Evaluation of implantable collamer lens sizing developed by reviewing the horizontal compression-vault coefficient.

PURPOSE: To evaluate the implantable collamer lens (ICL)-sizing method using the partial regression coefficient of the implanted ICL size to review the conventional horizontal compression coefficient and match the results of clinical observation. SETTING: Nagoya Eye Clinic, Nagoya, Japan. DESIGN: Interventional case series. METHODS: Patients who underwent ICL V4c implantation to correct myopia and myopic astigmatism were enrolled. The stepwise multiple regression analysis used achieved vault as a dependent variable and preoperative biometric parameters as explanatory variables. The partial regression coefficient of the implanted ICL size was obtained to develop the optimal ICL-sizing formula, the Nakamura-Kojima formula version 3 (NK-formula V3). 85 eyes of 45 patients were implanted with an ICL size recommended by the NK-formula V3. At 3 months postoperatively, the achieved vault was measured using anterior segment optical coherence tomography to validate the NK-formula V3. RESULTS: The study enrolled 174 patients (174 eyes). The partial regression coefficient of the implanted ICL size adopted as the compression-vault coefficient in the multiple regression equation predicting the vault was 0.729. To validate the NK-formula V3, 77 (90.6%), 7 (8.2%), and 1 (1.2%) eyes were in the moderate-vault, low-vault, and high-vault categories, respectively. The mean difference between the achieved and predicted vaults was 0.064 ± 0.190 (range: -0.264 to 0.742) mm for the NK-formula V3 and 0.176 ± 0.217 (range: -0.254 to 0.907) mm for the NK-formula V2. CONCLUSIONS: As in vivo coefficient measurement experiments are not possible, the partial regression coefficient is the best option for developing a formula to predict the optimal ICL size.

Long-term In Vivo Stability of Posterior Chamber Phakic Intraocular Lens: Properties and Light Transmission Characteristics of Explants.

PURPOSE: To evaluate the in vivo durability of the surface and optical properties of the implantable Collamer lens (ICL). DESIGN: Retrospective case series. METHODS: We included patients who developed cataracts after having undergone ICL implantation from March 2003 to May 2014 and underwent ICL explantation followed by cataract surgery from March 2017 to December 2019 at the Nagoya Eye Clinic. ICL explants were submitted to Chukyo Medical Co, Ltd (Nagoya City, Japan) for laboratory analysis using ultraviolet-visible light spectroscopy, light microscopy (LM), and scanning electron microscopy. Patients' demographic and clinical data were collected and reviewed. RESULTS: Thirteen eyes from 10 patients were studied. The average age at ICL explantation was 50.5 ± 8.5 years (range, 34.5-66.3 years). The average length of ICL stay in the eye (from implantation to explantation) was 10.5 ± 2.7 years (range, 4.4-13.7 years). No opacification or coloring of the ICL explants was observed by LM. The ICL explants showed almost the same light transmittance as that of unused ICLs. Scanning electron microscopy revealed no irregularities at the surface of the center and periphery of the optic and haptic footplate. The positioning holes did not show any deposition. CONCLUSION: The ICLs remained in-eye for >10 years without any deterioration in the surface and optical properties of the ICL, despite their contact with the ciliary body and iris tissues and the continuous interaction with the aqueous humor components. The present study shows long-term in vivo stability of the ICL.

Optimization of implantable collamer lens sizing based on swept-source anterior segment optical coherence tomography.

PURPOSE: To optimize the implantable collamer lens (ICL) sizing method using anterior segment optical coherence tomography (AS-OCT). SETTING: Nagoya Eye Clinic, Nagoya, Japan. DESIGN: Interventional case series. METHODS: A stepwise multiple regression analysis was performed using the optimal ICL size as a dependent variable and preoperative AS-OCT parameters as explanatory variables for 81 eyes of 41 patients, and the NK-formula version 2 (NK-formula V2) was obtained. Thereafter, 68 eyes of 42 patients were implanted with the ICLs selected as closest to the optimal ICL size calculated by the NK-formula V2. At 3 months postoperatively, the achieved vault was measured by AS-OCT to evaluate the optimization of the sizing method. RESULTS: The anterior chamber width (ACW) and crystalline lens rise were selected as significant parameters for the regression model (R = 0.61, P < .001), as with the previous NK-formula. Of the 68 eyes, 36 patients/62 eyes (91.2%), 5 patients/5 eyes (7.3%), and 1 patient/1 eye (1.5%) were in the moderate, high, and low vault categories, respectively. In the 68 eyes, the vault showed no correlation with the optimal ICL size (R = 0.0185, P = .269), whereas the vault showed a negative correlation with the optimal ICL size in both the 12.6 mm ICL subgroup (R = -0.409, P = .0088) and the 13.2 mm ICL subgroup (R = -0.818, P = .0013). CONCLUSIONS: This optimization approach showed excellent ability to select an appropriate ICL to be implanted regardless of the value of other ocular parameters and age, except ACW.

