The use of benzalkonium chloride in topical glaucoma treatment
ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence‐based treatment i...
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| Veröffentlicht in: | Acta ophthalmologica (Oxford, England) England), 2023-12, Vol.101, p.3-21 |
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| description | ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence‐based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first‐choice treatment option, the most common approach for managing glaucoma is IOP‐lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta‐analyses investigate potential differences in efficacy and safety between BAK‐preserved and BAK‐free anti‐glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK‐preserved eye drops. However, the meta‐analyses addressing hyperemia, number of ocular adverse events, and tear break‐up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta‐analysis finds that there are no differences in the IOP‐lowering effect between BAK‐preserved and BAK‐free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK‐preserved and BAK‐free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may dama |
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| fullrecord | <record><control><sourceid>wiley</sourceid><recordid>TN_cdi_wiley_primary_10_1111_aos_15808_AOS15808</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>AOS15808</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2358-64582dfdf78666a32362a2dee0705abb925bf880057a79f56dded19d62a421793</originalsourceid><addsrcrecordid>eNo9j8tKAzEYhYMoWKsL3yAvMG0uk8tshFLUCoUuWsFd-GeS2GhmUuaC1Kd3rNKzOd_icOBD6J6SGR0zh9TNqNBEX6AJVUJkXEl9eWbxdo1uuu6DEEmlzCfoYbd3eOgcTh6XrvmG-JmaMNS42sfUButwaHCfDqGCiN8jDFWqAfetg752TX-LrjzEzt399xS9Pj3ulqtsvXl-WS7WWcW40JnMhWbWW6-0lBI445IBs84RRQSUZcFE6bUmRChQhRfSWmdpYcdVzqgq-BTN_36_QnRHc2hDDe3RUGJ-rc1obU7WZrHZnoD_ANG2TGI</addsrcrecordid><sourcetype>Publisher</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The use of benzalkonium chloride in topical glaucoma treatment</title><source>Wiley Free Content</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Nagstrup, Anne Hedengran</creator><creatorcontrib>Nagstrup, Anne Hedengran</creatorcontrib><description>ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence‐based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first‐choice treatment option, the most common approach for managing glaucoma is IOP‐lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta‐analyses investigate potential differences in efficacy and safety between BAK‐preserved and BAK‐free anti‐glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK‐preserved eye drops. However, the meta‐analyses addressing hyperemia, number of ocular adverse events, and tear break‐up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta‐analysis finds that there are no differences in the IOP‐lowering effect between BAK‐preserved and BAK‐free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK‐preserved and BAK‐free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP‐lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK‐preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative‐free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK‐preserved travoprost is found to be cytotoxic in a time‐dependent manner, while Polyquad®‐preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK‐preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad‐preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)‐6 and IL‐8, unlike BAK‐preserved latanoprost. A review highlights the active and inactive components of IOP‐lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro‐inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.
RESUMÉ
Danish Summary: Glaukom (grøn stær) er en af de hyppigste årsager til blindhed på verdensplan. Årsagen til glaukom kendes ikke, men de væsentligste risikofaktorer er alder, genetik og forhøjet intraokulært tryk. Den eneste evidensbaserede behandling er sænkning af øjentrykket med enten øjendråber, laser eller kirurgi. Omend laserbehandling er blevet tiltagende anerkendt som førstevalgsbehandling, er øjendråber den mest udbredte behandlingsform. Da øjendråber mod glaukom kan medføre væsentlige bivirkninger, er det en stor udfordring, at patienter med glaukom ikke bruger deres øjendråber korrekt. I denne sammenhæng er øjenoverfladen et område, der vækker bekymring, da langt de fleste glaukompatienter lider af øjenoverfladesygdom, som overvejende skyldes øjendråbebehandling. Konservering med benzalkoniumklorid (BAK) er kontroversiel, da BAK menes at være en væsentlig årsag til øjenoverfladesygdom. Et systematisk review og metaanalyser undersøger forskelle i effekt og bivirkningsprofil mellem BAK‐konserverede og BAK‐frie øjendråber (I). Flere studier rapporterer om skade på øjets overflade ved brug af BAK‐konserverede øjendråber. Dog findes der ikke forskelle i metaanalyserne, der undersøger hyperæmi, antal lokale bivirkninger og tåreopbrydningstid. De inkluderede studier har meget varierende outcomes, varighed og målemetoder. Det er derfor muligt, at de store variationer studierne imellem maskerer BAK's egentlige