title: Effects of novel hybrids of caffeic acid phenethyl ester and NSAIDs on experimental ocular inflammation.
abstract: In this study, we report the design and synthesis of novel hybrids of caffeic acid phenetyl ester (CAPE) and non-steroidal anti-inflammatory drugs (NSAIDs). We assessed their effects on an experimental ocular inflammation in New Zealand rabbits. The formulations of CAPE-aspirin and CAPE-indomethacin hybrids were topical instilled in the rabbit׳s eye. Afterwards, the anti-inflammatory activity was evaluated by grading the clinical signs and by assessing the inflammatory cell count, protein, PGE2 and TNFα levels in the aqueous humor. Furthermore, ocular tolerability of hybrids formulations was evaluated in a separate set of animals by using a modified Draize test. The ocular inflammation in the control group was significantly higher than in both the hybrid-treated groups, as indicated by clinical grading and biomarkers assessment. However, only the CAPE-aspirin hybrid reduced, in a significant dose-dependent manner, the ocular inflammation elicited by paracentesis. CAPE-indomethacin hybrid was able to significantly attenuate the clinical grading and the PGE2 aqueous levels only at the highest dose (0.1%). CAPE-aspirin significantly reduced PGE2 and TNFα levels in the aqueous humor as well as proteins and PMNs. Finally, all formulations showed no ocular irritation compared with vehicle-treated group. In conclusion, CAPE-aspirin shows full anti-inflammatory efficacy in experimental model of ocular inflammation demonstrating an optimal pharmacological and safety profile. Taken together these data indicate that CAPE-aspirin hybrid represents a valid and safe new chemical entity potentially useful for the treatment of ocular inflammation.
authors.affiliation: Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.affiliation: Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.affiliation: Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.affiliation: Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Siracusa
authors.affiliation: Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Maria Nunziata
authors.initials: MN
authors.lastname: Modica
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Romano
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, viale A. Doria 6, 95125 Catania, Italy. Electronic address: claudio.bucolo@unict.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001241:Aspirin / Q000737:chemistry*; D002109:Caffeic Acids / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005128:Eye Diseases / Q000188:drug therapy* / Q000473:pathology*; D007213:Indomethacin / Q000737:chemistry*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D010626:Phenylethyl Alcohol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002109:Caffeic Acids; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D001241:Aspirin; D007213:Indomethacin
keywords: Aspirin; Caffeic acid phenethyl ester; Eye; Heme oxygenase-1 inducer; Indomethacin; Inflammation