Surgical outcomes of endoscopic dacryocystorhinostomy for eyes with nasolacrimal duct obstruction via tear meniscus height evaluation.

PURPOSE: To evaluate the association of tear meniscus height (TMH) with clinical outcomes of patients who underwent endonasal dacryocystorhinostomy. METHODS: We recruited 304 patients from two institutes. The TMH was measured using anterior segment optical coherence tomography before surgery. All patients underwent endoscopic DCR with lacrimal intubation stent insertion. The lacrimal stent was removed 2 months after surgery. The TMH was measured at 2 months and 12 months after surgery. Improvements in epiphora were assessed using a visual analogue scale (range, 0-2). Recurrence was determined based on lacrimal irrigation and endoscopic evaluation results. RESULTS: All patients experienced improvements in subjective symptoms 2 months after surgery. The mean TMH also decreased significantly compared with that before surgery. During the follow-up period, four patients experienced recurrence. The mean TMH 12 months after surgery was significantly lower than that before surgery. The rate of change in the TMH was significantly associated with the use of a dacryoendoscope during sheath-guided lacrimal stent intubation at all time points. Of the 251 patients who were followed up at 12 months after surgery, three reported recurrences, and 17 reported mild improvement of epiphora. The rate of change in the TMH was significantly associated with epiphora improvement. Height was also associated with epiphora improvement. CONCLUSIONS: Endoscopic DCR is an acceptable surgical procedure for managing nasolacrimal duct obstruction. Sheath-guided lacrimal stent intubation using a dacryoendoscope resulted in a greater reduction in postoperative TMH compared to the blind insertion technique, which may lead to favorable clinical outcomes.

Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro.

Nabumetone (NAB) is a non-steroidal anti-inflammatory drug used clinically, and its biotransformation includes the major active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). One of the key intermediates between NAB and 6-MNA may be 3-hydroxy nabumetone (3-OH-NAB). The aim of the present study was to investigate the role of flavin-containing monooxygenase (FMO) isoform 5 in the formation of 6-MNA from 3-OH-NAB. To elucidate the biotransformation of 3-OH-NAB to 6-MNA, an authentic standard of 3-OH-NAB was synthesised and used as a substrate in an incubation with human liver samples or recombinant enzymes. The formation of 3-OH-NAB was observed after the incubation of NAB with various cytochrome P450 (CYP) isoforms. However, 6-MNA itself was rarely detected from NAB and 3-OH-NAB. Further experiments revealed a 6-MNA peak derived from 3-OH-NAB in human hepatocytes. 6-MNA was also detected in the extract obtained from 3-OH-NAB by a combined incubation of recombinant human FMO5 and human liver S9. We herein demonstrated that the reaction involves carbon-carbon cleavage catalyzed by the Baeyer-Villiger oxidation (BVO) of a carbonyl compound, the BVO substrate, such as a ketol, by FMO5. Further in vitro inhibition experiments showed that multiple non-CYP enzymes are involved in the formation of 6-MNA from 3-OH-NAB.

Two-hole assisted phaco-chop technique: a more efficient method for safe nucleofractis vertical chopping.

PURPOSE: To evaluate the use of the two-hole technique in augmenting the efficiency of surgeons-in-training when performing the phaco-chop technique. We hypothesized that drilling two holes in opposite angles to each other adjacent to the capsulorhexis would mimic a new lens equator. The phaco-tip and the chopper can be inserted into these holes at appropriate depths and may sandwich and fracture the lens more easily than conventional methods. METHODS: The two-hole technique described above was performed by three first-year surgeons before they performed the standard phaco-chop technique. We collected data of their first 8 cases and analyzed a total of 64 cases: 16, divide-and-conquer; 24, two-hole method; 24, phaco-chop. The main outcome measures included the cumulative dissipated energy (CDE) and case ultrasound time (UST) with different phacoemulsification techniques. RESULTS: The young practicing surgeons eventually performed the standard phaco-chop more safely after repeated practice using the two-hole method. The drilling of holes enabled deep and effortless impaling of the nucleus. Although there was no significant difference in the CDE among the techniques, there was a significant difference in the UST (P < 0.05). CONCLUSION: The two-hole method enabled surgeons-in-training to acquire standard phaco-chop skills more efficiently. However, further studies with higher statistical power will be needed to validate these findings. Additionally, a variation of this technique, the four-hole method, is applicable even for experienced surgeons in cases of a hardened nucleus.

