DOCSLIB.ORG

Supplementary Information for Drug Metabolism and Disposition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Supplementary Information for Drug Metabolism and Disposition Supplementary Information for Drug Metabolism and Disposition Identification of Clinically Utilized Drugs that Activate Pregnane X Receptors Sunita J. Shukla, Srilatha Sakamuru, Ruili Huang, Timothy A. Moeller, Paul Shinn, Danielle Van Leer, Douglas S. Auld, Christopher P. Austin and Menghang Xia 1 Table S1—Final 1,536-well hPXR assay protocol Step Parameter Value Description 1 Reagent 5 µL HepG2 (DPX-2) cells 2 Incubation time 5 hr 37°C incubation 3 Library compounds 23 nl Compound dilution series 4 Controls 23 nl Rifampicin 5 Incubation time 24 hr 37°C incubation 6 Reagent 5 µL Detection Reagent 7 Incubation time 30 min Room temperature 8 Detection 30 sec ViewLux luminescent read Step Notes 1 Medium-binding white solid bottom Greiner plates. 2K cells/well/5 µL plated using an FRD. 3 Pin-tool transfer NPC compound library for a (final) range of 46 µM to 2.8 nM (15 point titration). Pin-tool transfer, Column 1: two-fold sixteen-point rifampicin titration starting at 46 µM to 1.4 nM 4 (final); Column 2: 23 µM rifampicin (final); Column 3: DMSO; Column 4: 9.2 µM rifampicin (final). Pin-tool transfer tip wash sequence: DMSO, iPA, MeOH, >3 s vacuum dry. 6 ONE-Glo™ Luciferase Assay Reagent. 8 30 s exposure, gain high, and 2x binning luminescent read on Perkin Elmer ViewLux. 2 Table S2—Final 1,536-well rPXR assay protocol Step Parameter Value Description 1 Reagent 5 µL HepG2 cells 2 Incubation time 5 hr 37°C incubation 3 Library compounds 23 nl Compound dilution series 4 Controls 23 nl Dexamethasone 5 Incubation time 24 hr 37°C incubation 6 Reagent 5 µL Detection Reagent 7 Incubation time 30 min Room temperature 8 Detection 40 sec ViewLux luminescent read Step Notes 1 Medium-binding white solid bottom Greiner plates. 2K cells/well/5 µL plated using an FRD. 3 Pin-tool transfer NPC compound library for a (final) range of 46 µM to 2.8 nM (15 point titration). Pin-tool transfer, Column 1: two-fold sixteen-point dexamethasone titration starting at 92 µM to 2.8 4 nM (final); Column 2: 46 µM dexamethasone (final); Column 3: DMSO; Column 4: 23 µM dexamethasone (final). Pin-tool transfer tip wash sequence: DMSO, iPA, MeOH, >3 s vacuum dry. 6 ONE-Glo™ Luciferase Assay Reagent. 8 40 s exposure, gain high, and 3x binning luminescent read on Perkin Elmer ViewLux. 3 Table S3—Final 1,536-well CYP3A4 induction assay protocol Step Parameter Value Description 1 Reagent 5 µL HepG2 cells (DPX-2) 2 Incubation time 3.5 hr 37°C incubation 3 Library compounds 23 nl Compound dilution series 4 Controls 23 nl Rifampicin 5 Incubation time 24 hr 37°C incubation 6 Reagent 1 µL Assay substrate 7 Incubation time 3 hr 37°C incubation 8 Reagent 5 µL Detection reagent 9 Incubation time 30 min Room temperature 10 Detection 30 sec ViewLux luminescent read Step Notes 1 Medium-binding white solid bottom Greiner plates. 