{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:16:56Z","timestamp":1778696216129,"version":"3.51.4"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-38843-7","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T15:53:27Z","timestamp":1778687607000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic antidiabetic efficacy of dorzolamide and metformin: HPTLC quantification and biological evaluation"],"prefix":"10.1038","volume":"16","author":[{"given":"Noha G.","family":"Abdel-Hafez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanan H.","family":"Abd-Elhafeez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed M.","family":"Abd-Eldayem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noha N.","family":"Atia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samia M.","family":"El-Gizawy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa F. B.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"38843_CR1","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.2337\/diabetes.49.12.2063","volume":"49","author":"RS Hundal","year":"2000","unstructured":"Hundal, R. S. et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49, 2063\u20132069 (2000).","journal-title":"Diabetes"},{"key":"38843_CR2","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1056\/NEJM199508313330903","volume":"333","author":"M Stumvoll","year":"1995","unstructured":"Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. & Gerich, J. E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333, 550\u2013554 (1995).","journal-title":"N. Engl. J. Med."},{"key":"38843_CR3","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","volume":"15","author":"M Foretz","year":"2019","unstructured":"Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 15, 569\u2013589 (2019).","journal-title":"Nat. Rev. Endocrinol."},{"key":"38843_CR4","doi-asserted-by":"publisher","first-page":"965","DOI":"10.3346\/jkms.2014.29.7.965","volume":"29","author":"SH Ko","year":"2014","unstructured":"Ko, S. H. et al. Association of vitamin B12 deficiency and Metformin use in patients with type 2 diabetes. J. Korean Med. Sci. 29, 965\u2013972 (2014).","journal-title":"J. Korean Med. Sci."},{"key":"38843_CR5","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s11739-014-1157-5","volume":"10","author":"M Niafar","year":"2015","unstructured":"Niafar, M., Hai, F., Porhomayon, J. & Nader, N. D. The role of metformin on vitamin B12 deficiency: A meta-analysis review. Intern. Emerg. Med. 10, 93\u2013102 (2015).","journal-title":"Intern. Emerg. Med."},{"key":"38843_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100379","volume":"9","author":"Q Liu","year":"2014","unstructured":"Liu, Q., Li, S., Quan, H. & Li, J. Vitamin B12 status in metformin treated patients: Systematic review. PLoS One. 9, e100379 (2014).","journal-title":"PLoS One."},{"key":"38843_CR7","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1001\/archinte.166.18.1975","volume":"166","author":"RZW Ting","year":"2006","unstructured":"Ting, R. Z. W., Szeto, C. C., Chan, M. H. M., Ma, K. K. & Chow, K. M. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch. Intern. Med. 166, 1975\u20131979 (2006).","journal-title":"Arch. Intern. Med."},{"key":"38843_CR8","doi-asserted-by":"publisher","first-page":"916","DOI":"10.4239\/wjd.v12.i7.916","volume":"12","author":"M Infante","year":"2021","unstructured":"Infante, M., Leoni, M., Caprio, M. & Fabbri, A. Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind. World J. Diabetes 12, 916\u2013931 (2021).","journal-title":"World J. Diabetes"},{"key":"38843_CR9","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000017918","volume":"98","author":"J Kim","year":"2019","unstructured":"Kim, J., Ahn, C. W., Fang, S., Lee, H. S. & Park, J. S. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Med. (Baltim.). 98, e17918 (2019).","journal-title":"Med. (Baltim.)."