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{{Short description|Chemical compound}} |
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{{Use dmy dates|date=August 2021}} |
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{{distinguish|glipizide|glyburide}} |
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{{distinguish|glipizide|glyburide}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 442678331 |
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| verifiedrevid = 459476800 |
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| IUPAC_name = ''N''-(hexahydrocyclopentapyrrol-2(1''H'')-ylcarbamoyl)-4-methylbenzenesulfonamide |
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| image = Gliclazide.svg |
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| image = Gliclazide.svg |
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| image_class = skin-invert-image |
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| image2 = Gliclazide-xtal-1999-ball-and-stick.png |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = Diamicron, Diaprel, Azukon, others<ref>{{cite web|title=Gliclazide - Drugs.com|url=https://www.drugs.com/international/gliclazide.html|website=www.drugs.com|access-date=27 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161227200850/https://www.drugs.com/international/gliclazide.html|archive-date=27 December 2016}}</ref> |
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| tradename = |
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| Drugs.com = {{drugs.com|CONS|gliclazide}} |
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| Drugs.com = {{drugs.com|CONS|gliclazide}} |
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| pregnancy_AU = C |
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| pregnancy_category = |
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| routes_of_administration = ] |
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| legal_status = |
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| ATC_prefix = A10 |
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| routes_of_administration = |
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| ATC_suffix = BB09 |
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<!-- Legal status --> |
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| legal_AU = S4 |
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| legal_AU_comment =<ref>{{cite web | title=Gliclazide GH MR, Gliclazide LAPL MR, Gliclazide Lupin MR (Lupin Australia Pty Limited) | website=Therapeutic Goods Administration (TGA) | date=5 December 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/gliclazide-gh-mrgliclazide-lapl-mr-gliclazide-lupin-mr-lupin-australia-pty-limited | access-date=7 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318044702/https://www.tga.gov.au/resources/prescription-medicines-registrations/gliclazide-gh-mrgliclazide-lapl-mr-gliclazide-lupin-mr-lupin-australia-pty-limited | url-status=live }}</ref> |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = Rx-only |
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| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=] | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=3 April 2024 | archive-date=29 March 2024 | archive-url=https://web.archive.org/web/20240329200203/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | url-status=live }}</ref> |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = <ref name=UK2016 /><ref>{{cite web | title=Diamicron 30 mg MR Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=11 May 2020 | url=https://www.medicines.org.uk/emc/product/1321/smpc | access-date=29 December 2021 | archive-date=23 December 2023 | archive-url=https://web.archive.org/web/20231223041250/https://www.medicines.org.uk/emc/product/1321/smpc | url-status=live }}</ref><ref>{{cite web | title=Dacadis MR 30mg Modified Release Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=15 July 2020 | url=https://www.medicines.org.uk/emc/product/11631/smpc | access-date=29 December 2021 | archive-date=8 November 2023 | archive-url=https://web.archive.org/web/20231108080545/https://www.medicines.org.uk/emc/product/11631/smpc | url-status=live }}</ref> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_US_comment = |
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| legal_EU = |
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| legal_EU_comment = |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 21187-98-4 |
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| CAS_number = 21187-98-4 |
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| ATC_prefix = A10 |
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| ATC_suffix = BB09 |
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| PubChem = 3475 |
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| PubChem = 3475 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D01599 |
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| KEGG = D01599 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 31654 |
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| ChEBI = 31654 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| IUPAC_name = ''N''-(hexahydrocyclopentapyrrol-2(1''H'')-ylcarbamoyl)-4-methylbenzenesulfonamide |
