Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.

The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis.

AIMS: To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients. METHODS: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model. RESULTS: A 2-compartment model with sequential zero- and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and -10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 106 /L, respectively, and mean changes in CL of -17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m2 , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m2 ) compared with patients with reference eGFR (91.5 mL/min/1.73m2 ). CONCLUSION: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.

A drug-drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers.

PURPOSE: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers. METHODS: Inhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug-drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5-11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography-tandem mass spectrometry and its pharmacokinetic parameters calculated. RESULTS: Peficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration-time curve from 0 h extrapolated to infinity (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated. CONCLUSION: Slight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects.

BACKGROUND AND OBJECTIVE: Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. RESULTS: Dose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. CONCLUSIONS: Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01225224.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects with Normal and Impaired Renal Function.

BACKGROUND AND OBJECTIVE: This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose. METHODS: This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose. RESULTS: Peficitinib plasma concentration-time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration-time curve and maximum concentration were 0.8- to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal. CONCLUSIONS: Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT02603497.

Results of switchback from ranibizumab to aflibercept in patients with exudative age-related macular degeneration.

PURPOSE: Intravitreal injection of anti-VEGF drugs has become standard therapy for patients with exudative age-related macular degeneration (AMD). However, some patients do not exhibit sufficient response to the drugs for suppression of choroidal neovascularization activity. We investigated the efficacy of switchback from ranibizumab to aflibercept in patients with AMD who could not achieve further benefit beyond initial therapy of aflibercept injection. METHODS: Eleven eyes of eleven patients were included in this study. Two patients were nonresponders, and nine exhibited tachyphylaxis to aflibercept. All patients received three monthly injections of ranibizumab as an initial phase of switching and received aflibercept as a switchback drug. We investigated changes in injection interval, visual acuity, and central retinal thickness. RESULTS: In four patients (36.4%), injection interval was extended. The interval was 6.73 weeks before switch and 9.27 weeks after switchback (P=0.96). LogMAR visual acuity was 0.22 before switch and 0.24 after switchback (P=0.62). Central retinal thickness was 306.8 µm before switch and 256.1 after switchback (P=0.13). In all patients who were nonresponders to aflibercept, injection interval could not be extended. CONCLUSION: A switchback from ranibizumab to aflibercept may be beneficial in some patients with AMD who exhibit tachyphylaxis to aflibercept.

Reduction of Intraocular Pressure by Additional Trabeculotomy Ab Externo in Eyes With Primary Open-angle Glaucoma.

PURPOSE: The purpose of this study was to determine whether a second trabeculotomy (LOT) can reduce the intraocular pressure (IOP) in eyes with primary open-angle glaucoma (POAG) that had undergone an unsuccessful LOT as the initial surgery. PATIENTS AND METHODS: LOT ab externo was performed as a second surgery on 37 eyes of 34 POAG patients who had undergone an unsuccessful LOT as the initial surgery. The main outcome measure was the postoperative IOPs, and surgical failures were defined as eyes with a post-LOT IOP>20 mm Hg. The eyes were divided into 3 groups; those that underwent LOT as both the initial and additional surgery (L-L group), those that underwent LOT as the initial surgery and combined LOT and cataract surgery (cLOT-IOL) as the additional surgery (L-cL group), and those that underwent cLOT-IOL as the initial surgery and LOT as the additional surgery (cL-L group). RESULTS: The IOP was reduced after the additional LOT at postoperative 24 months in the L-L group from 20.0±3.0 mm Hg to 15.3±2.6 mm Hg (P<0.001), the L-cL group from 19.8±1.6 mm Hg to 15.8±3.2 mm Hg (P=0.029), and the cL-L group from 20.1±2.7 mm Hg to 15.5±2.3 mm Hg (P=0.014). There were no differences in the preoperative and postoperative IOPs between the initial-operated and additional-operated eyes. The success rates were improved by the additional surgery in the L-L group (P<0.001) and the L-cL group (P=0.029), but the rate was worsened in the cL-L group (P<0.001). CONCLUSIONS: These results indicate that LOT is a reasonable choice as an additional glaucoma surgery after failure of an initial LOT.

Selegiline increases on time without exacerbation of dyskinesia in 6-hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements.

3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa-induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration (on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l-Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements (l-Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin (PDy) and activity-regulated cytoskeleton-associated protein (Arc), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia.

