The Effect of Antioxidants on Sperm Quality Parameters and Pregnancy Rates for Idiopathic Male Infertility: A Network Meta-Analysis of Randomized Controlled Trials.

Purpose: Male infertility is a global public health issue recognized by the WHO. Recently, antioxidants are increasingly used to treat idiopathic male infertility. However, the lack of available evidence has led to the inability to rank the effects of antioxidants on the sperm quality parameters and pregnancy rate of infertile men. This network meta-analysis studied the effects of different antioxidants on the sperm quality and pregnancy rate of idiopathic male infertility. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for randomized controlled trials (RCTs). The weighted mean difference (WMD) and odds ratio (OR) were applied for the comparison of continuous and dichotomous variables, respectively, with 95% CIs. The outcomes were sperm motility, sperm concentration, sperm morphology, and pregnancy rate. Results: A total of 23 RCTs with 1,917 patients and 10 kids of antioxidants were included. l-Carnitine, l-carnitine+l-acetylcarnitine, coenzyme-Q10, ω-3 fatty acid, and selenium were more efficacious than placebo in sperm quality parameters. l-Carnitine was ranked first in sperm motility and sperm morphology (WMD 6.52% [95% CI: 2.55% to 10.05%], WMD 4.96% [0.20% to 9.73%]). ω-3 fatty acid was ranked first in sperm concentration (WMD 9.89 × 106/ml, [95% CI: 7.01 to 12.77 × 106/ml]). In terms of pregnancy rate, there was no significant effect as compared with placebo. Conclusions: l-Carnitine was ranked first in sperm motility and sperm morphology. ω-3 fatty acid was ranked first in sperm concentration. Coenzyme-Q10 had better effective treatment on sperm motility and concentration. Furthermore, high-quality RCTs with adequate sample sizes should be conducted to compare the outcomes of different antioxidants.

Prevention and reversal of chlorpromazine induced testicular dysfunction in rats by synergistic testicle-active flavonoids, taurine and coenzyme-10.

Evidences have shown that alterations in testicular dehydrogenase and ionic-ATPase activities have important implications in spermatogenesis and sperm capacitation, a penultimate biochemical change required for fertilization. Previous studies have revealed that taurine and coenzyme-Q10 (COQ-10), which are synergistic testicle-active bioflavonoids, with proven gonadotropin-enhancing properties reduce testicular damage in rats. Hence, this study investigated the effects of taurine and COQ-10 or their combination alone, and in the preventive and reversal of chlorpromazine-induced inhibition of testicular dehydrogenase enzymes, electrogenic pumps, sperm capacitation and acrosomal-reaction in male Wister rats. In the drug-treatment alone or preventive-protocol, rats received oral treatment of saline (10 mL/kg), taurine (150 mg/kg/day), COQ-10 (10 mg/kg/day) or both alone repeatedly for 56 days, or in combination with chlorpromazine (30 mg/kg/p.o./day) from days 29-56. In the reversal-protocol, the animals received chlorpromazine for 56 days prior to saline, taurine, COQ-10 or the combination from days 29-56. Thereafter, spermatogenesis (sperm count, viability, motility and morphology), testicular dehydrogenase [3beta-hydroxysteroid dehydrogenase (3ß-HSD), 17beta-hydroxysteroid dehydrogenase (17ß-HSD), glucose-6-phosphate dehydrogenase (G6PDH), lactate dehydrogenase-X (LDH-X)], ATPase (Na+/K+, Ca2+, Mg2+, H+) activities, sperm capacitation and acrosomal reaction were evaluated. Taurine and COQ-10 or their combination increased spermatogenesis, testicular 3ß-HSD, 17ß-HSD, G6PDH and LDH-X enzymes of naïve and chlorpromazine-treated rats. Both taurine and COQ-10 increased Na+/K+, Ca2+, Mg2+ and H+-ATPase activities. Also, taurine and COQ-10 or their combination prevented and reversed chlorpromazine-induced inhibition of sperm capacitation and acrosomal-reaction. The study showed that taurine and COQ-10 prevent and reverse chlorpromazine-induced inhibition of spermatogenesis, epididymal sperm capacitation and acrosomal reaction in rats through increased testicular dehydrogenases and electrogenic pump activities.

