A Novel Eye Drop Candidate for Age-Related Macular Degeneration Treatment: Studies on its Pharmacokinetics and Distribution in Rats and Rabbits.

Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin® software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.

Protective effect of RIPK1-inhibitory compound in in vivo models for retinal degenerative disease.

Receptor interacting protein kinase 1 (RIPK1) plays a key role in necroptosis, which is a type of programmed necrosis that is involved in ocular diseases, including glaucoma and dry age-related macular degeneration (AMD). We previously introduced RIPK1-inhibitory compound (RIC), which has biochemical characteristics and a mode of action that are distinct from those of the prototype RIPK1 inhibitor necrostatin-1. The intraperitoneal administration of RIC exerts a protective effect on retinal ganglion cells against a glaucomatous insult. In this study, we examined the protective effect of RIC on retinal pigment epithelium (RPE) against sodium iodate (SI) insult, which is associated with dry AMD pathogenesis. The eye drop administration of RIC that reached on the retina prevented RPE loss in SI-induced retinal degeneration. RIC consistently demonstrated retinal protection in the funduscopy and electroretinogram analyses in SI-injected rabbits and iodoacetic acid-treated mini-pigs. Moreover, the in vivo protective effects of RIC were superior to those of ACU-4429 and doxycycline, which are other medications investigated in clinical trials for the treatment of dry AMD, and RIC did not induce retinal toxicity following topical administration in rats. Collectively, RIC displayed excellent retinal penetration and prevented retinal degeneration in the pathogenesis of dry AMD with a high in vivo efficacy.

Efficacy of gastro-retentive forms of ecabet sodium in the treatment of gastric ulcer in rats.

The purpose of the present study is to investigate the influence of gastric retention of ecabet sodium (ECS) on its mucoprotective effect in rat ulcer models. Mini-tablets containing 9 mg ECS were prepared using the direct compression method. The release rates of ECS mini-tablets were controlled by the amount and viscosity grade of hydroxypropylmethyl cellulose incorporated. Gastric retention of ECS mini-tablets after oral administration to rats was visually confirmed using a fluorescence imaging system. Because ECS mini-tablets exhibited size-dependent gastric retention, their gastric retention time was prolonged as the release rate decreased. In the in vivo efficacy study, gastro-retentive dosage forms of ECS did not influence the mucoprotective effect in the immediate irritation model but enhanced the effect in the delayed irritation model compared with ECS suspension. This finding indicates that the duration of the mucoprotective effect of ECS can be extended by the employment of gastro-retentive dosage formulations and provides a rationale for development of ECS gastro-retentive dosage forms.

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase.

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9 approximately 67.5 microg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 microg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC(50) values of 100.1, 118.4, 140.1 microM for RLAR and 168.1, 187.3, 154.2 microM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.

Inhibitory effects of Nelumbo nucifera leaves on rat lens aldose reductase, advanced glycation endproducts formation, and oxidative stress.

The preventive and therapeutic potency against oxidative stress and diabetic complications of Nelumbo nucifera were evaluated via the 1,1-diphenyl-2-picrylhydrazyl (DPPH), Trolox equivalent antioxidant capacity (TEAC), and total reactive oxygen species (ROS) assays, as well as the rat lens aldose reductase (RLAR) and advanced glycation endproducts (AGE) assays. The leaf extract of N. nucifera exerted potent antioxidant effects as well as marked inhibitory effects for RLAR and AGE formation, corresponding to high values for total phenolic content (TPC) and total flavonoid content (TFC). Among several solvent fractions, the EtOAc and n-BuOH fractions, having prominent TPC and TFC values, showed significant antioxidant effects in the DPPH and TEAC assays. Moreover, the EtOAc fraction exhibited superior inhibitory effects in the total ROS, RLAR, and AGE assays, with IC(50) values of 9.4, 2.4, and 28.2microg/ml, respectively. Also, the HPLC profiles of the active EtOAc fraction indicated that quercetin 3-O-beta-d-glucopyranoside (Qc-3-Glc) and Qc 3-O-beta-d-glucuronopyranoside (Qc-3-Gln) were two of its major components, as well as Qc 3-O-beta-d-galactopyranoside (Qc-3-Gal) as a minor compound. Therefore, the results suggest that two key antioxidant flavonoids, Qc-3-Glc and Qc-3-Gln, may play important roles in the antioxidant and RLAR inhibitory effects of N. nucifera leaves. Also, the leaves, and the flavonoids contained within them, would clearly have potential uses in the development of therapeutic or preventive agents for diabetic complications and oxidative stress-related diseases.