ABSTRACT
Lipid DNA nanoparticles (NPs) exhibit an intrinsic affinity to the ocular surface and can be loaded by hybridization with fluorophore-DNA conjugates or with the anti-glaucoma drug travoprost by hybridizing an aptamer that binds the medication. In the travoprost-loaded NPs (Trav-NPs), the drug is bound by specific, non-covalent interactions, not requiring any chemical modification of the active pharmaceutical ingredient. Fluorescently labeled Trav-NPs show a long-lasting adherence to the eye, up to sixty minutes after eye drop instillation. Biosafety of the Trav-NPs was proved and in vivo. Ex vivo and in vivo quantification of travoprost via LC-MS revealed that Trav-NPs deliver at least twice the amount of the drug at every time-point investigated compared to the pristine drug. The data successfully show the applicability of a DNA-based drug delivery system in the field of ophthalmology for the treatment of a major retinal eye disease, i.e. glaucoma.
Subject(s)
DNA/chemistry , Drug Delivery Systems , Glaucoma/drug therapy , Nanoparticles/chemistry , Animals , Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/pharmacology , Containment of Biohazards , DNA/pharmacology , Disease Models, Animal , Humans , Lipids/chemistry , Lipids/pharmacology , Mice , Rats , Swine , Travoprost/chemistry , Travoprost/pharmacologyABSTRACT
Topical ophthalmic formulations of analogues of the endogenous arachidonic acid cyclooxygenase metabolite, PGF2α , are the standard of care treatment for the blinding disease glaucoma. These are the most potent and efficacious medical therapies for lowering intraocular pressure (IOP), the most important risk factor identified for disease progression. They have few side effects and offer the convenience of once-a-day dosing. It was initially believed that endogenous PGs raised IOP and caused substantial ocular surface adverse effects. However, carefully designed experiments demonstrated that esterification of the carboxylic acid afforded potent and efficacious topical ocular hypotensive activity. The final hurdle to be overcome was improvement of the side effect profile. A hypothesis was advanced that the IOP-lowering effect of PGF2α isopropyl ester was due to activation of its cognate PG-FP receptor, while side effects were largely due to promiscuous interaction with other PG receptors. This hypothesis was validated by modification of the ω chain (carbons 13-20) to a phenyl group. This provided the first marketed FP-class PG agonist analogue (FP-PGA) ocular hypotensive agent, latanoprost. Since the introduction of latanoprost into clinical medicine to lower and control IOP, a number of additional FP-PGAs have been discovered, characterized and marketed, including travoprost, tafluprost, unoprostone isopropyl ester and bimatoprost (an amide). LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
Subject(s)
Antihypertensive Agents/therapeutic use , Drug Discovery/methods , Glaucoma/drug therapy , Prostaglandins/agonists , Animals , Antihypertensive Agents/chemistry , Bimatoprost/chemistry , Bimatoprost/therapeutic use , Drug Discovery/trends , Glaucoma/metabolism , Humans , Prostaglandins/metabolism , Prostaglandins F/chemistry , Prostaglandins F/therapeutic use , Travoprost/chemistry , Travoprost/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: To evaluate some clinically important features of benzalkonium chloride (BAK) toxicity by comparing tafluprost with 0.001% BAK and travoprost preserved with SofZia applied to the ocular surface of the eyes with glaucoma. METHODS: This was a prospective, randomized, observer unmasked, multicenter crossover trial. A total of 195 patients were randomized and 174 patients completed the study at 19 clinics between November 2011 and August 2012. Topical BAK-preserved tafluprost or SofZia-preserved travoprost was newly administered or continued. Superficial punctate keratopathy (SPK), tear break-up time (BUT), the conjunctival hyperemia score, and intraocular pressure (IOP) were compared at the baseline visit, 4, and 12 weeks after the start of therapy. The eye drops were switched to another eye drop after 12 weeks of observation. RESULTS: The total SPK and conjunctival hyperemia scores were significantly lower in the tafluprost compared with those in the travoprost phase (both P=0.038). There were no significant differences in the SPK scores of the superior area (P=0.679), central area (P=0.089), inferior area (P=0.090), and tear BUT (P=0.271). The IOP-lowering effects were similar (P=0.155). CONCLUSIONS: SPK, hyperemia score, and tear BUT while using tafluprost with 0.001% BAK were not inferior compared with those caused by travoprost with SofZia.
Subject(s)
Antihypertensive Agents/adverse effects , Benzalkonium Compounds/adverse effects , Preservatives, Pharmaceutical/adverse effects , Prostaglandins F/adverse effects , Travoprost/adverse effects , Aged , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Benzalkonium Compounds/chemistry , Cross-Over Studies , Female , Glaucoma, Open-Angle/drug therapy , Glaucoma, Open-Angle/pathology , Humans , Intraocular Pressure/drug effects , Male , Ocular Hypertension/drug therapy , Ocular Hypertension/pathology , Ophthalmic Solutions/administration & dosage , Ophthalmic Solutions/adverse effects , Ophthalmic Solutions/chemistry , Preservatives, Pharmaceutical/chemistry , Prospective Studies , Prostaglandins F/administration & dosage , Prostaglandins F/chemistry , Travoprost/administration & dosage , Travoprost/chemistryABSTRACT
OBJECTIVE: The aim of this study is to compare the effect of prostaglandin analogues preserved with either 0.015% or 0.001% benzalkoium chloride (BAK); or 0.001% polyquad (PQ) on the ocular surface of rabbit eyes. METHODS: Forty white rabbits were randomized to receive four-times daily instillation of either 0.0015% tafluprost (TF) preserved with 0.001% BAK (TF-BAK); 0.004% travoprost (TR) with 0.015% BAK (TR-BAK) or 0.001% PQ (TR-PQ); or preservative-free artificial tears in one eye for a 4-week period. Tear samples collected from the 40 rabbits were analyzed by enzyme-linked immunosorbent assays (ELISA) to identify the presence of inflammatory cytokines: interleukin (IL)-1ß and IL-6 on day 14. Subsequently, harvested cornea and bulbar conjunctiva were evaluated using light and transmission electron microscopy (TEM). RESULTS: IL-6 was significantly increased in TF-BAK and TR-BAK groups compared to controls and TR-PQ group (p = 0.005); however, IL-1ß level was not significantly different among four groups (p = 0.360). Rabbits treated with TR-BAK showed decreased goblet cell density of bulbar conjunctiva and increased pyknotic change and vacuolization of corneal epithelial cells on light microscopy; similar change occurred but was less severe in TF-BAK group. The TR-PQ group showed similar results as the controls. The destruction of the microvillar architecture of bulbar conjunctiva and cornea was most prominent in the TR-BAK group. CONCLUSIONS: Preservatives included in the anti-glaucoma eye-drops showed different ocular surface changes according to the concentration and type in the rabbits. Prostaglandin analogues preserved with higher level of BAK may cause more harmful effects on the ocular surface than PQ-preserved medications.
