Oxidation can’t be avoided
Living in an atmosphere rich in oxygen to permit breading has obliged the living beings to get mechanisms which permit them neutralization of free radicals produced; oxidized unstable molecules, having lost one or both electrons from their external orbital, are ready to steel them from molecules being in their neighborhood which are constituting the organs and noble tissues from our bodies (proteins, carbohydrates, fatty acids, DNA,…) and inducing their dysfunction.
Aging is a vulnerability factor
Our genetic, our life style, and the type of food we eat are having intense influences on the protection mechanisms against oxidation, favoring health or disease. Some of them are being slowed down during our aging process, making this collective of people more vulnerable.
Mechanisms of protection
Inflammation associated to chronic eye diseases, as in dry eye, in glaucoma, in diabetes, in age related macular degeneration (AMD) are inducing intense oxidative stress, making necessary to reinforce both the endogen protecting mechanisms (antioxidant enzymes, glutathione, uric acid,…), which are fighting against the oxidative stress, and the exogenous protecting nutrients (antioxidants vitamins, trace elements, flavonoids, carotenoids, and essential fatty acids,…).
Our diet as a source of antioxidants
Today research is clearly demonstrating that an intervention based on the type of diet, with the contribution of certain nutrients showing a proven protecting efficacy, can permit the clinician to make an intervention in order to mitigate the vulnerability and helplessness of this group of patients, in parallel with the specific treatment of their disease.
The European Commission has approved the use of some claims of health benefices offered by DHA supplementation to humans, but with the obligation to inform about the daily recommended doses for the different indications and ages: eye function, brain function, heart function, blood pressure, fasting control of serum level of triglycerides, in newborns and infants, in children, in adults, and in pregnant and lactating women: it is pointed a well-established role of DHA in the retina function, with a clear cause and effect relation between DHA consumption and the maintenance of a normal vision. The panel is also admitting a well-established role of DHA consumption and the physiological benefice of the maintenance of a normal brain function. To make such claims in the texts of the box or in the leaflet of the food supplement it is considered that the daily minimum quantity of DHA that should be given is 250 mg in one single or in different servings. It is also accepted that DHA is necessary to maintain the fasting normal levels of triglycerides in the blood, but to make this claim it’s necessary to give a daily dose of DHA of 2g. This is confirming the great importance that DHA has in the human diet to promote a normal development of the visual, brain and intellectual functions, and on its effects reducing the level of triglycerides in moderate hypertriglyceridemia (150-500mg/dl) that can be lowered to a 30%.
Our Clinical experience with DHA-TG in Dry Eye Syndrome
Dry eye is a syndrome, meaning that its origin can be due to different causes. Due to a lowered tear secretion: when tear secretion is reduced because of aging, or because of pharmacologic activity (beta-blockers and other drugs), due to autoimmunity conditions affecting the lacrimal glands, or due to the influence of a nutritional deficit (Vitamin A deficiency). Due to excessive evaporation: when there is an accelerated tear evaporation, due to an excessive exposition of the ocular surface, as it occurs in a facial palsy, or in the intensive use of computer screens, or even due to exposition to excessive environmental factors which promote desiccation (wind, air conditioning, heating), also when quality or quantity of tear lipid film produced in Meibomian glands (inside the lids) is reduced, as it can be seen in the menopause (hormonal dry eye) due to an androgenic deficit, or in Meibomian Gland Dysfunction (posterior blepharitis). Due to refractive surgery, after cutting the corneal nerve fibers with the microkeratome, leaving the cornea temporarily unable to detect its own level of humidity (invalidated feed-back mechanism of tear production). Hormonal type is the most prevalent; it is calculated 3,2 million women over 50 years of age in the USA suffering this type of dry eye1. Bothering symptoms of dry eye are vague but persistent and making the patient uncomfortable: scratchy and stinging sensation in the eyes, eye redness, grittiness, painful eyes, tired eyes, grating sensation, and blurry vision.
Treatment options will depend on the type of dry eye suffered by the patient. And should be adapted in each individual case: avoiding drugs causing dryness, supplementing vitamin A if there exist any deficit, prescribing artificial tears to hydrate and lubricate the ocular surface, by plugging the orifices for tear drainage in the lid margins, use of anti-inflammatory eye drops, lid massage and hygiene.