The Potential Use of Metabolic Cofactors in Treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is caused by the imbalance between lipid deposition and lipid removal from the liver, and its global prevalence continues to increase dramatically. NAFLD encompasses a spectrum of pathological conditions including simple steatosis and non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver cancer. Even though there is a multi-disciplinary effort for development of a treatment strategy for NAFLD, there is not an approved effective medication available. Single or combined metabolic cofactors can be supplemented to boost the metabolic processes altered in NAFLD. Here, we review the dosage and usage of metabolic cofactors including l-carnitine, Nicotinamide riboside (NR), l-serine, and N-acetyl-l-cysteine (NAC) in human clinical studies to improve the altered biological functions associated with different human diseases. We also discuss the potential use of these substances in treatment of NAFLD and other metabolic diseases including neurodegenerative and cardiovascular diseases of which pathogenesis is linked to mitochondrial dysfunction.

Immobilization induced degeneration in intervertebral discs of rats and protective effects of omega 3 fatty acids and CoQ10

The aim of the study was to determine the effects of immobilization on the radiological indices of rats' intervertebral disc (IVD) and observe the protective effects of Omega 3 fatty acids and Co-enzyme Q 10 (CoQ10). The study comprised 40 Sprague-Dawley rats weighing 250-300g. After random selection, rats were divided into four groups having 10 animals in each. Group A rats, on standard lab diet, served as control group. Group B rats were disc immobilized by using an Illizarov-type apparatus which was applied for 60 days. Group C and D rats after disc immobilization were administrated with Omega 3 fatty acids (260 mg/kg/day) (Abdou and Hassan, 2014) and CoQ10 (150 mg/kg/day) (Kwong et al., 2002) through oral gavage respectively. Radiographs of rat tails were taken at the start and end of experiment to measure disc height index (DHI) and disc wedge index (DWI).On radiological examination, mean DHI of group A was measured as 0.0581 ± 0.004 while of Group B was 0.0324 ± 0.008 which was significantly lower as compared to group A (p-value <0.001). Whereas in groups C and D, mean DHI were 0.0552 ± 0.003 and 0.0563 ± 0.003 respectively. Similarly mean DWI of group A was calculated as 1.086 ± 0.020 and for Group B it was 1.628 ± 0.355 which was significantly increased than group A (p value < 0.001). Mean DWI of group C and D were calculated as 1.147 ± 0.038 and 1.188 ± 0.023 respectively showing improvement after administration of Omega 3 and CoQ10.In this study, radiological changes induced by immobilization in IVDs of the experimental rats and its reversal by omega 3 and CoQ10 were proven. Omega 3 and CoQ10 administration minimized immobilization induced degeneration of IVDs

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Mecanismos de aterosclerosis y enfermedad cardiovascular en el síndrome antifosfolípido y el lupus eritematoso sistémico. Alternativas terapéuticas / Mechanisms of atherosclerosis and cardiovascular disease in antiphospholipid syndrome and systemic lupus erythematosus. New therapeutic approaches

La aterotrombosis en el síndrome antifosfolípido primario (SAF) y el lupus eritematoso sistémico (LES) constituye una enfermedad de carácter sistémico, en cuyo desarrollo interviene una compleja red de mediadores inmunológicos, procoagulantes, componentes inflamatorios y el estrés oxidativo, todos ellos conducentes a la activación del complemento, el daño endotelial y la activación leucocitaria. Estudios genómicos y epigenéticos han contribuido asimismo a identificar nuevos biomarcadores que, junto a factores de riesgo tradicionales, han permitido delinear nuevos mecanismos patogénicos implicados en el desarrollo de trombosis y enfermedad cardiovascular (CV) en estos pacientes. Actualmente se están estudiando nuevas herramientas terapéuticas para la prevención de la enfermedad CV, tales como las estatinas, los inhibidores del interferón α o la coenzima Q10, entre otros. Los nuevos anticoagulantes orales pueden suponer también avances importantes en el tratamiento de estos pacientes. El presente estudio examina aspectos moleculares y terapéuticos asociados al diagnóstico y el seguimiento de la enfermedad CV en SAF y LES (AU)