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| C=15 | H=21 | N=3 | O=3 | S=1 |
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| C=15 | H=21 | N=3 | O=3 | S=1 |
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| SMILES = O=S(=O)(c1ccc(cc1)C)NC(=O)NN3CC2CCCC2C3 |
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| molecular_weight = 323.412 ]/] |
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| smiles = O=S(=O)(c1ccc(cc1)C)NC(=O)NN3CC2CCCC2C3 |
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| InChI = 1/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) |
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| InChIKey = BOVGTQGAOIONJV-UHFFFAOYAB |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) |
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| StdInChI = 1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = BOVGTQGAOIONJV-UHFFFAOYSA-N |
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| StdInChIKey = BOVGTQGAOIONJV-UHFFFAOYSA-N |
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| melting_point = 180 |
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| melting_high = 182 |
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}} |
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}} |
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'''Gliclazide''' is an oral hypoglycemic (]) and is classified as a ]. It is marketed as '''Glizid''', '''Glyloc''' and '''Reclide''' in India and '''Diamicron''' in Canada. In the Philippines, ] markets it as '''Diamicron MR''', like in most countries across the world. Many generic equivalents are also available e.g. '''Glubitor-OD''', '''Clizid'''. It is not marketed in the United States. A modified-release formulation is also marketed. Its classification has been ambiguous, as literature uses it as both a first-generation <ref name="pmid2106423">{{cite journal |pages=109–14 |doi=10.1016/0168-8227(90)90020-T |title=Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds |year=1990 |last1=Ballagi-Pordány |first1=György |last2=Köszeghy |first2=Anna |last3=Koltai |first3=Mária-Zsófia |last4=Aranyi |first4=Zoltán |last5=Pogátsa |first5=Gábor |journal=Diabetes Research and Clinical Practice |volume=8 |issue=2 |pmid=2106423}}</ref> and second-generation<ref>{{cite journal |pages=722–30 |doi=10.1016/j.metabol.2006.01.019 |title=Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation |year=2006 |last1=Shimoyama |first1=Tatsuhiro |last2=Yamaguchi |first2=Shinya |last3=Takahashi |first3=Kazuto |last4=Katsuta |first4=Hidenori |last5=Ito |first5=Eisuke |last6=Seki |first6=Hiroyuki |last7=Ushikawa |first7=Kenji |last8=Katahira |first8=Hiroshi |last9=Yoshimoto |first9=Katsuhiko |journal=Metabolism |volume=55 |issue=6 |pmid=16713429}}</ref> sulfonylurea. Gliclazide was proven to protect human pancreatic beta-cells from hyperglycemia-induced apoptosis.<ref>{{cite journal |pages=234–8 |doi=10.1002/dmrr.680 |title=Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose |year=2007 |last1=Del Guerra |first1=S |last2=Grupillo |first2=M |last3=Masini |first3=M |last4=Lupi |first4=R |last5=Bugliani |first5=M |last6=Torri |first6=S |last7=Boggi |first7=U |last8=Del Chiaro |first8=M |last9=Vistoli |first9=F |journal=Diabetes/Metabolism Research and Reviews |volume=23 |issue=3 |pmid=16952202}}</ref> It was also proven to have a potent antiatherogenic effect in type 2 diabetes.<ref>{{cite journal |pages=1906–13 |doi=10.1007/s00125-004-1547-8 |title=Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes |year=2004 |last1=Katakami |first1=N. |last2=Yamasaki |first2=Y. |last3=Hayaishi-Okano |first3=R. |last4=Ohtoshi |first4=K. |last5=Kaneto |first5=H. |last6=Matsuhisa |first6=M. |last7=Kosugi |first7=K. |last8=Hori |first8=M. |journal=Diabetologia |volume=47 |issue=11 |pmid=15565373}}</ref> |
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<!-- Definition and medical uses --> |
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== Form and composition == |
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'''Gliclazide''', sold under the brand name '''Diamicron''' among others, is a sulfonylurea type of ], used to treat ].<ref name=BNF69/> It is used when dietary changes, exercise, and weight loss are not enough.<ref name=UK2016>{{cite web | title=Gliclazide Accord-UK 30mg Prolonged-release Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=12 February 2021 | url=https://www.medicines.org.uk/emc/medicine/31089 | access-date=30 December 2021 | archive-date=22 September 2022 | archive-url=https://web.archive.org/web/20220922022052/https://www.medicines.org.uk/emc/medicine/31089 | url-status=dead }}</ref> It is taken by mouth.<ref name=BNF69>{{cite book|title=British National Formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=474|edition=69}}</ref> |
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Each immediate-release tablet contains 80 mg. Modified release formulations contain 30 mg and 60 mg of gliclazide. In the Philippines, all three formulations are available.{{Citation needed|date=September 2011}} |
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<!-- Side effects and mechanism --> |
