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{{Short description|Pharmaceutical drug}} |
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{{drugbox |
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{{Drugbox |
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| verifiedrevid = 383289346 |
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| Verifiedfields = changed |
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| IUPAC_name = chloromethyl 17-ethoxycarbonyloxy- 11-hydroxy- 10,13-dimethyl-3-oxo- 7,8,9,11,12,14,15, 16-octahydro- 6''H''-cyclopenta phenanthrene-17-carboxylate |
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| Watchedfields = changed |
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| verifiedrevid = 407631517 |
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| IUPAC_name = Chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6''H''-cyclopentaphenanthrene-17-carboxylate |
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| image = Loteprednol etabonate.svg |
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| image = Loteprednol etabonate.svg |
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| alt = |
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| imagename = Loteprednol etabonate |
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| drug_name = |
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| CASNo_Ref = {{cascite}} |
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| CAS_number = 82034-46-6 |
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<!-- Clinical data --> |
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| ATC_prefix = S01 |
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| ATC_suffix = BA14 |
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| tradename = Lotemax |
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| Drugs.com = {{drugs.com|CONS|loteprednol}} |
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| ATC_supplemental = |
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| PubChem = 444025 |
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| MedlinePlus = |
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| DrugBank = APRD01078 |
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| KEGG = D01689 |
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| C=24 | H=31 | Cl=1 | O=7 |
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| molecular_weight = 466.951 g/mol |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = C |
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| pregnancy_category = |
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| pregnancy_category = |
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| routes_of_administration = Eye drops |
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| legal_AU = <!-- Unscheduled / S2 / S4 / S8 --> |
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| class = ]; ] |
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| ATC_prefix = S01 |
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| ATC_suffix = BA14 |
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| ATC_supplemental = |
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| legal_AU = S4 |
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| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}}</ref> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_US = Rx-only |
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| legal_US = Rx-only |
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| legal_status = |
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| legal_status = |
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| routes_of_administration = |
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<!-- Pharmacokinetic data --> |
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| bioavailability = None |
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| protein_bound = 95% |
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| onset = ≤2 hrs (]) |
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| metabolism = ] |
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| metabolites = Δ<sup>1</sup>-cortienic acid and its etabonate |
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| elimination_half-life = 2.8 hrs |
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| excretion = |
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<!-- Identifiers --> |
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| IUPHAR_ligand = 7085 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 82034-46-6 |
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| PubChem = 444025 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = DB14596 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 392049 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = YEH1EZ96K6 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D01689 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1200865 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 31784 |
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| synonyms = 11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate |
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<!-- Chemical data --> |
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| C=24 | H=31 | Cl=1 | O=7 |
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| smiles = CCOC(=O)O1(CC21(C(32CCC4=CC(=O)C=C34C)O)C)C(=O)OCCl |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI=1S/C24H31ClO7/c1-4-30-21(29)32-24(20(28)31-13-25)10-8-17-16-6-5-14-11-15(26)7-9-22(14,2)19(16)18(27)12-23(17,24)3/h7,9,11,16-19,27H,4-6,8,10,12-13H2,1-3H3/t16-,17-,18-,19+,22-,23-,24-/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = DMKSVUSAATWOCU-HROMYWEYSA-N |