A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes.

The pathway for the transformation of the prodrug nabumetone, 4-(6-methoxynaphthalen-2-yl)butan-2-one, to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), a potent cyclooxygenase-2 inhibitor, has not yet been clarified in humans.To confirm the activation pathway, authentic standards of the nabumetone intermediates, 2-(6-methoxynaphthalen-2-yl)ethyl acetate (6-MNEA), 2-(6-methoxynaphthalen-2-yl)ethan-1-ol (6-MNE-ol) and 2-(6-methoxynaphthalen-2-yl)acetaldehyde (6-MN-CHO) were synthesized. High performance liquid-chromatography and gas chromatography-mass spectrometry on nabumetone oxidation revealed the generation of three metabolites.The formation of 6-MNA after a 60-min incubation of nabumetone was detected and 6-MNE-ol, an alcohol-related intermediate, was also generated by in cryopreserved hepatocytes. However, 6-MNA was below detection limit, but 4-(6-methoxynaphthalen-2-yl)butan-2-ol (MNBO) and 4-(6-hydroxynaphthalen-2-yl)butan-2-one (M3) peak were found in both the microsomes and S9 extracts with any cofactors.Nabumetone has recently been proposed as a typical substrate of flavin-containing monooxygenase isoform 5 (FMO5) and was shown to be efficiently oxidized in vitro to 6-MNEA. 6-MNA was detected in the extract obtained from a combined incubation of recombinant FMO5 and S9 fractions.The specificity of FMO5 towards catalyzing this Baeyer-Villiger oxidation (BVO) was demonstrated by the inhibition of the BVO substrate, 4-methoxyphenylacetone. Further in vitro inhibition studies demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of 6-MNA.

Determination of the Absolute Configuration of the Nabumetone Metabolite 4-(6-Methoxy-2-naphthyl)butan-2-ol Using the Chiral Derivatizing Agent, 1-Fluoroindan-1-carboxylic Acid.

The absolute configuration of (+)-4-(6-methoxy-2-naphthyl)butan-2-ol ((+)-MNBO), a nabumetone metabolite, was determined using 1-fluoroindan-1-carboxylic acid (FICA). Both enantiomers of the FICA methyl esters were derivatized to diastereomeric esters of (+)-MNBO by an ester exchange reaction. The results of 1H- and 19F-NMR spectroscopy of the diastereomeric FICA esters of (+)-MNBO confirmed the absolute configuration of (+)-MNBO was (S).

Repair of angle recession prevents pupillary capture of intrasclerally fixed intraocular lenses.

PURPOSE: We evaluated a new concept for treating pupillary capture of the intraocular lens (IOL) following intrascleral fixation of the IOL. Pupillary capture of the IOL is a common postoperative complication that occurs after suturing and intrascleral fixation of the IOL. In such cases, blunt trauma is often related to zonular dialysis, iris retraction, iridodonesis, and angle recession. Several methods such as barricading by suturing, pupilloplasty, and pars plana fixation are reported to prevent pupillary capture. Although effective, none of these techniques fix iris-malposition and angle recession. We considered that repairing angle recession could correct the iris position and prevent pupillary capture recurrence. METHODS: We repaired angle recession in four cases and have followed up. RESULTS: Pupillary capture was not observed in all three cases of larger IOLs for more than 9 months, but observed after 1 month in an IOL with normal 6 mm diameter, in which the angle was not properly lifted. CONCLUSION: In select cases, repairing angle recession may be useful for preventing pupillary capture after IOL suturing and intrascleral fixation.

Suturing repair of subtotal iridodialysis.