},{"key":"38843_CR10","doi-asserted-by":"publisher","first-page":"S64","DOI":"10.2337\/dc17-S011","volume":"40","author":"8","year":"2017","unstructured":"8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 40, S64\u2013S74 (2017).","journal-title":"Diabetes Care"},{"key":"38843_CR11","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1136\/bjophthalmol-2021-319530","volume":"106","author":"A Stoner","year":"2022","unstructured":"Stoner, A. et al. Topical carbonic anhydrase inhibitors and glaucoma in 2021: where do we stand? Br. J. Ophthalmol. 106, 1332\u20131337 (2022).","journal-title":"Br. J. Ophthalmol."},{"key":"38843_CR12","unstructured":"PubChem Compound Summary for CID 5284549. Dorzolamide | C10H16N2O4S3 | CID 5284549 - PubChem. National Center for Biotechnology Information (2024). https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Dorzolamide"},{"key":"38843_CR13","first-page":"337","volume":"7","author":"IS Ismail","year":"2017","unstructured":"Ismail, I. S. Metformin-carbonic anhydrase interaction facilitate lactate accumulation in type 2 diabetes. Diabetes Manag. 7, 337\u2013342 (2017).","journal-title":"Diabetes Manag."},{"key":"38843_CR14","doi-asserted-by":"publisher","first-page":"138","DOI":"10.3109\/14756366.2011.597749","volume":"27","author":"F Fabrizi","year":"2012","unstructured":"Fabrizi, F. et al. A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary Pharmacology. J. Enzyme Inhib. Med. Chem. 27, 138\u2013147 (2012).","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"38843_CR15","doi-asserted-by":"publisher","first-page":"197","DOI":"10.2165\/00003088-200241030-00004","volume":"41","author":"J Martens-Lobenhoffer","year":"2002","unstructured":"Martens-Lobenhoffer, J. & Banditt, P. Clinical pharmacokinetics of dorzolamide. Clin. Pharmacokinet. 41, 197\u2013205 (2002).","journal-title":"Clin. Pharmacokinet."},{"key":"38843_CR16","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1186\/s13071-015-1098-5","volume":"8","author":"R Zolfaghari Emameh","year":"2015","unstructured":"Zolfaghari Emameh, R. et al. Ascaris lumbricoides \u03b2 carbonic anhydrase: a potential target enzyme for treatment of ascariasis. Parasit. Vectors. 8, 479 (2015).","journal-title":"Parasit. Vectors"},{"key":"38843_CR17","doi-asserted-by":"publisher","first-page":"108","DOI":"10.2174\/1573399812666161214122351","volume":"14","author":"IS Ismail","year":"2018","unstructured":"Ismail, I. S. The role of carbonic anhydrase in hepatic glucose production. Curr. Diabetes Rev. 14, 108\u2013112 (2018).","journal-title":"Curr. Diabetes Rev."},{"key":"38843_CR18","first-page":"1","volume":"05","author":"S Ismail","year":"2016","unstructured":"Ismail, S., Amodu, D., Carbonic Anhydrase, A. & I. &, A new therapeutic target for managing diabetes. J. Metab. Syndr. 05, 1\u20137 (2016).","journal-title":"J. Metab. Syndr."},{"issue":"8","key":"38843_CR19","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.2337\/db11-0578","volume":"61","author":"N Konstantopoulos","year":"2012","unstructured":"Konstantopoulos, N. et al. Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo. Diabetes 61(8), 2146\u20132154 (2012).","journal-title":"Diabetes"},{"key":"38843_CR20","doi-asserted-by":"publisher","first-page":"849","DOI":"10.2174\/156802607780636735","volume":"7","author":"F Mincione","year":"2007","unstructured":"Mincione, F., Scozzafava, A. & Supuran, C. T. The development of topically acting carbonic anhydrase inhibitors as anti-glaucoma agents. Curr. Top. Med. Chem. 7, 849\u2013854 (2007).","journal-title":"Curr. Top. Med. Chem."},{"key":"38843_CR21","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.52711\/0974-360X.2024.00314","volume":"17","author":"A Krishnamanjari Pawar","year":"2024","unstructured":"Krishnamanjari Pawar, A. & Mannepalli, C. Development and validation of stability indicting HPLC method for the separation and simultaneous analysis of Timolol, dorzolamide and Latanoprost inophthalmic formulations. Res. J. Pharm. Technol. 17, 1983\u20131990 (2024).","journal-title":"Res. J. Pharm. Technol."