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Pharmacological Properties (pharmacological + property)
Selected AbstractsSynthesis of New Derivatives of 5,6,7,8-Tetrahydro-1,6-naphthyridines and Their Pharmacological Properties.CHEMINFORM, Issue 2 2006S. Z. Vatsadze Abstract For Abstract see ChemInform Abstract in Full Text. [source] Cyclization of 1-{[(4-Methyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetyl}thiosemicarbazides to 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives and Their Pharmacological Properties.CHEMINFORM, Issue 26 2005Alicja Maliszewska-Guz Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis and Biological Characterization of [3H]BBL454, a New CCK2 Selective Radiolabeled Agonist Displaying Original Pharmacological Properties.CHEMINFORM, Issue 16 2004Bruno Bellier No abstract is available for this article. [source] Synthesis and Pharmacological Properties of N,N-Dialkyl(dialkenyl)amides of 7-Methyl-3-phenyl-1- [2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl] -2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic Acid.CHEMINFORM, Issue 22 2003Helena Sladowska Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis and Pharmacological Properties of 3-Amino-1,2-dihydro-3H-1,4-benzodiazepin-2-one Derivatives.CHEMINFORM, Issue 50 2002K. S. Andronati Abstract For Abstract see ChemInform Abstract in Full Text. [source] Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofunginMYCOSES, Issue 4 2005Georg Maschmeyer Summary Caspofungin, a semisynthetic derivative of the pneumocandin B0, is the first licensed compound of a new class of antifungal agents, the echinocandins. It attacks the fungal cell by selective inhibition of the beta-(1,3)- d -glucan synthase, which is not present in mammalian cells. In vitro studies have indicated a potent fungicidal effect on Candida species, and in vivo studies in immunocompromised animals with invasive candidiasis demonstrated a favourable outcome. In randomized clinical trials in patients with oropharyngeal/oesophageal and invasive candidiasis, caspofungin was at least as effective as amphotericin B deoxycholate, yet showed a significantly superior safety profile. Of patients with invasive aspergillosis refractory to or intolerant of other antifungal agents, 45% showed a partial or complete response to caspofungin given as a salvage treatment. Also, it demonstrated comparable clinical efficacy but superior tolerability in the empirical antifungal therapy in neutropenic patients compared with liposomal amphothericin B. Caspofungin has an excellent tolerability and a low potential for drug interactions. Thus, caspofungin represents an interesting and clinically valuable new antifungal drug that broadens the available therapeutic armamentarium for the treatment of invasive fungal infections. [source] Pharmacological properties of the methanol extract from Mentha suaveolens Ehrh.PHYTOTHERAPY RESEARCH, Issue S1 2002Lucrecia Moreno Abstract The present study analyses the pharmacological activity in in vivo and in vitro models of the methanol extract obtained from the leaves and steams of Menta suaveolens Ehrh. This extract lacked toxicity, but exhibited a central nervous system depressant action; an analgesic effect in models of chemical and mechanical stimulation suggesting the induction of a peripheral analgesic response. The extract also exhibited an antiinflammatory action inhibiting the rat paw oedema induced by carrageenin. Moreover, the in vitro studies showed a significant diminution in the contractile effects induced by histamine, serotonin and acetylcholine. Copyright © 2002 John Wiley & Sons, Ltd. [source] Molecular mechanisms supporting a paracrine role of GABA in rat adrenal medullary cellsTHE JOURNAL OF PHYSIOLOGY, Issue 20 2008Hidetada Matsuoka GABA is known to produce membrane depolarization and secretion in adrenal medullary (AM) cells in various species. However, whether the GABAergic system is intrinsic or extrinsic or both in the adrenal medulla and the role that GABA plays are controversial. Therefore, these issues were addressed by combining a biochemical and functional analysis. Glutamic acid decarboxylase (GAD), a GABA synthesizing enzyme, and vesicular GABA transporter (VGAT) were expressed in rat AM cells at the mRNA and protein levels, and the adrenal medulla had no nerve fibre-like structures immunoreactive to an anti-GAD Ab. The double staining for VGAT and chromogranin A indicates that GABA was stored in chromaffin granules. The ,1, ,3, ,2/3, ,2 and , subunits of GABAA receptors were identified in AM cells at the mRNA and protein levels. Pharmacological properties of GABA-induced Cl, currents, immunoprecipitation experiments and immunocytochemistry indicated the expression of not only ,2-, but also ,-containing GABAA receptors, which have higher affinities for GABA and neurosteroids. Expression of GATs, which are involved in the