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Flower Pollen Extract in Association with Vitamins (Deprox 500®) Versus Serenoa repens in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Comparative Analysis of Two Different Treatments.
Macchione, N, Bernardini, P, Piacentini, I, Mangiarotti, B, Del Nero, A
Anti-inflammatory & anti-allergy agents in medicinal chemistry. 2019;(2):151-161
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Abstract
OBJECTIVE Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is reported in the literature ranging from 1 to 14.2%. The aim of the present study was to assess the impact on patient's quality of life and symptoms of Flower pollen extract in association with vitamins (Deprox 500®) in comparison with Serenoa repens 320 mg (Permixon 320 mg® by Pierre Fabre) in patients with CP/CPPS. METHODOLOGY All consecutive patients, with a diagnosis of CP/CPPS, referred to our center from January to August 2016, were screened to be enrolled in this single-center, randomized, controlled trial. The main outcome measure was the evaluation of IPSS/NIHCPSI (International Prostatic Symptom Score/NIH-Chronic Prostatitis Symptom Index) score variation and the assessment of the quality of life and symptoms at the end of the therapy. The second outcome measure was the evaluation of the comorbidity role in the CP/CPPS therapy. 63 patients were analyzed; patients were randomized into two groups: 29 patients were treated with Deprox 500® 2 tablets/day for 6 weeks and 34 patients with Serenoa repens 320 mg, 1 tablet/day for 6 weeks. RESULTS The mean score variation for IPSS was -12.7 ± 4.3 in the Deprox 500® group and -7.8 ± 4.7 in the Serenoa repens group (p=0.0005) while for NIH-CPSI was -17.3±3.1 in the Deprox 500® group and -13.6±4.8 in the Serenoa repens group (p=0.0016). By accounting only the symptoms part of NIH-CPSI questionnaire, the mean score variation reported was -11.5±2.5 in the Deprox 500® group and -9.02±4.0 in the Serenoa repens group (p=0.009321). Furthermore, analyzing the comorbidity subgroups, in patients with hypertension, the mean IPSS score variation was -14.3±3.2 in the Deprox 500® group and - 9.02±4.0 in the Serenoa repens group. CONCLUSION In conclusion, in patients with CP/CPPS, Deprox 500® improves IPSS and NIH-CPSI scores up to 74.5% and 84.5% respectively. Furthermore, in patients with hypertension, the antioxidant effect of Deprox 500® reduces the mean IPSS score of 82.7%.
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Safety and efficacy of riboflavin-assisted collagen cross-linking of cornea in progressive keratoconus patients: A prospective study in North East India.
Bhattacharyya, A, Sarma, P, Das, K, Agarwal, B, Medhi, J, Das Mohapatra, SS
Indian journal of pharmacology. 2019;(3):157-167
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INTRODUCTION Riboflavin- and ultraviolet (UV)-A-mediated collagen cross-linking of the cornea is a frequently used therapeutic measure for the treatment of progressive keratoconus (PK). First, riboflavin increases cross-linking and second, it serves as a protective shield to other deep ocular structures. However, pharmacogenomic variation in riboflavin efficacy is reported. As the Northeast Indian population represents a genetically diverse group of population compared to mainstream India, we have assessed the efficacy of the procedure in a northeastern population with PK. METHODS In this study, 78 eyes with PK were included (n = 39 in the treatment arm and n = 39 in the control arm). The primary objective was to evaluate the effect of corneal collagen cross-linking using riboflavin (C3R) (epithelium off) on maximum keratometry. The secondary objectives were evaluation of change in corneal topography parameters, i.e., minimum keratometry (Kmin), simulated keratometry (Sim K), subjective refraction (cylinder power, spherical power, and spherical equivalent [SE]), uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and contrast sensitivity (CS) and safety (intraocular pressure, endothelial cell density, and percentage hexagonality) at 1, 3, and 6 months following C3R procedure. RESULTS Statistically significant improvement was noted in Kmin (6 months), Sim K (3 and 6 months), cylinder power (3 and 6 months), spherical power (3 and 6 months), SE (3 and 6 months), BCVA (6 months), and UCVA (1, 6 months) in the C3R group (n = 39) when compared to the control group (n = 39). The mean CS decreased at 1 month and gradually improved to achieve statistically significant value at 6 months in the C3R group (P < 0.05). CONCLUSION Riboflavin-assisted C3R treatment showed promising efficacy in the treatment of PK patients in our population. As the collagen turnover rate of cornea is 2-3 years and the progression of PK is highly variable, we need long-term studies to evaluate the efficacy of C3R over time, requirement of repeat therapy, and safety of repeat cross-linking.
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Riboflavin Concentrations at the Endothelium During Corneal Cross-Linking in Humans.