},{"key":"38843_CR22","first-page":"745","volume":"50","author":"N Sharma","year":"2012","unstructured":"Sharma, N., Rao, S. S. & Reddy, A. M. A novel and rapid validated stability-indicating UPLC method of related substances for dorzolamide hydrochloride and timolol maleate in ophthalmic dosage form. J. Chromatogr. Sci. 50, 745\u2013755 (2012).","journal-title":"J. Chromatogr. Sci."},{"key":"38843_CR23","doi-asserted-by":"crossref","unstructured":"Thangabalan, B., Kahsay, G. & Eticha, T. New RP-HPLC Method Development and Validation for Dorzolamide in Ophthalmic Dosage Form. J. Anal. Methods Chem. 4596141 (2018). (2018).","DOI":"10.1155\/2018\/4596141"},{"key":"38843_CR24","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1016\/j.talanta.2009.06.004","volume":"79","author":"F Al-Rimawi","year":"2009","unstructured":"Al-Rimawi, F. Development and validation of an analytical method for Metformin hydrochloride and its related compound (1-cyanoguanidine) in tablet formulations by HPLC-UV. Talanta 79, 1368\u20131371 (2009).","journal-title":"Talanta"},{"key":"38843_CR25","first-page":"728","volume":"57","author":"MC Ranetti","year":"2009","unstructured":"Ranetti, M. C. et al. Validation of a HPLC method for the simultaneous analysis of Metformin and Gliclazide in human plasma. Farmacia 57, 728\u2013735 (2009).","journal-title":"Farmacia"},{"issue":"3","key":"38843_CR26","doi-asserted-by":"publisher","first-page":"201","DOI":"10.5958\/2349-2988.2019.00030.5","volume":"11","author":"GS Shinde","year":"2019","unstructured":"Shinde, G. S., Rahul, K. G. & Jadhav, R. Quantitative estimation and validation of Metformin hydrochloride and Gliclazide in their tablet dosage form by RP-HPLC. Res. J. Sci. Technol. 11201. (2019).","journal-title":"Res. J. Sci. Technol."},{"key":"38843_CR27","first-page":"169","volume":"3","author":"AA Sakalgaonkar","year":"2008","unstructured":"Sakalgaonkar, A. A., Mirgane, S. R. & Arbad, B. R. Validated high performance liquid chromatographic stability indicating method for analysis of Metformin HCl. Int. J. Appl. Environ. Sci. 3, 169\u2013177 (2008).","journal-title":"Int. J. Appl. Environ. Sci."},{"key":"38843_CR28","doi-asserted-by":"publisher","first-page":"107","DOI":"10.4314\/tjpr.v11i1.14","volume":"11","author":"P Umapathi","year":"2012","unstructured":"Umapathi, P., Ayyappan, J. & Darlin Quine, S. Quantitative determination of Metformin hydrochloride in tablet formulation containing croscarmellose sodium as disintegrant by HPLC and UV spectrophotometry. Trop. J. Pharm. Res. 11, 107\u2013116 (2012).","journal-title":"Trop. J. Pharm. Res."},{"key":"38843_CR29","first-page":"162","volume":"1","author":"K Lakshmi","year":"2009","unstructured":"Lakshmi, K., Tirumala, R. & Sharma, S. Simultaneous determination of Metformin and Pioglitazone by reversed phase HPLC in pharmaceutical dosage forms | Request PDF. Int. J. Pharm. Pharm. Sci. 1, 162\u2013166 (2009).","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"38843_CR30","doi-asserted-by":"crossref","unstructured":"Havele, S. S., Dhaneshwar, S. R. & Stability-Indicating HPTLC-Densitometric Method for Estimation of Dorzolamide Hydrochloride in Eye Drops. Int. Sch. Res. Not. 414075 (2012). (2012).","DOI":"10.5402\/2012\/414075"},{"key":"38843_CR31","first-page":"65","volume":"84","author":"RP Bhole","year":"2017","unstructured":"Bhole, R. P., Gandhi, J. S. & Wankhede, S. B. Development and validation of HPTLC method for simultaneous estimation of Canagliflozin and Metformin hydrochloride in bulk and tablet dosage form. S. A. Pharm. J. 84, 65\u201371 (2017).","journal-title":"S. A. Pharm. J."},{"key":"38843_CR32","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.ab.2013.03.019","volume":"438","author":"MB Gholivand","year":"2013","unstructured":"Gholivand, M. B. & Mohammadi-Behzad, L. Differential pulse voltammetric determination of Metformin using copper-loaded activated charcoal modified electrode. Anal. Biochem. 438, 53\u201360 (2013).","journal-title":"Anal. Biochem."