PURPOSE: To report a case of subtotal iridodialysis that was repaired using suturing with the assistance of a guide needle. PATIENT AND METHODS: A 52-year-old man had subtotal iridodialysis of approximately 300° with massive hyphema and vitreous hemorrhage after blunt trauma. The patient was treated with pars plana vitrectomy, and then suturing repair of iridodialysis was performed. RESULTS: After the surgeries, the ratio of pupil area to corneal area is improved from 82.1 to 42.4%. The visual acuity improved to 30/20, and subjective symptoms of glare and monocular diplopia disappeared. There was no remarkable postoperative complication for up to 12 months. CONCLUSIONS: Suturing repair is useful for subtotal iridodialysis and may be an alternative for an iris implant.

The in Vitro Release of Indomethacin from Suppositories: Effects of Bases and Comparison of Different Dissolution Methods.

The suitability of apparatuses for the quality control of indomethacin (IND, 50 mg) compounded suppositories was evaluated and the effects of the type of suppository base on release profiles was investigated. The release characteristics of hydrophilic and lipophilic suppositories containing IND were compared using four types of dissolution methods: basket (RB), paddle (PD), dialysis tubing (DT) and flow-through cell (FTC). The release process was evaluated using the following model independent parameters: the mean dissolution time (MDT), cumulative percent of drug released (Q) at the end of the sampling time, and dissolution efficiency (DE). The fastest and most reproducible release profiles were observed for a hydrophilic base (macrogols), which resulted in more than 90% of the drug being released in 30 min using PD, RB and FTC. After 90 min, 90% of the total amount of the drug was released from a mixture of hydrophilic bases with a lipophilic base (macrogols and hard fat) in compendial dissolution methods and the mixture base was the second fastest only to the hydrophilic base. The slowest release profiles in each method were observed for the lipophilic base (hard fat). Poor drug release from any type of suppository base was noted using DT. Based on the results of the present study, FTC may be regarded as an adequate technique allowing sufficient discriminating power for the quality control of IND compounded suppositories.

Comparative release studies on suppositories using the basket, paddle, dialysis tubing and flow-through cell methods I. Acetaminophen in a lipophilic base suppository.

The release characteristics of lipophilic suppositories containing acetaminophen (AAP) were examined using four types of dissolution methods: the basket, paddle, dialysis tubing (DT) and flow-through cell (FTC) methods. The suitability of each apparatus for quality control in AAP compounded suppositories was evaluated using statistical procedures. More than 80% of the drug was released over 60 min in all the release methods studied, with the exception of the basket method. Reproducible and faster release was achieved using the paddle method at 100 and 200 rpm, whereas poor release occurred with the basket method. The mean dissolution time (MDT), maximum dissolved quantity of AAP at the end of the sampling time (Q) and dissolution efficiency (DE) were calculated by model-independent methods. The FTC method with a single chamber used in this study was also appreciable for AAP suppositories (Q of 100%, MDT of 71-91 min and DE of 75-80%). The DT apparatus is considered similar to the FTC apparatus from a quality control perspective for judging the release properties of lipophilic base suppositories containing AAP. However, even the single chamber FTC used in this study has potential as an in vitro drug release test for suppositories. The comparative dissolution method is expected to become one of the valuable tools for selecting an adequate dissolution test.

Reductive metabolism of nabumetone by human liver microsomal and cytosolic fractions: exploratory prediction using inhibitors and substrates as marker probes.

The metabolic reduction of nabumetone was examined by inhibition and correlation studies using human liver microsomes and cytosol. This reduction was observed in both fractions, with the V(max) values for reduction activity being approximately fourfold higher, and the V(max)/K(m) values approximately three-fold higher, in the microsomes than in the cytosol. The reduction of nabumetone was inhibited by 18ß-glycyrrhetinic acid, an 11ß-hydroxysteroid dehydrogenase (11ß-HSD) inhibitor, in the microsomal fraction. The reduction activity was also inhibited by quercetin and menadione [carbonyl reductase (CBR) inhibitors], and by phenolphthalein and medroxyprogesterone acetate [potent inhibitors of aldo-keto reductase (AKR) 1C1, 1C2 and 1C4] in the cytosol. A good correlation (r² = 0.93) was observed between the reduction of nabumetone and of cortisone, as a marker of 11ß-HSD activity, in the microsomal fractions. There was also an excellent relationship between reduction of nabumetone and of the AKR1C substrates, acetohexamide, and ethacrynic acid (r 2 = 0.92 and 0.93, respectively), in the cytosol fractions. However, a poor correlation was observed between the formation of 4-(6-methoxy-2-naphthyl)-butan-2-ol (MNBO) from nabumetone and CBR activity (with 4-benzoyl pyridine reduction as a CBR substrate) in the cytosol fractions (r² = 0.24). These findings indicate that nabumetone may be metabolized by 11ß-HSD in human liver microsomes, and primarily by AKR1C4 in human liver cytosol, although multiple enzymes in the AKR1C subfamily may be involved. It cannot be completely denied that CBR is involved to some extent in the formation of MNBO from nabumetone in the cytosol fraction.