clearance of GABA at GABAergic synapses, were conspicuously suppressed in the adrenal medulla, compared with expression levels of GABAA receptors. Increases in Ca2+ signal in AM cells evoked trans-synaptically by nerve stimulation were suppressed during the response to GABA, and this suppression was attributed to the shunt effect of the GABA-induced increase in conductance. Overall Ca2+ responses to electrical stimulation and GABA in AM cells were larger or smaller than those to electrical stimulation alone, depending on the frequency of stimulation. The results indicate that GABA functions as a paracrine in rat AM cells and this function may be supported by the suppression of GAT expression and the expression of not only ,2-, but also ,-GABAA receptors. [source] Signalling and pharmacological properties of the P2Y14 receptorACTA PHYSIOLOGICA, Issue 2 2010T. K. Harden Abstract The P2Y14 receptor is a relatively broadly expressed G protein-coupled receptor that is prominently associated with immune and inflammatory cells as well as with many epithelia. This receptor historically was thought to be activated selectively by UDP-glucose and other UDP-sugars. However, UDP is also a very potent agonist of this receptor, and may prove to be one of its most important cognate activators. [source] Preclinical abuse potential assessment of the anticonvulsant zonisamideDRUG DEVELOPMENT RESEARCH, Issue 2 2001Jenny L. Wiley Abstract Zonisamide (Zonegran®) is a broad-spectrum antiepileptic agent that shares some pharmacological properties with other anticonvulsants, including phenytoin, carbamazepine, and valproic acid, but is differentiated from these agents by the ability to significantly block T-type calcium channels. Zonisamide interacts with the ,-amino-butyric acid (GABA) receptor in an allosteric manner, and thus does not modulate GABA receptor effects. However, given the potential of drugs within the latter class for drug abuse in humans, an evaluation of zonisamide for abuse potential is an important component of its potential side-effect profile. In the present study, zonisamide was tested in animal models of the subjective and reinforcing effects of central nervous system (CNS) depressant drugs, e.g., diazepam discrimination in rats and intravenous self-administration in rhesus monkeys, respectively. In addition, zonisamide was evaluated for physical dependence liability in a chronic infusion model using rats. Zonisamide did not substitute for diazepam in rats trained to discriminate 2.5-mg/kg diazepam from vehicle nor was it self-administered by rhesus monkeys experienced in methohexital-reinforced responding. Continuous infusion of zonisamide (400 or 600 mg/kg/day) did not prevent the loss of body weight associated with discontinued pentobarbital infusion. These doses of zonisamide did produce some incomplete attenuation of observable signs of pentobarbital withdrawal, likely due to direct sedative or depressant effects of these high doses. These results suggest that zonisamide would not produce diazepam-like intoxication in humans nor would it likely be subject to abuse when made more widely available. Further, when administered chronically, zonisamide would not be expected to produce physical dependence of the CNS depressant type. Taken together, these results support the prediction that zonisamide would have low abuse liability. Drug Dev. Res. 54:66,74, 2001. © 2001 Wiley-Liss, Inc. [source] Classification of abused inhalantsADDICTION, Issue 6 2009Robert L. Balster ABSTRACT Many hundreds of household and industrial products can be volatilized readily and are subject to abuse. Inhalant abuse research has been hampered by a lack of consensus on whether or not there are subclassifications of abused inhalants based on chemical structure, form or intended use of the product or pharmacological properties. This paper discusses strengths and weaknesses of various approaches to classification of inhalants and suggests areas for future research in this area. It is concluded that classification of inhalants by form or product types is not useful for scientific purposes; rather, subclassification of inhalants should be based on a yet-to-be-determined combination of chemical and pharmacological similarity and shared patterns of abuse. One of the ways in which we can improve our understanding of inhalant abuse is to obtain more detailed information on individual products and chemicals, their patterns of use and the geographical distribution of their use. [source] Dihydropyridine- and voltage-sensitive Ca2+ entry in human parathyroid cellsEXPERIMENTAL PHYSIOLOGY, Issue 7 2009Keitaro Yokoyama Patch-clamp and fluorescence measurements of cytoplasmic Ca2+ concentration ([Ca2+]i) were performed to directly detect extracellular Ca2+ entry into cultured parathyroid cells from patients with secondary hyperparathyroidism. Cells loaded with fluo-3 AM or fluo-4 AM showed