2K cells/well/5 µL plated using an FRD. 3 Pin-tool transfer NPC compound library for a (final) range of 46 µM to 2.8 nM (15 point titration). Pin-tool transfer, Column 1: two-fold sixteen-point rifampicin titration starting at 46 µM to 1.4 nM 4 (final); Column 2: 46 µM rifampicin (final); Column 3: 23 µM rifampicin (final); Column 4: DMSO. Pin-tool transfer tip wash sequence: DMSO, iPA, MeOH, >3 s vacuum dry. 6 P450-Glo™ Assay substrate [3uM (final)] 8 P450-Glo™ Assay Reagent. 10 30 s exposure, gain high, and 2x binning luminescent read on Perkin Elmer ViewLux. 4 Table S4—Assay statistics Assay Positive controls EC50 (mean, μM) S/B ratio* Z’ hPXR Rifampicin 3.5 5.7 0.23 hPXR LBD SR12813 0.44 3.1 0.68 rPXR Dexamethasone 2.6 4.9 0.24 CYP3A4 Rifampicin 3.3 2.7 0.36 * S/B = Signal to Background 5 Table S5--Potencies (μM) and efficacies (%) of 72 compounds from cherry-pick studies Compound Structure hPXR EC50, μM hPXR LBD EC50, rPXR CYP3A4 (Efficacy, %) μM (Efficacy, %) EC50, μM EC50, μM (Efficacy, %) (Efficacy, %) AA-861 28.2 (44.3) 12.6 (119.8) inactive 7.1 (29.3) Alpha-Lipoic acid inactive 2.8 (107.9) inactive inactive Ambrisentan 31.6 (46.7) Inactive inactive 31.6 (117.4) AMI-193 inactive 31.6 (138.7) inactive inactive Amlodipine Besylate 31.6 (90.5) 28.2 (47.2) inactive 31.6 (257.6) Aurothioglucose inactive 2.5 (111.7) inactive inactive Bithionol Inactive 1.0 (50.0) Inactive 12.6 (269.9) 6 Bosentan 14.1 (71.5) 8.9 (82.8) Inactive 12.6 (163.5) Bumecainum 31.6 (200) 5.0 (80.8) Inactive 7.9 (237.0) Cephaloridine inactive 3.2 (97.7) inactive inactive Choroxine OH 39.8 (107.9) inactive inactive inactive Cl N Cl Ciglitazone 14.1 (96.1) 4.5 (108.0) inactive 10 (209.4) Clofenvinfosum 12.6 (87.2) 7.9 (108.7) 12.6 (63.4) 10 (198.8) Colforsin 7.9 (120.6) 14.1 (54.7) 7.9 (76.0) 2.8 (237.0) 7 Demecolcine 12.6 (51.1) 14.1 (103.0) 0.09 (103.0) inactive Desoximetasone inactive inactive 10 (239.4) 31.6 (101.9) Dibunate Sodium 25.1 (187.1) 6.3 (98.8) inactive 8.9 (165.6) N Diclazuril Cl 31.6 (48.8) 7.9 (128.3) inactive 35.5 (96.2) N N Cl Cl O N O H Dimercaprol inactive 5.0 (88.0) inactive 50.1 (35.5) Dinaline 28.2 (52.5) inactive 12.6 (324.2) inactive Docusate Calcium 25.1 (129.4) 0.89 (104.1) inactive 15.8 (68.8) Dodecylbenzenesulfonic inactive 15.8 (100.1) inactive inactive acid, sodium salt 8 Dronabinol 31.6 (79.3) 12.6 (60.8) inactive 12.6 (81.5) Droxidopa inactive 3.2 (84.9) 63.1 (48.4) 0.004 (29.9) Eburnamonine (-) 14.1 (60.3) 12.6 (49.9) 14.1 (144.3) inactive Ecopipamum 4.0 (84.7) 6.3 (68.3) Inactive 12.6 (264.0) Enzacamene 31.6 (60.4) 5.0 (93.2) inactive 31.6 (118.1) Epothilone B 12.6 (62.5) 31.6 (89.9) 0.01 (102.9) inactive 9 Famprofazone 8.9 (98.3) 1.3 (97.8) 12.6 (41.8) 4.0 (136.2) Febantel 15.8 (67.6) inactive 31.6 (136.5) 10 (54.2) Felodipine 12.6 (69.5) 7.1 (79.9) 28.2 (77.3) 2.5 (53.3) Fenbendazole 10 (33.7) inactive 4.0 (317.2) inactive Fentanyl 31.6 (93.9) 31.6 (102.9) inactive 31.6 (205.6) Fluorometholone 12.6 (31.0) 1.3 (88.2) 1.6 (221.0) 3.2 (182.4) 10 Haloprogin Inactive 10 (123.8) inactive inactive Hetacillin Potassium Inactive 6.3 (84.0) inactive inactive Hydralazine Hydrochloride inactive Inactive 0.45 (48.1) inactive Idinavir Sulfate 14.1 (79.2) inactive inactive 15.8 (221.6) OH O Lasalocid Sodium Na+ inactive 5.6 (93.6) inactive 17.8 (140.7) O- OH O O O HO Levothyroxine Inactive 11.2 (105.2) Inactive 100 (87.7) Linolenic Acid inactive 2.5 (110.6) inactive 0.002 (16.3) 11 LOE 908 Hydrochloride 3.2 (35.8) 15.8 (72.8) 12.6 (56.7) inactive Loratadine Cl 10.0 (60.0) 10 (97.4) inactive 12.6 (297.1) N N O O Methacycline Inactive 3.2 (79.5) inactive 12.6 (50.6) Hydrochloride 6-α-Methylprednisolone inactive inactive 4.0 (84.7) 12.6 (112.2) Nilvadipine 10.0 (133.4) 0.89 (102.4) 14.1 (61.2) 4.0 (273.7) 12 Nisoldipine 10.0 (46.1) 7.9 (77.5) 31.6 (75.4) 12.6 (223.5) Norelgestromin 25.1 (64.5) inactive inactive inactive Orlistat Inactive 1.6 (52.0) inactive 28.2 (49.6) Oxatomide 7.1 (67.9) 7.9 (71.5) 25.1 (52.2) 4.0 (129.4) Plicamycin inactive 15.8 (36.7) 0.32 (116.5) inactive Proadifen Hydrochloride 25.1 (97.2) 14.1 (70.2) 35.5 (61.9) 12.6 (259.7) Rifampicin 7.9 (147.0) 0.20 (43.9) Inactive 3.2 (459.2) 13 Rifaximin 14.1 (65.3) inactive inactive 14.1 (265.6) Rimexolone 4.5 (82.1) 2.5 (118.5) 1.4 (165.4) 1.6 (140.8) Riodipine 11.2 (96.7) 14.1 (82.3) 22.4 (150.6) 1.6 (122.3) Sirolimus inactive 0.89 (80.7) Inactive 10 (93.2) Spiroxatrine 20.0 (49.3) 25.1 (71.0) inactive 35.5 (95.1) Suberoylanilide 35.5 (55.1) 25.1 (82.7) 2.5 (307.6) inactive Suramin Inactive 1.3 (66.0) inactive inactive Tacrolimus inactive 5.0 (109.3) inactive inactive 14 Tenilidona 11.2 (119.0) 10 (57.2) 4.5 (70.7) inactive Terconazole 8.9 (32.3) inactive Inactive 14.1 (46.1) Testosterone Isocaproate 31.6 (21.4) 11.2 (75.5) Inactive 28.2 (50.9) Thiamylal Sodium 25.1 (115.7) 14.1 (62.3) Inactive 8.9 (228.1) Thonzonium Bromide inactive 11.2 (134.3) Inactive 11.2 (36.0) Tianeptinum 22.4 (66.1) 39.8 (80.6) Inactive 14.1 (49.6) Triiodothyronine, Reverse inactive 12.6 (103.5) Inactive inactive Troglitazone 31.6 (79.5) 8.9 (90.1) Inactive 31.6 (136.8) Tropanyl 3,5- 11.2 (62.1) 14.1 (35.8) Inactive 28.2 (244.0) Dimethulbenzoate 15 Zafirlukast 14.1 (76.4) 0.71 (101.8) Inactive 12.6 (188.2) Zearalanol 31.6 (77.5) 4.0 (73.7) Inactive 25.1 (123.2) 16 Table S6--Potencies (μM) and efficacies (%) of 26 re-acquired compounds from confirmation studies Compound Structure hPXR hPXR LBD rPXR CYP3A4 CYP3A4 EC50, μM EC50, μM EC50, μM EC50, μM EC50, µM (Efficacy, %) (Efficacy, %) (Efficacy, %) (Efficacy, %) (Hepatocytes) Bumecainum 11 (158) inactive 38 (117.2) 7 (102) 1.1 Ciglitazone Chiral 23.6 (170.3) 41 (110.9) inactive 10.8 (84.1) N/A O O S HN O Colforsin O Chiral 9 (283.4) inactive 7.1 (158.1) 2.7 (93.2) 0.7 HO O H O HO OHO N Diclazuril Cl 38.7(45.2) inactive 9 (50.9) inactive N/A N N Cl Cl ONO H O Famprofazone Chiral 5.1 (83.1) inactive 9.8 (102.7) 3.1 (78.2) 1.4 N N N 17 Felodipine 3.9 (86) 17.1 (81.1) 23.4 (188) 1.9 (60) N/A Fenbendazole 29.8 (180.2) inactive 5.1 (183.6) inactive N/A Fluorometholone Chiral 26.9 (63.5) inactive 1.7 (219.3) inactive N/A O F OHO HO Hetacillin Potassium inactive 19.5 (72) inactive inactive N/A Hydralazine inactive inactive 1.6 (87.5) inactive N/A Hydrochloride Methacycline inactive 30 (61.5) inactive inactive N/A Hydrochloride 6-α- inactive inactive 10 (146.5) inactive N/A Methylprednisolone 18 Nilvadipine 2 (92.8) inactive 10.5 (175.2) 1.9 (99.7) 1.4 Oxatomide 9.7 (174.5) 36.4 (76.3) 27.7 (86.8) 3.5 (56.1) 0.4 H H HH HO H H H H H H H O Plicamycin O H H inactive inactive 0.4 (172.8) inactive N/A O H H O H HO O H O O H H H H H H H H H HH H H O H H OH H H H O H H H O OOH H H H H O H H H H O H H H HH H H H O H H HO O H O H H H H O H O H H H HH O H H H H Rimexolone 4 (104.7) inactive
Load more

Recommended publications
  • Combination of Cabazitaxel and Plicamycin Induces Cell Death in Drug Resistant B-Cell Acute Lymphoblastic Leukemia
    Clinical and Translational Science Institute Centers 9-1-2018 Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia Rajesh R. Nair West Virginia University Debbie Piktel West Virginia University Werner J. Geldenhuys West Virginia University Laura F. Gibson West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/ctsi Part of the Medicine and Health Sciences Commons Digital Commons Citation Nair, Rajesh R.; Piktel, Debbie; Geldenhuys, Werner J.; and Gibson, Laura F., "Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia" (2018). Clinical and Translational Science Institute. 34. https://researchrepository.wvu.edu/ctsi/34 This Article is brought to you for free and open access by the Centers at The Research Repository @ WVU. It has been accepted for inclusion in Clinical and Translational Science Institute by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Leuk Res Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 September 01. Published in final edited form as: Leuk Res. 2018 September ; 72: 59–66. doi:10.1016/j.leukres.2018.08.002. Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia Rajesh R. Naira, Debbie Piktelb, Werner J. Geldenhuysc,
    [Show full text]
  • The National Drugs List
    ^ ^ ^ ^ ^[ ^ The National Drugs List Of Syrian Arab Republic Sexth Edition 2006 ! " # "$ % &'() " # * +$, -. / & 0 /+12 3 4" 5 "$ . "$ 67"5,) 0 " /! !2 4? @ % 88 9 3: " # "$ ;+<=2 – G# H H2 I) – 6( – 65 : A B C "5 : , D )* . J!