Clinical trials performed with DHA-TG supplementation in evaporative Dry Eye and in the post-refractive surgery
In the last 5 years we have promoted different clinical trials that have been published from varied collectives suffering dry eye of different causes, which permit us getting a clear evidence of the benefits that can be obtained with DHA-TG supplementation. Supplemented doses have been between 700mg to 1.000mg/day with a follow-up period of 90 days.
Our clinical experience with DHA-TG supplementation in Dry Eye
All the trials (articles 1 to 8) have offered statistically significant clinical benefits: showing improvements in all the studied clinical variables: in the tear stability (Tear Break-up Time: B.U.T), in the degree of the ocular surface hydration (Schirmer test), in an evident and significant reduction of the bothering dry eye symptoms (validated OSDI questionnaire), in lowering the expression of inflammatory markers (Cytokines) present in reflex tears (trials 1, 4 and 6), in improvements in the redness of the lid margin, in the quality of the Meibomian lipid expression, and in quality of life of patients suffering MGD (article 5). In two of the open-label, non-comparative, interventional trials (articles 2 and 3) of large series of patients suffering moderate dry eye, users of artificial tears, but not being fully satisfied, after 90 days of supplementation a statistically significant improvement of all clinical variables (BUT, Schirmer test, Oxford test) and symptoms (OSDI) are obtained. The level of satisfaction rated either by patients and clinicians are above 80% (satisfied or very satisfied).3 Other interventional trials performed by some other researchers with Omega-3 PUFA supplementation are confirming our results.4 All in all, it can be clearly established that enriching the diet with DHA-TG can bring benefits for this group of patients not satisfied with the use of artificial tears in the sense of improving their comfort.
A Double blind, interventional, randomized, placebo-controlled trial looking for any possible beneficial effects of Omega-3 PUFA (DHA+EPA) supplementation in patients submitted to refractive surgery.
Estudio clínico realizado con AGPI Omega-3 (DHA+EPA) en un colectivo de pacientes sometidos a cirugía refractiva.
9. Patients with dry eye derived from refractive surgery (PDF DOWNLOAD TRIAL)
Not only a significant quicker corneal rate of epithelialization is detected in the supplemented group, but also improvement in the BUT, and a quicker visual acuity recovery.
Own clinical experience with DHA-TG in Glaucoma
Chronic open angle glaucoma is a neurodegenerative disease affecting the head of the optic nerve, showing a progressive loss of axons in it (ganglion cells optic fibers) arriving from the entire retina, which is manifested by a progressive excavation (cupping) in the optic disc, and a progressive visual field loss, predominantly from the periphery of the retina. Frequently it develops with a progressive increase of the intraocular pressure (IOP) going over the normal levels of between 10 to 20 mmHg. Treatment is established following different stages, starting with antiglaucoma drugs and following to different surgical techniques when pharmacology is not able to get the control: laser trabeculectomy, Trabeculoplasty (filtering surgery), or with valve implants, to favor the aqueous humor drainage. Most recent research is pointing towards a severe oxidative problem suffered by this population (Primary open angle glaucoma and Exfoliation type of glaucoma). When comparing the levels of glutathione (endogen antioxidant protein) from these patients, both in serum and in aqueous humor, with that obtained from normal healthy controls, significant lower levels of glutathione can be detected, but also showing a significant elevation on the peroxidation of lipids found in serum and at aqueous humor level. This is thought to happen due to a genetic-metabolic disturbance, and would explain why this group of population is submitted at a higher prevalence of suffering cardiovascular disturbances (thrombosis, acute myocardial infarction and so). The intense oxidative stress is favoring lesions on to the vascular endothelial cells, inducing premature sclerosis. The same events happening at the trabecular mesh endothelial cells (the aqueous humor drainage site) would be the cause of an accelerated trabecular sclerosis, and a blocking for aqueous drainage, inducing an increase of the intraocular pressure (IOP).
