-
1.
An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy.
Anayo, L, Magnussen, A, Perry, A, Wood, M, Curnow, A
Lasers in surgery and medicine. 2018;(5):552-565
-
-
Free full text
-
Abstract
OBJECTIVES Non-melanoma skin cancers are the most frequently occurring type of cancer worldwide. They can be effectively treated using topical dermatological photodynamic therapy (PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease remains superficial. Novel iron chelating agents are being investigated to enhance the effectiveness and extend the applications of this treatment modality, as limiting free iron increases the accumulation of PpIX available for light activation and thus cell kill. METHODS Human lung fibroblasts (MRC-5) and epithelial squamous carcinoma (A431) cells were treated with PpIX precursors (aminolaevulinic acid [ALA] or methyl-aminolevulinate [MAL]) with or without the separate hydroxypyridinone iron chelating agent (CP94) or alternatively, the new combined iron chelator and PpIX producing agent, AP2-18. PpIX fluorescence was monitored hourly for 6 hours prior to irradiation. PDT effectiveness was then assessed the following day using the lactate dehydrogenase and neutral red assays. RESULTS Generally, iron chelation achieved via CP94 or AP2-18 administration significantly increased PpIX fluorescence. ALA was more effective as a PpIX-prodrug than MAL in A431 cells, corresponding with the lower PpIX accumulation observed with the latter congener in this cell type. Addition of either iron chelating agent consistently increased PpIX accumulation but did not always convey an extra beneficial effect on PpIX-PDT cell kill when using the already highly effective higher dose of ALA. However, these adjuvants were highly beneficial in the skin cancer cells when compared with MAL administration alone. AP2-18 was also at least as effective as CP94 + ALA/MAL co-administration throughout and significantly better than CP94 supplementation at increasing PpIX fluorescence in MRC5 cells as well as at lower doses where PpIX accumulation was observed to be more limited. CONCLUSIONS PpIX fluorescence levels, as well as PDT cell kill effects on irradiation can be significantly increased by pyridinone iron chelation, either via the addition of CP94 to the administration of a PpIX precursor or alternatively via the newly synthesized combined PpIX prodrug and siderophore, AP2-18. The effect of the latter compound appears to be at least equivalent to, if not better than, the separate administration of its constituent parts, particularly when employing MAL to destroy skin cancer cells. AP2-18 therefore warrants further detailed analysis, as it may have the potential to improve dermatological PDT outcomes in applications currently requiring enhancement. Lasers Surg. Med. 50:552-565, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.
-
2.
Prospective Randomized Trial of Corneal Cross-linking Riboflavin Dosing Frequencies for Treatment of Keratoconus and Corneal Ectasia.
Price, MO, Fairchild, K, Feng, MT, Price, FW
Ophthalmology. 2018;(4):505-511
Abstract
PURPOSE To investigate whether the riboflavin dosing frequency affects corneal cross-linking efficacy or safety, given that isotonic riboflavin solution is viscous and each installation coats the corneal surface with a film that absorbs some of the incident ultraviolet A light. DESIGN Prospective, randomized, single-center equivalence trial. PARTICIPANTS Patients with progressive keratoconus or ectasia after refractive surgery (n = 510). METHODS One eye per patient was prospectively randomized to 2-minute or 5-minute riboflavin dosing intervals with standard corneal cross-linking (epithelial removal and 30-minute irradiation with 3 mW/cm2 ultraviolet A light). Block randomization resulted in comparable representation of keratoconus and ectasia after refractive surgery in the 2 treatment arms. Treatment equivalence was assessed using the 2 one-sided test. Fellow eyes (n = 207) were treated with 5-minute dosing and considered in the safety analysis. MAIN OUTCOME MEASURES The primary hypothesis was equivalent change in the topography-derived maximum keratometry value from baseline to 6 months with 2-minute vs. 5-minute dosing. A ±0.75-diopter margin of equivalence for the treatment difference between dosing regimens was considered clinically relevant. Adverse events and changes from baseline to 6 months in corrected distance visual acuity (CDVA), uncorrected distance visual acuity, and minimum corneal thickness were assessed. RESULTS The mean reduction in maximum keratometry from baseline was equivalent with 2-minute and 5-minute riboflavin dosing intervals at 6 months (0.97 and 0.76 diopters, respectively; 90% confidence interval for treatment difference, -0.23 to 0.66; per-protocol population). With both dosing intervals, the mean improvement in CDVA was 0.07 logarithm of the minimum angle of resolution or 3.5 letters at 6 months. Of the 635 study and fellow eyes examined at 6 months, 134 (21%) gained and 32 (5%) lost 2 or more lines of CDVA. Three eyes (0.4%) developed sterile infiltrates, 1 (0.1%) had delayed epithelial healing with dendrites, and 3 (0.4%) had recurrent epithelial defects. Three eyes (0.4%) were re-treated. CONCLUSIONS The 2 riboflavin dosing regimens produced equivalent reduction in the maximum keratometry value, with a favorable safety profile.
