Clinical Ophthalmology Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Management of chronic anterior uveitis relapses: efficacy of oral phospholipidic curcumin treatment. Long-term follow-up Pia Allegri1 Abstract: Curcumin has been successfully applied to treat inflammatory conditions in Antonio Mastromarino1 experimental research and in clinical trials. The purpose of our study is to evaluate the efficacy Piergiorgio Neri2 of an adjunctive-to-traditional treatment with Norflo tablets (curcumin-phosphatidylcholine complex; Meriva) administered twice a day in recurrent anterior uveitis of different etiologies. The 1Uveitis Center, Ophthalmological Department of Lavagna Hospital, study group consisted of 106 patients who completed a 12-month follow-up therapeutic period. Genova, Italy; 2Uveitis Unit, The We divided the patients into three main groups of different uveitis origin: group 1 (autoimmune Eye Clinic, Azienda Ospedaliero- uveitis), group 2 (herpetic uveitis), and group 3 (different etiologies of uveitis). The primary Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy end point of our work was the evaluation of relapse frequency in all treated patients, before and after Norflo treatment, followed by the number of relapses in the three etiological groups. Wilcoxon signed-rank test showed a P , 0.001 in all groups. The secondary end points were the evaluation of relapse severity and of the overall quality of life. The results showed that Norflo was well tolerated and could reduce eye discomfort symptoms and signs after a few weeks of treatment in more than 80% of patients. In conclusion, our study is the first to report the potential therapeutic role of curcumin and its efficacy in eye relapsing diseases, such as anterior uveitis, and points out other promising curcumin-related benefits in eye inflammatory and degenerative conditions, such as dry eye, maculopathy, glaucoma, and diabetic retinopathy. Keywords: curcumin, anterior recurrent uveitis, phosphatidylcholine-bound-curcumin (Meriva) Introduction In recent clinical studies, curcumin showed its antioxidant, chemopreventive, and anti- inflammatory activity in acute and chronic inflammation both in clinical practice (used in neurodegenerative, pulmonary, metabolic, autoimmune, and neoplastic diseases) and in experimental models. In the latter case, eg, Mohan et al showed that curcuminoids target fibroblast growth factor-2 and inhibit expression of gelatinase B in the angiogenic process by using the cultured corneal cells of a transgenic mouse.9 In an experimental dry eye model, Chen et al investigated the anti-inflammatory effects of curcumin in curcumin pretreated cultured corneal epithelial cells exposed to hyperosmotic condi- tions.29 Kumar et al30 reported that curcumin feeding to rats with chemical-induced hyperglycemia can reduce oxidative stress that is the main cause of progression of 1–12 Correspondence: Pia Allegri cataract. The beneficial effects of this drug appear now to be related to the effect on Uveitis Center Head, Ophthalmological upregulation of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is a ligand- Department of Lavagna Hospital, inducible transcription factor involved mainly in controlling inflammation in peripheral Corso Valparaiso 96/3, Chiavari 16043, Genova, Italy organs. Activation of PPAR-γ has been shown to control the response in microglial cells Tel +39 0185 329626 and limit inflammation.13–17 Curcumin has poor systemic availability, but recent stud- Fax +39 0185 329627 Email [email protected] ies have shown that the phosphatidylcholine formulation (Meriva®) increases its oral submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4 1201–1206 1201 Dovepress © 2010 Allegri et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article DOI: 10.2147/OPTH.S13271 which permits unrestricted noncommercial use, provided the original work is properly cited. Allegri et al Dovepress bioavailability.18–21 Yadav et al showed the inhibitory effect of 180, and 360 days. The evaluation of the results at the end of curcumin on cell proliferation and production of cytokines, the follow-up period was carried out by comparing the results which are the main phenomena involved in inflammation.12 before and after 1 year of follow-up in patients presenting Many studies have been conducted on curcumin, but only Lal 4, 3, 2, or 1 relapses per year. We also studied the percentage et al have shown the efficacy of curcumin on chronic anterior of satisfaction and tolerance to additional therapy by means uveitis.22 Based on the previous data, we report our experi- of a detailed questionnaire (included into the clinical record ence in patients suffering from relapsing anterior uveitis of sheet) developed with the purpose of analyzing the patient different etiologies. tolerance and compliance to treatment at the end of 1 year Norflo therapy. Material and methods A total of 122 patients (68 men and 54 women) with recurrent Statistical analysis anterior uveitis (RAU) were enrolled