APPLICATIONS

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.

  1. Comparative, randomized, interventional trial in moderate dry eye  (PDF DOWNLOAD TRIAL)
  2. Open-label, non comparative, interventional trial including 905 patients suffering moderate dry eye (PDF DOWNLOAD TRIAL)
  3. Open-label, non-comparative, interventional trial including 1.419 patients suffering moderate dry eye (PDF DOWNLOAD TRIAL)
  4. Comparative, randomized, interventional trial in Glaucoma patients with dry eye symptoms derived from the chronic use of topical eye antiglaucoma medications (PDF DOWNLOAD TRIAL)
  5. Open label, non-comparative, interventional trial in 1.255 patients suffering Glaucoma and dry eye symptoms derived from the chronic use of topical antiglaucoma medications (PDF DOWNLOAD TRIAL)
  6. Comparative, randomized, interventional trial in intensive users of computer video-screens (PDF DOWNLOAD TRIAL)
  7. Randomized, double blind, placebo controlled Patients suffering posterior blepharitis with Meibomian Gland Dysfunction (PDF DOWNLOAD TRIAL A) (PDF DOWNLOAD TRIAL B)
  8. Comparative, randomized, interventional trial to investigate the influences of DHA supplementation on the tear Metabolomics in dry eye patients  (PDF DOWNLOAD TRIAL)

 

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 Chronic Open Angle 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.

 

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]

 

DHA-Triglyceride (Tridocosahexaenoin-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 (Tridocosahexaenoine-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. We are preparing protocols to develop clinical trials in groups of children suffering Autism and ADHD in different hospitals during 2016.

 

 

BIBLIOGRAPHIC REFERENCES:

  1. Oleñik A, et al; A randomized, double-masked study to evaluate the effect of omega-3 fatty acids supplementation in meibomian gland dysfunction; Clinical Interventions in Aging 2013:8 1133–1138
  2. Oleñik A, et al; Benefits of omega-3 fatty acid dietary supplementation on health related quality of life in patients with meibomian gland dysfunction; Clin Ophthalmology 2014; 8:831-836
  3. Oleñik A, et al; Effectiveness and tolerability of dietary supplementation with a combination of omega-3 polyunsaturated fatty acids and antioxidants in the treatment of dry eye symptoms: results of a prospective study; Clinical Ophthalmology 2014:8 169–176
  4. Haleh Kangari, et al; Short-term Consumption of Oral Omega-3 and Dry Eye Syndrome; Ophthalmology 2013;120:2191-2196
  5. Tellez-Vazquez Jeús; Omega-3 Fatty Acids Supplementation Improves Dry Eye Symptoms in Glaucoma Patients: Results of a Prospective Multicenter Study; Sent for publication to Journal of Glaucoma 2015
  6. Galbis-Estrada C, et al; Patients undergoing long-term treatment with antihypertensive eye drops responded positively with respect to their ocular surface disorder
    to oral supplementation with antioxidants and essential fatty acids; Clinical Interventions in Aging 2013:8 711–719
  7. Lafuente M, et al; Tratamiento del Edema Macular Diabético con inyecciones intravítreas de Ranibizumab en régimen PRN mensual estricto. Influencia de la suplementación con DHA de alta concentración. Resultados a 24 meses; Congreso de la Sociedad Española de Retina y Vítreo, Madrid., 6 de Marzo 2015; Publicación pendiente.
  8. Schuchard JP, et al; Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children; Eur J Pediatr (2010) 169:149–164
  9. Birch EE, et al; The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid; Am J Clin Nutr 2010;91:848–59
  10. Diario Oficial de la Unión Europea; Reglamento (UE) Nº 440/2011 de 6 de Mayo , 2011 y Nº 432/2012 de 16 de Mayo 2012 por el que se establece la lista de declaraciones autorizadas de propiedades saludables de los alimentos.
  11. Ramakrishnan U, et al; Role of docosahexaenoic acid in maternal and child mental health; Am J Clin Nutr 2009;89 (Suppl): 958S-62S
  12. McNamara RK, et al; Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance Imaging; Am J Clin Nutr 2010; 91:1060-7
  13. Alexandra J Richardson, et al; Docosahexaenoic Acid for Reading, Cognition and Behavior in Children Aged 7–9 Years: A Randomized, Controlled Trial (The DOLAB Study); PLOS One 2012;7(9):e43909. doi: 10.1371/journal.pone.0043909. Epub 2012 Sep 6.
  14. Caryl J Antalis, et al; Omega-3 fatty acid status in attention-deficit/hyperactivity disorder; Prostaglandins, Leukotrienes and Essential Fatty Acids 2006; 75: 299–308
  15. Gow RV, et al; Omega-3 fatty acids are inversely related to callous and unemotional traits in adolescent boys with attention deficit hyperactivity disorder; Prostaglandins, Leukotrienes and Essential Fatty Acids 2013; 88(6):411-8
  16. Antalis CJ, et al; Omega-3 fatty acid status in attenttion-deficit/hyperactivity disorder; Prostaglandins Leukotrienes and EssentialFatty Acids 2006; 75:299-308
  17. Estudio de dosis-respuesta en membrana de eritrocito tras 30 días de administración repetida en 44 voluntarios. Grupo Consolidado “Transporte y vehiculación de fármacos” (2009 SGR-367). Departamento de Bioquímica y Biología Molecular, Universidad de Barcelona.
  18. Milte CM, et al; Increased erithrocyte eicosapentaenoic acida and docosahexaenoic acid are associated with improved attention and behavior in children with ADHD in a randomized controlled three-way crossover trial; J Atten Disord 2013, Nov 8 (Epub ahead of print)
  19. Milte CM, et al; Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: A randomized controlled trial; Nutrition 2012;28:670-677
  20. Sinn N, et al; Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD; J Dev Behav Pediatr 2007; 28:82-91
  21. Johnson M, et al; Omega-3/Omega-6 fatty acids for attention deficit hyperactivity disorder. A randomized placebo-controlled trial in children and adolescents; J of Att Dis 2009; 12(5):394-401
  22. Perera H, et al; Combined n-3 and n-6 supplementation in children with Attention-deficit Hyperactivity Disorder (ADHD) refractory to Methylphenidate treatment: A double-blind, placebo-controlled study; J Child Neurol 2012; 27(6):747-5

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