a transient increase in fluorescence (Ca2+ transient) following 10 s exposure to 150 mm K+ solution in the presence of millimolar concentrations of external Ca2+. The Ca2+ transient was completely inactivated after 30,40 s exposure to the high-K+ solution, was reduced by dihydropyridine antagonists and was enhanced by FPL-64176, an L-type Ca2+ channel agonist. The electrophysiological and pharmacological properties of the whole-cell Ca2+ and Ba2+ currents were similar to those of L-type Ca2+ channels. The Ca2+ transients induced by 10 s exposure to 3.0 mm extracellular Ca2+ concentration ([Ca2+]o) were inhibited by dihydropyridine antagonists and were partly inactivated following 30,40 s exposure to the high-K+ solution. These results demonstrate, for the first time, that human parathyroid cells express L-type-like Ca2+ channels that are possibly involved in the [Ca2+]o -induced change in [Ca2+]i. This Ca2+ entry system might provide a compensatory pathway for the negative feedback regulation of parathyroid hormone secretion, especially in hyperplastic conditions in which the Ca2+ -sensing receptor is poorly expressed. [source] A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonistFEBS JOURNAL, Issue 9 2006Brian E. Kane Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL-2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity. [source] Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatristsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2006Amadou Moctar Dičye Abstract Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine prescription poses problems particularly in training, and national authorities must take urgent measures for rational use of these drugs. [source] Structure,hepatoprotective activity relationship of 3,4-dihydroxycinnamic acid (caffeic acid) derivativesJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2001V. Pérez-Alvarez Abstract 3,4-Dihydroxycinnamic acid (caffeic acid, CAF) is a natural product containing a catechol group with an ,,,-unsaturated carboxylic acid chain that has shown hepatoprotective properties. The aim of this work was to determine the importance of the 4-hydroxy, 3-hydroxy, 3,4-dihydroxy substituents and the double bond moiety on the hepatic pharmacological effects of the molecule. We compared the ability of the caffeic, 4-hydroxycinnamic, 3-hydroxycinnamic, cinnamic and 3,4-dihydroxyhydrocinnamic (a caffeic acid analogue without the double bond) acids at a dose of 50 mg kg,1, p.o., to reduce the liver damage produced by CCl4 (4 g kg,1, p.o.) intoxication in the rat. Cinnamic acid, the non-hydroxylated analogue, only modestly protected the experimental animals challenged with CCl4, suggesting that hydroxyl groups participate in the pharmacological properties of CAF. The 3,4-dihydroxyhydrocinnamic derivative did not show any significant differences when compared with the CAF effect in this model, suggesting that the double bond does not account for the liver pharmacological properties of CAF. In contrast, the 4-hydroxy substituent seems to be very important for hepatoprotective activity because the 4-hydroxy analogue improved almost every hepatic injury marker altered by CCl4, and in a better way than CAF did. Copyright © 2001 John Wiley & Sons, Ltd. [source] Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11JOURNAL OF NEUROCHEMISTRY, Issue 4 2007D. Vandame Abstract Over-stimulation of NMDA receptors (NMDARs) is involved in many neurodegenerative disorders. Thus, developing safe NMDAR antagonists is of high therapeutic interest. GK11 is a high affinity uncompetitive NMDAR antagonist with low intrinsic neurotoxicity, shown to be promising for treating CNS trauma. In the present study, we investigated the molecular basis of its interaction with NMDARs and compared this with the reference molecule MK801. We show, on primary cultures of hippocampal neurons, that GK11 exhibits neuroprotection properties similar to those of MK801, but in contrast with MK801, GK11 is not toxic to neurons. Using patch-clamp techniques, we also show that on NR1a/NR2B receptors, GK11 totally blocks the NMDA-mediated currents but has a six-fold lower IC50 than MK801. On NR1a/NR2A receptors, it displays similar affinity but fails to totally prevent the currents. As NR2A is preferentially localized at synapses and NR2B at extrasynaptic sites, we investigated, using calcium imaging and patch-clamp approaches, the effects of GK11 on either synaptic or extrasynaptic NMDA-mediated responses. Here we demonstrate that in contrast with MK801, GK11 better preserve the synaptic NMDA-mediated currents. Our study supports that the selectivity of GK11 for NR2B containing receptors accounts contributes, at least partially, for its safer pharmacological profile. [source] Trafficking and potential assembly patterns of ,-containing GABAA receptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Brian L. Jones Abstract