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== Indication == |
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Side effect may include ], ], ], ], and ].<ref name=UK2016/><ref name=BNF69/> Use by those with significant ] or liver problems or who are ] is not recommended.<ref name=BNF69/><ref name=UK2016/> Gliclazide is in the ] family of medications.<ref name=BNF69/> It works mostly by increasing the release of ].<ref name=BNF69/> |
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Gliclazide is used for control of hyperglycemia in gliclazide-responsive ] of stable, mild, non-] prone, type 2 diabetes. It is used when diabetes cannot be controlled by proper dietary management and exercise or when insulin therapy is not appropriate.{{Citation needed|date=September 2011}} |
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<!-- History and culture --> |
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== Mode of action == |
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Gliclazide was patented in 1966 and approved for medical use in 1972.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title= Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=449|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA449|language=en|url-status=live|archive-url=https://web.archive.org/web/20161227201818/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA449|archive-date=27 December 2016}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is not available for sale in the United States.<ref>{{cite web|title=Gliclazide Advanced Patient Information - Drugs.com|url=https://www.drugs.com/cons/gliclazide.html|website=www.drugs.com|access-date=27 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161227202213/https://www.drugs.com/cons/gliclazide.html|archive-date=27 December 2016}}</ref> |
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Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic beta-cells. It was shown to provide cardiovascular protection as it does not bind to sulfonylurea receptors (SUR-2A) in the heart.<ref>{{cite journal |pages=1019–25 |doi=10.1007/s001250100595 |title=Gliclazide produces high-affinity block of K ATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells |year=2001 |last1=Lawrence |first1=C. L. |last2=Proks |first2=P. |last3=Rodrigo |first3=G. C. |last4=Jones |first4=P. |last5=Hayabuchi |first5=Y. |last6=Standen |first6=N. B. |last7=Ashcroft |first7=F. M. |journal=Diabetologia |volume=44 |issue=8 |pmid=11484080}}</ref> This binding effectively closes the K+ ion channels. This decreases the efflux of potassium from the cell which leads to the depolarization of the cell. This causes voltage dependent Ca++ ion channels to open increasing the Ca++ influx. The calcium can then bind to and activate calmodulin which in turn leads to exocystosis of insulin vesicles leading to insulin release.{{Citation needed|date=September 2011}} |
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== Dosage == |
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== Medical uses == |
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Gliclazide is used for control of hyperglycemia in gliclazide-responsive ] of stable, mild, non-] prone, type 2 diabetes. It is used when diabetes cannot be controlled by proper dietary management and exercise and when metformin has already been tried.<ref>{{Cite web |title=My Site - Special Article: Remission of Type 2 Diabetes |url=https://guidelines.diabetes.ca/cpg/special-article-remission-of-type-2-diabetes |access-date=2023-06-01 |website=guidelines.diabetes.ca |archive-date=2 June 2023 |archive-url=https://web.archive.org/web/20230602185226/https://guidelines.diabetes.ca/cpg/special-article-remission-of-type-2-diabetes |url-status=live }}</ref> |
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The dosage for the 80 mg formulation is 40 to 320 mg daily in two divided doses, while the 30 mg and 60 mg modified release formulation may be given at a dose of 30 to 120 mg once daily at breakfast.{{Citation needed|date=September 2011}} |
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National Kidney Foundation (2012 Update) claims that Gliclazide does not require ] even in end stage kidney disease. |
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== Properties == |
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*Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin sensitivity.{{Citation needed|date=September 2011}} |
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*Glycemia-independent hemovascular effects, antioxidant effect.{{Citation needed|date=September 2011}} |
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*No active circulating metabolites.{{Citation needed|date=September 2011}} |
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== Contraindications == |
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== Contraindications == |
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*Type 1 diabetes<ref name="Drugs">{{cite web |title=GLICLAZIDE 60 MG MR TABLETS DRUG LEAFLET |url=https://www.drugs.com/uk/gliclazide-60-mg-mr-tablets-leaflet.html |website=Drugs.com |access-date=23 March 2020 |language=en |archive-date=21 April 2019 |archive-url=https://web.archive.org/web/20190421171118/https://www.drugs.com/uk/gliclazide-60-mg-mr-tablets-leaflet.html |url-status=live }}</ref> |