* HK"3 H"$ T ) 4 B K<) +$ LMA N O 3 4P<B &Q / RS ) H< C4VH /430 / 1988 V W* < C A GQ ") 4V / 1000 / C4VH /820 / 2001 V XX K<# C ,V /500 / 1992 V "!X V /946 / 2004 V Z < C V /914 / 2003 V ) < ] +$, [2 / ,) @# @ S%Q2 J"= [ &<\ @ +$ LMA 1 O \ . S X '( ^ & M_ `AB @ &' 3 4" + @ V= 4 )\ " : N " # "$ 6 ) G" 3Q + a C G /<"B d3: C K7 e , fM 4 Q b"$ " < $\ c"7: 5) G . HHH3Q J # Hg ' V"h 6< G* H5 !" # $%" & $' ,* ( )* + 2 ا اوا ادو +% 5 j 2 i1 6 B J' 6<X " 6"[ i2 "$ "< * i3 10 6 i4 11 6! ^ i5 13 6<X "!# * i6 15 7 G!, 6 - k 24"$d dl ?K V *4V h 63[46 ' i8 19 Adl 20 "( 2 i9 20 G Q) 6 i10 20 a 6 m[, 6 i11 21 ?K V $n i12 21 "% * i13 23 b+ 6 i14 23 oe C * i15 24 !, 2 6\ i16 25 C V pq * i17 26 ( S 6) 1, ++ &"r i19 3 +% 27 G 6 ""% i19 28 ^ Ks 2 i20 31 % Ks 2 i21 32 s * i22 35 " " * i23 37 "$ * i24 38 6" i25 39 V t h Gu* v!* 2 i26 39 ( 2 i27 40 B w< Ks 2 i28 40 d C &"r i29 42 "' 6 i30 42 " * i31 42 ":< * i32 5 ./ 0" -33 4 : ANAESTHETICS $ 1 2 -1 :GENERAL ANAESTHETICS AND OXYGEN 4 $1 2 2- ATRACURIUM BESYLATE DROPERIDOL ETHER FENTANYL HALOTHANE ISOFLURANE KETAMINE HCL NITROUS OXIDE OXYGEN PROPOFOL REMIFENTANIL SEVOFLURANE SUFENTANIL THIOPENTAL :LOCAL ANAESTHETICS !67$1 2 -5 AMYLEINE HCL=AMYLOCAINE ARTICAINE BENZOCAINE BUPIVACAINE CINCHOCAINE LIDOCAINE MEPIVACAINE OXETHAZAINE PRAMOXINE PRILOCAINE PREOPERATIVE MEDICATION & SEDATION FOR 9*: ;< " 2 -8 : : SHORT -TERM PROCEDURES ATROPINE DIAZEPAM INJ.
    [Show full text]
  • PEMD-91-12BR Off-Label Drugs: Initial Results of a National Survey
    11 1; -- __...._-----. ^.-- ______ -..._._ _.__ - _........ - t Ji Jo United States General Accounting Office Washington, D.C. 20648 Program Evaluation and Methodology Division B-242851 February 25,199l The Honorable Edward M. Kennedy Chairman, Committee on Labor and Human Resources United States Senate Dear Mr. Chairman: In September 1989, you asked us to conduct a study on reimbursement denials by health insurers for off-label drug use. As you know, the Food and Drug Administration designates the specific clinical indications for which a drug has been proven effective on a label insert for each approved drug, “Off-label” drug use occurs when physicians prescribe a drug for clinical indications other than those listed on the label. In response to your request, we surveyed a nationally representative sample of oncologists to determine: . the prevalence of off-label use of anticancer drugs by oncologists and how use varies by clinical, demographic, and geographic factors; l the extent to which third-party payers (for example, Medicare intermediaries, private health insurers) are denying payment for such use; and l whether the policies of third-party payers are influencing the treatment of cancer patients. We randomly selected 1,470 members of the American Society of Clinical Oncologists and sent them our survey in March 1990. The sam- pling was structured to ensure that our results would be generalizable both to the nation and to the 11 states with the largest number of oncologists. Our response rate was 56 percent, and a comparison of respondents to nonrespondents shows no noteworthy differences between the two groups.