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are 2 highly related autoimmune-rheumatic diseases associated with an increased risk of developing cardiovascular (CV) diseases. Despite the great progresses made in understanding the pathological mechanisms leading to CV diseases in those pathologies, there is still the unmet need to improve long term prognosis. CV diseases in SLE and APS is thought to happen as the result of a complex interaction between traditional CV risk factors, immune deregulation and disease activity, including the synergic effect of cytokines, chemokines, adipokines, proteases, autoantibodies, adhesion receptors, oxidative stress and a plethora of intracellular signalling molecules. Genomic and epigenomic analyses have further allowed the identification of specific signatures explaining the proathero-thrombotic profiles of APS and SLE patients. This review examines the complex role of these heterogeneous factors, and analyses new therapeutic approaches under study to reduce the CV risk in these autoimmune disorders (AU)

[Novel therapies in neurometabolic diseases: the importance of early intervention]. / Terapias novedosas en enfermedades neurometabolicas: importancia de una intervencion precoz.

INTRODUCTION: Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. DEVELOPMENT: Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis. It has been proven that very early treatment of mucopolysaccharidoses can change their natural course. Intrathecal enzyme replacement therapy is being tried in some mucopolysaccharidoses with cognitive involvement, in an attempt to halt neurodegeneration. Very positive results have been obtained with genetically modified autotransplants in late-onset infantile metachromatic leukodystrophy and research is being conducted on other pathologies (mucopolysaccharidosis type III, X-linked adrenoleukodystrophy). Novel outcomes are also being achieved in the treatment of some encephalopathies that are sensitive to vitamins or cofactors: triple therapy in pyridoxine dependency, treatment with thiamine for some subacute encephalopathies with involvement of the basal ganglia, treatment with folinic acid for children with cerebral folate deficiency, or treatment with cyclic pyranopterin monophosphate in molybdenum cofactor deficiency type A. CONCLUSIONS: As neuropaediatricians we must update our knowledge, especially in the case of treatable neurometabolic pathologies, since early treatment can change their prognosis significantly.

TITLE: Terapias novedosas en enfermedades neurometabolicas: importancia de una intervencion precoz.Introduccion. Las enfermedades neurometabolicas son individualmente ultrarraras, pero algunas de ellas tienen un tratamiento eficaz. Desarrollo. Se revisan algunas novedades terapeuticas. Las enfermedades lisosomales tienen actualmente mejores posibilidades de tratamiento. En los ultimos años se ha extendido el uso de la terapia enzimatica sustitutiva a la mucopolisacaridosis tipo IVA (Morquio A), a la mucopolisacaridosis tipo VII (enfermedad de Sly), al deficit de lipasa acida lisosomal y a la alfa-manosidosis. Se ha constatado que un tratamiento muy precoz de las mucopolisacaridosis puede cambiar su historia natural. Se esta probando la terapia enzimatica sustitutiva intratecal en algunas mucopolisacaridosis con afectacion cognitiva, en el intento de frenar la neurodegeneracion. Se han obtenido resultados muy positivos con autotrasplante modificado geneticamente en leucodistrofia metacromatica infantil tardia y se esta trabajando en otras patologias (mucopolisacaridosis tipo III, adrenoleucodistrofia ligada a X). Tambien hay novedades en la terapia de algunas encefalopatias sensibles a vitaminas o cofactores: la triple terapia en la dependencia de piridoxina, el tratamiento con tiamina de algunas encefalopatias subagudas con afectacion de ganglios basales, el tratamiento con acido folinico de niños con deficiencia de folato cerebral, o el tratamiento con monofosfato de piranopterina ciclico en los defectos de cofactor de molibdeno de tipo A. Conclusiones. Los neuropediatras debemos actualizar nuestro conocimiento especialmente en aquellas patologias neurometabolicas tratables, dado que una terapia precoz puede cambiar de forma significativa su pronostico.

[Metabolic correction: a biochemical option against diseases]. / Corrección metabólica: Una opción bioquímica contra las enfermedades.

Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept of optimal metabolic correction as a functional cost-effective mechanism against disease, in addition, to contribute to diseases prevention and regeneration of the body and health.

The elusive magic pill: finding effective therapies for mitochondrial disorders.

The incidence of mitochondrial diseases has been estimated at 11.5/100,000 (1:8500) worldwide. In the USA up to 4000 newborns annually are expected to develop a mitochondrial disease. More than 50 million adults in the USA also suffer from diseases in which primary or secondary mitochondrial dysfunction is involved. Mitochondrial dysfunction has been identified in cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities. Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases, such as Parkinson and Alzheimer diseases. Yet most treatments available are based on empiric data and clinician experience because of the lack of randomized controlled clinical trials to provide evidence-based treatments for these disorders. Here we explore the current state of research for the treatment of mitochondrial disorders.

