| 词条 | Sodium zirconium cyclosilicate |
| 释义 |
| drug_name = | IUPAC_name = Silicic acid, sodium zirconium(4+) salt (3:2:1), hydrate | image = ZS-9 structure.png | caption = Crystal structure of ZS-9. Blue spheres = oxygen atoms, red spheres = zirconium atoms, green spheres = silicon atoms. | pronounce = | tradename = Lokelma | Drugs.com = | MedlinePlus = | pregnancy_AU = | pregnancy_AU_comment = | pregnancy_US = | pregnancy_category= | legal_AU = | legal_AU_comment = | legal_CA = | legal_NZ = | legal_UK = | legal_US_comment = Rx-only | legal_UN = | legal_status = | routes_of_administration = Oral | bioavailability = Not absorbed | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion = Stool | CAS_number = 242800-27-7 | ATCvet = | ATC_prefix = none | ATC_suffix = | PubChem = | DrugBank = | UNII = D652ZWF066 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D10727 | chemical_formula = (2Na·H2O·3H4SiO4·H4ZrO6)n | molecular_weight = }}Sodium zirconium cyclosilicate (ZS-9) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma and AstraZeneca for the treatment of hyperkalemia (elevated serum potassium levels).[1] Background{{Main article|Hyperkalemia}}Hyperkalemia occurs in 3 to 10% of hospitalized patients[2] but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin–angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.[2][4][5][6] There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe. However, if hyperkalemia causes any ECG change it is considered a medical emergency due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently. serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively. Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[2] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes significant underlying medical problems.[2] Accordingly, these problems are both proximate and ultimate causes of death,[2] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factor for cardiovascular mortality.[14] Several approaches are used in the treatment of hyperkalemia. In October 2015, the U.S. Food and Drug Administration (FDA) approved patiromer which works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange. Previously, the only approved product was sodium polystyrene sulfonate (Kayexalate),[16] an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.[17] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.[16][20][21] Mechanism of actionZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[1] 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels.[2] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized. Clinical studiesA phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation). A double-blind, phase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.[25] Patients were randomly assigned to receive either ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9 mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5 g, 5 g, and 10 g ZS-9 groups. During the maintenance phase, once daily 5 g or 10 g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.[25] A double-blind, phase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.[27] All patients received 10 g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0 mEq/L) were randomly assigned to receive either ZS-9 (5 g, 10 g, or 15 g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5 g, 10 g, and 15 g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemia occurred in more patients in the 10 g and 15 g ZS-9 groups (10% and 11%, respectively), versus none in the 5 g ZS-9 or placebo groups.[27] RegulatoryIn the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration in May 2016 due to issues associated with manufacturing.[3] On May 18, 2018, the FDA approved ZS-9 (now known as Lokelma®) for treatment of adults with hyperkalemia.[4] See also