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 8,343,962 B2 Kisak Et Al
    US008343962B2 (12) United States Patent (10) Patent N0.: US 8,343,962 B2 Kisak et al. (45) Date of Patent: *Jan. 1, 2013 (54) TOPICAL FORMULATION (58) Field of Classi?cation Search ............. .. 514/226.5, 514/334, 420, 557, 567 (75) Inventors: Edward T. Kisak, San Diego, CA (US); See application ?le fOr Complete Search history. John M. NeWsam, La Jolla, CA (US); _ Dominic King-Smith, San Diego, CA (56) References C‘ted (US); Pankaj Karande, Troy, NY (US); Samir Mitragotri, Goleta, CA (US) US' PATENT DOCUMENTS 5,602,183 A 2/1997 Martin et al. (73) Assignee: NuvoResearchOntano (CA) Inc., Mississagua, 6,328,979 2B1 12/2001 Yamashita et a1. 7,001,592 B1 2/2006 Traynor et a1. ( * ) Notice: Subject to any disclaimer, the term of this 7,795,309 B2 9/2010 Kisak eta1~ patent is extended or adjusted under 35 2002/0064524 A1 5/2002 Cevc U.S.C. 154(b) by 212 days. FOREIGN PATENT DOCUMENTS This patent is subject to a terminal dis- W0 WO 2005/009510 2/2005 claimer- OTHER PUBLICATIONS (21) APPI' NO‘, 12/848,792 International Search Report issued on Aug. 8, 2008 in application No. PCT/lB2007/0l983 (corresponding to US 7,795,309). _ Notice ofAlloWance issued on Apr. 29, 2010 by the Examiner in US. (22) Med Aug- 2’ 2010 Appl. No. 12/281,561 (US 7,795,309). _ _ _ Of?ce Action issued on Dec. 30, 2009 by the Examiner in US. Appl. (65) Prior Publication Data No, 12/281,561 (Us 7,795,309), Us 2011/0028460 A1 Feb‘ 3’ 2011 Primary Examiner * Raymond Henley, 111 Related U 5 Application Data (74) Attorney, Agent, or Firm * Foley & Lardner LLP (63) Continuation-in-part of application No.
    [Show full text]
  • Upregulation of Peroxisome Proliferator-Activated Receptor-Α And
    Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer Chih-Yang Wang, Ying-Jui Chao, Yi-Ling Chen, Tzu-Wen Wang, Nam Nhut Phan, Hui-Ping Hsu, Yan-Shen Shan, Ming-Derg Lai 1 Supplementary Table 1. Demographics and clinical outcomes of five patients with ampullary cancer Time of Tumor Time to Age Differentia survival/ Sex Staging size Morphology Recurrence recurrence Condition (years) tion expired (cm) (months) (months) T2N0, 51 F 211 Polypoid Unknown No -- Survived 193 stage Ib T2N0, 2.41.5 58 F Mixed Good Yes 14 Expired 17 stage Ib 0.6 T3N0, 4.53.5 68 M Polypoid Good No -- Survived 162 stage IIA 1.2 T3N0, 66 M 110.8 Ulcerative Good Yes 64 Expired 227 stage IIA T3N0, 60 M 21.81 Mixed Moderate Yes 5.6 Expired 16.7 stage IIA 2 Supplementary Table 2. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of an ampullary cancer microarray using the Database for Annotation, Visualization and Integrated Discovery (DAVID). This table contains only pathways with p values that ranged 0.0001~0.05. KEGG Pathway p value Genes Pentose and 1.50E-04 UGT1A6, CRYL1, UGT1A8, AKR1B1, UGT2B11, UGT2A3, glucuronate UGT2B10, UGT2B7, XYLB interconversions Drug metabolism 1.63E-04 CYP3A4, XDH, UGT1A6, CYP3A5, CES2, CYP3A7, UGT1A8, NAT2, UGT2B11, DPYD, UGT2A3, UGT2B10, UGT2B7 Maturity-onset 2.43E-04 HNF1A, HNF4A, SLC2A2, PKLR, NEUROD1, HNF4G, diabetes of the PDX1, NR5A2, NKX2-2 young Starch and sucrose 6.03E-04 GBA3, UGT1A6, G6PC, UGT1A8, ENPP3, MGAM, SI, metabolism