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*Type 1 diabetes{{Citation needed|date=September 2011}} |
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*Hypersensitivity to ]{{Citation needed|date=September 2011}} |
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*Hypersensitivity to ]<ref name="Drugs"/> |
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*Severe renal or hepatic failure{{Citation needed|date=September 2011}} |
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*Severe renal or hepatic failure<ref name="Drugs"/> (But relatively useful in mild renal impairment e.g. CKD stage 3) |
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*Pregnancy and lactation{{Citation needed|date=September 2011}} |
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*Pregnancy and lactation<ref name="Drugs"/> |
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*] coprescription{{Citation needed|date=September 2011}} |
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== Metabolism == |
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== Adverse effects == |
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Gliclazide undergoes extensive metabolism to several inactive metabolites in humans, mainly methylhydroxygliclazide and carboxygliclazide. CYP2C9 is involved in the formation of hydroxygliclazde in human liver microsomes and in a panel of recombinant human P450sin vitro.<ref>{{cite journal |pmid=8719909 |year=1995 |last1=Rieutord |first1=A |last2=Stupans |first2=I |last3=Shenfield |first3=GM |last4=Gross |first4=AS |title=Gliclazide hydroxylation by rat liver microsomes |volume=25 |issue=12 |pages=1345–54 |journal=Xenobiotica |doi=10.3109/00498259509061922}}</ref><ref>{{cite journal |pages=450–7 |doi=10.1111/j.1365-2125.2007.02943.x |pmc=2048545 |title=Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination |year=2007 |last1=Elliot |first1=David J. |last2=Lewis |first2=Benjamin C. |last3=Gillam |first3=Elizabeth M. J. |last4=Birkett |first4=Donald J. |last5=Gross |first5=Annette S. |last6=Miners |first6=John O. |journal=British Journal of Clinical Pharmacology |volume=64 |issue=4 |pmid=17517049 |last7=Miners |first7=JO}}</ref> But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.<ref>{{cite journal |doi=10.1111/j.1365-2125.2007.02846.x |title=Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects |year=2007 |last1=Zhang |first1=Yifan |last2=Si |first2=Dayong |last3=Chen |first3=Xiaoyan |last4=Lin |first4=Nan |last5=Guo |first5=Yingjie |last6=Zhou |first6=Hui |last7=Zhong |first7=Dafang |journal=British Journal of Clinical Pharmacology |volume=64 |pages=67–74 |pmid=17298483 |issue=1 |pmc=2000619}}</ref><ref>{{cite journal |pages=1579–86 |doi=10.1038/sj.bjp.0707685 |title=Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide |year=2009 |last1=Xu |first1=H |last2=Williams |first2=K M |last3=Liauw |first3=W S |last4=Murray |first4=M |last5=Day |first5=R O |last6=McLachlan |first6=A J |journal=British Journal of Pharmacology |volume=153 |issue=7 |pmid=18204476 |pmc=2437900}}</ref> |
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Common adverse effects over 10%:<ref name="Lexicomp">{{Cite web | publisher = Wolters Kluwer N.V. | title = Gliclazide | url = https://www.wolterskluwer.com/en/solutions/lexicomp | work = Lexicomp | access-date = 1 June 2023 | archive-date = 2 June 2023 | archive-url = https://web.archive.org/web/20230602191128/https://www.wolterskluwer.com/en/solutions/lexicomp | url-status = live }}</ref> |
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* ] (11 - 12%) - while it was shown to have the same efficacy as glimepiride, one of the newer sulfonylureas, the European GUIDE study has shown that it has approximately 50% less hypoglycemic confirmed episodes in comparison with glimepiride.<ref>{{cite journal | vauthors = Schernthaner G, Grimaldi A, Di Mario U, Drzewoski J, Kempler P, Kvapil M, Novials A, Rottiers R, Rutten GE, Shaw KM | display-authors = 6 | title = GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients | journal = European Journal of Clinical Investigation | volume = 34 | issue = 8 | pages = 535–542 | date = August 2004 | pmid = 15305887 | doi = 10.1111/j.1365-2362.2004.01381.x | hdl-access = free | s2cid = 13636359 | hdl = 1874/10657 }}</ref> |
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Uncommon adverse effect between 1 - 10%:<ref name="Lexicomp" /> |
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* ] (3 - 4% incidence) |
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* Dizziness (2% incidence) |
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* ] (2% incidence) |
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* Viral infection (6 - 8% incidence) |
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* Back pain (4 - 5% incidence) |
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Rare adverse effects (under 1%):<ref name="Lexicomp" /> |
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* ] |
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* weight gain |
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* Vomiting |