},{"key":"38843_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17122027","author":"NA Alarfaj","year":"2016","unstructured":"Alarfaj, N. A. & El-Tohamy, M. F. New electrochemically-modified carbon paste inclusion \u03b2-cyclodextrin and carbon nanotubes sensors for quantification of dorzolamide hydrochloride. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms17122027 (2016).","journal-title":"Int. J. Mol. Sci."},{"key":"38843_CR34","doi-asserted-by":"publisher","first-page":"43","DOI":"10.22159\/ijpps.2017v9i9.18646","volume":"9","author":"HA Hendawy","year":"2017","unstructured":"Hendawy, H. A., Elwy, H. M. & Fekry, A. M. Electrochemical and chemometric determination of dorzolamide and timolol in eye drops using modified multiwall carbon nanotube electrode. Int. J. Pharm. Pharm. Sci. 9, 43\u201350 (2017).","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"38843_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s13065-023-01021-1","volume":"17","author":"MM Mora","year":"2023","unstructured":"Mora, M. M., Ismail, N. S., Zaazaa, H. E. & Boltia, S. A. Electrochemically-selective electrode for quantification of dorzolamide in bulk drug substance and dosage form. BMC Chem. 17, 103 (2023).","journal-title":"BMC Chem."},{"key":"38843_CR36","first-page":"17","volume":"5","author":"AA Almrasy","year":"2018","unstructured":"Almrasy, A. A. Validated spectrofluorimetric method for the determination of dorzolamide hydrochloride in its pure form and pharmaceutical formulations via derivatization with 4-chloro-7-nitrobenzo-2-oxa-1, 3-diazole (NBD-CL). Int. J. Sci. 5, 17\u201320 (2018).","journal-title":"Int. J. Sci."},{"key":"38843_CR37","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.jpba.2005.02.037","volume":"38","author":"SK Branch","year":"2005","unstructured":"Branch, S. K. Guidelines from the International Conference on Harmonisation (ICH). J. Pharm. Biomed. Anal. 38, 798\u2013805 (2005).","journal-title":"J. Pharm. Biomed. Anal."},{"key":"38843_CR38","doi-asserted-by":"publisher","first-page":"40","DOI":"10.14715\/cmb\/2022.68.7.7","volume":"68","author":"M Makhdoom","year":"2022","unstructured":"Makhdoom, M. et al. Antidiabetic and pancreas-protective potential of parthenium hysterophorous (Carrot grass) in Alloxan induced diabetic rabbits. Cell. Mol. Biol. (Noisy-le-grand). 68, 40\u201345 (2022).","journal-title":"Cell. Mol. Biol. (Noisy-le-grand)"},{"key":"38843_CR39","doi-asserted-by":"crossref","unstructured":"Wang, J. et al. Creating a long-term diabetic rabbit model. Exp. Diabetes Res. 289614 (2010). (2010).","DOI":"10.1155\/2010\/289614"},{"key":"38843_CR40","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.medici.2018.02.001","volume":"53","author":"OM Ighodaro","year":"2017","unstructured":"Ighodaro, O. M., Adeosun, A. M. & Akinloye, O. A. Alloxan-induced diabetes, a common model for evaluating the glycemic-control potential of therapeutic compounds and plants extracts in experimental studies. Medicina 53, 365\u2013374 (2017).","journal-title":"Medicina"},{"key":"38843_CR41","doi-asserted-by":"crossref","unstructured":"D\u00edez, R. et al. Hypoglycemic and hypolipidemic potential of a high fiber diet in healthy versus diabetic rabbits. Biomed Res. Int. 960568 (2013). (2013).","DOI":"10.1155\/2013\/960568"},{"key":"38843_CR42","doi-asserted-by":"publisher","first-page":"e04103","DOI":"10.1016\/j.heliyon.2020.e04103","volume":"6","author":"M Bacevic","year":"2020","unstructured":"Bacevic, M., Rompen, E., Radermecker, R., Drion, P. & Lambert, F. Practical considerations for reducing mortality rates in alloxan-induced diabetic rabbits. Heliyon 6, e04103 (2020).","journal-title":"Heliyon"},{"key":"38843_CR43","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/S0367-326X(02)00235-6","volume":"73","author":"MS Akhtar","year":"2002","unstructured":"Akhtar, M. S., Khan, M. A. & Malik, M. T. Hypoglycaemic activity of alpinia galanga rhizome and its extracts in rabbits. Fitoterapia 73, 623\u2013628 (2002).","journal-title":"Fitoterapia"},{"key":"38843_CR44","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.fitote.2004.03.013","volume":"75","author":"O