[Risk-sharing scheme in Israel--Kuvan as an allegory].

Healthcare systems worldwide are dealing with the uncertainty characterizing new and expensive health technoLogies, particularly aspects involving drug effectiveness and the extent and doses required for utilization. Reducing this uncertainty can be achieved mainly by using either coverage with evidence development methods or risk-sharing schemes (RSS). In 2011, the first phenylketonuria (PKU) risk-sharing scheme was set up in Israel, through the public funding health services updating process. This was done in order to ensure that people with PKU could access PKU sole treatment--sapropterin dihydrochloride, Kuvan. The apparent effectiveness of the treatment, on one hand, and the uncertainty regarding the number of patients and average treatment dosage, on the other hand, dictated the RRS. This scheme determined a ceiling number of tablets to be funded by the insurer, above this ceiling the manufacturer would finance Kuvan. Furthermore, it was agreed that after 3 years Kuvan would be brought to the public committee for updating reimbursement decisions. It is inevitable that risk sharing and conditional coverage agreements will become a common practice in the reimbursement process in the future. This will allow competent authorities and pharmaceutical companies to build clinical experience and other required data with medicines which might normally not be eLigible for reimbursement. Before it becomes the common practice in Israel, the RSS for Kuvan, process and outcomes, should be monitored and analyzed by the Ministry of Health, to ensure patients access to treatment, the effective collection of the research data and the effective interaction between Israel's four health funds and the manufacturer.

The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response.

The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.

Activation of phenylalanine hydroxylase induces positive cooperativity toward the natural cofactor.

Protein misfolding with loss-of-function of the enzyme phenylalanine hydroxylase (PAH) is the molecular basis of phenylketonuria in many individuals carrying missense mutations in the PAH gene. PAH is complexly regulated by its substrate L-Phenylalanine and its natural cofactor 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)). Sapropterin dihydrochloride, the synthetic form of BH(4), was recently approved as the first pharmacological chaperone to correct the loss-of-function phenotype. However, current knowledge about enzyme function and regulation in the therapeutic setting is scarce. This illustrates the need for comprehensive analyses of steady state kinetics and allostery beyond single residual enzyme activity determinations to retrace the structural impact of missense mutations on the phenylalanine hydroxylating system. Current standard PAH activity assays are either indirect (NADH) or discontinuous due to substrate and product separation before detection. We developed an automated fluorescence-based continuous real-time PAH activity assay that proved to be faster and more efficient but as precise and accurate as standard methods. Wild-type PAH kinetic analyses using the new assay revealed cooperativity of activated PAH toward BH(4), a previously unknown finding. Analyses of structurally preactivated variants substantiated BH(4)-dependent cooperativity of the activated enzyme that does not rely on the presence of l-Phenylalanine but is determined by activating conformational rearrangements. These findings may have implications for an individualized therapy, as they support the hypothesis that the patient's metabolic state has a more significant effect on the interplay of the drug and the conformation and function of the target protein than currently appreciated.

Synergistic anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model.

We propose that elevation of mitochondrial enzyme cofactors may prevent or ameliorate neurodegenerative diseases by improving mitochondrial function. In the present study, we investigated the effects of high doses of B vitamins, the precursors of mitochondrial enzyme cofactors, on mitochondrial dysfunction, oxidative stress, and Parkinsonism in a 4-week long rotenone treatment-induced cellular model of Parkinson's disease (PD). Pretreatment with B vitamins (also 4 weeks) prevented rotenone-induced: (1) mitochondrial dysfunction, including reduced mitochondrial membrane potential and activities of complex I; (2) oxidative stress, including increase in reactive oxygen species, oxidative DNA damage and protein oxidation, and (3) Parkinsonism parameters, including accumulation of alpha-synuclein and poly-ubiquitin. The optimum doses were found around 2.5- and 5-fold of that in normal MEM medium. The 4-week pretreatment was chosen based on time-dependent experiments that pretreatments longer than 2 weeks resulted in a decrease in oxidants, an increase in oxygen consumption, and up-regulation of complex I activity and PGC-1alpha expression. Individual B vitamins at the same doses did not show a similar effect suggesting that these B vitamins work synergistically. These results suggest that administration of high doses of B vitamins sufficient to elevate mitochondrial enzyme cofactors may be effective in preventing PD by reducing oxidative stress and improving mitochondrial function.