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== Interactions == |
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== Interactions == |
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Hyperglycemic action may be caused by ], ], ], ], or β-2 agonists. Its hypoglycemic action may be potentiated by ], alcohol, ], β-blockers, and possibly ]. It has been found that rifampin increases gliclazide metabolism in humans in vivo.<ref>{{cite journal |doi=10.1016/S0009-9236(03)00221-2 |title=Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide |year=2003 |last1=Park |first1=J |journal=Clinical Pharmacology & Therapeutics |volume=74 |issue=4 |pmid=14534520 |pages=334–40 |last2=Kim |first2=KA |last3=Park |first3=PW |last4=Park |first4=CW |last5=Shin |first5=JG}}</ref> |
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Hyperglycemic action may be caused by ], ], ], ], or β-2 agonists. Its hypoglycemic action may be potentiated by ], alcohol, ], β-blockers, and possibly ]. It has been found that rifampin increases gliclazide metabolism in humans in vivo.<ref>{{cite journal | vauthors = Park JY, Kim KA, Park PW, Park CW, Shin JG | title = Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide | journal = Clinical Pharmacology and Therapeutics | volume = 74 | issue = 4 | pages = 334–340 | date = October 2003 | pmid = 14534520 | doi = 10.1016/S0009-9236(03)00221-2 | s2cid = 21519151 | doi-access = free }}</ref> |
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== Adverse effects == |
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== Overdose == |
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Gliclazide overdose may cause severe hypoglycemia, requiring urgent administration of glucose by IV and Monitoring.<ref name=":1">{{cite journal | vauthors = Mégarbane B, Chevillard L, Khoudour N, Declèves X | title = Gliclazide disposition in overdose - a case report with pharmacokinetic modeling | journal = Clinical Toxicology | volume = 60 | issue = 4 | pages = 541–542 | date = April 2022 | pmid = 34698608 | doi = 10.1080/15563650.2021.1993245 | s2cid = 239887850 }}</ref> |
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*] - while it was proven to have the same efficacy as glimepiride, one of the newer sulfonylureas, the European GUIDE study has shown that it has approximately 50% fewer confirmed hypoglycaemic episodes in comparison with glimepiride.<ref>{{cite journal |doi=10.1111/j.1365-2362.2004.01381.x |title=GUIDE study: Double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients |year=2004 |last1=Schernthaner |first1=G. |last2=Grimaldi |first2=A. |last3=Di Mario |first3=U. |last4=Drzewoski |first4=J. |last5=Kempler |first5=P. |last6=Kvapil |first6=M. |last7=Novials |first7=A. |last8=Rottiers |first8=R. |last9=Rutten |first9=G. E. H. M. |journal=European Journal of Clinical Investigation |volume=34 |issue=8 |pages=535–42 |pmid=15305887}}</ref> |
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*Gastrointestinal disturbance (reported){{Citation needed|date=September 2011}} |
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*Skin reactions (rare){{Citation needed|date=September 2011}} |
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*Hematological disorders (rare){{Citation needed|date=September 2011}} |
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*Hepatic enzyme rises (exceptional){{Citation needed|date=September 2011}} |
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== Overdosage == |
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== Mechanism of action == |
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Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic beta-cells. It was shown to provide cardiovascular protection as it does not bind to sulfonylurea receptors (SUR-2A) in the heart.<ref>{{cite journal | vauthors = Lawrence CL, Proks P, Rodrigo GC, Jones P, Hayabuchi Y, Standen NB, Ashcroft FM | title = Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells | journal = Diabetologia | volume = 44 | issue = 8 | pages = 1019–1025 | date = August 2001 | pmid = 11484080 | doi = 10.1007/s001250100595 | doi-access = free }}</ref> This binding effectively closes these K<sup>+</sup> ion channels. This decreases the efflux of potassium from the cell which leads to the depolarization of the cell. This causes voltage dependent Ca<sup>2+</sup> ion channels to open increasing the Ca<sup>2+</sup> influx. The calcium can then bind to and activate calmodulin which in turn leads to exocytosis of insulin vesicles leading to insulin release.<ref name=":12">{{cite journal | vauthors = Mégarbane B, Chevillard L, Khoudour N, Declèves X | title = Gliclazide disposition in overdose - a case report with pharmacokinetic modeling | journal = Clinical Toxicology | volume = 60 | issue = 4 | pages = 541–542 | date = April 2022 | pmid = 34698608 | doi = 10.1080/15563650.2021.1993245 | s2cid = 239887850 }}</ref> |
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Gliclazide overdose may cause severe hypoglycemia, requiring urgent administration of glucose by IV and monitoring.{{Citation needed|date=September 2011}} |