Most patients suffering chronic open angle glaucoma will end developing an ocular surface disease, due to the chronic use of ocular topical antiglaucoma medication. The derived dry eye sensation ends inducing a bad tolerance to the instillation of topical hypotensive drugs, promoting bad compliance and disturbing the IOP control.
An open, prospective, multicenter, interventional trial has been performed recruiting 1255 glaucoma patients suffering dry eye symptoms derived from instillation of topical eye hypotensives.5 After a follow-up period of 90 days supplementing BRUDYPIO 3 capsules per day (DHA-TG 1g/day), we have been able to detect a highly significant (p<0.001) improvement of all subjective dry eye symptoms: stinging, itching, irritation, tearing, photophobia, redness, fatigue, fluctuating visual acuity, and blurred vision, so as also a significant improvement in all the evaluated objective signs: Oxford, B.U.T., Schirmer. Also a small, but significant reduction in the IOP has been detected (P<0.001), perhaps related with an improvement in the compliance of the hypotensive treatment (possibly due to an improvement in the topical tolerance to their instillation). A total of 82% of the patients answered being satisfied (60%) or very satisfied (21,9%), in front of only 18% being unsatisfied. From the ophthalmologist point of view, 88% define themselves as finding an improvement (56,4%), or a great improvement (31,3%), against 12% admit ting no improvement at all. In a previous trial that we performed with a shorter sample of patients with the same characteristics, the results obtained were similar, but we were also able to detect a significant reduction in the inflammatory markers (cytokines) present in the reflex tears obtained by comparing the pre-supplementation situation with that after 90 days of effective supplementation with 3 capsules per day (DHA-TG 1g/day).6 This is showing a real anti-inflammatory effect of DHA on the ocular surface.
On the other hand, long term (24 months) 3 capsules per day DHA-TG supplementation (1g/day DHA-TG) patented as a cell antioxidant in adult type 2 diabetic patients suffering Central Macular Edema, randomized either to receive or not supplementation besides intra-vitreal ranibizumab injections, has shown a significant improvement in the Total Antioxidant Capacity of the the supplemented group.7 This is demonstrating a significant improvement in the oxidative protection of this group of patients. So, this much higher vulnerability to oxidation in glaucoma patients could get benefit from the antioxidant protection offered by DHA-TG supplementation and would contribute reducing the rhythm of sclerosis progression of the trabecular mesh-work and hopefully also delaying the IOP increase.
In a clinical study with 47 patients with Pseudoexfoliation secondary glaucoma25 being randomized at 50% to receive or not 1g / day of DHA Triglyceride (BRUDYPIO 3 capsules per day) for 6 months, we have not seen significant differences in the clinical variables studied (visual acuity, thickness of nerve fibers with OCT), but we have seen significant improvements in the levels of IOP in both eyes (despite having a controlled IOP), as well as significant improvements in oxidative protection of these patients, with an increase in Total Antioxidant Capacity, a reduction in the peroxidation of plasma lipids, an increase in the erythrocyte membrane concentration of DHA, plus a reduction in the Omega-6 / Omega-3 index, as well as a significant lowering in plasma expression (lower levels) of IL-6. All of this indicates that DHA triglyceride contributes to the hypotensive effect of the administered antiglaucoma agents, and that it not only offers effective antioxidant protection, but also reduces the systemic inflammatory state of these patients.
Our clinical experience with DHA-TG in Diabetic Retinopathy
This is a degenerative microangiopathy affecting the vessels of the retina, due to some toxic metabolites derived from glucose anomalous fermentation. The excess of glucose in the blood turns into polyols, which are toxic for endothelial cells and pericytes, being also the cause of the glycation of proteins and inducing an intensified oxidative stress. The consequences are a progressive deterioration of the vessel walls in the retina, which become incompetent. The excessive permeability facilitates the leaking of fluids and proteins leaving yellowish hard exudates in the surrounding tissues, showing microaneurysms in the vessel walls and some microhemorrhages. This initial phase is called as the non proliferative, because after some time, the disease keeps progressing, entering into a proliferative phase; the resolving mechanisms turns into degeneration of the retina. Some vessels become obliterated leaving pale-ischemic areas shown as diffused white cotton-wool exudates. Ischemic cells start producing inflammatory mediators, as the Vascular Endothelial Growing Factor (VEGF), promoting neovascularization of the retina and macula. The walls of the newly created vessels are weak and break easily leaving macrohemorrhages. The healing process at long term leaves retractions of the hyaloid membrane favoring retinal detachments.