toksiske effekt. I metaanalysen, der undersøger dråbernes tryksænkende effekt, findes der ingen forskel mellem BAK‐konserverede og BAK‐frie øjendråber, hvilket indikerer, at BAK ikke er nødvendig for dråbernes tryksænkende effekt. For at bane vejen for mere ensartede valg af end points og metoder i kliniske forsøg, der undersøger BAK‐konserverede og BAK‐frie antiglaukomatøse øjendråber, er der lavet et Delphi konsensus studie (II). I studiet er eksperter i glaukom og overfladesygdom blevet enige om de vigtigste elementer, der bør inkluderes, når sådanne kliniske studier designes. Håbet er at øge mængden af studier med sammenlignelige end points og metoder som systematisk kan vise BAK's potentielt uhensigtsmæssige effekt på øjendråbers bivirkningsprofil. De prækliniske studier i den foreliggende afhandling fokuserer på de konjunktivale bægerceller, da bægercellerne er vigtige for øjets overflade. Bægerceller frigiver mucinet MUC5AC, som er en vigtig bestanddel i tårefilmens inderste lag. BAK‐konservering kan beskadige bægercellerne og forårsage lav bægercelledensitet. Dette vil medføre en ustabil tårefilm og øjenoverfladesygdom. Da de hyppigst anvendte tryksænkende øjendråber er prostaglandinanaloger (PGA), undersøges hvorledes forskelligt konserverede PGA‐øjendråber påvirker bægercellerne. BAK‐konserveret latanoprost er toksisk overfor primære humane konjunktivale bægercellekulturer og forårsager spredt ekspression af MUC5AC. Dette er sammenlignet med negative kontroller, hvor MUC5AC er lokaliseret rundt om cellekernen (III). Konserveringsfri latanoprost er ikke cytotoksisk og påvirker ikke MUC5AC ekspressionen. Ydermere er BAK‐konserveret travoprost tidsafhængigt toksisk, hvilket ikke er tilfældet for Polyquad®‐konserveret travoprost (VI). Både BAK‐ og Polyquad‐konserveret travoprost forårsager spredt MUC5AC ekspression. BAK‐konserverede PGA‐øjendråber er mere toksiske end PF og Polyquad‐konserverede PGA‐øjendråber (V). Derudover øger BAK‐konserveret latanoprost frigivelsen af IL‐6 og IL‐8, hvilket PF latanoprost ikke gør. Et review fokuserer på både de aktive og inaktive komponenter i tryksænkende øjendråber (VI). Flere kliniske og prækliniske studier viser, at BAK er skadeligt. Mens andre komponenter såsom det aktive stof og fosfater også kan være årsag til bivirkninger, fremgår det tydeligt af reviewet, at BAK alene er en betydelig kilde til øjenoverfladesygdom. Konklusionen på denne afhandling er, at BAK konservering er unødvendig og skadelig for øjets overflade. I de prækliniske studier findes det, at BAK dræber bægercellerne og forårsager et inflammatorisk respons. Det inkluderede review konkluderer, at BAK bør udfases fra øjendråber, der bruges livslangt. Overordnet set øger BAK risikoen for at udvikle øjenoverfladesygdom, hvilket gør, at patienterne ikke bruger deres øjendråber korrekt. Dette kan ultimativt føre til sygdomsprogression og blindhed.</description><identifier>ISSN: 1755-375X</identifier><identifier>EISSN: 1755-3768</identifier><identifier>DOI: 10.1111/aos.15808</identifier><language>eng</language><ispartof>Acta ophthalmologica (Oxford, England), 2023-12, Vol.101, p.3-21</ispartof><rights>2023 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2358-64582dfdf78666a32362a2dee0705abb925bf880057a79f56dded19d62a421793</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Faos.15808$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Faos.15808$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids></links><search><creatorcontrib>Nagstrup, Anne Hedengran</creatorcontrib><title>The use of benzalkonium chloride in topical glaucoma treatment</title><title>Acta ophthalmologica (Oxford, England)</title><description>ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence‐based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first‐choice treatment option, the most common approach for managing glaucoma is IOP‐lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta‐analyses investigate potential differences in efficacy and safety between BAK‐preserved and BAK‐free anti‐glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK‐preserved eye drops. However, the meta‐analyses addressing hyperemia, number of ocular adverse events, and tear break‐up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta‐analysis finds that there are no differences in the IOP‐lowering effect between BAK‐preserved and BAK‐free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK‐preserved and BAK‐free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP‐lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK‐preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative‐free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK‐preserved travoprost is found to be cytotoxic in a time‐dependent manner, while Polyquad®‐preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK‐preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad‐preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)‐6 and IL‐8, unlike BAK‐preserved latanoprost. A review highlights the active and inactive components of IOP‐lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro‐inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.