A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome.

Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.

Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging.

Dogs develop cognitive decline and a progressive accumulation of oxidative damage. In a previous longitudinal study, we demonstrated that aged dogs treated with either an antioxidant diet or with behavioral enrichment show cognitive improvement. The antioxidant diet included cellular antioxidants (vitamins E and C, fruits and vegetables) and mitochondrial cofactors (lipoic acid and carnitine). Behavioral enrichment consisted of physical exercise, social enrichment, and cognitive training. We hypothesized that the antioxidant treatment improved neuronal function through increased mitochondrial function. Thus, we measured reactive oxygen species (ROS) production and bioenergetics in mitochondria isolated from young, aged, and treated aged animals. Aged canine brain mitochondria show significant increases in ROS production and a reduction in NADH-linked respiration. Mitochondrial function (ROS and NADH-linked respiration) was improved selectively in aged dogs treated with an antioxidant diet. In contrast, behavioral enrichment had no effect on any mitochondrial parameters. These results suggest that an antioxidant diet improves cognition by maintaining mitochondrial homeostasis, which may be an independent molecular pathway not engaged by behavioral enrichment.

The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies.

Mitochondrial cytopathies ultimately lead to a reduction in aerobic energy transduction, depletion of alternative energy stores, increased oxidative stress, apoptosis and necrosis. Specific combinations of nutraceutical compounds can target many of the aforementioned biochemical pathways. Antioxidants combined with cofactors that can bypass specific electron transport chain defects and the provision of alternative energy sources represents a specific targeted strategy. To date, there has been only one randomized double-blind clinical trial using a combination nutraceutial therapy and it showed that the combination of creatine monohydrate, coenzyme Q10, and alpha-lipoic acid reduced lactate and markers of oxidative stress in patients with mitochondrial cytopathies. Future studies need to use larger numbers of patients with well defined clinical and surrogate marker outcomes to clarify the potential role for combination nutraceuticals ("mitochondrial cocktail") as a therapy for mitochondrial cytopathies.

[Metabolic therapy for early treatment of age-related macular degeneration]. / Metabolikus terápia az idoskori makuladegeneráció korai kezelésére.

Currently, age-related macular degeneration is one of the most common eye diseases causing severe and permanent loss of vision. This disease is estimated to affect approximately 300-500 thousand Hungarians. While earlier no treatment was available, in the recent decade an antioxidant therapy became very popular using combinations of high dosage antioxidant vitamins C, E, beta carotene and zinc. Based on theoretical concepts and mostly in vitro experiences, this combination was thought to be effective through neutralizing reactive oxygen species. According to a large clinical trial (AREDS) it reduced progression of intermediate state disease to advanced state, but did not influence early disease. This original combination, due to potential severe side effects, is not on the market anymore. However, the efficacy of modified formulas has not been proved yet. Recently, the metabolic therapy, a combination of omega-3 fatty acids, coenzyme Q10 and acetyl-L-carnitine has been introduced for treating early age-related macular degeneration through improving mitochondrial dysfunction, specifically improving lipid metabolism and ATP production in the retinal pigment epithelium, improving photoreceptor turnover and reducing generation of reactive oxygen species. According to a pilot study and a randomized, placebo-controlled, double blind clinical trial, both central visual field and visual acuity slightly improved after 3-6 months of treatment and they remained unchanged by the end of the study. The difference was statistically significant as compared to the base line or to controls. These functional changes were accompanied by an improvement in fundus alterations: drusen covered area decreased significantly as compared to the base line or to control. Characteristically, all these changes were more marked in less affected eyes. A prospective case study on long-term treatment confirmed these observations. With an exception that after slight improvement, visual functions remained stable, drusen regression continued for years. Sometimes significant regression of drusen was found even in intermediate and advanced cases. All these findings strongly suggested that the metabolic therapy may be the first choice for treating age-related macular degeneration. Currently, this is the only combination of ingredients corresponding to the recommended daily allowance, and at the same time, which showed clinically proved efficacy.