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| melting_point = 220.5 |
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| melting_high = 223.5 |
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| solubility = 0.0005 |
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}} |
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}} |
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'''Loteprednol''' (as the ] '''loteprednol etabonate''') is a ] used in ]. Marketed by ] as '''Lotemax''' in the U.S., ocular applications for this drug include the treatment of inflammation of the eye due to allergies (according to the prescription information sheet), as well as chronic forms of ] (e.g.: ] and ]), ], ], and ]. The drug has little or no effect on ]. |
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'''Loteprednol''' (synthesized as the ] '''loteprednol etabonate''') is a topical ] used to treat inflammations of the eye. It is marketed by ] as '''Lotemax'''<ref name="AC" /> and '''Loterex'''. |
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<!-- Society and culture --> |
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It was patented in 1980 and approved for medical use in 1998.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR | name-list-style = vanc |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=488 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA488 }}</ref> It is available as a ].<ref>{{cite web | title=First Generic Drug Approvals 2023 | website=U.S. ] (FDA) | date=30 May 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003621/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref> |
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==Medical uses== |
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Applications for this drug include the reduction of ] after eye surgery,<ref name="AC" /> seasonal ], ],<ref name="Drugs.com" /> and chronic forms of ] - such as ], ], ],], giant papillary conjunctivitis, and ].<ref>{{cite journal | vauthors = Pavesio CE, Decory HH | title = Treatment of ocular inflammatory conditions with loteprednol etabonate | journal = The British Journal of Ophthalmology | volume = 92 | issue = 4 | pages = 455–459 | date = April 2008 | pmid = 18245274 | doi = 10.1136/bjo.2007.132621 | s2cid = 25873047 }}</ref> |
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==Contraindications== |
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] As corticosteroids are ], loteprednol is contraindicated in patients with ], ] or ] infections of the eye.<ref name="AC" /><ref name="Drugs.com" /><ref name="Dinnendahl" /> |
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==Adverse effects== |
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The most common ] in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%).<ref name="FDA"/> |
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== Interactions == |
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Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.<ref name="AC" /> |
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==Pharmacology== |
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===Mechanism of action=== |
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{{main article|Glucocorticoid#Mechanism of action}}Corticosteroids mediate their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level. Preclinical studies demonstrated that loteprednol etabonate is highly lipophilic and has strong binding affinity to glucocorticoid receptors. After it binds to the GR in the cytoplasm, the activated corticosteroid-GR complex migrates to the nucleus, where it upregulates the expression of anti-inflammatory proteins and represses the expression of proinflammatory proteins. Corticosteroids inhibit inflammatory cytokines, chemokines, adhesion molecules, and other inflammatory mediators. They also reduce synthesis of histamine, stabilize cell membranes, and inhibit degranulation of mast cells. Recent work suggests that the activated corticosteroid-GR complex also elicits nongenomic effects, particularly the inhibition of vasodilation, vascular permeability, and migration of leukocytes. <ref>{{cite journal | vauthors = Comstock TL, Decory HH | title = Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate | journal = International Journal of Inflammation | volume = 2012 | pages = 789623 | date = 2012 | pmid = 22536546 | pmc = 3321285 | doi = 10.1155/2012/789623 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Amon M, Busin M | title = Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use | journal = International Ophthalmology | volume = 32 | issue = 5 | pages = 507–517 | date = October 2012 | pmid = 22707339 | pmc = 3459083 | doi = 10.1007/s10792-012-9589-2 }}</ref><ref>{{cite journal | vauthors = Sheppard JD, Comstock TL, Cavet ME | title = Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure | journal = Advances in Therapy | volume = 33 | issue = 4 | pages = 532–552 | date = April 2016 | pmid = 26984315 | pmc = 4846687 | doi = 10.1007/s12325-016-0315-8 }}</ref> |
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===Pharmacokinetics=== |
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Neither loteprednol etabonate nor its inactive ]s Δ<sup>1</sup>-] and Δ<sup>1</sup>-cortienic acid ] are detectable in the bloodstream, even after ]. A study with patients receiving loteprednol eye drops over 42 days showed no ], which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.<ref name="AC" /> |
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] affinity was 4.3 times that of ] in animal studies.<ref name="AC" /> |
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===Retrometabolic drug design=== |