in the study. The age Frequency of total relapses, before and after 1 year of Norflo of the patients ranged from 21 to 68 (mean, 37 ± 4.7). All therapy, was assessed with Wilcoxon signed-rank test. patients signed a written informed consent before entering into the study in accordance with the Helsinki International Results Treaty criteria. The patients included in the study were We compared the results, before and after the treatment with selected from those followed in our tertiary referral uveitis Norflo, of the total number of patients with relapses and the centre (Lavagna Hospital, Genova, Italy) in a previous period number of total relapses. of about 2 years (mean ± 3 months) and affected by RAU with As shown in Figure 1A, 106 patients (corresponding 1–4 relapses in a year. The RAU diagnosis was made by two to the global number of patients included into the study) different ophthalmologists with more experience on uveitis had relapses before the treatment with Norflo, and only and was based on standard clinical criteria of International 19 patients had relapses after the treatment with Norflo. Uveitis Study Group (IUSG).23 Ophthalmological examina- As shown in Figure 1B, there were in total 275 relapses 1 tion included each time: slit-lamp examination with IUSG year before the treatment with Norflo and only 36 relapses at grading of anterior segment cells and flare (from 0 to +4 ), the end of the 12-month follow-up period, after the treatment Early Treatment Diabetic Retinopathy Study (ETDRS) visual with Norflo (88% of improvement). acuity measurement, intraocular pressure measurement, and Tables 1 and 2 show the detailed results before and after fundus examination with Volk + 90 lens. We developed a Norflo treatment in all treated patients, respectively. Thetab le specific medical record in which, at each check-up visit, we specifies the number of patients with 4, 3, 2, or 1 relapses per registered the findings for each patient included in the study. year and the total number of relapses per year. Recurrent anterior bilateral or unilateral uveitis etiology For instance, in Table 1 (before the treatment with Norflo) was mainly of autoimmune origin (56 patients), followed six patients had four relapses per year, which means a total by RAU of herpetic origin (28 patients), and of different or number of 24 relapses per year. In Table 2 (after the treatment unknown origin (22 patients). All the patients received an with Norflo) we can see that no patients had four relapses per orally administered product, Norflo® (Eye Pharma Co, Italy) year, with no relapses in 1 year. Therefore, the six patients containing 600 mg of Meriva (Indena, Milano, Italy) in each who had four relapses per year before the treatment had zero tablet, at the dosage of two tablets/day during the follow-up relapses after Norflo additional therapy. In the second row period. An ongoing therapy with systemic drugs (steroids, of the same tables, 58 patients had three relapses per year, immune-suppressants, antiherpetic, and antitoxoplasmic which means a total of 174 relapses before treatment, and drugs) or eye drops (steroids, mydriatics, and cycloplegics only four patients had three relapses per year, which means nonsteroidal anti-inflammatory drug) was maintained, and a total of 12 relapses per year after treatment. Norflo tablets were added as an adjunctive treatment. The As shown in the tables, the results were highly significant therapy was only administered to patients who had frequent with the Wilcoxon signed-rank test at a P , 0.001 in all relapses in the last 2 years of follow-up and was started at groups. There was also an improvement in symptoms the time of a relapse. The follow-up period varied from 12 and signs associated with relapses after Norflo treatment, to 18 months (mean ± 3 months), and 106 patients (61 men including ocular pain, blurring of vision, pericorneal and 45 women) completed the study. All patients underwent hyperemia and aqueous or vitreous cells, and flare in 42% complete ophthalmological examination at 0, 7–15, 30, 90, of patients. Only seven patients worsened, and they required 1202 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4 Dovepress Dovepress Management of chronic anterior uveitis relapses AB300 120 250 100 200 80 60 150 40 100 20 50 0 0 106 19 275 36 Figure 1 A) Total number of patients with relapses before and after Norflo therapy.B ) Total relapse number before and after Norflo therapy. Note: Wilcoxon signed-rank test: P , 0.001. subtenon injections of steroids. Among the first 128 patients degeneration, retinal ischemia, and diabetic retinopathy) selected, only one subject had to interrupt therapy because are now considered from an inflammatory point of view. of gastric intolerance related to reflux esophagitis. Fifteen Therefore, the treatment of inflammation could represent an patients dropped out of the study because of noncompliance important target to manage ocular diseases. Based on these with therapy or with follow-up visits.