Long-Term Stability of Minimally Invasive Radial Keratotomy for Mild to Moderate Keratoconus.

PURPOSE: This study aimed to evaluate the long-term stability of minimally invasive radial keratotomy (mini-RK) for eyes with mild to moderate keratoconus. DESIGN: Retrospective observational case series. METHODS: Eleven eyes from 6 patients with hard contact lens (HCL)-intolerant keratoconus underwent mini-RK and were followed up for more than 5 years. The mini-RK consisted of 8 radial incisions with depths of 90% of the thinnest corneal thickness, based on the Lindstrom nomogram. Best-corrected visual acuity (BCVA), keratometry, and corneal endothelial cell density (ECD) were examined preoperatively and for 5 to 10 years postoperatively. Changes in keratometric astigmatism were evaluated using power vector analysis. Severities of keratoconus preoperatively and 1 year postoperatively were graded using the Amsler-Krumeich classification. RESULTS: The postoperative observation periods were from 6 to 10 years (mean, 7.9 years). There were no changes in the BCVA, ECD, and keratometric astigmatism. The mean keratometric refraction significantly decreased from 47.5 diopters (D) preoperatively to 44.0 D at 1 month after mini-RK (P = 0.037) and was stable over 5 years, whereas keratometric astigmatism did not change from preoperatively through the postoperative period (P > 0.59). Keratoconus of grade 2 or higher improved to lower grades. CONCLUSIONS: The mini-RK treatment was safe and effective for HCL-intolerant eyes with mild to moderate keratoconus.

Psychomotor effect differences between l-methamphetamine and d-methamphetamine are independent of murine plasma and brain pharmacokinetics profiles.

l-Methamphetamine has been occasionally referred to as a stimulant similar to d-methamphetamine, probably owing to insufficient comparative studies. Here, we directly compared psychomotor efficacies and pharmacokinetics of methamphetamine enantiomers in mice. Only d-methamphetamine, but not l-methamphetamine, induced stereotypy and sensitization at 1-10 mg/kg. However, plasma pharmacokinetic parameters of 10 mg/kg l-methamphetamine were ≥tenfold those of 1 mg/kg d-methamphetamine. These results clearly indicate that differential psychomotor efficacies of methamphetamine enantiomers are independent of their pharmacokinetic profiles.

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa. METHODS: In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5-13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10. RESULTS: Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C max) by 18 and 15%, respectively and increased peficitinib AUC and C max by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C max was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall. CONCLUSION: In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1. CLINICALTRIALS. GOV NUMBER: NCT01959399.

Three-year results of a modified photodynamic therapy procedure (Ironing PDT) for age-related macular degeneration patients with large lesions.

BACKGROUND: To evaluate the effect of photodynamic therapy (PDT) using a modified procedure on exudative age-related macular degeneration having been conventionally difficult to treat. METHODS: The medical records of eight consecutive patients (eight eyes) with age-related macular degeneration treated with modified PDT were reviewed retrospectively. Modified PDT was used for the lesions that could not be covered by conventional use of PDT, either because the lesion was too large or too close to the optic disc. A moving PDT laser spot at constant speed, for 83 seconds, was used to cover the entire lesion, and was named "Ironing PDT." This retrospective study was performed with informed patient consent. It was approved by the Institutional Review Board of Kansai Medical University. RESULTS: No exudation could be found 36 months after treatment in five eyes (62.5%). There was no significant difference between the best-corrected visual acuity before PDT (0.95 logMAR) and after PDT (1.09 logMAR). The logMAR best-corrected visual acuity was improved in one eye, maintained in five eyes, and deteriorated in two eyes. CONCLUSION: Ironing PDT decreased subfoveal fluid and preserved visual acuity in some patients with age-related macular degeneration difficult to treat with conventional therapy.

Case of Primary Intraocular Lymphoma with Extraocular Extension.