    [Show full text]
  • Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies
    Chinese Journal of Physiology 61(1): 1-13, 2018 1 DOI: 10.4077/CJP.2018.BAG516 Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies Tzu-Tung Chang, Chia-Jung Yang, Yu-Chi Lee, and Sheng-Nan Wu Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan, Republic of China Abstract Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel + increased the peak amplitude of voltage-gated Na (NaV) current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of INa in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented + + to predict changes in membrane potentials (V) as a function of maximal Na (GNa), K conductance (GK), or both. As inactivation time course of INa was increased, the bifurcation point of V versus GNa became lower, and the range between subcritical and supercritical values at the bifurcation of V versus GK correspondingly became larger.
    [Show full text]
  • REVIEW Peroxisome Proliferator-Activated Receptors In
    199 REVIEW Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition P Froment, F Gizard1, D Defever2, B Staels1, J Dupont3 and P Monget3 INSERM U.418, UMR Communications Cellulaire et Différenciation, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon, France 1INSERM U.545, Institut Pasteur de Lille et Faculté de Pharmacie Université de Lille 2, 1 rue du Pr Calmette, 59019 Lille, France 2LMCB, Department of Molecular Biomedical Research, V.I.B., Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium 3Physiologie de la reproduction et des comportements, UMR 6175 INRA-CNRS-Université F. Rabelais de Tours-Haras Nationaux, 37380 Nouzilly, France (Requests for offprints should be addressed to P Froment; [email protected]) Abstract Peroxisome proliferator-activated receptors (PPAR, granulosa cell proliferation and steroidogenesis in vitro. All PPAR/ and PPAR) are a family of nuclear receptors these recent data raise new questions about the biologic that are activated by binding of natural ligands, such as actions of PPARs in reproduction and their use in polyunsaturated fatty acids or by synthetic ligands. Syn- therapeutic treatments of fertility troubles such as PCOS thetic molecules of the glitazone family, which bind to or endometriosis. In this review, we first describe the roles PPAR, are currently used to treat type II diabetes and of PPARs in different compartments of the reproductive also to attenuate the secondary clinical symptoms fre- axis (from male and female gametogenesis to parturition), quently associated with insulin resistance, including poly- with a focus on PPAR. Secondly, we discuss the possible cystic ovary syndrome (PCOS). PPARs are expressed molecular mechanisms underlying the effect of glitazones in different compartments of the reproductive system on PCOS.