Seiler, TG, Batista, A, Frueh, BE, Koenig, K
Investigative ophthalmology & visual science. 2019;(6):2140-2145
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PURPOSE To determine the riboflavin concentration in the posterior corneal stroma, Descemet's membrane, and endothelium prior to UV irradiation in corneal cross-linking (CXL) in humans. METHODS Five human deepithelialized cadaver corneas were mounted into artificial anterior chambers. After the establishment of stable physiological hydration, two-photon imaging with a certified multiphoton tomograph was used to determine fluorescence intensity and second harmonic generation signals from collagen throughout each cornea by optical sectioning, with a step size of 2.5 μm. Afterward, 0.1% riboflavin solution was applied to the anterior corneal surface, similar to the standard CXL protocol. To determine the absolute riboflavin concentration immediately before UV irradiation, corneas were measured by two-photon imaging just at the end of the riboflavin imbibition and after riboflavin saturation. RESULTS The topical application of 0.1% riboflavin results in a riboflavin concentration that decreases to 0.035% in the posterior stroma. Inside Descemet's membrane and endothelium, the concentration drops further to only approximately 0.015% at the endothelial level. Local riboflavin distribution indicates a predominantly paracellular passive diffusion of riboflavin into the anterior chamber. CONCLUSION The experimentally determined riboflavin concentration of 0.015% at the endothelium shows a substantial discrepancy of a factor of 1.7 to the previously theoretically calculated 0.025%. A lower riboflavin concentration at the endothelium may enable higher radiant exposures and further improve the efficacy of CXL.
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Improved in vitro quality of stored red blood cells upon oxygen reduction prior to riboflavin/UV light treatment of whole blood.
Schubert, P, Culibrk, B, Chen, D, Serrano, K, Levin, E, Chen, Z, Zoescher, P, Goodrich, RP, Yoshida, T, Devine, DV
Transfusion. 2019;(10):3197-3204
Abstract
BACKGROUND The application of riboflavin/UV-based pathogen inactivation (PI) to whole blood (WB) is currently limited by its negative impact on red blood cell (RBC) quality. The generation of reactive oxidative species in RBC products contributes to increased hemolysis. This study evaluated the impact of deoxygenation of WB prior to riboflavin/UV light treatment versus deoxygenation of RBC concentrates after PI treatment by monitoring RBC in vitro quality parameters. STUDY DESIGN AND METHODS Six ABO-matched WB units were pooled and split. Within three pairs, one unit was treated with riboflavin/UV light while the other was kept as an untreated control prior to manufacture into red cell concentrates (RCCs). The first pair (Cntr; Cntr-PI) served as the normoxic controls. Deoxygenation was performed at the RCC level for the second pair (RCCdeox; PI-RCCdeox), and at the WB level of the third pair (WBdeox; WBdeox-PI). In vitro qualities of the respective RBC units were assessed throughout storage. RESULTS The data for the Cntr and Cntr-PI units were comparable to previous reports. The PI-RCCdeox units exhibited worse in vitro quality for most parameters tested compared to Cntr-PI and WBdeox-PI units throughout storage. Hemolysis and microvesicle release was significantly (p < 0.05) higher on Days 21 and 42 in Cntr-PI units compared to WBdeox-PI units. CONCLUSION WB deoxygenation may help to decrease the accelerated deterioration in RCC in vitro quality caused by treatment with riboflavin/UV light. Treatment of WB under reduced oxygen levels needs to be assessed for PI effectiveness.
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Randomized Study of Collagen Cross-Linking With Conventional Versus Accelerated UVA Irradiation Using Riboflavin With Hydroxypropyl Methylcellulose: Two-Year Results.
Hagem, AM, Thorsrud, A, Sandvik, GF, Drolsum, L
Cornea. 2019;(2):203-209
Abstract
PURPOSE To compare the clinical outcome 2 years after corneal collagen cross-linking (CXL) with conventional and accelerated ultraviolet A (UVA) irradiation using riboflavin with hydroxypropyl methylcellulose. METHODS Prospective randomized controlled study. Forty patients with keratoconus (40 eyes) were randomized to either CXL using conventional 3 mW/cm UVA irradiation for 30 minutes (CXL30 group) or accelerated 9 mW/cm UVA irradiation for 10 minutes (CXL10 group). In both groups, a solution of 0.1% riboflavin with 1.1% hydroxypropyl methylcellulose (methylcellulose-riboflavin) was used. Uncorrected distance visual acuity, corrected distance visual acuity (CDVA), and Scheimpflug tomography were performed at baseline and after 24 months. RESULTS Both groups had statistically significant improvement in CDVA and maximum keratometric reading compared with baseline; however, with no statistically significant difference in the change between the 2 groups. No significant changes in flattest, steepest and mean keratometry (K1, K2 and K mean) were found in either of the groups. There were no statistically significant changes in ECD in either group after 2 years or in the difference in the change between the 2 groups. A literature review showed comparative clinical outcome after accelerated CXL compared with conventional CXL; however, in several studies, there was a tendency for less pronounced corneal flattening after accelerated CXL. CONCLUSIONS Improvement in visual acuity and maximum keratometric reading 2 years after CXL was found after both conventional and accelerated UVA irradiation using methylcellulose-riboflavin. This suggests that when using riboflavin with methylcellulose, the less time-consuming accelerated protocol is a valuable and effective option in CXL treatment.
