Ocufolin^®

The Effects of Vitamin Supplementation Containing L-Methylfolate (Ocufolin^® forte) on Retinal Venous Pressure and Homocysteine Plasma Levels in Patients with Glaucoma

Thibaut Devogelaere,¹ Andreas Schötzau,²

Purpose: To report our observations of the effects of Ocufolin^® forte on elevated retinal venous pressure (RVP) and elevated serum homocysteine (Hcy) in patients with glaucoma and/or ocular vascular diseases.
Methods: A total of 26 patients with glaucoma and/or ocular vascular diseases in at least one eye, abnormal steady-state pattern electroretinography, RVP measured using an ophthalmodynamometer at least 15 mmHg higher than intra-ocular pressure (IOP), fasting serum Hcy level >12 μmol/l and stable and well-controlled IOP (with or without IOP-lowering treatment) received supplementation with Ocufolin^® forte for 3 months.
Results: As additional treatment was needed in 2 patients their results were excluded from analysis. In the remaining 24 patients, 42 eyes of 21 patients qualified for RVP analysis. Mean IOP remained stable (p=0.15) during the study, but mean RVP dropped by 8.8 mmHg (p<0.001), from 28.1±11.7 mmHg at pre-supplementation to 19.3±7.4 mmHg at 3 months. In 22 of the 24 patients, serum Hcy was analyzed again between 3 days and almost 41 weeks after cessation of supplementation. Serum Hcy levels dropped from 15.8±2.8 μmol/l before to 12.51±2.90 μmol/l after supplementation (p<0.001).
Conclusions: In this pilot study, Ocufolin^® forte had a clinically relevant and statistically significant RVP lowering effect and led to a clinically relevant and statistically significant Hcy decrease, offering a new treatment modality for eye diseases with increased RVP, such as glaucoma.

Devogelaere Schötzau_healthbook TIMES Schw Aerztej_3(2021)54_L-Methylfolate formulation Retinal Venous pressure Homocysteine Glaucoma

https://schw-aerztej.healthbooktimes.org/article/30108-the-effects-of-vitamin-supplementation-containing-l-methylfolate-ocufolin-forte-on-retinal-venous-pressure-and-homocysteine-plasma-levels-in-patien

Measuring and Treating Retinal Venous Pressure: Efforts and Benefits

Expert Opinion by Josef Flammer

Dr. Thibaut Devogelaere studied the effect of Ocufolin^® forte on retinal venous pressure (RVP) in glaucoma patients. This seemingly unspectacular information is, in our opinion, a big step forward for many patients, especially glaucoma patients. Therefore, it has prompted us to write some general thoughts on the measurement and treatment of elevated RVP in glaucoma.

Editorial Times Healthbook November 2021

Can we improve ocular blood flow and protect the eye?

Expert Opinion by A. David Smith

Maintenance of a good blood flow through the eye is crucial and impairment or dysregulation of blood flow is a likely cause of several diseases of the eye. In particular, raised retinal venous pressure (RVP) has many adverse effects. The blood vessels in the retina are unusual in that they are not innervated by autonomic nerves and the control of blood flow is largely mediated by local release of vasoactive substances, mainly from the vascular endothelium. Hence, impaired blood flow is often the consequence of the impaired function of the vascular endothelium (vascular endotheliopathy), which can be caused by hypertension, diabetes, oxidative stress and raised plasma homocysteine or by primary vascular dysregulation (the Flammer syndrome).

Editorial Times Healthbook November 2021

A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes

Doreen Schmidl,¹ Kinga Howorka,² Stephan Szegedi,¹ Kristina Stjepanek,^1,3 Stefan Puchner,^1,2 Ahmed Bata,¹ Ulrike Scheschy,¹ Gerold Aschinger,² René M. Werkmeister,² Leopold Schmetterer,^{1,2,4,5,6,7,8} Gerhard Garhofer¹