Incorporation of the , subunit into the GABAA receptor has been suggested to confer unusual, but variable, biophysical and pharmacological characteristics to both recombinant and native receptors. Due to their structural similarity with the , subunits, , subunits have been assumed to substitute at the single position of the , subunit in assembled receptors. However, prior work suggests that functional variability in ,-containing receptors may reflect alternative sites of incorporation and of not just one, but possibly multiple , subunits in the pentameric receptor complex. Here we present data indicating that increased expression of ,, in conjunction with ,2 and ,3 subunits, results in expression of GABAA receptors with correspondingly altered rectification, deactivation and levels of spontaneous openings, but not increased total current density. We also provide data that the , subunit, like the ,3 subunit, can self-export and data from chimeric receptors suggesting that similarities between the assembly domains of the ,3 and the , subunits may allow the , subunit to replace the ,, as well as the ,, subunit. The substitution of an , for a ,, as well as the , subunit and formation of receptors with alternative patterns of assembly with respect to , incorporation may underlie the observed variability in both biophysical and pharmacological properties noted not only in recombinant, but also in native receptors. [source] RNA editing and alternative splicing of human serotonin 2C receptor in schizophreniaJOURNAL OF NEUROCHEMISTRY, Issue 6 2003Stella Dracheva Abstract Serotonin 2C receptor (5-HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5-HT2CR mRNA undergoes adenosine-to-inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5-HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5-HT2CR-tr) which encodes a non-functional serotonin receptor. 5-HT2CR mRNA editing efficiencies and the expression of the full-length and the truncated 5-HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5-HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5-HT2CR and 5-HT2CR-tr mRNA variants revealed that the expression of 5-HT2CR-tr was ,,50% of that observed for the full-length isoform. [source] Characterization of a novel G-protein coupled receptor from the parasitic nematode H. contortus with high affinity for serotoninJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Martin W. Smith The neurotransmitter serotonin (5HT) has been shown to modulate mobility, feeding, egg-laying, and defecation behaviors in the saprophytic nematode Caenorhabditis elegans. Although the effects of serotonin on these behaviors in parasitic nematodes is under study, little is known about the diversity, ontogeny, signaling, and pharmacology of serotonin receptors in these organisms. In an effort to increase our understanding of this system, we cloned and characterized a novel cDNA (5HT1Hc) from the parasitic nematode Haemonchus contortus that has high amino acid sequence homology with known G-protein coupled 5HT1-receptors from invertebrates and vertebrates. Transcript expression studies in four development stages (egg, L1/L2, L3, and adult) revealed the presence of the mRNA in the L1/L2, L3, and adult stages. Membranes from insect cells (Sf9) expressing the 5HT1Hc -receptor cDNA displayed nanomolar binding affinity to serotonin and a unique pharmacological profile distinct from known invertebrate and mammalian 5HT-receptors. Receptor signaling studies with mammalian AV12 cells expressing the 5HT1Hc -receptor and the promiscuous G-protein, G,15, demonstrated dose-dependent intracellular signals with serotonin acting as an agonist. Together, these studies describe a novel invertebrate 5HT-receptor with high affinity for the indolealkylamine, serotonin, and pharmacological properties that do not conform to any known members of this superfamily of metabotropic receptors. [source] P2X2, P2X2,2 and P2X5 receptor subunit expression and function in rat thoracolumbar sympathetic neuronsJOURNAL OF NEUROCHEMISTRY, Issue 5 2001H. Schädlich The present study investigated the pharmacological properties of excitatory P2X receptors and P2X2 and P2X5 receptor subunit expression in rat-cultured thoracolumbar sympathetic neurons. In patch-clamp recordings, ATP (3,1000 µm; applied for 1 s) induced inward currents in a concentration-dependent manner. Pyridoxal-phosphate-6-azophenyl-2,,4,-disulfonate (PPADS; 30 µm) counteracted the ATP response. In contrast to ATP, ,,,-meATP (30 µm; for 1 s) was virtually ineffective. Prolonged application of ATP (100 µm; 10 s) induced receptor desensitization in a significant proportion of sympathetic neurons in a manner typical for P2X2,2 splice variant-mediated responses. Using single-cell RT-PCR, P2X2, P2X2,2 and P2X5 mRNA expression was detectable in individual tyrosine hydroxylase-positive neurons; coexpression of both P2X2 isoforms was not observed. Laser