Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models
The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-...
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| Veröffentlicht in: | Experimental eye research 2011-09, Vol.93 (3), p.250-255 |
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| creator | Krauss, Achim H.P. Impagnatiello, Francesco Toris, Carol B. Gale, David C. Prasanna, Ganesh Borghi, Valentina Chiroli, Valerio Chong, Wesley K.M. Carreiro, Samantha T. Ongini, Ennio |
| description | The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
► BOL-303259-X is a novel nitric oxide donating PGF2a agonist. ► Ocular hypotensive activity in primates, dogs and rabbits was assessed. ► IOP reduction greater than latanoprost was observed in all three animal models. |
| doi_str_mv | 10.1016/j.exer.2011.03.001 |
| format | Article |
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► BOL-303259-X is a novel nitric oxide donating PGF2a agonist. ► Ocular hypotensive activity in primates, dogs and rabbits was assessed. ► IOP reduction greater than latanoprost was observed in all three animal models.</description><identifier>ISSN: 0014-4835</identifier><identifier>EISSN: 1096-0007</identifier><identifier>DOI: 10.1016/j.exer.2011.03.001</identifier><identifier>PMID: 21396362</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Topical ; Animals ; Antihypertensive Agents - pharmacokinetics ; Antihypertensive Agents - pharmacology ; Aqueous Humor - enzymology ; BOL-303259-X ; Cell Line ; Ciliary Body - metabolism ; Cyclic GMP - metabolism ; Dinoprost - agonists ; Disease Models, Animal ; Dogs ; Drug Evaluation, Preclinical ; Female ; glaucoma ; Glaucoma - drug therapy ; Glaucoma - metabolism ; Guanylate Cyclase - metabolism ; Intraocular Pressure - drug effects ; IOP ; Iris - metabolism ; Macaca fascicularis ; Male ; nitric oxide ; Nitric Oxide - metabolism ; Nitric Oxide Donors - pharmacokinetics ; Nitric Oxide Donors - pharmacology ; Ocular Hypertension - drug therapy ; Ocular Hypertension - metabolism ; pharmacokinetics ; prostaglandin ; Prostaglandins F, Synthetic - pharmacokinetics ; Prostaglandins F, Synthetic - pharmacology ; Rabbits ; Rats ; Tonometry, Ocular</subject><ispartof>Experimental eye research, 2011-09, Vol.93 (3), p.250-255</ispartof><rights>2011 Elsevier Ltd</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c355t-6cbc3f67f67e797683ffda74d6d92c7d9ceb4e016d5b64d8d7c2429f7c35b3843</citedby><cites>FETCH-LOGICAL-c355t-6cbc3f67f67e797683ffda74d6d92c7d9ceb4e016d5b64d8d7c2429f7c35b3843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.exer.2011.03.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21396362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krauss, Achim H.P.</creatorcontrib><creatorcontrib>Impagnatiello, Francesco</creatorcontrib><creatorcontrib>Toris, Carol B.</creatorcontrib><creatorcontrib>Gale, David C.</creatorcontrib><creatorcontrib>Prasanna, Ganesh</creatorcontrib><creatorcontrib>Borghi, Valentina</creatorcontrib><creatorcontrib>Chiroli, Valerio</creatorcontrib><creatorcontrib>Chong, Wesley K.M.</creatorcontrib><creatorcontrib>Carreiro, Samantha T.</creatorcontrib><creatorcontrib>Ongini, Ennio</creatorcontrib><title>Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models</title><title>Experimental eye research</title><addtitle>Exp Eye Res</addtitle><description>The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
► BOL-303259-X is a novel nitric oxide donating PGF2a agonist. ► Ocular hypotensive activity in primates, dogs and rabbits was assessed. ► IOP reduction greater than latanoprost was observed in all three animal models.</description><subject>Administration, Topical</subject><subject>Animals</subject><subject>Antihypertensive Agents - pharmacokinetics</subject><subject>Antihypertensive Agents - pharmacology</subject><subject>Aqueous Humor - enzymology</subject><subject>BOL-303259-X</subject><subject>Cell Line</subject><subject>Ciliary Body - metabolism</subject><subject>Cyclic GMP - metabolism</subject><subject>Dinoprost - agonists</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>glaucoma</subject><subject>Glaucoma - drug therapy</subject><subject>Glaucoma - metabolism</subject><subject>Guanylate Cyclase - metabolism</subject><subject>Intraocular Pressure - drug effects</subject><subject>IOP</subject><subject>Iris - metabolism</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Donors - pharmacokinetics</subject><subject>Nitric Oxide Donors - pharmacology</subject><subject>Ocular Hypertension - drug therapy</subject><subject>Ocular Hypertension - metabolism</subject><subject>pharmacokinetics</subject><subject>prostaglandin</subject><subject>Prostaglandins F, Synthetic - pharmacokinetics</subject><subject>Prostaglandins F, Synthetic - pharmacology</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Tonometry, Ocular</subject><issn>0014-4835</issn><issn>1096-0007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM-KUzEUxoMoTh19AReSnZu51_y7SQNudHBUKNSFgruQm5xbU26TmqRl-li-iM9kSkeXwoEDH9_3cc4PoZeU9JRQ-Wbbwz3knhFKe8J7QugjtKBEy44Qoh6jRVNEJ5Z8uELPStk2lQslnqIrRrmWXLIFOq7dYbYZ_zjtU4VYwhGwdTUcQz3hNOH361XHCWeD7r7fYItjqDk4nO6DB-xTtDXEDf6SU6l2M9voQ8R37PcvbDcphlJvcBP2GdwcYnB2xrvkYS7P0ZPJzgVePOxr9O3uw9fbT91q_fHz7btV5_gw1E660fFJqjagtJJLPk3eKuGl18wprx2MAhoLP4xS-KVXjgmmJ9XiI18Kfo1eX3r3Of08QKlmF4qDuV0K6VCMJpSTgQndnOzidO2XkmEy-xx2Np8MJeaM22zNGbc54zaEmwa3hV491B_GHfh_kb98m-HtxdB-hmNo8eICRAc-NCbV-BT-1_8HnrCR0w</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Krauss, Achim H.P.