We have been able to show some DHA cytokine inhibition properties, either incubating it in human cell cultures (microglia) but also in the reflex tears of dry eye patients being supplemented during 90 days. Significant reduction of some cytokines as IL-6, TNF-α, IL-1β, IL-10, and some other have been obtained in the supplemented groups. DHA also induces production of eicosanoids of the E3 series, which show an anti-inflammatory profile, and promotes production of some metabolites with inflammatory resolution properties as the Resolvine D1 and the Protectine D1.
In order to assess the anti-inflammatory effect of Tricocosahexaenoin-AOX® both at retina and human macula level, we have developed a randomized, controlled, simple-blind trial lasting 2 years, to verify if intravitreal Ranibizumab together with dietetic supplementation of a DHA rich triglyceride with antioxidants in 62 patients suffering Diabetic Macular Edema.
Ranibizumab is a monoclonal antibody, which destroys the Vascular Endothelial Growing Factor (VEGF).
One of the two randomization groups (50%) is supplemented with 3 capsules per day of BRUDYRETINA (350mg x 3= 1050mg of DHA) during two years.
It is shown after 24 months, and from the very first month a significant difference between groups relating to the Central Macular Thickness (measured with the OCT) in favor to the DHA supplemented group is stablished (95% Confidence Interval from the difference 7.20 – 97.656; P=0.024), even though the difference in best corrected visual acuity measured with the Early Treatment Diabetic Retinopathy Study optotype does not reach statistical difference (95% Confidence Interval -022 -7.09, P<0.066). After 24 months, >5 and >10 letters improvements were significanty greater in the DHA supplemented group versus the non supplemented group when comparing the vision of the worst and the best eye, but no other differences at 12 and 24 months were found. It is concluded that the combination of intravitreal Ranibizumab together with DHA supplementation is more effective reducing the central macular thickness after 2 years than only receiving intravitreal Ranibizumab in patients suffering Diabetic Macular Edema. The anatomic improvement is followed by a tendency towards an improvement of vision.
Read original study
María Lafuente, et al; Combined intravitreal Ranibizumab and oral supplementation with Docosahexaenoic acid and antioxidants for Diabetic Macular Edema: two-year randomized single-blind controlled trial results. Retina. 2016 Oct 26. [Epub ahead of print]
The same study at its completion at 36 months period23 confirms that the supplemented group maintains significant differences of at least 50 microns in thickness in the central macula, and a better, although not significant, situation of visual acuity. There is also an increase in antioxidant protection with significant differences with respect to the non-supplemented group by showing an improvement of Total Antioxidant Capacity in plasma, also a reduction in the percentage of glycosylated hemoglobin in plasma, a membrane increase DHA concentration, and a reduction in the expression levels of plasma IL-6. All these results are showing that DHA triglyceride is offering a clear antioxidant and anti-inflammatory protection to diabetic patients.
We also wanted to analyze the effects of supplementation on the macular sensitivity by using the technique of analysis of the macular microperimetry, in a study with 24 patients affected of a non-proliferative diabetic retinopathy, randomized to 50% to receive or not 1g / day of DHA Triglyceride (BRUDYRETINA 3 capsules / day) for 3 months24. We have seen significant differences between both groups in favor of the supplemented group in their improvement on the macular sensitivity and on the macular integrity index. We have also observed an improvement in the Total Plasma Antioxidant Capacity, an elevation in the DHA in the erythrocyte membrane, an improvement in the SF-36 vision quality test and a significant reduction in the plasma levels of IL-6. Again, the antioxidant and anti-inflammatory protection offered by DHA triglyceride in diabetic patients is revealed.
