Jaeseong Oh

Short-term effect of intracameral triamcinolone acetonide on corneal endothelium using the rabbit model.

PurposeTo investigate the effect of intracameral injection of triamcinolone acetonide on the corneal endothelium in rabbit eyes.MethodsTriamcinolone acetonide (40 mg/ml, 0.2 cm3) after filtering and resuspension in balanced salt solution (BSS) was injected intracamerally for 3 min into 10 rabbit eyes and irrigated with 5 cm3 of BSS. Triamcinolone without resuspension and BSS were injected, respectively, into five rabbit eyes. Endothelial toxicity was evaluated and compared by measurements of endothelial cell counts and central corneal thickness. The endothelial viability was determined using vital staining with alizarin red and trypan blue at 2 h after injection. The scanning electron microscopy (SEM) was performed in one cornea from each group.ResultsEndothelial cell counts and central corneal thickness following intracameral injection of triamcinolone acetonide did not significantly change when compared to controls. The mean percentage of viable endothelial cells was 99.50, 99.52, and 99.49% in the resuspended triamcinolone group, triamcinolone without resuspension group, and BSS group, respectively (P=0.46, Kruskall–Wallis test). But SEM showed reduced microvilli of endothelial surface in an eye of the triamcinolone without resuspension group.ConclusionsThe intracameral injection of triamcinolone acetonide did not induce a significant visable change of endothelium in rabbit eyes. However, ultrastructural villi changes observed suggest a possibility of microstructural damages in endothelium with triamcinolone acetonide injection when used without filtering and resuspension.

Intraocular pharmacokinetics of intravitreal vascular endothelial growth factor-Trap in a rabbit model

PurposeTo determine intraocular pharmacokinetic properties of intravitreally injected vascular endothelial growth factor (VEGF)-Trap in a rabbit model.MethodsVEGF-Trap was intravitreally injected in 18 rabbit eyes. Eyes were enucleated 1 h and 1, 2, 5, 14, and 30 days after injections and immediately frozen at −80 °C. Concentration of VEGF-Trap in vitreous, aqueous humor, and retina/choroid was determined using an indirect enzyme-linked immunosorbent assay and analyzed to obtain pharmacokinetic properties.ResultsMaximum concentration of VEGF-Trap was achieved at 1 h in all three tissues. A one-compartment model of distribution was selected as the final model for all tissues studied. Estimated half-life of VEGF-Trap in vitreous, aqueous humor, and retinal/choroid was 87.1, 36.8, and 35.0 h, respectively, and estimated mean residence time was 125.7, 53.1, and 50.5 h, respectively. Area under the curve from time 0 to the end point was 10009.8, 3945.1, and 1189.3, respectively. Total exposure of the aqueous humor and retina/choroid to VEGF-Trap was 39.4% and 11.9% of vitreous exposure, respectively.ConclusionThe vitreous half-life of VEGF-Trap is 3.63 days. This is shorter than that of bevacizumab (6.99 days) and longer than that of ranibizumab (2.51 days), as shown in studies using the same experimental settings. The concentration of VEGF-Trap peaked at 1 h after injections in all eye tissues studied.

Inhibition of the multidrug and toxin extrusion (MATE) transporter by pyrimethamine increases the plasma concentration of metformin but does not increase antihyperglycaemic activity in humans.

We hypothesized that the pharmacodynamic (PD) characteristics of metformin would change with inhibition of the multidrug and toxin extrusion (MATE) transporter, which mediates renal elimination of metformin. Twenty healthy male subjects received two doses (750/500 mg) of metformin, with and without 50 mg of pyrimethamine (a potent MATE inhibitor), with 1 week of washout in between each dose. The PD characteristics of metformin were assessed using oral glucose tolerance tests (OGTTs) before and after the metformin dose. Metformin concentrations in plasma and urine were determined using liquid chromatography‐electrospray ionization‐tandem mass spectrometry. When metformin was co‐administered with pyrimethamine, its area under the concentration–time curve from 0 to 12 h was 2.58‐fold greater (p < 0.05), whereas the antihyperglycaemic effects of metformin were decreased. The mean differences (90% confidence interval) in mean and maximum serum glucose concentrations and in 2‐h‐post‐OGTT serum glucose concentration were −0.6 (−1, −0.2), −0.9 (−1.6, −0.3) and −0.5 (−1.1, 0.1) mmol/l, respectively. These findings indicate that the response to metformin is not only related to the plasma exposure of metformin but is also related to other factors, such as inhibition of uptake transporters and the gastrointestinal‐based pharmacology of metformin.

Aspirin Decreases Systemic Exposure to Clopidogrel Through Modulation of P‐Glycoprotein But Does Not Alter Its Antithrombotic Activity

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P‐gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75‐mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once‐daily 100‐mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P‐gp microRNA miR‐27a increased by up to 7.67‐fold (P = 0.004) and the clopidogrel area under the concentration–time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low‐dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.