scanning microscopy revealed both P2X2 and P2X5 immunoreactivity in virtually every TH-positive neuron. P2X2 immunoreactivity was largely distributed over the cell body, whereas P2X5 immunoreactivity was most distinctly located close to the nucleus. In summary, the present study demonstrates the expression of P2X2, P2X2,2 and P2X5 receptor subunits in rat thoracolumbar neurons. The functional data in conjunction with a preferential membranous localization of P2X2/P2X2,2 compared with P2X5 suggest that the excitatory P2X responses are mediated by P2X2 and P2X2,2 receptors. Apparently there exist two types of P2X2 receptor-bearing sympathetic neurons: one major population expressing the unspliced isoform and another minor population expressing the P2X2,2 splice variant. [source] trans -Resveratrol Protects Embryonic Mesencephalic Cells from tert -Butyl HydroperoxideJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Electron Param Abstract : In recent years, the antioxidant and other pharmacological properties of resveratrol, a natural product present in grapes and wine, have attracted considerable interest from the biomedical research community. In an examination of the potential neuroprotective properties of the compound, we have investigated the ability of resveratrol to protect rat embryonic mesencephalic tissue, rich in dopaminergic neurones, from the prooxidant tert -butyl hydroperoxide. Using the electron paramagnetic resonance (EPR) spin-trapping technique, the main radicals detected in cell suspensions were the tert -butoxyl radical and the methyl radical, indicating the one-electron reduction of the peroxide followed by a ,-scission reaction. The appearance of EPR signals from the trapped radicals preceded the onset of cytotoxicity, which was almost exclusively necrotic in nature. The inclusion of resveratrol in incubations resulted in the marked protection of cells from tert -butyl hydroperoxide. In parallel spin-trapping experiments, we were able to demonstrate the scavenging of radicals by resveratrol, which involved direct competition between resveratrol and the spin trap for reaction with the radicals. To our knowledge, this is the first example in which cytoprotection by resveratrol has been demonstrated by EPR spin-trapping competition kinetics to be due to its scavenging of the radicals responsible for the toxicity of a prooxidant. [source] Introduction of lipidization,cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activitiesJOURNAL OF PEPTIDE SCIENCE, Issue 9 2010Brad R. Green Abstract The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization,cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization,cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis and biological properties of the seven alanine-modified analogues of the marine cyclopeptide hymenamide CJOURNAL OF PEPTIDE SCIENCE, Issue 8 2002Assunta Napolitano Abstract The synthesis and biological activity of the marine cyclopeptide hymenamide C(1), showing an inhibitory effect on human neutrophil elastase degranulation release, were recently described. Based on this result, it was decided to undertake a systematic structure,activity relationship study of this cyclopeptide, based on the Ala-scan technique, in order to obtain useful information for the rational design of additional analogues. The synthesis and characterization of the seven Ala modified analogues are reported and their biological and pharmacological properties are described. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] Human receptor kinetics, tissue binding affinity, and stability of mometasone furoateJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Anagnostis Valotis Abstract Mometasone furoate (MF) is a topically used glucocorticoid with high anti-inflammatory potency. In contrast to the wealth of data derived from clinical studies, information about the molecular pharmacology of the compound is lacking or contradictory. Thus, we elucidated the characteristics of receptor binding kinetics and receptor affinity in a bioassay. Metabolite formation was determined in human plasma and lung tissue as well as binding affinity to human lung tissue. Fast and extensive association of MF to the human glucocorticoid receptor was observed while the dissociation of the MF,receptor complex was faster compared to fluticasone propionate (FP). The relative receptor affinity of MF was calculated as 2200 (dexamethasone,=,100, FP,=,1800) and confirmed in a bioassay measuring the induction of the glucocorticoid regulated protein CD163 in human monocytes. In plasma and human lung tissue MF formed a 9,11-epoxy degradation product. The binding affinity of MF to human lung tissue was low compared to FP due to fast redistribution from tissue into plasma. These molecular pharmacological properties are in accordance with clinical data. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1337,1350, 2004 [source] Preparation and characterization of quercetin-loaded polymethyl methacrylate microcapsules using a polyol-in-oil-in-polyol emulsion solvent evaporation methodJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2007Dong-Hwan Lee Flavonoids and related compounds exhibit a wide range of useful pharmacological properties but present challenges related to their stability and solubility in commonly available solvents. In this study, polymethyl methacrylate (PMMA) microcapsules were prepared using a novel polyol-in-oil-in-polyol (P/O/P) emulsion solvent evaporation method as a means of stabilizing the flavonoids, using quercetin as a model flavonoid drug. The morphology of the microcapsules was evaluated using a scanning electron microscope, revealing a spherical shape with a smooth surface. The cross-section image of the PMMA microcapsules prepared with an amphiphilic polymer in the inner polyol phase showed that the microcapsule was filled with several submicron microspheres. The mean diameter varied from 1.03 ± 0.12 ,m to 2.39 ± 0.42 ,m, and the encapsulation efficiency ranged from 12.7% to 26.9%. When free quercetin was stored at 42°C, the residual quercetin content gradually decreased to 18% over 28 days as a result of oxidation. However, when encapsulated in PMMA microcapsules with an amphiphilic polymer in the inner polyol phase, the residual quercetin content decreased to just 82%. In-vitro release studies indicated a sustained release pattern throughout the 36-h study. The release kinetics of the microcapsules with an amphiphilic polymer followed a diffusion-controlled mechanism and the microcapsule without amphiphilic polymer followed an anomalous diffusion behaviour. This study suggests that the novel P/O/P emulsion solvent evaporation method can be applied to the encapsulation of flavonoids. [source] The role of nutrients in modulating diseaseJOURNAL OF SMALL ANIMAL PRACTICE, Issue 6 2008D. L. Chan The role of nutrition in the management of diseases has often centred on correcting apparent nutrient deficiencies or meeting estimated nutritional requirements of patients. Nutrition has traditionally been considered a supportive measure akin to fluid therapy and rarely it has been considered a primary means of ameliorating diseases. Recently, however, further understanding of the underlying mechanisms of various disease processes and how certain nutrients possess pharmacological properties have fuelled an interest in exploring how nutritional therapies themselves could modify the behaviour of various conditions. Nutrients such as omega-3 fatty acids, antioxidants and certain amino acids such as arginine and glutamine have all been demonstrated to have at least the potential to modulate diseases. Developments in the area of critical care nutrition have been particularly exciting as nutritional therapies utilising a combination of approaches have been shown to positively impact outcome beyond simply proving substrate for synthesis and energy. Application of certain nutrients for the modulation of diseases in veterinary patients is still in early stages, but apparent successes have already been demonstrated, and future studies are warranted to establish optimal approaches. This review describes the rationale of many of these approaches and discusses findings both in human beings and in animals, which may guide future therapy. [source] Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009D. BREILH Summary Background, The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated. Aim, To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin. Patients and methods, Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment. Results, At week 4, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = ,0.376, P = 0.002) and AUC0,12h of ribavirin plasma level (r = ,0.277, P = 0.018). At week 12, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = ,0.384, P < 0.0001) and AUC0,12h of ribavirin plasma level (r = ,0.257, P = 0.002). In genotype 1 patients, AUC0,12h ribavirin and Cmin were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12. Conclusion, Cmin of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR. [source] Pharmacological approaches towards rationalizing the use of endoparasitic drugs in small animalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2006S. F. SANCHEZ BRUNI Parasitic diseases are an important health concern to small animal veterinarians worldwide, and their zoonotic potential is also of relevance to human medicine. The treatment and control of such conditions relies heavily on pharmaceutical intervention using a range of antiparasitic drugs and/or their biologically active metabolites. Broad spectrum agents have been produced, although narrow and even monospecific drugs are used in some situations. Their efficacy may depend on dosage, the target pathogen(s), the host species and/or the site of infection. Optimal use of antiparasitics requires a detailed consideration of the pharmacokinetic and pharmacodynamic properties of the drugs in specific clinical contexts. This review summarizes the present status of knowledge on the metabolism, and physicochemical and pharmacological properties of the major antiparasitic drugs currently used in small animal veterinary practice. In addition, data relevant to therapeutic dosage, efficacy and clinical indication/contraindication, particularly in relation to combination drug therapy, are included. [source] Bilastine in allergic rhinoconjunctivitis and urticariaALLERGY, Issue 2010C. Bachert To cite this article: Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy 2010; 65 (Suppl. 