RESUMÉ
Danish Summary: Glaukom (grøn stær) er en af de hyppigste årsager til blindhed på verdensplan. Årsagen til glaukom kendes ikke, men de væsentligste risikofaktorer er alder, genetik og forhøjet intraokulært tryk. Den eneste evidensbaserede behandling er sænkning af øjentrykket med enten øjendråber, laser eller kirurgi. Omend laserbehandling er blevet tiltagende anerkendt som førstevalgsbehandling, er øjendråber den mest udbredte behandlingsform. Da øjendråber mod glaukom kan medføre væsentlige bivirkninger, er det en stor udfordring, at patienter med glaukom ikke bruger deres øjendråber korrekt. I denne sammenhæng er øjenoverfladen et område, der vækker bekymring, da langt de fleste glaukompatienter lider af øjenoverfladesygdom, som overvejende skyldes øjendråbebehandling. Konservering med benzalkoniumklorid (BAK) er kontroversiel, da BAK menes at være en væsentlig årsag til øjenoverfladesygdom. Et systematisk review og metaanalyser undersøger forskelle i effekt og bivirkningsprofil mellem BAK‐konserverede og BAK‐frie øjendråber (I). Flere studier rapporterer om skade på øjets overflade ved brug af BAK‐konserverede øjendråber. Dog findes der ikke forskelle i metaanalyserne, der undersøger hyperæmi, antal lokale bivirkninger og tåreopbrydningstid. De inkluderede studier har meget varierende outcomes, varighed og målemetoder. Det er derfor muligt, at de store variationer studierne imellem maskerer BAK's egentlige toksiske effekt. I metaanalysen, der undersøger dråbernes tryksænkende effekt, findes der ingen forskel mellem BAK‐konserverede og BAK‐frie øjendråber, hvilket indikerer, at BAK ikke er nødvendig for dråbernes tryksænkende effekt. For at bane vejen for mere ensartede valg af end points og metoder i kliniske forsøg, der undersøger BAK‐konserverede og BAK‐frie antiglaukomatøse øjendråber, er der lavet et Delphi konsensus studie (II). I studiet er eksperter i glaukom og overfladesygdom blevet enige om de vigtigste elementer, der bør inkluderes, når sådanne kliniske studier designes. Håbet er at øge mængden af studier med sammenlignelige end points og metoder som systematisk kan vise BAK's potentielt uhensigtsmæssige effekt på øjendråbers bivirkningsprofil. De prækliniske studier i den foreliggende afhandling fokuserer på de konjunktivale bægerceller, da bægercellerne er vigtige for øjets overflade. Bægerceller frigiver mucinet MUC5AC, som er en vigtig bestanddel i tårefilmens inderste lag. BAK‐konservering kan beskadige bægercellerne og forårsage lav bægercelledensitet. Dette vil medføre en ustabil tårefilm og øjenoverfladesygdom. Da de hyppigst anvendte tryksænkende øjendråber er prostaglandinanaloger (PGA), undersøges hvorledes forskelligt konserverede PGA‐øjendråber påvirker bægercellerne. BAK‐konserveret latanoprost er toksisk overfor primære humane konjunktivale bægercellekulturer og forårsager spredt ekspression af MUC5AC. Dette er sammenlignet med negative kontroller, hvor MUC5AC er lokaliseret rundt om cellekernen (III). Konserveringsfri latanoprost er ikke cytotoksisk og påvirker ikke MUC5AC ekspressionen. Ydermere er BAK‐konserveret travoprost tidsafhængigt toksisk, hvilket ikke er tilfældet for Polyquad®‐konserveret travoprost (VI). Både BAK‐ og Polyquad‐konserveret travoprost forårsager spredt MUC5AC ekspression. BAK‐konserverede PGA‐øjendråber er mere toksiske end PF og Polyquad‐konserverede PGA‐øjendråber (V). Derudover øger BAK‐konserveret latanoprost frigivelsen af IL‐6 og IL‐8, hvilket PF latanoprost ikke gør. Et review fokuserer på både de aktive og inaktive komponenter i tryksænkende øjendråber (VI). Flere kliniske og