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Evaluation of riboflavin photochemical treatment for inactivation of HCT116 tumor cells mixed in simulative intraoperative salvage blood.
Yu, Y, Yang, L, He, C, Tai, S, Ma, C, Yang, T, Wang, D
Transfusion. 2019;(10):3205-3213
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BACKGROUND Radiation and filtration have achieved satisfactory results in inactivation or removal of tumor cells mixed in salvage blood, but some drawbacks remain. This study evaluated the inactivation on HCT116 cells mixed in simulative salvage blood by riboflavin photochemical treatment. METHODS HCT116 cells were added to the whole blood to simulate contaminated salvaged blood. The mixed blood was added with riboflavin of 50 μmol/L final concentration and illuminated by ultraviolet light. The samples were divided into control group and Experimental Groups 1 (18 J/cm2 ), 2 (23.4 J/cm2 ), and 3 (28.8 J/cm2 ). An autotransfusion system (Cell Saver Elite, Haemonetics) was used to simulate the intraoperative blood salvage procedure to deal with whole blood. The apoptosis rate and tumorigenicity of HCT116 cells and the superimposed damage to red blood cells (RBCs) were evaluated. RESULTS The apoptosis rates of HCT116 in Experimental Groups 1, 2, and 3 were much higher than that in the control group. Tumor growth was found in the control group, but no tumor growth was found in the three experimental groups. The hemolysis rates in the three experimental groups were significantly higher than that in the control group, but much lower than the quality standard of RBCs at the end of preservation. The concentration of adenosine triphosphate in RBCs was comparable in the control and experimental groups. CONCLUSION Riboflavin at a 50 μmol/L final concentration and 18 J/cm2 ultraviolet illumination can effectively inactivate HCT116 cells in salvaged blood, with minimum damage to the structure and function of RBCs, and the main quality indexes of salvaged RBCs were within the standard range.
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Noninvasive real-time assessment of riboflavin consumption in standard and accelerated corneal crosslinking.
Lombardo, M, Lombardo, G
Journal of cataract and refractive surgery. 2019;(1):80-86
Abstract
PURPOSE To estimate the noninvasive riboflavin concentration in the corneal stroma using a new ultraviolet-A (UVA) theranostic device for corneal crosslinking (CXL). SETTING Vision Engineering Italy srl, Rome, Italy. DESIGN Experimental study. METHODS Fourteen human donor corneas were treated according to conventional (UVA irradiance of 3 mW/cm2 for 30 minutes) and rapid (10 mW/cm2 for 9 minutes) riboflavin-UVA CXL protocols using a theranostic UVA device. Five additional samples were treated by 0.5 mW/cm2 for 9 minutes and used as positive controls to determine riboflavin photodegradation under near ambient lighting conditions. A 20% dextran-enriched 0.1% riboflavin solution was used in all cases. The device consisted of a UVA light source; a red-green-blue camera, which acquires the fluorescence images of the cornea during treatment; and a single-board computer for managing the overall operations and the raw data processing. RESULTS Preirradiation stromal soaking for 30 minutes achieved highly consistent intrastromal riboflavin concentration in all tissues (mean 0.015% ± 0.003% [SD]). There were no differences in the kinetics curves of riboflavin consumption between the 2 UVA irradiation protocols; the intrastromal riboflavin concentration decreased exponentially, with a mean constant energy rate of 2.8 ± 0.2 J/cm2. In the control group, the intrastromal riboflavin concentration decreased quasilinearly. CONCLUSIONS The theranostic device provided estimates of the intrastromal concentration of riboflavin noninvasively during treatment. In the 3 to 10 mW/cm2 range of power densities, the consumption of riboflavin in the stroma by UVA irradiation was only energy dependent in accordance with the Bunsen-Roscoe law.
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Medical Applications of Rose Bengal- and Riboflavin-Photosensitized Protein Crosslinking.
Redmond, RW, Kochevar, IE
Photochemistry and photobiology. 2019;(5):1097-1115
Abstract
This review summarizes research on many of the potential applications of photosensitized crosslinking of tissue proteins in surgery and current knowledge of the photochemical mechanisms underlying formation of the covalent protein-protein crosslinks involved. Initially developed to close wounds or reattach tissues, protein photocrosslinking has also been demonstrated to stiffen and strengthen tissues, decrease inflammatory responses and facilitate tissue bioengineering. These treatments appear to result largely from crosslinks within and between collagen molecules in tissue that typically form by an oxygen-dependent mechanism. Surgical applications discussed include sealing wounds in skin, cornea and bowel; reattaching severed nerves, blood vessels and tendons; strengthening cornea and vein; reducing capsular contracture after breast implants; and regenerating joint cartilage.
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Corneal Cross-Linking: The Science Beyond the Myths and Misconceptions.
Rubinfeld, RS, Caruso, C, Ostacolo, C
Cornea. 2019;(6):780-790
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PURPOSE There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. METHODS Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. RESULTS Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen-Roscoe law of reciprocity and the Lambert-Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. CONCLUSIONS Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.
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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
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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.