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; ²Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; ³Department of Ophthalmology, Vienna Institute for Research in Ocular Surgery – Karl Landsteiner Institute, Hanusch Hospital, Vienna, Austria; ⁴Singapore Eye Research Institute, Singapore, Singapore; ⁵Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; ⁶Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore; ⁷SERI-NTU Advanced Ocular Engineering (STANCE), Singapore, Singapore; ⁸Institute of Ophthalmology, Basel, Switzerland

Purpose: The aim of the present study was to investigate the effect of a three-month dietary supplementation with a methylfolate formulation on homocysteine plasma concentrations and ocular blood flow parameters in patients with diabetes. Methods: Twenty-four patients with diabetes received a dietary supplement (Ocufolin^®, Aprofol AG, Switzerland) containing 900 µg L-methylfolate (levomefolate calcium or [6S]-5-methyltetrahydrofolic acid, calcium salt), methylcobalamin, and other ingredients for three consecutive months. The patients’ plasma homocysteine concentration and retinal blood flow were assessed at baseline and after three months of folate intake. Retinal blood flow was measured using a custom-built dual-beam Doppler optical coherence tomography (OCT) system. In addition, flicker-induced retinal vasodilatation was assessed by means of a commercially available dynamic vessel analyzer (IMEDOS, Jena, Germany). Results: Supplementation was well tolerated by all patients. After three months, plasma homocysteine concentration significantly decreased from 14.2 ± 9.3 to 9.6 ± 6.6 µmol/L (p < 0.001). In addition, a tendency toward an increased total retinal blood flow from 36.8 ± 12.9 to 39.2 ± 10.8 µl/min was observed, but this effect did not reach the level of significance (p = 0.11). Supplementation had no effect on retinal vessel diameter or flicker-induced vasodilatation. Conclusions: The present data show that a three-month intake of a dietary supplement containing methylfolate can significantly reduce blood homocysteine levels in patients with diabetes. This is of importance because higher homocysteine plasma levels have been found to be associated with an increased risk of vascular associated systemic diseases and eye diseases. Whether systemic methylfolate supplementation affects retinal perfusion must be studied in a larger population.

http://www.molvis.org/molvis/v26/326

Improved Retinal Microcirculation in Mild Diabetic Retinopathy Patients Carrying MTHFR Polymorphisms Who Received the Medical Food, Ocufolin^®

Zhiping Liu^1,2, Hong Jiang^2,3, Justin H Townsend², Jianhua Wang²

¹Ophthalmic Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China;
²Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; ³Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

Purpose: To evaluate the effects of Ocufolin^® on retinal microcirculation in patients with mild diabetic retinopathy carrying MTHFR polymorphisms.
Methods: In a prospective, case-controlled study, eight patients with mild diabetic retinopathy and MTHFR polymorphisms and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The eight retinopathy patients received Ocufolin^® for 6 months, and their imaging was performed at baseline, 4 months, and 6 months. The NC group was imaged once.
Results: BCVA and vascular indices of DR + PM patients at baseline were below those of NC and improved after Ocufolin^®administration. Compared to baseline, DR + PM patients had significantly improved BCVA during the follow-up period (P < 0.05). RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05), approaching NC.
Conclusion: Ocufolin^® may be effective in improving both visual acuity and retinal microcirculation in patients with DR + PM. Further studies with increasing sample size, and longer duration, including cases with severe DR, are needed.

https://www.dovepress.com/improved-retinal-microcirculation-in-mild-diabetic-retinopathy-patient-peer-reviewed-fulltext-article-OPTH

Ocufolin^® as a supplement therapy in patients with AMD

T. Hergeldzhieva-Fileva, A. v. Scarpatetti

Purpose: To present our experience with Ocufolin^® as a supplement therapy in patients with age-related macular degeneration (AMD).