Fuentes","year":"2004","unstructured":"Fuentes, O., Arancibia-Avila, P. & Alarc\u00f3n, J. Hypoglycemic activity of bauhinia candicans in diabetic induced rabbits. Fitoterapia 75, 527\u2013532 (2004).","journal-title":"Fitoterapia"},{"key":"38843_CR45","doi-asserted-by":"crossref","unstructured":"Kowalska, T., Kaczmarski, K. & Prus, W. Theory and Mechanism of Thin-Layer Chromatography. Marcel Dekker, CRC Press 3rd Editio, 86\u2013129 (2003).","DOI":"10.1201\/9780203912430.ch2"},{"key":"38843_CR46","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s10517-021-05191-7","volume":"171","author":"MA Darenskaya","year":"2021","unstructured":"Darenskaya, M. A., Kolesnikova, L. I. & Kolesnikov, S. I. Oxidative stress: Pathogenetic role in diabetes mellitus and its complications and therapeutic approaches to correction. Bull. Exp. Biol. Med. 171, 179\u2013189 (2021).","journal-title":"Bull. Exp. Biol. Med."},{"key":"38843_CR47","first-page":"531","volume":"39","author":"A Sharif","year":"2024","unstructured":"Sharif, A. et al. International consensus on post-transplantation diabetes mellitus. Nephrol. Dial Transpl. Off Publ Eur. Dial Transpl. Assoc. - Eur. Ren. Assoc. 39, 531\u2013549 (2024).","journal-title":"Nephrol. Dial Transpl. Off Publ Eur. Dial Transpl. Assoc. - Eur. Ren. Assoc."},{"key":"38843_CR48","doi-asserted-by":"crossref","unstructured":"Hassan Bisar, G. et al. Effect of lentil and Buffalo Whey protein hydrolysates on histopathology of liver and kidney in diabetic rats. J Cytol. Histol 08, (2017).","DOI":"10.4172\/2157-7099.1000489"},{"key":"38843_CR49","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1007\/s40200-020-00580-7","volume":"19","author":"F Deeba","year":"2020","unstructured":"Deeba, F. et al. Short term therapeutic efficacy of camel milk Vis-\u00c0-Vis buffalo milk in Alloxan\u00ae induced diabetic rabbits. J. Diabetes Metab. Disord. 19, 915\u2013923 (2020).","journal-title":"J. Diabetes Metab. Disord."},{"key":"38843_CR50","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1111\/j.1365-2613.2008.00615.x","volume":"90","author":"SH Mir","year":"2009","unstructured":"Mir, S. H. & Darzi, M. M. Histopathological abnormalities of prolonged alloxan-induced diabetes mellitus in rabbits. Int. J. Exp. Pathol. 90, 66\u201373 (2009).","journal-title":"Int. J. Exp. Pathol."},{"key":"38843_CR51","doi-asserted-by":"publisher","first-page":"133","DOI":"10.4103\/njcp.njcp_600_20","volume":"26","author":"EB Celik","year":"2023","unstructured":"Celik, E. B., Kaya, K., Erdem, Z. & Hilal, A. Comparison of post-mortem vitreous fluid and blood glucose levels in diabetes-induced rabbit models. Niger J. Clin. Pract. 26, 133\u2013137 (2023).","journal-title":"Niger J. Clin. Pract."},{"key":"38843_CR52","doi-asserted-by":"publisher","first-page":"465","DOI":"10.4103\/ijp.IJP_845_19","volume":"53","author":"B Nagaraju","year":"2021","unstructured":"Nagaraju, B. & Anilkumar, K. V. Pharmacodynamic and pharmacokinetic interaction of losartan with glimepiride-metformin combination in rats and rabbits. Indian J. Pharmacol. 53, 465\u2013470 (2021).","journal-title":"Indian J. Pharmacol."},{"key":"38843_CR53","doi-asserted-by":"publisher","first-page":"106057","DOI":"10.1016\/j.isci.2023.106057","volume":"26","author":"L Zubiaga","year":"2023","unstructured":"Zubiaga, L. et al. Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes. iScience 26, 106057 (2023).","journal-title":"iScience"},{"key":"38843_CR54","doi-asserted-by":"publisher","first-page":"7664","DOI":"10.1002\/fsn3.3685","volume":"11","author":"M Kashif","year":"2023","unstructured":"Kashif, M. et al. Unlocking the anti-diabetic potential of Gymnema sylvestre, trigonella foenum-graecum, and their combination thereof: an in-vivo evaluation. Food Sci. Nutr. 11, 7664\u20137672 (2023).","journal-title":"Food Sci. Nutr."},{"key":"38843_CR55","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1080\/17460441.2017.1253677","volume":"12","author":"CT Supuran","year":"2017","unstructured":"Supuran, C. T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 12, 61\u201388 (2017).","journal-title":"Expert Opin. Drug Discov."