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The mouse model of ] (MODY) diabetes suggested that the reduced gliclazide clearance stands behind their therapeutic success in human MODY patients, but Urbanova et al. found that human MODY patients respond differently and that there was no consistent decrease in gliclazide clearance in randomly selected HNF1A-MODY and HNF4A-MODY patients.<ref name="Urbanova et al. 2015">{{cite journal | vauthors = Urbanova J, Andel M, Potockova J, Klima J, Macek J, Ptacek P, Mat'oska V, Kumstyrova T, Heneberg P | display-authors = 6 | title = Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model | journal = Current Pharmaceutical Design | volume = 21 | issue = 39 | pages = 5736–5748 | year = 2015 | pmid = 26446475 | doi = 10.2174/1381612821666151008124036 }}</ref> |
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==References== |
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{{reflist}} |
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Its classification has been ambiguous, as literature uses it as both a first-generation<ref name="pmid2106423">{{cite journal | vauthors = Ballagi-Pordány G, Köszeghy A, Koltai MZ, Aranyi Z, Pogátsa G | title = Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds | journal = Diabetes Research and Clinical Practice | volume = 8 | issue = 2 | pages = 109–114 | date = January 1990 | pmid = 2106423 | doi = 10.1016/0168-8227(90)90020-T }}</ref> and second-generation<ref>{{cite journal | vauthors = Shimoyama T, Yamaguchi S, Takahashi K, Katsuta H, Ito E, Seki H, Ushikawa K, Katahira H, Yoshimoto K, Ohno H, Nagamatsu S, Ishida H | display-authors = 6 | title = Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation | journal = Metabolism | volume = 55 | issue = 6 | pages = 722–730 | date = June 2006 | pmid = 16713429 | doi = 10.1016/j.metabol.2006.01.019 }}</ref> sulfonylurea. |
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==External links== |
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* clinical trial on diabetes |
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== Properties == |
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{{Oral hypoglycemics}} |
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According to the Biopharmaceutical Classification System (BCS), gliclazide falls under the BCS Class II drug, which is poorly soluble and highly permeable. |
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Water solubility = 0.027mg/L{{cn|date=June 2023}} |
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*Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin Sensitivity.<ref name=":13">{{cite journal | vauthors = Mégarbane B, Chevillard L, Khoudour N, Declèves X | title = Gliclazide disposition in overdose - a case report with pharmacokinetic modeling | journal = Clinical Toxicology | volume = 60 | issue = 4 | pages = 541–542 | date = April 2022 | pmid = 34698608 | doi = 10.1080/15563650.2021.1993245 | s2cid = 239887850 }}</ref> |
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*No active circulating Metabolites.<ref name="Lexicomp" /> |
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== Metabolism == |
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Gliclazide undergoes extensive metabolism to several inactive metabolites in human beings, mainly methylhydroxygliclazide and carboxygliclazide. CYP2C9 is involved in the formation of hydroxygliclazide in human liver microsomes and in a panel of recombinant human P450s in vitro.<ref>{{cite journal | vauthors = Rieutord A, Stupans I, Shenfield GM, Gross AS | title = Gliclazide hydroxylation by rat liver microsomes | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 25 | issue = 12 | pages = 1345–1354 | date = December 1995 | pmid = 8719909 | doi = 10.3109/00498259509061922 }}</ref><ref>{{cite journal | vauthors = Elliot DJ, Lewis BC, Gillam EM, Birkett DJ, Gross AS, Miners JO | title = Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination | journal = British Journal of Clinical Pharmacology | volume = 64 | issue = 4 | pages = 450–457 | date = October 2007 | pmid = 17517049 | pmc = 2048545 | doi = 10.1111/j.1365-2125.2007.02943.x }}</ref> But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.<ref>{{cite journal | vauthors = Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D | title = Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects | journal = British Journal of Clinical Pharmacology | volume = 64 | issue = 1 | pages = 67–74 | date = July 2007 | pmid = 17298483 | pmc = 2000619 | doi = 10.1111/j.1365-2125.2007.02846.x }}</ref><ref>{{cite journal | vauthors = Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ | title = Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide | journal = British Journal of Pharmacology | volume = 153 | issue = 7 | pages = 1579–1586 | date = April 2008 | pmid = 18204476 | pmc = 2437900 | doi = 10.1038/sj.bjp.0707685 }}</ref> |
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== References == |
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{{reflist}} |
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{{Oral hypoglycemics}} |
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{{Ion channel modulators}} |
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