DHA-Triglyceride (Tridocosahexanoina-AOX®) in Attention Deficit Hyperactivity Disorder (ADHD)
This disorder in its diverse forms has an elevated prevalence among the pediatric population (5-7%), inducing a poor school performance, but also family tensions and undermining the self-esteem of the child. It’s three times more prevalent in boys than in girls. In boys it predominates the composed subtype, with attention deficit with hyperactivity and impulsivity, while in girls it predominates the subtype with isolated attention deficit. It’s thought to have a multifactorial origin with the participation of both pre and perinatal aspects possibly related with the inadequate supply of some nutrients essential for a normal fetal and post-natal neurodevelopment, resulting in a disturbance on the phospholipids conforming the neuronal membranes, and/or in the neurotransmitters metabolism.8 DHA is a long chain Omega-3 polyunsaturated fatty acid essential for humans, necessary for brain maturation, for cognitive and visual development,9 and for normal brain functioning.10 The elevated DHA concentration found in neuronal membrane phospholipids is conferring them flexibility, fluidity, and permeability, based on the 6 double bonds present in each one of DHA molecules structure; this has influence on the neurons, in the synaptic transduction of signals, and in the neurotransmitters metabolism.11 Its deficit could be causing anomalies in the systems modulating the attention, motivation and emotion much conditioning human behavior.12 Some trials have detected that some groups of children having a poor school performance are improving their reading capacity and their behavior after having had a period of DHA supplementation.13 It has also been detected a correlation between ADHD and low levels of DHA in neuronal membranes (in red blood cell membranes).14, 15, 16 Also showing that supplementation is able to elevate the membrane deposits17 followed by an improvement in behavior, in attention, in literacy17 and emotivity.15 The existing trials show groups of children responding well to supplementation, getting significant improvements on attention, hyperactivity, impulsivity and behavior,19, 20, 21 also showing improvements in some groups having had bad response to methylfenidate,22 but also showing some groups with bad response. It should be kept in mind that ADHD treatment should be multimodal, based mainly on psychological intervention, counseling, diet, and on pharmacology.
BRUDY have two products in the marked with a high concentration in DHA in a triglyceride form (Tridocosahexanoina-AOX®), with now vitamins and trace elements included, to facilitate supplementation to children suffering ADHD: BRUDYNEN EMULSIÓN (as a Dietetic Food for Special Medical Purposes) in a box containing 30 single dose sachets containing 1g of DHA-TG in form of a drinkable emulsion. Has been specially designed for children not yet able to swallow capsules, with a banana flavor and fructose as a natural sweetener (gluten and diary free). The administration of the product requires medical prescription and supervision. BRUDY PLUS (as a Food Supplement) containing 90 soft gelatin capsules, including 350mg of DHA in each one, best alternative for children that are able to swallow capsules.
A clinical study has been carried out In the Faculty of Psychology of Oviedo, with 95 children, aged 6 to 18 years with a diagnosis of ADHD (DSM-5) of any subtype, with or without treatment with psychostimulants, double blind , and placebo-controlled, with a 6-month follow-up26. The experimental group has been given a Food for Special Medical Purposes (BRUDYNEN EMULSION drinkable sachets) containing 1g of DHA triglyceride (1 sachet per day if <32Kg; 2 sachets per day if > 32Kg). Selective attention was assessed by d2 test and sustained attention by the AULA NESPLORA test, as well as measures based on the observation of behavior through the EDAH scales and Conners scale, comparing the baseline situation with the final at 6 months. The pharmacological treatment had no effect on the analysis of the test variables. The magnitude of the intragroup differences in the variables of the d2 test and the AULA NESPLORA test were higher in the DHA group than in the Placebo group, but the inter-group differences were not significant. In the behavioral variables, there were significant differences in the attention deficit, and in the attention deficit with hyperactivity, also a significant intra-group difference in the Conners scale, but not inter-group differences, although in the DHA group the ADHD symptoms decreased, while in the placebo group, the symptoms worsened. The magnitude of the intra-group improvements in the cognitive variables and the inter-group differences in behavioral variables gives support to a clear benefit of a DHA supplementation. The results indicate that DHA Triglyceride dietary supplementation may constitute an effective non-pharmacological complementary strategy in children and adolescents suffering ADHD.