93): 1,13. Abstract Allergic rhinoconjunctivitis and urticaria are increasing in prevalence in many developed countries. The role of histamine in such conditions is well documented and clinical guidelines recommend non-sedating H1 -receptor antagonists as first-line treatment choices. Bilastine is a novel non-sedating histamine H1 -receptor antagonist developed for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this review is to critique the scientific evidence relating to the pharmacological properties of bilastine and the clinical evidence regarding its potential as an antihistamine. In vitro binding studies and investigations in animal tissue have demonstrated the high specificity of bilastine for H1 -receptors, and preclinical animal studies have also yielded promising results in terms of a reduction of histamine-mediated inflammatory effects, including capillary permeability and bronchospasm. In pharmacodynamic studies bilastine was found to down-regulate histamine-induced flare and wheal responses in healthy volunteers. Preclinical and clinical pharmacokinetic studies showed that bilastine has dose-dependent kinetics following oral administration. Excretion is almost exclusively via urine and faeces as unchanged drug. Early clinical trials have shown that bilastine has similar efficacy to other second-generation H1 -receptor antagonists such as cetirizine, desloratadine, fexofenadine and levocetirizine, in terms of reducing allergic symptoms. Clinical findings also indicate that bilastine has a rapid onset of action and a 20 mg single dose is effective throughout a 24-h period. Furthermore, bilastine has been associated with improved quality of life in allergic rhinoconjunctivitis and urticaria patients. Adverse effects have generally been minimal in these studies and doses up to twice those proposed did not exhibit differences in adverse events compared to placebo. Moreover, in vivo investigations have found no evidence of accumulation of bilastine in the central nervous system, and various studies have confirmed minimal effects on psychomotor performance in healthy volunteers administered up to four times the usual dose. Clinical studies have also found no effect of bilastine on the QTc interval and other ECG parameters, even at supratherapeutic dosages, confirming the good cardiac safety profile of this newer antihistamine. Given its pharmacodynamic profile, which appears to be similar to other second-generation H1 -receptor antagonists, and its favourable safety and tolerability, bilastine has the attributes of a potentially clinically useful non-sedating antihistamine. Larger clinical studies are now necessary to fully elucidate the clinical potential of this novel antihistamine. [source] Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2003Yasuhisa Kurogi Abstract Mesangial cells (MC) serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of glomerular hemodynamics, and a phagocytic function allowing removal of macromolecules and immune complexes. The proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental animal models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix in the mesangium and glomerulosclerosis. Reduction of MC proliferation in glomerular disease models by treatment with heparin, low-protein diet, or antibodies to platelet-derived growth factor (PDGF), have been shown to reduce extracellular matrix expansion and glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer therapeutic opportunities for the treatment of proliferative glomerular disease. It is also known that the MC proliferation is inhibited by many kinds of pharmacological drugs, for example, angiotensin converting enzyme (ACE) inhibitors, leukotriene D4 (LTD4) antagonists, PDGF inhibitors, matrix metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG-CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This review summarizes the recently reported MC proliferation inhibitors with their pharmacological properties on the basis of their chemical structures. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 15,31, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10028 [source] | |||||||||||||||||||||||||||||||