PURPOSE: To describe a case of primary intraocular lymphoma (PIOL) with an extension through the sclera that was confirmed to be part of the PIOL by histopathological examinations. CASE: An 89-year-old woman was referred to a local clinic with a 1-year history of persistent blurred vision in her left eye. After 2 years without aggressive treatments, she had a marked reduction of vision and pain in her left eye. The clinical diagnosis was panophthalmitis, and the eye was enucleated and submitted for histopathological study. RESULTS: Light microscope examination showed that atypical lymphocytic cells had infiltrated into both the intraocular and extraocular areas. The anterior chamber angle was blocked by infiltrating tumor cells, which were also detected around the optic nerve. The tumor cells destroyed Bruch's membrane and infiltrated around the perineural and perivascular areas within the sclera. Immunohistochemistry showed that the tumor cells were positive for B-lymphocyte surface antigen (CD20), B-cell antigen receptor complex-associated protein alpha chain (CD79-alpha), and had a high positive rate for anti-Ki-67 antibody. CONCLUSION: The finding in our case indicates that early diagnosis and treatment are important for eyes with PIOL because the tumor can spread and penetrate the sclera and invade extraocular tissues.

Favorable anatomic and visual outcomes with 25-gauge vitrectomy for myopic foveoschisis.

PURPOSE: To report the surgical outcomes of 25-gauge vitrectomy in eyes with myopic foveoschisis (MF). METHODS: The medical records of 40 eyes of 36 patients that had undergone 25-gauge vitrectomy with internal limiting membrane peeling for MF were studied. The main outcome measures were the best-corrected visual acuity (BCVA) and the optical coherence tomography (OCT) findings. The eyes were divided into two groups: 1) those with a foveal detachment (FD; FD group); and 2) those without a FD (no-FD group). RESULTS: The postoperative OCT images showed a resolution of the MF with a significant reduction in the central foveal thickness from the preoperative values in both the FD group (479±150 µm to 196±56 µm; P=0.002, mean ± standard deviation) and in the no-FD group (369±116 µm to 245±50 µm; P=0.001). The final mean BCVA significantly improved from the preoperative values in the FD group (0.96±0.53 logarithm of the minimum angle of resolution [logMAR] units to 0.70±0.56 logMAR units; P=0.009) and in the no-FD group (0.46±0.38 logMAR units to 0.34±0.36 logMAR units; P=0.007). The final BCVA in the FD group improved in 63%, remained unchanged in 31%, and worsened in 6%. In the no-FD group, the final BCVA improved in 21%, remained unchanged in 71%, and worsened in 8% of the eyes. A better final BCVA was significantly correlated with a better preoperative BCVA in both groups (P<0.001). CONCLUSION: Twenty five-gauge vitrectomy results in favorable visual and anatomic outcomes for MF. We recommend that 25-gauge vitrectomy be used to treat eyes with MF.

Clinical features of diabetic patients referred by general physicians due to less ophthalmic examinations.

BACKGROUND: The purpose of this study was to determine the clinical features of patients with type 2 diabetes, and less ophthalmic examinations, referred by general physicians to ophthalmologists. METHODS: The medical charts of 327 patients with type 2 diabetes referred to our department from general physicians were reviewed. A detailed medical history was taken and a complete ophthalmic examination was performed for all patients. The patients were divided into two groups, ie, those with a history of missing ophthalmic examinations for more than a year (noncompliant group) and those with no previous ophthalmic examinations (never-examined group). Serum levels of glycosylated hemoglobin and creatinine, estimated glomerular filtration rate, and urine albumin/creatinine ratio were obtained from medical records. RESULTS: Of the 327 patients, 102 had diabetic retinopathy (31.2%), with a mean best-corrected visual acuity of 0.037±0.36 logMAR (logarithm of the minimum angle of resolution) units. Of the 327 patients, 203 were in the never-examined group and 124 were in the noncompliant group. The incidence of diabetic retinopathy in the noncompliant group was significantly higher than that in the never-examined group (P<0.001). Best-corrected visual acuity in the noncompliant group was significantly worse than in the never-examined group (P=0.004). Glycosylated hemoglobin levels and estimated glomerular filtration rate in the noncompliant group were significantly lower than in the never-examined group (P<0.001 and P<0.003, respectively); serum creatinine levels and urine albumin/creatinine ratio were significantly higher (P=0.020 and P=0.001, respectively). The severity of the diabetic retinopathy was significantly correlated with compliance in terms of ophthalmic examinations and with urine albumin/creatinine ratio (multiple regression analysis, P=0.047 and P<0.001, respectively). CONCLUSION: Our results show that diabetic patients referred from general physicians due to less ophthalmic examinations generally have good visual acuity, but one third of them have diabetic retinopathy. A history of missing ophthalmic examinations and albuminuria are risk factors for diabetic retinopathy.

Usefulness of dual echo volumetric isotropic turbo spin echo acquisition (VISTA) in MR imaging of the temporomandibular joint.