Settings: Eye Clinic Dr. A. v. Scarpatetti, Teufen, Switzerland

Methods: We retrospectively reviewed the clinical records of all consecutive patients with Ocufolin^® supplement therapy between August 2015 and September 2016. A thorough ocular, medical and family history were obtained in all cases. The clinical evaluation included best-corrected visual acuity (BCVA), biomicroscopy, measurement of intraocular pressure, and dilated ophthalmoscopy. Color fundus photography and Spectral Domain Optical Coherence Tomography were useful to document the disease and to monitor its progression. Genetic testing for the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298T gene mutations were also performed in majority of patients. Ocufolin^® contains the active metabolite of folic acid (L-methylfolate) and other vitamins, which reduce homocysteine levels and protect retinal, choroidal, and macular tissues from oxidative stress caused by high levels of homocysteine¹,²,³,⁴ as well as minerals and carotenoids known from the ARED-studies. Ocufolin^® was given in a dosage of 1 capsule orally per day to all patients. Surgical procedures (intravitreal injections, cataract surgery etc.) were also done depending on indications. The follow up examinations were performed at the first and third month, and in three months intervals thereafter.

Results: Between August 2015 and September 2016 Ocufolin^® supplement therapy was prescribed to 42 patients. AMD was the reason for therapy in 35 patients (83%). Eighteen female (51.4%) and 17 male (48.6%) patients with an average age of 79.2 years (range 58-98) were included in this retrospective study. Twenty three patients (65.7%) had dry AMD, 6 patients (17.2%) had neovascular AMD, and 6 patients (17.2%) had both forms of AMD. The mean BCVA at the baseline and the last follow up visit was 0.81 logMAR (interval 0.0 - +1.5) and 0.76 logMAR (interval 0.0 - +1.5) respectively. Genetic testing was performed in 26 patients (74.3%) with AMD and in 20 cases (57%) mutations were diagnosed suggesting reduction of the function of MTHFR enzyme and higher homocysteine blood levels respectively. Twelve patients (34.3%) needed surgical interventions- intravitreal injections (9 patients, 25.7%), FALCS (2 patients, 5.7%), and PPV with silicone oil tamponade (1 patient, 2.9%). None of the patients reported ocular or systemic serious adverse events. The average period of observation was 9 months (interval 3-19 months). Reasons for discontinuation of supplement therapy were mainly financial issues since the Ocufolin^® is not reimbursed by the health insuarence.

Conclusions: Despite retrospective design, relatively short follow up period and limited number of patients in our study our observations show that Ocufolin^® is well tolerated as a supplement therapy in individuals with AMD. Futher studies are needed to confirm its effect in preservation and stabilization of vision during the course of AMD.

¹ Huang P, Wang F, Sah BK, et al. Homocysteine and the risk of age-related macular degeneration: a systematic review and meta-analysis. Sci Rep 2015;5:10585.

² Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med 2009;169:335-341.

³ Merle BM, Silver RE, Rosner B, Seddon JM. Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study. Am J Clin Nutr 2016;103:1135-1144.

⁴Gopinath B, Flood VM, Rochtchina E, Wang JJ, Mitchell P. Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. Am J Clin Nutr 2013;98:129-135.

Effects of Ocufolin^® on retinal microvasculature in patients with mild non-proliferative diabetic retinopathy carrying polymorphisms of the MTHFR gene

Zhiping Liu, Hong Jiang, Justin H Townsend, Jianhua Wang

Introduction: To evaluate effects of Ocufolin^® on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR +MTHFRP).

Research design and methods: This is a prospective cohort study. Eight DR +MTHFRP (administrated Ocufolin^® for 6 months) and 15 normal controls (NCs) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal vessel density (VD) and microstructure were evaluated by optical coherence tomography angiography.

Results: BCVA and vascular indices of DR +MTHFRP at baseline were worse than those of NC and improved. Compared with baseline, DR +MTHFRP had significantly improved BCVA during follow-up period (p<0.05). VD of superficial vascular plexus was increased at 4 months (p=0.012), while VD of retinal vascular network did not change (p>0.05). Carriers of A1298C and C677T showed statistically significant increase in VD at all layers by 6 months, while carriers of C677T alone showed no significant change and carriers of A1298C alone showed decreased density from 4 months to 6 months. Microstructure did not change during the follow-up period.