-
3.
Outcomes of Simultaneous and Sequential Cross-linking With Excimer Laser Surface Ablation in Keratoconus.
Bardan, AS, Lee, H, Nanavaty, MA
Journal of refractive surgery (Thorofare, N.J. : 1995). 2018;(10):690-696
Abstract
PURPOSE To evaluate the outcomes of simultaneous and sequential corneal crosslinking (CXL) and excimer laser surface ablation protocols in keratoconus. METHODS A literature review was conducted using MEDLINE. The studies were divided into three groups: the sequential group included studies with CXL followed by excimer laser surface ablation later, the simultaneous group included simultaneous excimer laser surface ablation and CXL, and the no CXL group included excimer laser surface ablation only with no CXL. The data on change in logMAR uncorrected distance visual acuity (UDVA), spectacle corrected distance visual acuity (CDVA), change in spherical equivalent (SE) and refractive astigmatism, change in maximum keratometry (Kmax), complications, and safety and efficacy indices were presented for the latest follow-up visits in all groups. RESULTS Twenty-one studies (3 = sequential; 11 = simultaneous, 7 = no CXL) were included. UDVA improved in all groups. CDVA improved more in the sequential group. SE change was greatest in the no CXL group and the refractive astigmatism reduced comparably in the sequential and no CXL groups but less in the simultaneous group. Kmax reduced in all groups. Only the sequential group showed no progression. Corneal haze was reported in 100%, 54.5%, and 57.1% studies, respectively. Safety and efficacy indices were 1.96 and 1.58, 1.41 ± 0.32 and 0.91 ± 0.41, and 1 and 0.82, respectively. CONCLUSIONS The sequential group showed greater improvement in CDVA, SE, and refractive astigmatism. Corneal haze was frequently reported in all protocols. Safety and efficacy indices were highest when CXL was performed before excimer laser and least when excimer laser was performed alone without CXL. [J Refract Surg. 2018;34(10):690-696.].
-
4.
Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron.
Ito, H, Nishio, Y, Hara, T, Sugihara, H, Tanaka, T, Li, XK
European journal of pharmacology. 2018;:25-33
-
-
Free full text
-
Abstract
Heme oxygenase-1 (HO-1) is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance through affecting the differentiation of dendritic cells. The aim of this study is to determine whether the combination of 5-aminolevulinic acid (ALA) and iron induces HO-1 expression in healthy human peripheral blood mononuclear cells (PBMC). The study was an open labeled, non-randomized, non-placebo-controlled trial using healthy male adults and consisted of three parts. Study A aimed to find the peak HO-1 expression at 0, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration. Study B aimed to examine HO-1 dose dependency at 150, 300, and 600 mg of ALA and the need for iron supplementation. Study C aimed to investigate HO-1 changes during a three-day, repetitive administration of ALA and iron. The combination of ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated with ALA+SFC. Clear dose dependency of ALA+SFC was not detected, and a slight tendency towards a cumulative effect of HO-1 after three-day, repetitive administration was observed. ALA, which is already approved for use in several countries as a diagnosis agent for cancer, has the potential to become a novel therapeutic drug for diseases stemming from unwanted immune response such as autoimmune diseases and the rejection response following organ transplantation.
-
5.
Low light visual function after accelerated corneal Cross-Linking Protocols: 18 mW/cm2 vs. 9 mW/cm2.