PURPOSE: We investigated the ability to detect the articular disk and joint effusion of the temporomandibular joint (TMJ) of a method of dual echo volumetric isotropic turbo spin echo acquisition (DE-VISTA) additional fusion images (AFI). METHODS: DE-VISTA was performed in the 26 TMJ of 13 volunteers and 26 TMJ of 13 patients. Two-dimensional (2D) dual echo turbo spin echo was performed in the 26 TMJ of 13 volunteers. On a workstation, we added proton density-weighted images (PDWI) and T2 weighted images (T2WI) of the DE-VISTA per voxel to reconstruct DE-VISTA-AFI. Two radiologists reviewed these images visually and quantitatively. RESULTS: Visual evaluation of the articular disk was equivalent between DE-VISTA-AFI and 2D-PDWI. The sliding thin-slab multiplanar reformation (MPR) method of DE-VISTA-AFI could detect all articular disks. The ratio of contrast (CR) of adipose tissue by the articular disk to that of the articular disk itself was significantly higher in DE-VISTA-AFI than DE-VISTA-PDWI (P<0.05) in patients and volunteers with closed or open mouth. In volunteers, the CR between adipose tissue and the disk on DE-VISTA-AFI was marginally significant to that on 2D-PDWI at opened mouth (P=0.071) and not significantly different (P=0.18) from that at closed mouth. Joint effusion could be identified in DE-VISTA-AFI in all 8 joints that had joint effusion in DE-VISTA-T2WI but in only 3 of those joints in 2D-T2WI. The CR of joint effusion to adipose tissue on DE-VISTA-AFI did not differ significantly from that on DE-VISTA-PDWI. However, using DE-VISTA-T2WI in addition to DE-VISTA-PDWI, we could visually identify joint effusion on DE-VISTA-AFI that could not be identified on DE-VISTA-PDWI alone. CONCLUSION: DE-VISTA-AFI can depict the articular disk and a small amount of joint effusion by the required plane of MPR using the sliding thin-slab MPR method.

Fever of unknown origin successfully treated by oren-gedoku-to (huanglian-jie-du-tang).

Oren-gedoku-to is a traditional medicine used for treating inflammatory conditions and is given by prescription in Japan, People's Republic of China, and Korea. Its anti-inflammatory effect is related to the arachidonate cascade and inhibition of cyclo-oxygenase, but research on other anti-inflammatory pathways is ongoing. We report a case of fever of unknown origin in a 33-year-old woman. The possibility of infection due to human immunodeficiency virus, autoimmune, neoplastic, or other disease was examined and excluded. Oren-gedoku-to was successfully used to treat her symptoms and may thus be a suitable treatment for patients with undiagnosed fever of unknown origin.

Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD).

BACKGROUND: Patients with exudative age-related macular degeneration (AMD) who did not respond to ranibizumab at the induction phase were assessed and referred to as initial non-responders. METHODS: We retrospectively reviewed the medical records of 215 patients (218 eyes) with exudative AMD. For the initial treatments, patients received three intravitreal injections of ranibizumab (IVR) every 4 weeks. Minimum follow-up period was 12 months. We defined patients with no improvement of best corrected logMAR visual acuity (BCVA), and with no decrease of central retinal thickness (CRT) at the end of the initial treatment, as initial non-responders. Patients who had previous treatment history prior to this investigation were included, but patients who had photodynamic therapy (PDT) with IVR were excluded. RESULTS: Twenty-two eyes (10.1%) were identified as initial non-responders. The mean BCVA of initial non-responders before IVR and after induction phase were 0.39 and 0.36, respectively. There was no significant difference between these values, however the mean BCVA decreased significantly to 0.55 at 12 months after the beginning of the induction phase (P = 0.021). The mean greatest linear dimension (GLD) of the lesion before IVR of initial non-responders was 4,121 µm. We found 16 eyes with typical AMD, and six eyes with polypoidal choroidal vasculopathy. One eye had predominantly classic choroidal neovascularization (CNV), and others had occult CNV of typical AMD. As additional treatments, twelve eyes received PDT, and in three of the eyes exudation remained after PDT. CONCLUSION: Initial non-responders were more prevalent in patients with occult CNV than in patients with other CNV types. Some of the initial non-responders did not respond to PDT. This study suggested possible involvement of other factors, in addition to vascular endothelial growth factor, in the occurrence of CNV in initial non-responder patients.