    [Show full text]
  • Bovine Coccidiosis - a Review
    PEER REVIEWED Bovine Coccidiosis - A Review DL Step, DVM, DACVIM; RN Streeter, DVM, MS, DACVIM; JG Kirkpatrick, DVM, DABVP Department of Veterinary Clinical Sciences, Boren Veterinary Teaching Hospital, Oklahoma State University, Stillwater, OK 74078 Abstract mune en hiver meme dans les cas de confinement. Les :feces peuvent contenir des oocystes meme lorsque les Coccidians are protozoa! parasites that are host animaux ne montrent pas de signes cliniques de sorte specific, transmitted by the fecal-oral route and cause qu'un diagnostic de coccidiose doit se baser sur les signes enteritis. Economically significant species discussed in cliniques et exclure les autres maladies. L'identification this paper that cause disease in cattle belong to the ge­ post-mortem de coccidies aide a supporter le diagnostic. nus Eimeria. Young animals are more susceptible to Les elements de regie qui reduisent le stress et clinical disease than older cattle. Coccidiosis is fre­ previennent la contamination de l'eau et de la nourriture quently observed in stressed, overcrowded and confined sont importants pour prevenir la coccidiose. Les conditions, however, .the disease can occur on pasture. programmes de controle efficaces incluent souvent The disease can occur any time of the year but is more !'utilisation de nourriture et d'eau medicamentes. Les prevalent during winter months, even in confinement agents antimicrobiens couramment utilises aux Etats­ operations. Animals may pass oocysts in their feces with­ Unis pour le controle et la prevention de coccidiose out clinical disease, therefore, a diagnosis of coccidiosis incluent entre autres le monensin, le lasalocide, le is based on clinical signs and ruling out other diseases.
    [Show full text]
  • Identification of Compounds That Rescue Otic and Myelination
    RESEARCH ARTICLE Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant Elvira Diamantopoulou1†, Sarah Baxendale1†, Antonio de la Vega de Leo´ n2, Anzar Asad1, Celia J Holdsworth1, Leila Abbas1, Valerie J Gillet2, Giselle R Wiggin3, Tanya T Whitfield1* 1Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom; 2Information School, University of Sheffield, Sheffield, United Kingdom; 3Sosei Heptares, Cambridge, United Kingdom Abstract Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design. DOI: https://doi.org/10.7554/eLife.44889.001 *For correspondence: [email protected] †These authors contributed Introduction equally to this work Adgrg6 (Gpr126) is an adhesion (B2) class G protein-coupled receptor (aGPCR) with conserved roles in myelination of the vertebrate peripheral nervous system (PNS) (reviewed in Langenhan et al., Competing interest: See 2016; Patra et al., 2014).
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Pdf; Chi 2015 DPP Air in Cars.Pdf; Dodson 2014 DPP Dust CA.Pdf; Kasper-Sonnenberg 2014 Phth Metabolites.Pdf; EU Cosmetics Regs 2009.Pdf
    Bouge, Cathy (ECY) From: Nancy Uding <[email protected]> Sent: Friday, January 13, 2017 10:24 AM To: Steward, Kara (ECY) Cc: Erika Schreder Subject: Comments re. 2016 CSPA Rule Update - DPP Attachments: DPP 131-18-0 exposure.pdf; Chi 2015 DPP air in cars.pdf; Dodson 2014 DPP dust CA.pdf; Kasper-Sonnenberg 2014 phth metabolites.pdf; EU Cosmetics Regs 2009.pdf Please accept these comments from Toxic-Free Future concerning the exposure potential of DPP for consideration during the 2016 CSPA Rule update. Regards, Nancy Uding -- Nancy Uding Grants & Research Specialist Toxic-Free Future 206-632-1545 ext.123 http://toxicfreefuture.org 1 JES-00888; No of Pages 9 JOURNAL OF ENVIRONMENTAL SCIENCES XX (2016) XXX– XXX Available online at www.sciencedirect.com ScienceDirect www.elsevier.com/locate/jes Determination of 15 phthalate esters in air by gas-phase and particle-phase simultaneous sampling Chenchen Chi1, Meng Xia1, Chen Zhou1, Xueqing Wang1,2, Mili Weng1,3, Xueyou Shen1,4,⁎ 1. College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, China 2. Zhejiang National Radiation Environmental Technology Co., Ltd., Hangzhou 310011, China 3. School of Environmental and Resource Sciences, Zhejiang Agriculture and Forestry University, Hangzhou 310058, China 4. Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058, China ARTICLE INFO ABSTRACT Article history: Based on previous research, the sampling and analysis methods for phthalate esters (PAEs) Received 24 December 2015 were improved by increasing the sampling flow of indoor air from 1 to 4 L/min, shortening the Revised 14 January 2016 sampling duration from 8 to 2 hr.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]