Asgari, S, Hashemi, H, Jafarzadehpur, E, Mohamadi, A, Mehravaran, S, Fotouhi, A
Romanian journal of ophthalmology. 2018;(4):270-276
Abstract
Objective. To compare one-year results of vision, corneal aberrometry and contrast sensitivity (CS) in low light conditions between 5- and 10-minute accelerated cross-linking (CXL) protocols. Methods. Thirty eyes were evaluated in each studied group. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity by the SC-2000 Snellen chart, corneal higher order aberrations using the OPD Scan III and CS using MonCv3System was tested under mesopic (20 lux) and scotopic (0.5 lux) light conditions at pre-CXL and 6 and 12 months post-CXL. Results. At 12 months, a mean improvement of 0.06±0.22 (22.2%) and 0.02±0.25 logMAR (7.9%) in mesopic UDVA and 0.01±0.13 (14.3%) and 0.07±0.13 logMAR (87.9%) in mesopic CDVA was observed in the 5- and 10-minute groups, respectively. Mean decline in scotopic UDVA was 0.01±0.16 (1.0%) and 0.03±0.17 logMAR (11.9%) and mean improvement in scotopic CDVA was 0.03±0.10 (35.5%) and 0.02±0.07 logMAR (22.2%), respectively. Inter-group differences in the decrease of corneal aberrations were not statistically significant. Among CS variables, only inter-group changes in corrected CS 0.5 to 2.2 was significantly different (all P<0.050). The linear regression analysis showed that these differences were related to baseline values not CXL protocols; corrected CS 0.5 (Pgroup=0.261 and Pbaseline value<0.001), CS 1.1 (Pgroup=0.250 and Pbaseline value<0.001), and CS 2.2 (Pgroup=0.101 and Pbaseline value=0.054). Conclusions. Changing the intensity of UV in cross-linking from 18mW/ cm2 to 9mW/ cm2 does not affect the visual function under low-light conditions.
-
6.
Accelerated versus conventional corneal collagen cross-linking in patients with keratoconus: an intrapatient comparative study.
Sadoughi, MM, Einollahi, B, Baradaran-Rafii, A, Roshandel, D, Hasani, H, Nazeri, M
International ophthalmology. 2018;(1):67-74
Abstract
PURPOSE To compare the outcomes of the conventional and accelerated corneal collagen cross-linking (CXL) in patients with bilateral progressive keratoconus (KC). METHODS Fifteen consecutive patients with bilateral progressive KC were enrolled. In each patient, the fellow eyes were randomly assigned to the conventional CXL (3 mW/cm2 for 30 min) or accelerated CXL (ACXL) (9 mW/cm2 for 10 min) groups. Manifest refraction; uncorrected and corrected distant visual acuity; maximum and mean keratometry; corneal hysteresis and corneal resistance factor; endothelial cell density and morphology; central corneal thickness; and wavefront aberrations were measured before and 12 months after the CXL. RESULTS Manifest refraction spherical equivalent and refractive cylinder improved significantly only in conventional group. Uncorrected and corrected distant visual acuity did not change significantly in either group. Also there was no significant change in the maximum and mean keratometry after 12 months. There was significant decrease in central corneal thickness in both groups which was more prominent in conventional group. Endothelial cell density reduced only in the conventional group which was not statistically significant (P = 0.147). CH, CRF, and wavefront aberrations did not change significantly in either group. We did not observe any significant difference in the changes of the variables between the two groups. CONCLUSIONS Accelerated CXL with 9 mW/cm2 irradiation for 10 min had similar refractive, visual, keratometric, and aberrometric results and less adverse effects on the corneal thickness and endothelial cells as compared with the conventional method after 12 months follow-up. However, randomized clinical trials with longer follow-ups and larger sample sizes are needed.
-
7.
Comparison of Standard Versus Accelerated Corneal Collagen Cross-Linking for Keratoconus: A Meta-Analysis.
Wen, D, Li, Q, Song, B, Tu, R, Wang, Q, O'Brart, DPS, McAlinden, C, Huang, J
Investigative ophthalmology & visual science. 2018;(10):3920-3931
Abstract
PURPOSE To systematically compare epithelial-off standard (SCXL) to accelerated corneal collagen cross-linking (ACXL) for the treatment of keratoconus. METHODS PubMed, Embase, the Cochrane Library, and the US trial registry were searched for trials comparing SCXL and ACXL for keratoconus up to October 2017. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Primary outcomes were changes in uncorrected distance visual acuity, maximum keratometry (Kmax), and mean keratometry (mean K). Secondary outcomes were changes in corrected distance visual acuity, mean refractive spherical equivalent, central corneal thickness (CCT), and endothelial cell density (ECD). RESULTS Eleven trials were included. For primary outcomes, SCXL showed a greater reduction in Kmax (SMD 0.32; 95% CI 0.16, 0.48) than ACXL. For secondary outcomes, the decrease in CCT (SMD 0.32; 95% CI 0.03, 0.61) and ECD (SMD 0.26; 95% CI 0.06, 0.46) was less with ACXL than with SCXL. For the other outcomes, there were no statistically significant differences. CONCLUSIONS SCXL has a greater effect in terms of reduction in Kmax than ACXL, while ACXL induces less reduction in CCT and ECD than SCXL. Further well-designed randomized controlled trials comparing ACXL and SCXL are indicated.
