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Relative Potency (relative + potency)
Selected AbstractsRelative potencies of protease inhibitorsHIV MEDICINE, Issue 2000Bg Gazzard First page of article [source] 2,3,4,7,8-pentachlorodibenzofuran is a more potent cytochrome P4501A inducer than 2,3,7,8-tetrachlorodibenzo- p -dioxin in herring gull hepatocyte culturesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2010Jessica C. Hervé Abstract Concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) on cytochrome P4501A (CYP1A) induction were determined in primary cultures of embryonic herring gull (Larus argentatus) hepatocytes exposed for 24,h. Based on the concentration that induced 50% of the maximal response (EC50), the relative potencies of TCDD and TCDF did not differ by more than 3.5-fold. However, also based on the EC50, PeCDF was 40-fold, 21-fold, and 9.8-fold more potent for inducing ethoxyresorufin- O -deethylase (EROD) activity, CYP1A4 mRNA expression, and CYP1A5 mRNA expression than TCDD, respectively. The relative CYP1A-inducing potencies of PeCDF and of other dioxin-like chemicals (DLCs) in herring gull hepatocytes (HEH RePs), along with data on concentrations of DLCs in Great Lakes herring gull eggs, were used to calculate World Health Organization toxic equivalent (WHO-TEQ) concentrations and herring gull embryonic hepatocyte toxic equivalent (HEH-TEQ) concentrations. The analysis indicated that, when using avian toxic equivalency factors (TEFs) recommended by the WHO, the relative contribution of TCDD (1.1,10.2%) to total WHO-TEQ concentration was higher than that of PeCDF (1.7,2.9%). These results differ from the relative contribution of TCDD and PeCDF when HEH RePs were used; PeCDF was a major contributor (36.5,52.9%) to total HEH-TEQ concentrations, whereas the contribution by TCDD (1.2,10.3%) was less than that of PeCDF. The WHO TEFs for avian species were largely derived from studies with the domestic chicken (Gallus gallus domesticus). The findings of the present study suggest that it is necessary to determine the relative potencies of DLCs in wild birds and to re-evaluate their relative contributions to the biochemical and toxic effects previously reported in herring gulls and other avian species. Environ. Toxicol. Chem. 2010;29:2088,2095. © 2010 SETAC [source] Morphine, opioids, and the feline pulmonary vascular bedACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2008A. D. KAYE Background: Opioid-induced vasodepressor responses have been reported in a variety of species and laboratory models. The aim of this study was to ascertain the relative potencies of different clinically relevant opioids compared with traditional vasodepressor agents in the feline pulmonary vascular bed. A second aim was to study the effects of morphine and to identify the receptors involved in the mediation or the modulation of these effects. Methods: This was a prospective vehicle-controlled study involving an intact chest preparation of adult mongrel cats. The effects of various opioids, morphine, fentanyl, remifentanil, sufentanil, and meperidine were compared with other vasodepressor agents. Additionally, the effects of l - N5 -(1-iminoethyl) ornithine hydrochloride (l -NIO) (nitric oxide synthase inhibitor), nimesulide [selective cyclooxygenase (COX)-2 inhibitor], glibenclamide (ATP-sensitive K+ channel blocker), naloxone (non-selective opioid receptor antagonist), and diphenhydramine (histamine H1 -receptor antagonist) were investigated on pulmonary arterial responses to morphine and other selected agonists in the feline pulmonary vascular bed. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and recorded. Results: In the cat pulmonary vascular bed of the isolated left lower lobe, morphine, remifentanil, fentanyl, sufentanil, and meperidine induced a dose-dependent moderate vasodepressor response and it appeared that sufentanil was the most potent on a nanomolar basis. The effects of morphine were not significantly altered after administration of l -NIO, nimesulide, and glibenclamide. However, the vascular responses to morphine were significantly attenuated following administration of naloxone and diphenhydramine. Conclusion: The results of the present study suggest that sufentanil appears to have slightly more potency and morphine the least of the five opioid agonists studied on a nanomolar basis. Morphine-induced vasodilatory responses appeared to be mediated or modulated by both opioid receptor and histamine-receptor-sensitive pathways. [source] The local lymph node assay and the assessment of relative potency: status of validationCONTACT DERMATITIS, Issue 2 2007David A. Basketter For the prediction of skin sensitization potential, the local lymph node assay (LLNA) is a fully validated alternative to guinea-pig tests. More recently, information from LLNA dose,response analyses has been used to assess the relative potency of skin sensitizing chemicals. These data are then deployed for risk assessment and risk management. In this commentary, the utility and validity of these relative potency measurements are reviewed. It is concluded that the LLNA does provide a valuable assessment of relative sensitizing potency in the form of the estimated concentration of a chemical required to produce a threefold stimulation of draining lymph node cell proliferation compared with concurrent controls (EC3 value) and that all reasonable validation requirements have been addressed successfully. EC3 measurements are reproducible in both intra- and interlaboratory evaluations and are stable over time. It has been shown also, by several independent groups, that EC3 