Posterior Chamber Phakic Intraocular Lens Implantation for the Correction of Myopia and Myopic Astigmatism: A Retrospective 10-Year Follow-up Study.

PURPOSE: To assess the 10-year clinical outcomes of implantable collamer lens (ICL) implantation for myopia and astigmatism. DESIGN: Retrospective observational case series. METHODS: This study included 114 eyes of 61 patients who underwent ICL implantation for correction of myopia and myopic astigmatism. We assessed the safety, efficacy, predictability, stability, and adverse events preoperatively, at 6 months (106 eyes) and 1 (94 eyes), 3 (58 eyes), 5 (65 eyes), 8 (89 eyes), and 10 (70 eyes) years postoperatively. Only the eyes with clinical data available at each follow-up time were analyzed. RESULTS: The mean logMAR uncorrected and corrected distance visual acuities were -0.01 ± 0.24 and -0.18 ± 0.07 at 10 years postsurgery. The mean indices for safety and efficacy were 0.88 ± 0.15 and 0.66 ± 0.26, respectively. At 10 years postsurgery, 71.4% and 87.1% of the eyes were within 0.5 and 1.0 diopters (D), respectively, of the attempted spherical equivalent correction. The mean intraocular pressure was 13.1 ± 2.4 mmHg preoperatively and 13.1 ± 2.9 mmHg at 10 years postoperatively. The mean endothelial cell loss was 5.3% at 10 years postsurgery. Twelve of 114 eyes (10.5%) developed anterior subcapsular cataract during 5-10 years' follow-up; among these, 4 eyes (3.5%) were symptomatic and ICL explantation and phacoemulsification surgery were performed. No vision-threatening complications occurred during the observation period. CONCLUSION: ICL implantation offered good overall outcomes in all measures of safety, efficacy, predictability, and stability for the correction of myopia and myopic astigmatism throughout a long-term follow-up period of 10 years.

Refractive Outcomes After Phototherapeutic Refractive Keratectomy for Granular Corneal Dystrophy.

PURPOSE: This retrospective study aimed to evaluate the effectiveness of a novel procedure named phototherapeutic refractive keratectomy (PTRK), which is a sequential procedure composed of phototherapeutic keratectomy ablation for removal of opacities, followed by smoothing ablation for reducing the corneal surface irregularities and photorefractive keratectomy ablation for correcting refractive errors in eyes with primary granular corneal dystrophy. METHODS: Twenty-three eyes of 17 patients with granular corneal dystrophy were treated with PTRK. Preoperative and postoperative visual acuity, corneal topography, and changes in spherical equivalent and cylindrical refraction were examined and analyzed. RESULTS: The mean spherical equivalent power changed from -0.11 ± 1.36 diopters (D) to 0.19 ± 0.91 D postoperatively (P = 0.121). The change in the mean spherical equivalent was +0.30 ± 0.99 D. The mean preoperative uncorrected distance visual acuity (logMAR) of 0.40 ± 0.26 significantly improved to 0.075 ± 0.145 at 3 months after PTRK (P < 0.001). The mean preoperative corrected distance visual acuity (logMAR) of 0.18 ± 0.17 significantly improved to -0.02 ± 0.11 at 3 months after PTRK (P < 0.01). The surface regularity index was significantly decreased from 0.93 ± 0.46 preoperatively to 0.60 ± 0.30 postoperatively (P < 0.001). CONCLUSIONS: Our results showed that PTRK could improve corneal surface irregularities and remove opacities. Furthermore, both corrected visual acuity and uncorrected visual acuity improved by the addition of refractive correction. PTRK is a promising surgical procedure for improving postoperative quality of life with a high degree of patient satisfaction.