prækliniske studier viser, at BAK er skadeligt. Mens andre komponenter såsom det aktive stof og fosfater også kan være årsag til bivirkninger, fremgår det tydeligt af reviewet, at BAK alene er en betydelig kilde til øjenoverfladesygdom. Konklusionen på denne afhandling er, at BAK konservering er unødvendig og skadelig for øjets overflade. I de prækliniske studier findes det, at BAK dræber bægercellerne og forårsager et inflammatorisk respons. Det inkluderede review konkluderer, at BAK bør udfases fra øjendråber, der bruges livslangt. Overordnet set øger BAK risikoen for at udvikle øjenoverfladesygdom, hvilket gør, at patienterne ikke bruger deres øjendråber korrekt. Dette kan ultimativt føre til sygdomsprogression og blindhed.</description><issn>1755-375X</issn><issn>1755-3768</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNo9j8tKAzEYhYMoWKsL3yAvMG0uk8tshFLUCoUuWsFd-GeS2GhmUuaC1Kd3rNKzOd_icOBD6J6SGR0zh9TNqNBEX6AJVUJkXEl9eWbxdo1uuu6DEEmlzCfoYbd3eOgcTh6XrvmG-JmaMNS42sfUButwaHCfDqGCiN8jDFWqAfetg752TX-LrjzEzt399xS9Pj3ulqtsvXl-WS7WWcW40JnMhWbWW6-0lBI445IBs84RRQSUZcFE6bUmRChQhRfSWmdpYcdVzqgq-BTN_36_QnRHc2hDDe3RUGJ-rc1obU7WZrHZnoD_ANG2TGI</recordid><startdate>202312</startdate><enddate>202312</enddate><creator>Nagstrup, Anne Hedengran</creator><scope/></search><sort><creationdate>202312</creationdate><title>The use of benzalkonium chloride in topical glaucoma treatment</title><author>Nagstrup, Anne Hedengran</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2358-64582dfdf78666a32362a2dee0705abb925bf880057a79f56dded19d62a421793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagstrup, Anne Hedengran</creatorcontrib><jtitle>Acta ophthalmologica (Oxford, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagstrup, Anne Hedengran</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The use of benzalkonium chloride in topical glaucoma treatment</atitle><jtitle>Acta ophthalmologica (Oxford, England)</jtitle><date>2023-12</date><risdate>2023</risdate><volume>101</volume><spage>3</spage><epage>21</epage><pages>3-21</pages><issn>1755-375X</issn><eissn>1755-3768</eissn><abstract>ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence‐based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first‐choice treatment option, the most common approach for managing glaucoma is IOP‐lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta‐analyses investigate potential differences in efficacy and safety between BAK‐preserved and BAK‐free anti‐glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK‐preserved eye drops. However, the meta‐analyses addressing hyperemia, number of ocular adverse events, and tear break‐up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta‐analysis finds that there are no differences in the IOP‐lowering effect between BAK‐preserved and BAK‐free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK‐preserved and BAK‐free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP‐lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK‐preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative‐free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK‐preserved travoprost is found to be cytotoxic in a time‐dependent manner, while Polyquad®‐preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK‐preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad‐preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)‐6 and IL‐8, unlike BAK‐preserved latanoprost. A review highlights the active and inactive components of IOP‐lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro‐inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.
