, Boston Scientific, Natick, MA). This program comprises the largest data set of randomized controlled trials (RCTs) of DES to date, with over 6,200 patients enrolled since 2000. The program includes treatment of de novo lesions, as well as higher-risk lesion and patient populations. In this review, we discuss the results from the TAXUS family of randomized clinical trials, and compare the findings with data from TAXUS registries. The data from the randomized clinical trials suggest that the paclitaxel-eluting stent provides consistent and durable benefits across multiple lesion and patient types. Evidence from peri-and postapproval registries, where patient populations are more heterogeneous than those eligible and included in the RCTs, corroborate these findings, with overall low rates of cardiac events, including reinterventions. [source] The Interaction of Gestational and Postnatal Ethanol Experience on the Adolescent and Adult Odor-Mediated Responses to Ethanol in Observer and Demonstrator RatsALCOHOLISM, Issue 10 2010Amber M. Eade Background:, Gestational ethanol exposure enhances the adolescent reflexive sniffing response to ethanol odor. Postnatal exposures of naïve animals as either an observer (i.e., conspecific) or demonstrator (i.e., intoxicated peer) using a social transmission of food odor preference paradigm also yields enhanced odor-mediated responses. Studies on the interaction of fetal and postnatal exposures using the social transmission paradigm have been limited to the responses of observers. When combined, the enhanced response is greater than either form of exposure alone and, in observer females, yields adult persistence. The absence of a male effect is noteworthy, given that chemosensory mechanisms are suggested to be an important antecedent factor in the progression of ethanol preference. Observers gain odor information on the breath of the demonstrator through social interaction. Demonstrators experience the pharmacologic properties of ethanol along with retronasal and hematogenic olfaction. Thus, we tested whether augmentation of the fetal ethanol-induced behavioral response with postnatal exposure as a demonstrator differed from that as an observer. We also examined whether re-exposure as a demonstrator yields persistence in both sexes. Methods:, Pregnant dams were fed an ethanol containing or control liquid diet throughout gestation. Progeny received four ethanol or water exposures: one every 48 hours through either intragastric infusion or social interaction with the infused peer beginning on P29. The reflexive behavioral sniffing response to ethanol odor was tested at postnatal (P) day 37 or P90, using whole-body plethysmography. Results:, When tested in either adolescence or adulthood - fetal ethanol exposed adolescent ethanol observers and demonstrators significantly differed in their odor-mediated response to ethanol odor both between themselves and from their respective water controls. Nonetheless, adolescent ethanol re-exposure as a demonstrator, like an observer, enhanced the reflexive sniffing response to ethanol odor at both testing ages by augmenting the known effects of prior fetal ethanol experience. At each age, the magnitude of the enhanced odor response in demonstrators was similar to that of observers. Interestingly, only re-exposure as a demonstrator resulted in persistence of the behavioral response into adulthood in both sexes. Conclusions:, The method of ethanol re-exposure plays an important role in prolonging the odor-mediated effects of fetal exposure. While ethanol odor-specific exposure through social interaction is important, additional factors such as the pairing of retronasal and hematogenic olfaction with ethanol's intoxicating properties appear necessary to achieve persistence in both sexes. [source] New developments in incretin-based therapies: The current state of the fieldJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 2009CDE Diabetes Nurse Educator, Carolyn Robertson APRN Abstract Purpose: To update readers on developments in incretin therapies since the previous JAANP supplement in 2007; specifically, to describe clinical data for currently available incretin-based therapies as well as those under consideration by regulatory agencies. Data source: Medline search for peer-reviewed publications. Conclusions: Incretin-based therapies have pharmacologic properties that avoid some key limitations of previous treatments, such as hypoglycemia and weight gain. Certain agents also lower blood pressure and have the potential to reduce cardiovascular risk. The insulin-secreting action of incretin-based therapies only occurs under hyperglycemic conditions, thus minimizing the risk of hypoglycemia, unless combined with a sulfonylurea. The DPP-4 inhibitors are orally administered and demonstrate modest A1c reductions (0.6%,0.8%); the best results occur when combined with metformin. Glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide and exenatide have shown greater A1c reductions (typically , 1.1% and as high as 1.7%), and these agents have beneficial ancillary effects, including weight and systolic blood pressure reduction. Both DPP-4 inhibitors and GLP-1 receptor agonists have shown the ability to improve pancreatic beta-cell function in early studies. Implications for practice: Data are provided on the efficacy and tolerability of approved incretin therapies, and on treatments currently in regulatory review, in order to inform readers and guide their practice. [source] Origins and treatment of airway inflammation in childhood asthmaPEDIATRIC PULMONOLOGY, Issue S21 2001Robert F. Lemanske Jr. MD Abstract Several early events and risk factors are associated with the development of childhood asthma. Two significant risk factors are viral lower respiratory tract infections and atopy. Studies suggest that imbalances in TH1/TH2 cytokine responses in relationship to viral infections may play a role in the development of the childhood asthmatic phenotype. Airway inflammation is now recognized to contribute to the inception, persistence, and severity of asthmatic symptoms. The majority of information pertaining to airway inflammation in asthma has been derived from adult studies, but recent evaluations have been done in children. Available data are inconclusive as to the right medication to be used at the inception and during the evolution of the asthmatic phenotype in children. Inhaled corticosteroids (ICS( are not consistently effective in young children for a variety of reasons, including underlying pathophysiologic mechanisms that are unresponsive to the pharmacologic properties of ICS. The leukotriene receptor antagonists (LTRAs), recently approved for children as young as 2 years of age, address the relationship between leukotriene production and airway inflammation or remodeling in asthma. Therapeutic trials using LTRAs in children should prove beneficial. Pediatr Pulmonol. 2001; Supplement 21:17,25. © 2001 Wiley-Liss, Inc. [source] NMR-derived model of interconverting conformations of an ICAM-1 inhibitory cyclic nonapeptideCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2003L.O. Sillerud Abstract:, We have produced by phage-display a disulfide-linked cyclic nonapeptide (inhibitory peptide-01, IP01), CLLRMRSIC, that binds to intracellular adhesion molecule-1 (ICAM-1) and blocks binding to its counter-structure, leukocyte functional antigen-1 (LFA-1). As a first step towards improving its pharmacologic properties, we have performed a structural and functional analysis of this peptide inhibitor to determine the features relevant to ICAM-1 binding. We report here the solution model of our initial product, IP01, as derived from two-dimensional nuclear magnetic resonance (NMR) restraints and molecular modeling. Distance and dihedral angle restraints, generated from nuclear Overhauser effect spectroscopy (NOESY) and one-dimensional-NMR experiments respectively, were used to generate an ensemble of structures using distance geometry and simulated annealing. Molecular dynamic simulations produced three interconverting conformational families consistent with the NMR-derived constraints. We describe these conformations and their mechanism of interconversion. Furthermore, we have measured the IC50 s of a series of inhibitors generated from IP01 through alanine substitution of each residue. These results show that the L2-L3-R4-M5-R6 segment is functionally active, conformationally flexible, and contains a ,-turn involving residues R4-S7, while the C1-C9-I8-S7 segment is less functionally-active but adopts a more defined solution conformation, consistent with a scaffolding function. This model will be useful for designing nonpeptide-based organic inhibitors with improved pharmacologic properties. [source] | |||||||||||||