No abstract

Overall intraocular pharmacokinetic properties of ranibizumab in vitrectomized eyes were similar to those in nonvitrectomized eyes. Our data do not support the use of different dosing regimens of ranibizumab in vitrectomized eyes.

Citation: Park SJ, Choi Y, Na YM, et al. Intraocular pharmacokinetics of intravitreal aflibercept (eylea) in a rabbit model. Invest Ophthalmol Vis Sci. 2016;57:261257: -261757: . DOI:10.1167 PURPOSE. We determined the intraocular pharmacokinetic properties of intravitreally injected aflibercept (Eylea) in a rabbit model. METHODS.Aflibercept was injected intravitreally in 21 eyes from New Zealand White rabbits. The eyes were enucleated 1, 24, 48, 120, 216, 360, and 720 hours (1, 2, 5, 9, 15, and 30 days, respectively) after injection and immediately frozen at À808C. The concentrations of aflibercept in the vitreous, aqueous humor, and retina/choroid were determined by performing an indirect enzyme-linked immunosorbent assay, and analyzed to understand the pharmacokinetic properties of the drug. RESULTS.The maximum concentration of aflibercept was observed 1, 48 (2 days), and 24 (1 day) hours after intravitreal administration in the vitreous, aqueous humor, and retina/ choroid, respectively. The one-compartment model was selected as the final model for all three ocular tissues. In the vitreous, aqueous humor, and retina/choroid, the estimated halflives of aflibercept were 94.1, 48.0, and 58.2 hours, and the estimated mean residence times (MRTs) were 135.8, 69.2, and 84.0 hours, respectively. The area under curve from time 0 to the end point (AUC last ) was 135,810.6 hours 3 lg/mL for the vitreous, 13,889.7 hours 3 lg/ mL for the aqueous humor, and 2453.1 hours 3 lg/g for the retina/choroid. CONCLUSIONS.In rabbits, the vitreous half-life of aflibercept is 94.1 hours (3.92 days). This is shorter than that of bevacizumab (6.99 days), and longer than that of ranibizumab (2.51 days) and VEGF-Trap (3.63 days).

Metformin is a first-line drug for treating type 2 diabetes. Although metformin is known to phosphorylate AMP-activated protein kinase (AMPK), it is unclear how the glucose-lowering effect of metformin is related to AMPK activation. The aim of this study was to identify the urinary endogenous metabolites affected by metformin and to identify the novel underlying molecular mechanisms related to its anti-diabetic effect. Fourteen healthy male subjects were orally administered metformin (1000 mg) once. First morning urine samples were taken before and after administration to obtain metabolomic data. We then further investigated the anti-diabetic mechanism of metformin in vitro and in vivo. The fluctuation of the metabolite cortisol indicated that the neuroendocrine system was involved in the anti-diabetic effect of metformin. Actually we found that metformin induced AMPK/liver X receptor α (LXRα) phosphorylation, followed by pro-opiomelanocortin (POMC) suppression in rat pituitary cells. We confirmed this result by administering metformin in an animal study. Given that cortisol stimulates gluconeogenesis, we propose the anti-hyperglycemic effect of metformin is attributed to reduced POMC/adrenocorticotropic hormone (ACTH)/cortisol levels following AMPK/LXRα phosphorylation in the pituitaries.

Three dead dogs were brought to the College of Veterinary Medicine, Kyungpook National University for study. Clinically, all the dogs showed emaciation, anorexia, depression, hemorrhagic vomiting and diarrhea for 7~10 days before death. All the clinical signs were first noted for about one month after feeding the dogs with commercial diets. At necropsy, all 3 dogs had severe renal damage with the same green-yellowish colored nephroliths in the renal pelvis. They also showed systemic hemorrhage and calcification of several organs, which might have been induced by uremia. Microscopically, necrosis, calcification and calculi were detected in the renal tubules, and especially in the proximal convoluted tubules and collecting ducts of the kidney. These findings were supportive of a mycotoxic effect, and especially on their kidneys. However, the precise cause of the toxic effect in these cases of canine renal failure could not be determined.

Ursodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.

No abstract

The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80-1·25).