RESUMÉ
Danish Summary: Glaukom (grøn stær) er en af de hyppigste årsager til blindhed på verdensplan. Årsagen til glaukom kendes ikke, men de væsentligste risikofaktorer er alder, genetik og forhøjet intraokulært tryk. Den eneste evidensbaserede behandling er sænkning af øjentrykket med enten øjendråber, laser eller kirurgi. Omend laserbehandling er blevet tiltagende anerkendt som førstevalgsbehandling, er øjendråber den mest udbredte behandlingsform. Da øjendråber mod glaukom kan medføre væsentlige bivirkninger, er det en stor udfordring, at patienter med glaukom ikke bruger deres øjendråber korrekt. I denne sammenhæng er øjenoverfladen et område, der vækker bekymring, da langt de fleste glaukompatienter lider af øjenoverfladesygdom, som overvejende skyldes øjendråbebehandling. Konservering med benzalkoniumklorid (BAK) er kontroversiel, da BAK menes at være en væsentlig årsag til øjenoverfladesygdom. Et systematisk review og metaanalyser undersøger forskelle i effekt og bivirkningsprofil mellem BAK‐konserverede og BAK‐frie øjendråber (I). Flere studier rapporterer om skade på øjets overflade ved brug af BAK‐konserverede øjendråber. Dog findes der ikke forskelle i metaanalyserne, der undersøger hyperæmi, antal lokale bivirkninger og tåreopbrydningstid. De inkluderede studier har meget varierende outcomes, varighed og målemetoder. Det er derfor muligt, at de store variationer studierne imellem maskerer BAK's egentlige toksiske effekt. I metaanalysen, der undersøger dråbernes tryksænkende effekt, findes der ingen forskel mellem BAK‐konserverede og BAK‐frie øjendråber, hvilket indikerer, at BAK ikke er nødvendig for dråbernes tryksænkende effekt. For at bane vejen for mere ensartede valg af end points og metoder i kliniske forsøg, der undersøger BAK‐konserverede og BAK‐frie antiglaukomatøse øjendråber, er der lavet et Delphi konsensus studie (II). I studiet er eksperter i glaukom og overfladesygdom blevet enige om de vigtigste elementer, der bør inkluderes, når sådanne kliniske studier designes. Håbet er at øge mængden af studier med sammenlignelige end points og metoder som systematisk kan vise BAK's potentielt uhensigtsmæssige effekt på øjendråbers bivirkningsprofil. De prækliniske studier i den foreliggende afhandling fokuserer på de konjunktivale bægerceller, da bægercellerne er vigtige for øjets overflade. Bægerceller frigiver mucinet MUC5AC, som er en vigtig bestanddel i tårefilmens inderste lag. BAK‐konservering kan beskadige bægercellerne og forårsage lav bægercelledensitet. Dette vil medføre en ustabil tårefilm og øjenoverfladesygdom. Da de hyppigst anvendte tryksænkende øjendråber er prostaglandinanaloger (PGA), undersøges hvorledes forskelligt konserverede PGA‐øjendråber påvirker bægercellerne. BAK‐konserveret latanoprost er toksisk overfor primære humane konjunktivale bægercellekulturer og forårsager spredt ekspression af MUC5AC. Dette er sammenlignet med negative kontroller, hvor MUC5AC er lokaliseret rundt om cellekernen (III). Konserveringsfri latanoprost er ikke cytotoksisk og påvirker ikke MUC5AC ekspressionen. Ydermere er BAK‐konserveret travoprost tidsafhængigt toksisk, hvilket ikke er tilfældet for Polyquad®‐konserveret travoprost (VI). Både BAK‐ og Polyquad‐konserveret travoprost forårsager spredt MUC5AC ekspression. BAK‐konserverede PGA‐øjendråber er mere toksiske end PF og Polyquad‐konserverede PGA‐øjendråber (V). Derudover øger BAK‐konserveret latanoprost frigivelsen af IL‐6 og IL‐8, hvilket PF latanoprost ikke gør. Et review fokuserer på både de aktive og inaktive komponenter i tryksænkende øjendråber (VI). Flere kliniske og prækliniske studier viser, at BAK er skadeligt. Mens andre komponenter såsom det aktive stof og fosfater også kan være årsag til bivirkninger, fremgår det tydeligt af reviewet, at BAK alene er en betydelig kilde til øjenoverfladesygdom. Konklusionen på denne afhandling er, at BAK konservering er unødvendig og skadelig for øjets overflade. I de prækliniske studier findes det, at BAK dræber bægercellerne og forårsager et inflammatorisk respons. Det inkluderede review konkluderer, at BAK bør udfases fra øjendråber, der bruges livslangt. Overordnet set øger BAK risikoen for at udvikle øjenoverfladesygdom, hvilket gør, at patienterne ikke bruger deres øjendråber korrekt. Dette kan ultimativt føre til sygdomsprogression og blindhed.</abstract><doi>10.1111/aos.15808</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1755-375X |
| ispartof | Acta ophthalmologica (Oxford, England), 2023-12, Vol.101, p.3-21 |
| issn | 1755-375X 1755-3768 |
| language | eng |
| recordid | cdi_wiley_primary_10_1111_aos_15808_AOS15808 |
| source | Wiley Free Content; Wiley Online Library Journals Frontfile Complete |
| title | The use of benzalkonium chloride in topical glaucoma treatment |
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