Two cases of nasolacrimal duct obstruction operated by endoscopic dacryocystorhinostomy after orbital fracture reconstruction with an implant.

Purpose: To report two cases of nasolacrimal duct obstruction (NLDO) caused by orbital fracture reconstruction with an implant successfully treated with endoscopic dacryocystorhinostomy (EnDCR). Observations: Two patients presented with NLDO after orbital fracture reconstruction with an implant. Case 1 was a 67-year-old female. She became aware of epiphora in her left eye after undergoing orbital fracture reconstruction with an implant for a left orbital floor fracture 14 years previously. Dacryocystitis was diagnosed based on a lacrimal syringing test because of pus reflux. Computed tomography (CT) showed that the implant was inserted on the left orbital floor, crossing into the lacrimal sac; dacryoendoscopy showed that the implant blocked the nasolacrimal duct. EnDCR was performed without implant removal. The symptoms resolved postoperatively. Case 2 involved a 6-year-old male who had been aware of epiphora in his left eye since undergoing orbital fracture reconstruction with an implant for a left orbital floor fracture one month prior. Dacryocystitis was diagnosed based on a lacrimal syringing test because of pus reflux. CT showed an unclear implant location, but dacryoendoscopy showed that the implant blocked the nasolacrimal duct. The implant was removed. However, EnDCR was performed because there was no improvement in NLDO. The symptoms resolved after EnDCR. Conclusions and importance: One previous report of NLDO after orbital floor fracture reconstruction was performed with external dacryocystorhinostomy with implant removal. Dacryoendoscopy and CT are useful for confirming the location of the implant and obstruction. Depending on the implant's location, it may be possible to perform EnDCR without removing the implant.

Two Cases of Bilateral Rhegmatogenous Retinal Detachment During Orthokeratology Treatment.

Orthokeratology may be effective in slowing myopic progression. However, whether orthokeratology is beneficial enough to prevent rhegmatogenous retinal detachment formation remains unclear. Two cases of bilateral rhegmatogenous retinal detachment were seen during orthokeratology treatment and corrected with scleral buckling and cryopexy under general anesthesia. This is the first report of bilateral retinal detachment found during orthokeratology treatment. Although orthokeratology is effective for myopic correction and prevents axial length elongation, patients still have a risk of rhegmatogenous retinal detachment. Careful follow-up not only of the anterior segment but also of the peripheral retina is necessary.

Recording the direct surgeon's view with an operating microscopic view improves microscopic ophthalmic surgery training.

AIM: To establish a recording system with a direct view of the surgeon to supplement video recording under an operating microscope, which lacks information on the movement and position of the surgeon's hands, and to facilitate the reproduction of a skilled surgeon's technique by a surgeon in training. METHODS: A small camera was attached to the operating microscope with a custom adapter. Microscopic surgeon's view and direct surgeon's view through this new camera were recorded in the surgical recording system. Both movies were synchronized and analyzed how do surgeons handle the instruments. RESULTS: A small camera attached to the operating microscope allowed the surgeon's hands motion to be recorded without interfering with the surgeon's movements. Different surgeons used different methods to manipulate the ultrasound handpiece and the irrigation/aspiration device. Even in the simple paracentesis procedure, different surgeons used different methods. Surgeons-in-training were able to identify and improve their weaknesses by watching synchronized movies of their hand motions and microscopic view. CONCLUSION: Simultaneous recording the surgical field out of the operating microscopic view by a small camera set on the microscope is comprehensive and improves surgeons-in-training understanding and learning surgeries.

Weak Inhibitory Effects of Anthocyanins on Human Aldehyde Oxidase Activity: An In Vitro Study.