</creator><creator>Impagnatiello, Francesco</creator><creator>Toris, Carol B.</creator><creator>Gale, David C.</creator><creator>Prasanna, Ganesh</creator><creator>Borghi, Valentina</creator><creator>Chiroli, Valerio</creator><creator>Chong, Wesley K.M.</creator><creator>Carreiro, Samantha T.</creator><creator>Ongini, Ennio</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20110901</creationdate><title>Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models</title><author>Krauss, Achim H.P. ; Impagnatiello, Francesco ; Toris, Carol B. ; Gale, David C. ; Prasanna, Ganesh ; Borghi, Valentina ; Chiroli, Valerio ; Chong, Wesley K.M. ; Carreiro, Samantha T. ; Ongini, Ennio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c355t-6cbc3f67f67e797683ffda74d6d92c7d9ceb4e016d5b64d8d7c2429f7c35b3843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Topical</topic><topic>Animals</topic><topic>Antihypertensive Agents - pharmacokinetics</topic><topic>Antihypertensive Agents - pharmacology</topic><topic>Aqueous Humor - enzymology</topic><topic>BOL-303259-X</topic><topic>Cell Line</topic><topic>Ciliary Body - metabolism</topic><topic>Cyclic GMP - metabolism</topic><topic>Dinoprost - agonists</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Drug Evaluation, Preclinical</topic><topic>Female</topic><topic>glaucoma</topic><topic>Glaucoma - drug therapy</topic><topic>Glaucoma - metabolism</topic><topic>Guanylate Cyclase - metabolism</topic><topic>Intraocular Pressure - drug effects</topic><topic>IOP</topic><topic>Iris - metabolism</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Donors - pharmacokinetics</topic><topic>Nitric Oxide Donors - pharmacology</topic><topic>Ocular Hypertension - drug therapy</topic><topic>Ocular Hypertension - metabolism</topic><topic>pharmacokinetics</topic><topic>prostaglandin</topic><topic>Prostaglandins F, Synthetic - pharmacokinetics</topic><topic>Prostaglandins F, Synthetic - pharmacology</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Tonometry, Ocular</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krauss, Achim H.P.</creatorcontrib><creatorcontrib>Impagnatiello, Francesco</creatorcontrib><creatorcontrib>Toris, Carol B.</creatorcontrib><creatorcontrib>Gale, David C.</creatorcontrib><creatorcontrib>Prasanna, Ganesh</creatorcontrib><creatorcontrib>Borghi, Valentina</creatorcontrib><creatorcontrib>Chiroli, Valerio</creatorcontrib><creatorcontrib>Chong, Wesley K.M.</creatorcontrib><creatorcontrib>Carreiro, Samantha T.</creatorcontrib><creatorcontrib>Ongini, Ennio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental eye research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krauss, Achim H.P.</au><au>Impagnatiello, Francesco</au><au>Toris, Carol B.</au><au>Gale, David C.</au><au>Prasanna, Ganesh</au><au>Borghi, Valentina</au><au>Chiroli, Valerio</au><au>Chong, Wesley K.M.</au><au>Carreiro, Samantha T.</au><au>Ongini, Ennio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models</atitle><jtitle>Experimental eye research</jtitle><addtitle>Exp Eye Res</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>93</volume><issue>3</issue><spage>250</spage><epage>255</epage><pages>250-255</pages><issn>0014-4835</issn><eissn>1096-0007</eissn><abstract>The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
► BOL-303259-X is a novel nitric oxide donating PGF2a agonist. ► Ocular hypotensive activity in primates, dogs and rabbits was assessed. ► IOP reduction greater than latanoprost was observed in all three animal models.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21396362</pmid><doi>10.1016/j.exer.2011.03.001</doi><tpages>6</tpages></addata></record> |
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| ispartof | Experimental eye research, 2011-09, Vol.93 (3), p.250-255 |
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| subjects | Administration, Topical Animals Antihypertensive Agents - pharmacokinetics Antihypertensive Agents - pharmacology Aqueous Humor - enzymology BOL-303259-X Cell Line Ciliary Body - metabolism Cyclic GMP - metabolism Dinoprost - agonists Disease Models, Animal Dogs Drug Evaluation, Preclinical Female glaucoma Glaucoma - drug therapy Glaucoma - metabolism Guanylate Cyclase - metabolism Intraocular Pressure - drug effects IOP Iris - metabolism Macaca fascicularis Male nitric oxide Nitric Oxide - metabolism Nitric Oxide Donors - pharmacokinetics Nitric Oxide Donors - pharmacology Ocular Hypertension - drug therapy Ocular Hypertension - metabolism pharmacokinetics prostaglandin Prostaglandins F, Synthetic - pharmacokinetics Prostaglandins F, Synthetic - pharmacology Rabbits Rats Tonometry, Ocular |
| title | Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models |
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