Implantable Collamer Lens Sizing Method Based on Swept-Source Anterior Segment Optical Coherence Tomography.

PURPOSE: To develop and evaluate the accuracy of a size-determination formula using anterior segment optical coherence tomography (AS-OCT) parameters. DESIGN: Interventional case series. METHODS: This study included 46 eyes of 23 patients with implantable collamer lens (ICL). Preoperatively, the anterior segment parameters were measured using high-frequency ultrasound biomicroscopy and AS-OCT. Three months postoperatively, the vaults were measured and the optimal ICL size was calculated using a previously published method. Stepwise multiple regression analysis was performed using the optimal ICL size as a dependent variable; the NK-formula was obtained. Thereafter, 35 eyes of 18 patients were implanted with ICL after the size was calculated using the NK-formula. Vaults measured at 3 months postoperatively were used to evaluate the accuracy of the NK-formula. RESULTS: The distance between scleral spurs (ACW) and crystalline lens rise (CLR) were selected as significant parameters for the regression model (R2 = 0.68, P < .05). There were 25 (71%), 8 (23%), and 2 (6%) eyes in the moderate, high, and low vault categories, respectively. Using the STAAR nomogram for ICL sizing, 24 eyes (69%) were fitted in the moderate vault. The mean absolute error of the predicted vault was significantly lower with the NK-formula (0.190 ± 0.129 mm) than with the STAAR nomogram (0.331 ± 0.235 mm, P = .002, paired t test). CONCLUSION: AS-OCT is useful for ICL size determination, because it calculates the anterior segment parameters using automatic analysis. The NK-formula shows higher accuracy for predicting vault than the STAAR nomogram.

Structural analysis of actinidin and a comparison of cadmium and sulfur anomalous signals from actinidin crystals measured using in-house copper- and chromium-anode X-ray sources.

The structure of the 24 kDa cysteine protease saru-actinidin from the fruit of Actinidia arguta Planch. (sarunashi) was determined by the cadmium/sulfur-SAD method with X-ray diffraction data collected using in-house Cu Kα and Cr Kα radiation. The anomalous scatterers included nine sulfurs and several cadmium ions from the crystallization solution. The high quality of the diffraction data, the use of chromium-anode X-ray radiation and the substantial anomalous signal allowed structure determination and automated model building despite both a low solvent content (<40%) and low data multiplicity. The amino-acid sequence of saru-actinidin was deduced from the cDNA and was modified based on experimental electron-density maps at 1.5 Šresolution. The active site of saru-actinidin is occupied by a cadmium ion and the active-site cysteine is found to be in an unmodified, cysteine sulfenic acid or cysteine sulfinic acid form. The cadmium sites, coordination geometries and polygonal water structures on the protein surface have also been extensively analyzed. An analysis and comparison of the sulfur/cadmium anomalous signals at the Cu Kα and Cr Kα wavelengths was carried out. It is proposed that the inclusion of cadmium salts in crystallization solutions coupled with chromium-anode radiation can provide a convenient route for structure determination.

Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation.

In order to elucidate the antiatherogenic effects of pioglitazone (a peroxisome proliferator-activated receptor [PPAR]gamma agonist with PPARalpha agonistic activity) and rosiglitazone (a more selective PPARgamma agonist), we examined gene expression and cholesteryl ester accumulation in THP-1-derived macrophages. Pioglitazone enhanced the mRNA expression of the proatherogenic factors CD36 and adipophilin, but was approximately 10 times less potent than rosiglitazone. The potencies of the two agents appeared to correspond to their PPARgamma agonistic activities in this respect. However, both agents were similarly potent in enhancing the mRNA expression of the antiatherogenic factors liver X receptor alpha and ATP-binding cassette-transporter A1. Furthermore, both agents enhanced cholesteryl ester hydrolase mRNA expression and inhibited acyl-CoA cholesterol acyltransferase-1 mRNA expression and cholesteryl ester accumulation in macrophages. In this respect, their potencies appeared to correspond to their PPARalpha agonistic activities. These results suggest that pioglitazone has an equally beneficial effect on antiatherogenic events to rosiglitazone, despite being almost 10 times less potent than a PPARgamma agonist.

Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes.

TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.

Changes in glycated haemoglobin levels in diabetic rats measured with an automatic affinity HPLC.

1. The level of glycated haemoglobin (GHb) in diabetic rats was measured using a newly developed automatic high-performance liquid chromatography (HPLC) with a boronate affinity column that requires only 2.5 min per sample for analysis. 2. Levels of GHb were 2.7% in normal 7-week-old Sprague-Dawley rats. These levels increased gradually following the abrupt induction of hyperglycaemia by intravenous injection of streptozotocin (STZ), reaching a maximal level of 10.1% after 6 weeks. 3. Glycosylated haemoglobin (HbA1) levels measured by cation-exchange chromatography were also increased by STZ treatment, although HbA1 values were lower than GHb measured by affinity column HPLC. 4. In Wistar fatty rats, GHb levels declined gradually over 5 weeks following the administration of pioglitazone (0.75 or 2.25 mg/kg per day) as a food admixture, which reduced plasma glucose (PG) levels to normal levels within 1 week. Glycated haemoglobin levels after 5 weeks treatment with pioglitazone correlated better with the area under the curve for PG over the entire 5 week treatment period than with the PG level at the end of treatment. 5. In addition, GHb determined by affinity column HPLC correlated well with HbA1 measured by cation-exchange chromatography, although the GHb value was higher than the HbA1 value. 6. Glycated haemoglobin levels in db/db and KKAy mice were higher than those in control normoglycaemic animals and were also higher than HbA1 values measured by the cation-exchange method, although the two values did show good correlation. 7. These results indicate that the newly developed affinity column HPLC system is useful for evaluating total GHb levels in rats as an index of antidiabetic treatment.

Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro.

1. Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED(50), 2.9 mg kg(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3. In marmosets, TAK-475 (30, 100 mg kg(-1), p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg(-1), p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4. TAK-475 (60 mg kg(-1), p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5. In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of (125)I-low-density lipoprotein (LDL) to LDL receptors. 6. These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.

Synthesis and biological activity of novel 5-(omega-aryloxyalkyl)oxazole derivatives as brain-derived neurotrophic factor inducers.

A novel series of 5-(omega-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neurotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were performed by construction of an oxazole ring as a key reaction. Most of the 5-(omega-aryloxyalkyl)oxazole derivatives markedly increased BDNF production in SK-N-SH cells. 4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-[3-(2-methoxyphenoxy)propyl]-1, 3-oxazole, one of the most promising compounds, showed potent activity (EC(50)=7.9 microM) and the improvement of the motor nerve conduction velocity and the tail-flick response accompanied by a recovery of the brain-derived neurotrophic factor level in the sciatic nerve of streptozotocin (STZ)-diabetic rats.

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia.

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.

Studies on non-thiazolidinedione antidiabetic agents. 2. Novel oxyiminoalkanoic acid derivatives as potent glucose and lipid lowering agents.

We previously reported that (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA(y). This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-gamma. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARgamma. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARgamma, were tested using KKA(y) mice. Among these compounds, (E)-4-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.

Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives.

A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA(y) mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-gamma. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.

Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis.

Modification of the carboxyl group at the 3-position and introduction of protective groups to the hydroxy group of the 4,1-benzoxazepine derivative 2 (metabolite of 1) were carried out, and the inhibitory activity for squalene synthase and cholesterol synthesis in the liver was investigated. Among these compounds, the glycine derivative 3a and beta-alanine derivative 3f exhibited the most potent inhibition of squalene synthase prepared from HepG2 cells (IC(50) = 15 nM). On the other hand, the piperidine-4-acetic acid derivative 4a, which was prepared by acetylation of 3j, was the most effective inhibitor of cholesterol synthesis in rat liver (ED(50) = 2.9 mg/kg, po). After oral administration, 4a was absorbed and rapidly hydrolyzed to deacylated 3j. Compound 3j was detected mainly in the liver, but the plasma level of 3j was found to be low. Compounds 3j and 4a were found to be competitive inhibitors with respect to farnesyl pyrophosphate. Further evaluation of 4a as a cholesterol-lowering and antiatherosclerotic agent is underway.