},{"key":"38843_CR56","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000434","volume":"3","author":"D Torella","year":"2014","unstructured":"Torella, D. et al. Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy. J. Am. Heart Assoc. 3, e000434 (2014).","journal-title":"J. Am. Heart Assoc."},{"key":"38843_CR57","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/978-3-030-79511-5_6","volume":"75","author":"Z Gurel","year":"2021","unstructured":"Gurel, Z. & Sheibani, N. Potential of carbonic anhydrase inhibitors in the treatment of oxidative stress and diabetes. Prog. Drug Res. 75, 121\u2013146 (2021).","journal-title":"Prog. Drug Res."},{"key":"38843_CR58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151833","volume":"11","author":"MB Hymowitz","year":"2016","unstructured":"Hymowitz, M. B., Chang, D., Feinberg, E. B. & Roy, S. Increased intraocular pressure and hyperglycemic level in diabetic patients. PLoS One 11, e0151833 (2016).","journal-title":"PLoS One"},{"key":"38843_CR59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107291","volume":"9","author":"I Soto","year":"2014","unstructured":"Soto, I. et al. DBA\/2J mice are susceptible to diabetic nephropathy and diabetic exacerbation of IOP elevation. PLoS One 9, e107291 (2014).","journal-title":"PLoS One"},{"key":"38843_CR60","doi-asserted-by":"publisher","DOI":"10.1177\/2042018820926000","volume":"11","author":"R Pu","year":"2020","unstructured":"Pu, R. et al. Effects of metformin in obesity treatment in different populations: A meta-analysis. Ther. Adv. Endocrinol. Metab. 11, 2042018820926000 (2020).","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"38843_CR61","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1007\/s00210-022-02228-0","volume":"395","author":"MCA Kehrenberg","year":"2022","unstructured":"Kehrenberg, M. C. A. & Bachmann, H. S. Diuretics: A contemporary pharmacological classification?. Naunyn Schmiedebergs Arch. Pharmacol. 395, 619\u2013627 (2022).","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"38843_CR62","doi-asserted-by":"crossref","unstructured":"Epstein, D. L. & Grant, W. M. Carbonic anhydrase inhibitor side effects. Serum chemical analysis. Arch. Ophthalmol. (Chicago, Ill.) 95, 1378\u20131382 (1977).) 95, 1378\u20131382 (1977). (1960).","DOI":"10.1001\/archopht.1977.04450080088009"},{"key":"38843_CR63","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1001\/jamaophthalmol.2021.5977","volume":"140","author":"MM Popovic","year":"2022","unstructured":"Popovic, M. M., Schlenker, M. B., Thiruchelvam, D. & Redelmeier, D. A. Serious adverse events of oral and topical carbonic anhydrase inhibitors. JAMA Ophthalmol. 140, 235\u2013242 (2022).","journal-title":"JAMA Ophthalmol."},{"key":"38843_CR64","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1139\/bcb-2016-0256","volume":"95","author":"MA Abd Eldaim","year":"2017","unstructured":"Abd Eldaim, M. A., Abd Elrasoul, S., Abd Elaziz, S. A. & A. & An aqueous extract from Moringa Oleifera leaves ameliorates hepatotoxicity in alloxan-induced diabetic rats. Biochem. Cell. Biol. 95, 524\u2013530 (2017).","journal-title":"Biochem. Cell. Biol."},{"key":"38843_CR65","first-page":"184","volume":"13","author":"MS Badiee","year":"2024","unstructured":"Badiee, M. S. et al. Quercetin and catechin protects leptin-deficient Lepob\/Ob mice against Alloxan-Induced diabetes and hepatotoxicity via suppression of oxidative stress and inflammation. Rep. Biochem. Mol. Biol. 13, 184\u2013195 (2024).","journal-title":"Rep. Biochem. Mol. Biol."},{"key":"38843_CR66","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1007\/s40200-022-01029-9","volume":"21","author":"GE Orumwense","year":"2022","unstructured":"Orumwense, G. E., Osagie, A. M., Omage, S. O., Omage, K. & Azeke, M. A. Synclisia scabrida protects against oxidative stress, hepatotoxicity and hyperglycaemia in alloxan-induced diabetic rats. J. Diabetes Metab. Disord. 