Aldehyde oxidase (AO) plays an important role in the metabolism of antitumor and antiviral drugs, including methotrexate, favipiravir, and acyclovir. The consumption of blueberry fruits or their extracts, which contain large amounts of anthocyanins, has recently increased. The intake of large amounts of anthocyanins occurs through the frequent consumption of blueberries or their functional foods, which may result in unwanted interactions between anthocyanins and medicinal drugs. Therefore, the present study examined the inhibition of AO by anthocyanins, anthocyanidins, and blueberry extracts in human liver cytosol using a HPLC assay. A comparison of the 50% inhibitory concentration (IC50) values of the test compounds showed that anthocyanidins slightly suppressed AO activity, whereas the inhibitory effects of anthocyanins and blueberry extracts were negligible. The inhibitory activities of the anthocyanins tested were approximately 60- to 130-fold weaker than that of the positive control menadione and were almost negligible. Furthermore, they were approximately 2,000-fold less potent than that of raloxifene, a typical AO inhibitor, and, thus, unlikely to interfere with drug metabolism by AO. In addition, since the plasma concentrations of anthocyanins after their administration were generally lower than the IC50 level, the inhibition of AO substrate metabolism by anthocyanins does not appear to be severe.

Coughing-induced retinal pigment epithelial tear after trabeculectomy combined with pars plana vitrectomy.

Purpose: To report a case of retinal pigment epithelial (RPE) tear after trabeculectomy combined with pars plana vitrectomy (PPV). Observations: A 65-year-old man with neovascular glaucoma due to proliferative diabetic retinopathy presented with visual impairment and elevated intraocular pressure (IOP) in the right eye and underwent trabeculectomy combined with PPV. Three weeks after surgery, the best-corrected visual acuity (logarithm of minimal angle of resolution) improved from 3.0 to 0.30, and the IOP was controlled within normal limits. Four weeks after the surgery, he noticed visual impairment and ocular pain in the right eye after continuous coughing associated with asthma. Fundus examination revealed bullous retinal detachment, choroidal detachment, and submacular hemorrhage (SMH) due to a giant RPE tear at the posterior pole. Visual acuity worsened considerably to 1.7, while IOP was not elevated (6 mmHg). The patient received PPV with recombinant tissue plasminogen activator (rt-PA) and fluid/air exchange for internal tamponade and achieved anatomic retinal and choroidal attachments. Conclusions and importance: The acute increase in hydrostatic pressure in the choroidal interstitium due to continuous coughing induces an RPE tear. Vitrectomy with rt-PA and fluid/air exchange may be a favorable treatment for exudative retinal detachment and SMH due to RPE tears.

In vitro characterization of the cytochrome P450 isoforms involved in the metabolism of 6-methoxy-2-napthylacetic acid, an active metabolite of the prodrug nabumetone.

The cytochrome P450 (CYP) isoforms that catalyze the oxidation metabolism of 6-methoxy-2-napthylacetic acid (6-MNA), an active metabolite of nabumetone, were studied in rats and humans. Using an extractive reversed-phase HPLC assay with fluorescence detection, monophasic Michaelis-Menten kinetics was obtained for the formation of 6-hydroxy-2-naphthylacetic acid (6-HNA) in liver microsomes of rats and humans, and kinetic analysis showed that the K(m) and V(max) values for the formation of 6-HNA in humans and rats were 640.0 ± 30.9 and 722.9 ± 111.7 µM, and 1167.5 ± 33.0 and 1312.7 ± 73.8 pmol min⁻¹ mg protein⁻¹, respectively. The CYPs responsible for metabolism of 6-MNA in liver microsomes of rats and humans were identified using correlation study, recombinant CYP supersomes, and specific CYP inhibitors and antibodies. Recombinant human CYP2C9 exhibited appreciable catalytic activity with respect to 6-HNA formation from 6-MNA. Among 14 recombinant rat CYPs examined, CYP2C6, CYP2C11 and CYP1A2 were involved in the metabolism of 6-MNA. Sulfaphenazole (a selective inhibitor of CYP2C9) inhibited the formation of 6-HNA in pooled human microsomes by 89%, but failed to inhibit this reaction in rat liver microsomes. The treatment of pooled human liver microsomes with an antibody against CYP2C9 inhibited the formation of 6-HNA by about 80%. The antibody against CYP2C11 suppressed the activity by 20 to 30% in rat microsomes, whereas that of CYP1A2 microsomes did not show drastic inhibition. These findings suggest that CYP2C9 has the highest catalytic activity of 6-MNA metabolism in humans. In contrast, metabolism of 6-MNA is suggested to be mediated mainly by CYP2C6 and CYP2C11 in rats.