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Loteprednol etabonate was developed using ]. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ<sup>1</sup>-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of ].<ref name="AC" /><ref name="Dinnendahl" /><ref name="Dekker" /> |
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<gallery> |
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File:Cortisol2.svg|], a naturally occurring corticosteroid, known as ] when used as a drug |
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File:Delta1-cortienic acid skeletal.svg|Δ<sup>1</sup>-Cortienic acid, inactive metabolite of loteprednol |
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File:Cortienic acid skeletal.svg|Cortienic acid, inactive metabolite of hydrocortisone |
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</gallery> |
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==Chemistry== |
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Loteprednol etabonate is an ester of loteprednol with ] (ethyl carbonate). The pure chemical compound has a melting point between {{convert|220.5|C|F}} and {{convert|223.5|C|F}}. Its solubility in water is 1:2,000,000,<ref name="Dinnendahl" /> therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.<ref name="drugs.com2"/> |
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Loteprednol is a ]. The ] side chain of classical corticosteroids such as ] is replaced by a cleavable ester, which accounts for the rapid inactivation.<ref name="Pavesio" /> (This is not the same as the etabonate ester.) |
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]]] |
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===Chemical synthesis=== |
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{{expand section|date=June 2016}} |
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<ref name="Druzgala" /> |
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== References == |
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Druzgala, P.; Hochhaus, G.; Bodor, N.; J. Steroid Biochem. Mol. Biol. 1991, 38, 149. |
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{{reflist|refs= |
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<ref name="Drugs.com">Loteprednol {{Drugs.com|ppa|loteprednol}}.</ref> |
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http://dx.doi.org/10.1016/0960-0760(91)90120-T |
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<ref name="drugs.com2">{{cite web|url=https://www.drugs.com/ppa/loteprednol.html|title=Loteprednol (Professional Patient Advice)|access-date=October 4, 2018}}</ref> |
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==References== |
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<ref name="Dinnendahl">{{cite book|title=Arzneistoff-Profile| vauthors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2008|edition=22|volume=6|isbn=978-3-7741-9846-3|language=German}}</ref> |
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* {{cite journal|last=Steward|first=R|coauthors=et al.|date=November 1998|title=Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation|journal=J Cataract Surg|volume=24|pages=1480–1489}} |
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* {{cite journal|last=Pavesio|first=CE|year=2008|title=Treatment of ocular inflammatory conditions with loteprednol etabonate|journal=Br J Ophthalmol|volume=92|pages=455–459|doi=10.1136/bjo.2007.132621|pmid=18245274|last2=Decory|first2=HH|issue=4}} |
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<ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=German}}</ref> |
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{{Corticosteroids}} |
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<ref name="Druzgala">{{cite journal | vauthors = Druzgala P, Hochhaus G, Bodor N | title = Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 38 | issue = 2 | pages = 149–154 | date = February 1991 | pmid = 2004037 | doi = 10.1016/0960-0760(91)90120-T | s2cid = 27107845 }}</ref> |
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<ref name="Dekker">{{cite book|title=Inhaled Steroids in Asthma. Optimizing Effects in the Airways|year=2002|publisher=Marcel Dekker, New York|pages=541–564| vauthors = Bodor N, Buchwald P |chapter=Design and development of a soft corticosteroid, loteprednol etabonate | veditors = Schleimer RP, O'Byrne PM, Szefler SJ, Brattsand R | series = Lung Biology in Health and Disease | volume = 163 }}</ref> |
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<ref name="Pavesio">{{cite journal | vauthors = Pavesio CE, Decory HH | title = Treatment of ocular inflammatory conditions with loteprednol etabonate | journal = The British Journal of Ophthalmology | volume = 92 | issue = 4 | pages = 455–459 | date = April 2008 | pmid = 18245274 | doi = 10.1136/bjo.2007.132621 | s2cid = 25873047 }}</ref> |
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{{pharma-stub}} |
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<ref name="FDA">{{cite web|title= Highlights of Prescribing Information: Lotemax |url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202872lbl.pdf |date=2012}}</ref> |
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}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite journal | vauthors = Stewart R, Horwitz B, Howes J, Novack GD, Hart K | title = Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1 | journal = Journal of Cataract and Refractive Surgery | volume = 24 | issue = 11 | pages = 1480–1489 | date = November 1998 | pmid = 9818338 | doi = 10.1016/s0886-3350(98)80170-3 | s2cid = 24423725 }} |
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{{refend}} |
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{{Glucocorticoids}} |
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{{Glucocorticoidics}} |
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