References1. ^Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307 [5][6][7][8][9][10][11][12][13][14][15][16]2. ^={{cite journal|journal=PLOS ONE|year=2014|volume=9|issue=12|page=e114686|title=Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap|last=Stavros|first=F|pmid=25531770|doi=10.1371/journal.pone.0114686|pmc=4273971}} 3. ^{{Cite news | publisher = FierceBiotech | title = AstraZeneca's $2.7B hyperkalemia drug ZS-9 rejected by FDA | author = Ben Adams | date = May 27, 2016 | url = http://www.fiercebiotech.com/biotech/astrazeneca-s-2-7b-hyperkalemia-drug-zs-9-rejected-by-fda}} 4. ^https://www.drugs.com/history/lokelma.html 5. ^1 2 {{cite journal |vauthors=Packham DK, etal |year= 2014|title= Sodium zirconium cyclosilicate in hyperkalemia|journal= New England Journal of Medicine |volume= 372|issue= 3|pages= 222–31|doi= 10.1056/NEJMoa1411487|pmid= 25415807}} 6. ^1 2 {{cite journal |vauthors=Kosiborod M, etal |year= 2014|title= Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia|journal= Journal of the American Medical Association |volume= 312|issue= 21|pages= 2223–33|doi= 10.1001/jama.2014.15688|pmid= 25402495}} 7. ^1 2 3 4 5 {{Cite journal | doi = 10.1503/cmaj.100461| title = Management of patients with acute hyperkalemia| journal = Canadian Medical Association Journal| volume = 182| issue = 15| pages = 1631–5| year = 2010| last1 = Elliott | first1 = M. J.| last2 = Ronksley | first2 = P. E.| last3 = Clase | first3 = C. M.| last4 = Ahmed | first4 = S. B.| last5 = Hemmelgarn | first5 = B. R. | pmid=20855477 | pmc=2952010}} 8. ^1 {{Cite journal | doi = 10.1016/0016-5085(95)90448-4| pmid = 7875477| title = Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion| journal = Gastroenterology| volume = 108| issue = 3| pages = 752–60| year = 1995| last1 = Emmett | first1 = M. | last2 = Hootkins | first2 = R. E. | last3 = Fine | first3 = K. D. | last4 = Santa Ana | first4 = C. A. | last5 = Porter | first5 = J. L. | last6 = Fordtran | first6 = J. S. }} 9. ^1 {{Cite journal | doi = 10.1046/j.1525-1497.2000.91021.x| pmid = 11119186| title = Serum potassium and cardiovascular mortality| journal = Journal of General Internal Medicine| volume = 15| issue = 12| pages = 885–90| year = 2000| last1 = Fang | first1 = J. | last2 = Madhavan | first2 = S. | last3 = Cohen | first3 = H. | last4 = Alderman | first4 = M. H. | pmc=1495719}} 10. ^1 {{Cite journal | doi = 10.1093/ndt/gfs293| title = Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?| journal = Nephrology Dialysis Transplantation| volume = 27| issue = 12| pages = 4294–7| year = 2012| last1 = Kamel | first1 = K. S.| last2 = Schreiber | first2 = M. | pmid=22989741}} 11. ^1 {{Cite journal | doi = 10.2215/CJN.02250409| pmid = 19808241| title = Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis| journal = Clinical Journal of the American Society of Nephrology| volume = 4| issue = 10| pages = 1565–74| year = 2009| last1 = Navaneethan | first1 = S. D.| last2 = Yehnert | first2 = H.| last3 = Moustarah | first3 = F.| last4 = Schreiber | first4 = M. J.| last5 = Schauer | first5 = P. R.| last6 = Beddhu | first6 = S. | pmc=2758256}} 12. ^1 {{Cite journal | doi = 10.1023/A:1007135517950| pmid = 11229629| year = 2000| last1 = Stevens | first1 = M. S. | journal = International Urology and Nephrology| volume = 32| issue = 2| pages = 177–80|title=Hyperkalemia in hospitalized patients| last2 = Dunlay | first2 = R. W. }} 13. ^1 {{Cite journal | doi = 10.1681/ASN.2010010079| title = Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?| journal = Journal of the American Society of Nephrology| volume = 21| issue = 5| pages = 733–5| year = 2010| last1 = Sterns | first1 = R. H.| last2 = Rojas | first2 = M.| last3 = Bernstein | first3 = P.| last4 = Chennupati | first4 = S. | pmid=20167700}} 14. ^1 {{Cite journal | doi = 10.1016/j.ahj.2004.10.005| pmid = 15632880| title = Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure| journal = American Heart Journal| volume = 148| issue = 6| pages = 971–8| year = 2004| last1 = Tamirisa | first1 = K. P. | last2 = Aaronson | first2 = K. D. | last3 = Koelling | first3 = T. M. }} 15. ^1 2 {{Cite journal | doi = 10.2215/CJN.03700410| title = Damned if You Do, Damned if You Don't: Potassium Binding Resins in Hyperkalemia| journal = Clinical Journal of the American Society of Nephrology| volume = 5| issue = 10| pages = 1723–6| year = 2010| last1 = Watson | first1 = M.| last2 = Abbott | first2 = K. C.| last3 = Yuan | first3 = C. M. | pmid=20798253}} 16. ^1 {{cite web|title=ZS-9. A selective potassium binder|publisher=ZS-Pharma|url=http://www.zspharma.com/clinical-development/zs9/}} }}{{Drugs for treatment of hyperkalemia and hyperphosphatemia}} 4 : Chelating agents used as drugs|Nephrology procedures|Zirconium compounds|Potassium |
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