Intraocular gas dynamics after 20-gauge and 23-gauge vitrectomy with sulfur hexafluoride gas tamponade.

PURPOSE: The purpose of this study was to evaluate the intraocular gas dynamics after 23-gauge transconjunctival sutureless vitrectomy (TSV) as compared with 20-gauge pars plana vitrectomy (PPV). METHODS: A consecutive series of 290 eyes that experienced 20-gauge or 23-gauge vitrectomy with 25% sulfur hexafluoride (SF6) gas tamponade were retrospectively reviewed. Intraocular gas bubble size on postoperative Day 1 and Gas50, the interval to dissipate to a 50% gas fill, were evaluated. RESULTS: The mean intraocular bubble size on postoperative Day 1 was 92.0 ± 8.3% in the 20-gauge PPV cases and 83.8 ± 13.7% in the 23-gauge TSV cases (P < 0.001). The mean Gas50 was 8.6 ± 1.6 days in the 20-gauge PPV cases and 6.6 ± 2.2 days in the 23-gauge TSV cases (P < 0.001). Thorough peripheral vitrectomy and 23-gauge TSV were significantly associated with Gas50 ≤ 4 days (odds ratio, 4.62 and 16.8; P = 0.036 and P = 0.007, respectively). Among thoroughly vitrectomized eyes, 13 eyes treated with 23-gauge PPV with intraoperative suture placement at the sclerotomy sites had gas longevity comparative to those with 20-gauge PPV. CONCLUSION: Eyes treated with 23-gauge TSV tend to have earlier gas disappearance or incomplete gas fill. Intraoperative suture placement would be a solution.

Repairing Cyclodialysis by Riveting: A Flanged Polypropylene Suture.

Cyclodialysis causes intraocular lens (IOL) pupillary capture. It requires surgical repair to prevent this risk of IOL pupillary capture. However, since repairing cyclodialysis is often technically difficult, other methods such as barricading by suturing, pupilloplasty, and pars plana fixation of the IOL were preferred. We applied a double-flanged (riveting) technique for repairing cyclodialysis to prevent IOL pupillary capture following intrascleral fixation of the IOL. Cyclodialysis was surgically repaired by riveting with double-flanged 6-0 polypropylene sutures in 3 cases with no recurrence of pupillary capture during at least 12 months of follow-up. When pupillary capture is related to cyclodialysis, repairing cyclodialysis may help prevent pupillary capture after intrascleral fixation of the IOL. Riveting using a double-flanged 6-0 polypropylene suture could possibly make the procedure simpler and more efficient.

A Modified Intrascleral Intraocular Lens Fixation Technique Using 27-Gauge Blunted Needles with Fewer Intraocular Manipulations.

A new method for intraocular lens (IOL) fixation in the scleral tunnel using two common 27G blunted needles and an ultrathin 30G needle with fewer intraocular manipulations was developed. Half-depth scleral flaps were prepared, and vertically angled sclerotomies were performed under each scleral flap, 2 mm from the limbs with a 20G microblade or a 26G needle. Two bent 27G blunted needles connected the sclerotomy and corneoscleral incisions. One haptic was inserted into this bent 27G blunted needle extraocularly and extruded through the sclerotomy site. Each haptic was inserted into the lumen of the preplaced ultrathin 30G needle and buried into the scleral tunnel. In this retrospective study, we reviewed the outcomes of this new technique in patients with at least 3 months' follow-up data. Iris capture of the IOL was not observed in any case, and IOL repositioning was not performed either. Astigmatism induced by intraocular aberration was almost as same as that with other methods. Our technique can be performed in any operation room without any extra instruments. This trial is registered with UMIN000044350.