21, 669\u2013680 (2022).","journal-title":"J. Diabetes Metab. Disord."},{"key":"38843_CR67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejphar.2019.02.004","volume":"850","author":"M Iranshahy","year":"2019","unstructured":"Iranshahy, M., Rezaee, R. & Karimi, G. Hepatoprotective activity of metformin: A new mission for an old drug? Eur. J. Pharmacol. 850, 1\u20137 (2019).","journal-title":"Eur. J. Pharmacol."},{"key":"38843_CR68","doi-asserted-by":"publisher","first-page":"248","DOI":"10.4103\/0976-500X.99426","volume":"3","author":"NR Hadi","year":"2012","unstructured":"Hadi, N. R., Al-Amran, F. G. & Swadi, A. Metformin ameliorates methotrexate-induced hepatotoxicity. J. Pharmacol. Pharmacother. 3, 248\u2013253 (2012).","journal-title":"J. Pharmacol. Pharmacother."},{"key":"38843_CR69","first-page":"307","volume":"34","author":"S Kousar","year":"2021","unstructured":"Kousar, S., Aslam, B., Muhammad, F. & Khan, J. A. Hepatoprotective and hypolipidemic activities of caesalpinia bonduc seed kernels and Gymnema sylvestre leaves extracts in alloxan-induced diabetic rats. Pak J. Pharm. Sci. 34, 307\u2013311 (2021).","journal-title":"Pak J. Pharm. Sci."},{"key":"38843_CR70","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.pharma.2022.01.005","volume":"80","author":"ZMM Omar","year":"2022","unstructured":"Omar, Z. M. M., Ahmed, A. A. N., El-Bakry, M. H., Ahmed, M. A. & Hasan, A. Metformin versus silymarin as hepatoprotective agents in mice fibrotic model caused by carbon tetrachloride. Ann. Pharm. Fr. 80, 659\u2013668 (2022).","journal-title":"Ann. Pharm. Fr."},{"key":"38843_CR71","doi-asserted-by":"publisher","first-page":"177160","DOI":"10.1016\/j.ejphar.2024.177160","volume":"987","author":"R Atre","year":"2025","unstructured":"Atre, R. et al. Dorzolamide intermediates with potential anti-inflammatory activity. Eur. J. Pharmacol. 987, 177160 (2025).","journal-title":"Eur. J. Pharmacol."},{"key":"38843_CR72","doi-asserted-by":"crossref","unstructured":"Iftikhar, A. et al. Effect of Caesalpinia bonduc Polyphenol Extract on Alloxan-Induced Diabetic Rats in Attenuating Hyperglycemia by Upregulating Insulin Secretion and Inhibiting JNK Signaling Pathway. Oxid. Med. Cell. Longev. 9020219 (2020). (2020).","DOI":"10.1155\/2020\/9020219"},{"key":"38843_CR73","doi-asserted-by":"publisher","first-page":"67","DOI":"10.9734\/BJMMR\/2011\/245","volume":"1","author":"Glycaemic Evaluation of Folk Recipe","year":"2011","unstructured":"Glycaemic Evaluation of Folk Recipe. Medicinal Plants) in Alloxan induced diabetic rabbits. Br. J. Med. Med. Res. 1, 67\u201384 (2011).","journal-title":"Br. J. Med. Med. Res."},{"key":"38843_CR74","first-page":"2335","volume":"77","author":"RAH Al-Sarray","year":"2022","unstructured":"Al-Sarray, R. A. H. & Al-Shaeli, S. J. J. Metformin and bee venom: A comparative detection of histological alteration of the pancreas and systemic inflammatory markers in diabetic mice. Arch. Razi Inst. 77, 2335\u20132343 (2022).","journal-title":"Arch. Razi Inst."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-38843-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-38843-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-38843-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:02:57Z","timestamp":1778695377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-38843-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["38843"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-38843-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"assertion":[{"value":"16 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study protocol was approved on 21\/12\/2023 by the \u201cInstitutional Review Board\u201d as well as the research ethics committee of the Faculty of Medicine in Assiut University, Assiut, Egypt (IRB approval number 04-2023-200631), applicable to human and animal studies. Urine samples were collected from human volunteers. Prior to participation, all sampled subjects were duly informed, and their consent was obtained.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"15060"}}