values correlate closely with data on relative human skin sensitization potency. Consequently, the recommendation made here is that LLNA EC3 measurements should now be regarded as a validated method for the determination of the relative potency of skin sensitizing chemicals, a conclusion that has already been reached by a number of independent expert groups. [source] Allergenicity evaluation of Bioban CS-1135 in experimental animalsCONTACT DERMATITIS, Issue 6 2004Tetsuo Yamano An industrial preservative, Bioban CS-1135, was evaluated for its contact allergenicity by means of multiple-dose guinea-pig maximization test and non-radioactive murine local lymph node assay. In the guinea-pig test, an induction dose of 0.5% Bioban CS-1135 sensitized all animals of the group. The dose,response study of the elicitation phase determined a minimum elicitation dose of 5% for positive skin reactions. In the murine assay, Bioban CS-1135 at doses of 10% and more exerted significant effects on lymphoid cell proliferation. Although the data clearly designated Bioban CS-1135 as a skin sensitizer, its relative potency was ranked lowest among skin-sensitizing biocides previously evaluated in this laboratory. [source] Vehicle effects on skin sensitizing potency of four chemicals: assessment using the local lymph node assayINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 2 2001Z M Wright Synopsis The murine local lymph node assay (LLNA) can be used to determine the relative skin sensitizing potency of chemicals via interpolation of the quantitative dose response data generated. Using this approach we have demonstrated previously that the vehicle matrix in which a chemical allergen is encountered on the skin can have a significant influence on sensitizing potency. Estimates of relative potency are calculated from LLNA dose responses as a function of the mathematically derived EC3 value, this being the concentration estimated to induce a stimulation index (SI) of 3. To investigate further the influence of application vehicle on sensitizing potency, the LLNA has been used to examine the activity of four recognized human contact allergens: isoeugenol and cinnamic aldehyde, two fragrance chemicals; 3-dimethylaminopropylamine (a sensitizing impurity of cocamidopropyl betaine, a surfactant used in shower gel) and dibromodicyanobutane (the sensitizing component of Euxyl K 400, a preservative used in cosmetics). The four chemicals were applied in each of seven different vehicles (acetone: olive oil [4 : 1]; dimethylsulphoxide; methylethylketone; dimethyl formamide; propylene glycol; and both 50 : 50 and 90 : 10 mixtures of ethanol and water). It was found that the vehicle in which a chemical is presented to the epidermis can have a marked effect on sensitizing activity. EC3 values ranged from 0.9 to 4.9% for isoeugenol, from 0.5 to 1.7% for cinnamic aldehyde, from 1.7 to > 10% for dimethylaminopropylamine and from 0.4 to 6.4% for dibromodicyanobutane. These data confirm that the vehicle in which a chemical is encountered on the skin has an important influence on the relative skin sensitizing potency of chemicals and may have a significant impact on the acquisition of allergic contact dermatitis. The data also demonstrate the utility of the LLNA as a method for the prediction of these effects and thus for the development of more accurate risk assessments. Résumé Le test local des ganglions lymphatiques murins (LLNA) peut être utilisé pour déterminer le potentiel relatif de sensibilisation de la peau de produits chimiques, par interpolation des données quantitatives de dose/réponse obtenues. En utilisant cette approche, nous avions démontré précédemment que la matrice vecteur par laquelle un allergène chimique est mis en contact avec la peau peut avoir une influence significative sur le potentiel de sensibilisation. Des estimations d'activité relative sont calculées à partir des doses/réponses de LLNA en fonction de la valeur EC3 dérivée mathématiquement, celle-ci étant la concentration estimée comme induisant un indice de stimulation (IS) de 3. Pour examiner plus avant l'influence du vecteur d'application sur l'activité de sensibilisation, on a utilisé le LLNA pour déterminer l'activité de quatre allergènes de contact humains reconnus: isoeugénol et aldéhyde cinnamique, deux substances chimiques de parfumerie; la 3-diméthylaminopropylamine (une impureté sensibilisante de la cocamidopropyl bétaïne, un tensioactif utilisé dans les gels douches) et le dibromodicyanobutane (le composant sensibilisant de Euxyl K 400, un conservateur utilisé dans les cosmétiques). Les quatre produits chimiques ont été appliqués dans chacun de sept vecteurs différents (acétone: huile d'olive [4: 1]; diméthylsulfoxyde; méthyléthylcétone; diméthylformamide; propy- lène glycol; et deux mélanges 50: 50 et 90: 10 d'éthanol et d'eau). On observe que le vecteur dans lequel le produit chimique est présentéà l'épiderme peut avoir un effet marqué sur l'activité sensibilisatrice. Les valeurs EC3 vont de 0,9 à 4,9 % pour l'isoeugénol, de 0,5 à 1,7 % pour l'aldéhyde cinnamique, de 1,7 à > 10 % pour la diméthylaminopropylamine et de 0,4 à 6,4 % pour le dibromodicyanobutane. Ces données confirment que le vecteur dans lequel un produit chimique est mis en contact avec la peau a une influence importante sur le potentiel relatif de sensibilisation de la peau des produits chimiques, et peut avoir un impact significatif sur l'apparition de dermatite allergique par contact. Les données démontrent aussi l'utilité du LLNA comme méthode de prévision de ces effets et donc pour le développement d'évaluations plus précises des risques. [source] Clinical pharmacology of the H1 -receptor antagonists cetirizine and loratadine in childrenPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 2 2000F. Estelle R. Simons H1 -receptor antagonists are widely used in children but are not as well-studied in children as they are in adults. Our objective was to determine the onset and duration of action and the relative potency of the H1 -receptor antagonists cetirizine and loratadine in children. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of cetirizine and loratadine using suppression of the histamine-induced wheal and flare as the primary outcome. In 15 allergic children, mean age 9 years, compared with baseline, cetirizine (10 mg) suppressed the wheals and flares significantly from 0.25 to 24 h, achieving nearly 100% of flare suppression from 2 to 24 h, inclusive, and loratadine (10 mg) suppressed the wheals and flares significantly from 0.75 to 24 h, inclusive. Cetirizine suppressed the wheals and flares significantly more than loratadine from 0.25 to 1 h, inclusive, and at 0.5, 1, 2, 3, 5, 6, 7, and 24 h, respectively. Placebo also suppressed the wheal and flare significantly at some assessment times. Cetirizine and loratadine both have excellent antihistaminic activity in children, with a rapid onset of action and a 24-h duration of action in this population. [source] Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2-chloroethyl)amineARCHIV DER PHARMAZIE, Issue 8 2009Krzysztof Bielawski Abstract Novel nitrogen mustard agents 7,12 involving 4-(N,N -bis(2-chloroethyl)aminophenyl)propylamine linked to a 5-(4- N -alkylamidinophenyl)-2-furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in-vitro cytotoxic activity against MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of 7,12 employing a MTT assay and inhibition of [3H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9, which possess a cationic amidine and 4,5-dihydro-1H -imidazol function moiety are approximately ten times more potent than 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7,12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors. [source] The use of sputum cell counts to evaluate asthma medicationsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001Krishnan Parameswaran Total and differential cell counts from hypertonic-induced, dithiothreitol-dispersed sputum provide reproducible measurements of airway inflammatory cell counts, which are responsive to treatment with anti-inflammatory drugs. They have helped to understand the kinetics of inflammatory cell changes in asthma after the reduction of corticosteroids and the subsequent re-introduction of treatment. They have identified that the presence of sputum eosinophilia in asthma, chronic cough and chronic airflow limitation is a predictor of steroid-responsiveness and of lack of ,asthma control'. They can be used to study the dose,response effect of inhaled corticosteroids and may be useful to establish the relative potency of different corticosteroid formulations and delivery devices. Sputum cell counts are also useful to study the potential anti-inflammatory effects of drugs like theophylline, long-acting ,-adrenoceptor agonists, leukotriene antagonists and newer drugs in development. They may be helpful to select add-on therapy to corticosteroids in ,difficult-to-control' asthma. [source] Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slicesBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2004Jacqueline Scuvée-Moreau We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on the SK channel subtypes and its ability to block AHPs of other neurones were unknown. Using whole-cell patch-clamp experiments in transfected cell lines, we found that the compound blocks SK1, SK2 and SK3 currents with equal potency: its mean IC50s were 1.2, 0.8 and 1.8 ,M, respectively. IK currents were unaffected. In rat brain slices, methyl-laudanosine blocked apamin-sensitive AHPs in serotonergic neurones of the dorsal raphe and noradrenergic neurones of the locus coeruleus with IC50s of 21 and 19 ,M, as compared to 15 ,M in dopaminergic neurones. However, at 100 ,M, methyl-laudanosine elicited a constant hyperpolarization of serotonergic neurones of about 9 mV, which was inconsistently (i.e. not in a reproducible manner) antagonized by atropine and hence partly due to the activation of muscarinic receptors. While exploring the pharmacology of related compounds, we found that methyl-noscapine also blocked SK channels. In cell lines, methyl-noscapine blocked SK1, SK2 and SK3 currents with mean IC50s of 5.9, 5.6 and 3.9 ,M, respectively. It also did not block IK currents. Methyl-noscapine was slightly less potent than methyl-laudanosine in blocking AHPs in brain slices, its IC50s being 42, 37 and 29 ,M in dopaminergic, serotonergic and noradrenergic neurones, respectively. Interestingly, no significant non-SK effects were observed with methyl-noscapine in slices. At a concentration of 300 ,M, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). Methyl-laudanosine and methyl-noscapine produced a rapidly reversible blockade of SK channels as compared with apamin. The difference between the IC50s of apamin (0.45 nM) and methyl-laudanosine (1.8 ,M) in SK3 cells was essentially due to a major difference in their k,1 (0.028 s,1 for apamin and 20 s,1 for methyl-laudanosine). These experiments demonstrate that both methyl-laudanosine and methyl-noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes. Methyl-noscapine may be superior in terms of specificity for the SK channels. British Journal of Pharmacology (2004) 143, 753,764. doi:10.1038/sj.bjp.0705979 [source] | ||||||||||||||||||||||