The diagnosis of diabetes mellitus in Korea: a pooled analysis of four community-based cohort studies

In 1997, the American Diabetes Association (ADA) proposed that the cut-off point for fasting plasma glucose (FPG) for diabetes should be reduced from 7.8 to 7.0 mmol/l. Since this report, several studies have shown poor agreement between criteria based on FPG and postchallenge 2-h plasma glucose (2-h PG). The association of FPG with 2-h PG may vary between populations due to different environmental or genetic backgrounds. The Committee of the Korean Diabetes Association on the Diagnosis and Classification of Diabetes Mellitus selected four of the community-based epidemiological studies in Korea that (i) were population based, (ii) were performed after 1990, (iii) included both men and women, (iv) studied patients who were at least 30 years of age, and (v) used a standard 2-h 75-g oral glucose tolerance test (OGTT). Using these four studies, we examined the diagnostic equivalence of FPG values to 2-h PG values of 7.8 and 11.1 mmol/l. The study subjects were 6234 (2473 in Yonchon [1], 774 in Mokdong [2], 1106 in Chongup [3] and 1881 in Ansan [4]). Yonchon and Chongup counties are rural communities, Mokdong is a residential district in metropolitan Seoul and Ansan is an urban area near Seoul. For statistical analysis, receiver operating characteristics (ROC) analysis was performed to reveal the optimal cut-off point of FPG to diagnose diabetes with a 2-h PG value ≥ 11.1 mmol/l, and impaired glucose tolerance (IGT) with a 2-h PG value ≥ 7.8 mmol/l. The mean age and body mass index of study subjects were 51.9 ± 13.7 years and 23.7 ± 3.2 kg/m 2 , respectively. The resulting ROC curve showed the optimal cut-off point of FPG values for the diagnosis of diabetes was 6.1 mmol/l, with sensitivity and specificity of 76.4% and 92.2%, respectively (Fig. 1). The sensitivity and specificity of the currently applied cut-off point for the diagnosis of diabetes, 7.0 mmol/l, were 56.5% and 98.8%, respectively. From the ROC curve, the optimal cut-off point of FPG values to diagnose IGT was 5.4 mmol/l, with 57.5% sensitivity and 71.0% specificity. There have been many reports that the optimal cut-off point of FPG for diabetes diagnosis is lower than that of the ADA recommendation, a result consistent with this study. In the DECODA study, the optimal FPG cut-off point corresponding to a 2-h PG of ≥ 11.1 mmol/l was 5.8 mmol/l by ROC analysis [5]. Chang et al . have also suggested that in a Taiwanese population the optimal FPG as a screening criterion for diabetes is 6.25 mmol/l, with sensitivity and specificity of 57.6% and 96.1%, respectively [6]. Recently, Miyazaki et al . reported that in a Japanese population, the optimal cut-off FPG level for the diagnosis of diabetes was 6.4 mmol/l. They showed a dramatic increase of retinopathy at this point [7]. Thus, the optimal cut-off point of FPG for the diagnosis of diabetes varies substantially between ethnic groups, and is slightly lower (range 5.6–6.4 mmol/l) in Asian than in Western populations. In this study, a FPG cut-off of 6.1 mmol/l corresponded to a 2-h PG value of 11.1 mmol/l. If this new cut-off value were used to diagnose diabetes, 11.3% of subjects would be classified as having diabetes, which is about two times higher than when a 2-h PG value of 11.1 mmol/l is used (5.1%). In this case, as the sensitivity increases, the specificity and positive predictive value decrease accordingly. As there have been no prospective cohort data of mortality to define the appropriate criteria for diagnosing diabetes in Korea and international comparison is important, it is prudent to retain the current fasting glucose value of 7.0 mmol/l as the cut-off for diagnosing diabetes in Korean adults.

Susceptibility of Porcine Keratocytes to Immune-Mediated Damage in Xeno-Related Rejection

We admixed cultured porcine keratocytes or corneal endothelial cells in the presence of human sera or peripheral blood mononuclear cells (PBMCs) for 4 to 72 hours to investigate their immune-related susceptibilities to xeno-related rejection. We evaluated complement deposition at 48 hours by flow cytometry after staining with the C3 anti-goat cy3 antibody. The inhibition of proliferation of porcine corneal cells by human sera was examined using the 3-[4,5-dimethy/thiazol-2,5-dephenyl tetrazolium bromide (MTT) assay over 24 to 72 hours. The amount of 51chromium (Cr)-release was estimated after a reaction between the porcine cells and human PBMCs for 4 hours. There was greater C3 deposition in keratocytes (60.2%) than in endothelial cells (26.9%; P = .05, Mann-Whitney U test). Both keratocytes and endothelial cells showed significant levels of proliferative inhibition over a period of 72 hours. The number of 51Cr-release cells on interleukin-2 addition was significantly higher among keratocytes (88.0%) than endothelial cells (51.4%) at a 1:100 target:effector ratio (P = .04, Mann-Whitney U test). Our present data suggested that porcine keratocytes might be key target cells in xeno-related rejections when the porcine cornea is transplanted to primates.

Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects

Evogliptin is a newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which is expected to be combined with metformin for treating type 2 diabetes mellitus. We investigated the potential pharmacokinetic and pharmacodynamic interactions between evogliptin and metformin. A randomized, open-label, multiple-dose, six-sequence, three-period crossover study was conducted in 36 healthy male subjects. All subjects received three treatments, separated by 7-day washout intervals: evogliptin, 5 mg od for 7 days (EVO); metformin IR, 1,000 mg bid for 7 days (MET); and the combination of EVO and MET (EVO + MET). After the last dose in a period, serial blood samples were collected for 24 hours for pharmacokinetic assessments. During steady state, serial blood samples were collected for 2 hours after an oral glucose tolerance test, and DPP-4, active glucagon-like peptide-1, glucose, glucagon, insulin, and C-peptide were measured to assess pharmacodynamic properties. EVO + MET and EVO showed similar steady state maximum concentration and area under the concentration–time curve at steady state values for evogliptin; the geometric mean ratios (90% confidence interval) were 1.06 (1.01–1.12) and 1.02 (0.99–1.06), respectively. EVO + MET slightly reduced steady state maximum concentration and area under the concentration–time curve at steady state values for metformin compared to MET, with geometric mean ratios (90% confidence interval) of 0.84 (0.79–0.89) and 0.94 (0.89–0.98), respectively. EVO + MET and EVO had similar DPP-4 inhibition efficacy, but EVO + MET increased active glucagon-like peptide-1 and reduced glucose to larger extents than either EVO or MET alone. Our results suggested that EVO+MET could provide therapeutic benefits without clinically significant pharmacokinetic interactions. Thus, the EVO + MET combination is a promising option for treating type 2 diabetes mellitus.

Outbreak of Gram-positive bacterial keratitis associated with epidemic keratoconjunctivitis in neonates and infants.

ObjectivesTo report the clinical characteristics of bacterial keratitis associated with epidemic keratoconjunctivitis (EKC) and to evaluate the risk factors for bacterial keratitis development in eyes with EKC.MethodsAfter 108 patients diagnosed as EKC were retrospectively reviewed, clinical characteristics and incidence of bacterial keratitis-associated EKC were described. To analyse the effect of steroid use and the methicillin-resistant Staphylococcus aureus (MRSA) colonization in conjunctiva on developing bacterial keratitis, HCU-stayed children (n=43) were divided into two groups: those with and those without bacterial keratitis. Other risk factors such as gestational age, duration of hospitalization, MRSA colonization rate of other sites, and interval between follow-ups were evaluated in neonates who stayed in a neonatal intensive care unit (NICU; n=29).ResultsEight out of nine bacterial keratitis developed in HCU-stayed children. All the eight cases of bacterial keratitis occurred in neonates and infants. MRSA keratitis was found in seven hospitalized infants. The incidence of bacterial keratitis was significantly higher in HCU-stayed children than in outpatients (P=0.03), although it never occurred in HCU-stayed adults. The culture-positive rate of MRSA in conjunctiva (P=0.047) and topical use of steroid (P=0.01) were significantly higher in HCU-stayed children who carried bacterial keratitis. The incidence of bacterial keratitis was significantly related with the longer interval of follow-up in early EKC period in NICU in patients (P=0.009).ConclusionsInfants and neonates show high tendency of MRSA keratitis accompanied with EKC, especially if they were in HCU, applied topical steroid or followed with long interval.

Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel DPP‐IV inhibitor, evogliptin (DA‐1229)

Evogliptin is a novel potent and selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor. The aim of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin in participants with renal impairment (RI). An open‐label, parallel‐group clinical study was conducted in participants with mild, moderate and severe RI and in matched participants with normal renal function (NRF). A single oral 5‐mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the PK and PD characteristics of evogliptin. Baseline urine samples were collected to evaluate endogenous CYP3A metabolic markers. The plasma exposure to evogliptin and degree of DPP‐4 activity inhibition increased with decreasing renal function. The mean areas under the concentration–time curves from 0 to 120 hours were increased 1.2‐, 1.8‐ and 1.98‐fold in the mild, moderate and severe RI groups, respectively, compared with the NRF group. The levels of CYP3A metabolic markers were lower in the RI group than in the NRF group. The increase in the plasma concentration of evogliptin is unlikely to result in changes in its efficacy or safety, considering the results of previous clinical studies.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers

ABSTRACT Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.)