Conclusion: A 6-month intake of Ocufolin^® is capable of reversing structural changes of microangiopathy in mild non-proliferative DR +MTHFRP. This suggests a novel way to address these impairments prior to catastrophic vision loss.

https://drc.bmj.com/content/9/1/e002327

Nutritional and medical food therapies for diabetic retinopathy

Ce Shi, Peng Wang, Shriya Airen, Craig Brown, Zhiping Liu, Justin H. Townsend, Jianhua Wang & Hong Jiang

Abstract: Diabetic retinopathy (DR) is a form of microangiopathy. Reducing oxidative stress in the mitochondria and cell membranes decreases ischemic injury and end-organ damage to the retina. New approaches are needed, which reduce the risk and improve the outcomes of DR while complementing current therapeutic approaches. Homocysteine (Hcy) elevation and oxidative stress are potential therapeutic targets in DR.

Common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity. Patients with DR have high incidences of deficiencies of crucial vitamins, minerals, and related compounds, which also lead to elevation of Hcy and oxidative stress. Addressing the effects of the MTHFR polymorphism and addressing comorbid deficiencies and insufficiencies reduce the impact and severity of the disease. This approach provides safe and simple strategies that support conventional care and improve outcomes.

Suboptimal vitamin co-factor availability also impairs the release of neurotrophic and neuroprotective growth factors. Collectively, this accounts for variability in presentation and response of DR to conventional therapy. Fortunately, there are straightforward recommendations for addressing these issues and supporting traditional treatment plans.

We have reviewed the literature for nutritional interventions that support conventional therapies to reduce disease risk and severity. Optimal combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid, and n-acetylcysteine are identified for protecting the retina and choroid. Certain medical foods have been successfully used as therapy for retinopathy. Recommendations based on this review and our clinical experience are developed for clinicians to use to support conventional therapy for DR.

DR from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have similar retinal findings and responses to nutritional therapies.

https://doi.org/10.1186/s40662-020-00199-y

Improving diabetic and hypertensive retinopathy with a medical food containing L-methylfolate: a preliminary report

Jianhua Wang, Craig Brown, Ce Shi, Justin Townsend, Giovana Rosa Gameiro, Peng Wang & Hong Jiang

Background: Homocysteine and vitamin D may play a role in the development of diabetic and hypertensive retinopathy in patients with diabetes mellitus (DM) and hypertension. Supplementing food with L-methylfolate and vitamin D theoretically may improve diabetic and hypertensive retinopathy, however, the outcome of these nutritional approaches has not been fully examined. A retrospective case review was done of cases of retinopathy reversal in patients on Ocufolin^® and a similar nonprescription multivitamin, Eyefolate™. In this study, they were administered L-methylfolate (2.7 mg and 3.0 mg, respectively) and vitamin D3 (4500 IU each). These dosages are significantly above the RDA but well below levels associated with toxicity.

Case presentation: Seven patients had nonproliferative diabetic retinopathy (NPDR) and some of them had hypertension. One patient had only hypertensive retinopathy. All patients were instructed to take Ocufolin^® medical food as a food supplement. Baseline genetic testing for MTHFR polymorphisms was conducted. Fundus photography was used to document the fundus condition of the enrolled eyes in 8 NPDR patients at the initial and follow-up visits. Microaneurysms (MA) and exudates were observed to be improved in some trial patients. All subjects had one or more MTHFR polymorphisms. All had diabetic retinopathy, hypertensive retinopathy, or both. MAs were resolved, and exudates were decreased in 8/8 cases after taking the medical food. Retinal edema was found in 2/8 cases and improved or resolved in both cases after taking the medical food or the supplement. The best corrected visual activity was stable or improved in 8/8 cases.

Conclusion: We report a series of diabetic and hypertensive retinopathy cases with MTHFR polymorphisms and the improvement of retinal microvasculature (mainly MAs) in serial fundus photography after taking a medical food or supplement containing L-methylfolate and vitamin D. It appears that the use of nutritional supplements and medical foods containing L-methylfolate and vitamin D may be effective in facilitating the improvement of diabetic and hypertensive retinopathy.

https://doi.org/10.1186/s40662-019-0147-0

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