-
8.
Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time.
Haberman, ID, Lang, PZ, Broncano, AF, Kim, SW, Hafezi, F, Randleman, JB
Journal of cataract and refractive surgery. 2018;(3):306-312
Abstract
PURPOSE To evaluate changes in regional corneal epithelial thickness after corneal crosslinking (CXL) using higher fluence (7.2 J/cm2) and accelerated treatment time (4 minutes) in eyes with progressive keratoconus using spectral-domain optical coherence tomography (SD-OCT) and to correlate focal epithelial and focal anterior curvature changes. SETTING Academic medical center in the United States. DESIGN Prospective case series. METHODS Patients had anterior segment SD-OCT (RTVue-100) with focal stromal and epithelial measurements and Scheimpflug imaging before and 1, 3, 6, and 12 months after accelerated CXL. RESULTS Twenty-seven eyes from 20 patients were evaluated. Before the accelerated CXL, the epithelium was thinnest in the inferior inner and outer temporal regions, whereas at 12 months postoperatively, the epithelium was significantly thinned in multiple inferior and nasal regions by 1.1 to 3.2 μm (P < .05, all measurements), with no significant changes from 6 to 12 months. Epithelial thickness standard deviation across the central 6.0 mm was significantly reduced by 3 months (1.4 μm, P = .09) and remained stable at 12 months (P = .009). Change in epithelial thickness was poorly correlated to change in anterior curvature (r = -0.035). CONCLUSIONS Significant epithelial remodeling occurred after accelerated CXL in eyes with progressive keratoconus, with improved regularity across the central 6.0 mm, by 6 months after treatment. There was poor correlation between focal epithelial thickness and anterior curvature changes, with wide variability between patients. Establishing the pattern of epithelial remodeling after CXL might help optimize future custom treatment protocols.
-
9.
Corneal Cross-Linking for Pediatric Keratcoconus Review.
Perez-Straziota, C, Gaster, RN, Rabinowitz, YS
Cornea. 2018;(6):802-809
-
-
Free full text
-
Abstract
PURPOSE To comprehensively review the available published literature for cross-linking in the pediatric population. METHODS Review of the literature published in English in PubMed. RESULTS Two hundred ten publications were considered. One hundred fifteen were considered relevant to this review. CONCLUSIONS Studies of cross-linking in pediatric patients are sparse, with relatively short follow-up times, and mostly on small groups of patients. Treatment with cross-linking halts progression of keratoconus in the pediatric population, and early treatment seems to be cost-effective compared with later penetrating keratoplasty. Long-term effects and regression rates remain unclear, and further studies are needed in this population.
-
10.
Epithelium-off versus transepithelial corneal collagen crosslinking for progressive corneal ectasia: a randomised and controlled trial.
Rush, SW, Rush, RB
The British journal of ophthalmology. 2017;(4):503-508
Abstract
AIM: To compare the outcomes of corneal collagen crosslinking (CXL) for the treatment of progressive corneal ectasia using a standard epithelium-off technique versus a transepithelial technique with enhanced riboflavin solution. METHODS One hundred and forty-four eyes with progressive corneal ectasia were prospectively randomised into a transepithelial CXL study arm or an epithelium-off CXL control arm. Follow-up examinations were set at 3, 6, 12 and 24 months. The primary outcome measure was change in the maximum simulated keratometry value (Ksteep) after 24 months of follow-up. The secondary outcome measure was change in the best spectacle-corrected visual acuity (BSCVA) after 24 months follow-up. RESULTS One hundred and thirty-one eyes completed the 24-month follow-up interval. Change in Ksteep was -1.52±0.66 dioptres (D) for the control group versus -0.54±0.58 D for the study group at 24 months of follow-up (p=0.0320). Change in BSCVA was -0.18±0.09 logMAR for the control group versus -0.14±0.08 logMAR for the study group at 24 months of follow-up (p=0.4978). Two eyes in the control group had minor postoperative complications that did not affect the final visual acuity, and one eye in the control group underwent keratoplasty during the study interval. CONCLUSIONS At 24 months of follow-up, subjects in the epithelium-off CXL group demonstrated a greater improvement in Ksteep compared with subjects in the transepithelial CXL group, but no statistically significant difference in BSCVA was found between groups. TRIAL REGISTRATION NUMBER NCT01708538; pre-results.