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Mechanisms are described in the text. The work of Carunchio et al. BCAAs are also important for the ammonia detoxification in skeletal muscle, promoting the synthesis of glutamate, which acts as a substrate for glutamine production.

On the other hand, an excess of BCAAs supplementation and, consequently, of glutamine synthesis, may increase glutamine breakdown and the production of ammonia in the intestine and kidneys. This condition might lead to the development of hepatic encephalopathy. For these reasons, attention should be given to the dose of BCAAs administrated [ 57 ].

The abuse of anabolic steroids might cause relevant side effects and alters the normal hormonal production in the body [ 59 ], especially in DMD patients already under steroid therapy v. Utrophin has a similar function in the maintenance of the dystrophin-glycoprotein complex DGC integrity and myofibre structure. NO is also critical to support mitochondrial function and biogenesis [ 62 , 63 ]. Interestingly, a recent study also showed that the levels of l -arginine and its precursor l -citrulline were significantly lower in mdx muscles with respect to wild type ones [ 64 ].

A recent study showed that l -homoarginine one of the direct products of l -Arg metabolism in human serum levels were significantly lower in Becker muscular dystrophy patients [61]. This evidence, if confirmed in DMD patients, might give more support to the requirement of l -arginine and l -citrulline supplementation through diet. Although no other clinical trials with l -arginine administration alone or in combination with different drugs in DMD boys are currently published, a wide range of evidence in healthy and unhealthy subjects have been collected [ 65 , 66 ] Table 1.

This marked heterogeneity in experimental procedures makes it difficult to establish the upper level of intake of l -arginine and the accurate evaluation of its safety and real effect. The absence of serious adverse effects related to l -arginine or l -citrulline administration in human trials confirms the safety profile of these amino acids.

However, the most common side effects reported were nausea and mild diarrhoea [ 67 , 68 ]. This is probably due to the increase of local NO synthesis by means of stimulation of intestinal NO synthase NOS-1 activity, promoted by l -arginine ingestion. As it is well known, NO is strictly related to intestinal function at different levels, including motility, water retention and electrolyte transport.

The excess of local NO synthesis might generate an imbalance in the equilibrium between intestinal absorption and secretion, promoting abnormal water loss and, consequently, nutrient depletion [ 69 ]. L-arginine contributes to the regulation of hemodynamic. In fact, animal and human studies demonstrated a hypotensive effect of l -arginine administration, not only related to the increase of NO synthesis but also to the enhanced endothelial cell function and the decreased resistance of peripheral blood vessels [ [70] , [71] , [72] ].

A recent study suggested that l -arginine and other dibasic amino acids increased plasma potassium levels, promoting the metal ion efflux from liver and pancreas to the extracellular aqueous environment [ 74 ]. L-arginine supplementation downregulates the expression, in liver and ileum, of cationic transporter-1 CAT-1 that is also able to transport other basic and essential amino acids, like lysine and histidine, with a consequent reduction of EAAs plasma levels.

This condition should be avoided in DMD patients. Furthermore, it was demonstrated that l -arginine affected the expression of enzymes involved in its metabolism, as such as arginase I, reducing its own bioavailability [ 75 ]. Considering these effects on vascular homeostasis and electrolytes balance, uncontrolled administration of l -arginine, particularly in unhealthy subjects, should be avoided. While an improvement of peripheral blood flow may contrast functional ischemia in DMD patients [ 76 ], l -arginine might cause excessive low blood pressure in DMD patients under treatment with antihypertensive drugs and could have a synergistic effect with agents that increase potassium levels, such as beta- and alpha-blockers.

In accordance with this assertion, three cases of palpitations, irregular heartbeat, tachycardia and syncope were reported in healthy subjects after taking arginine supplementation [ 77 ] see Table 2. No relevant contaminations have been reported for l -arginine. In , an investigation by the FDA discovered N-acetyl- l -leucine instead of l -citrulline in lots of these supplements with subsequent evidence of hyperammonaemia and related health hazards in patients [ 68 ].

According to this point, it is conceivable that the muscle-wasting condition would account for glutamine deficiency, paving the way for a proper rationale to proceed with glutamine supplementation in several muscle pathologies, including DMD. Nonetheless, clinical trials in DMD patients revealed a lack of functional benefits of glutamine supplementation compared to placebo [ 80 , 81 ], despite the encouraging results obtained on the reduction of whole-body protein degradation [ 82 ].

A vast number of studies in human subjects that investigated the safety profile of glutamine have been published. No evidence of adverse effects appeared, supporting the harmless of glutamine supplementation [ 67 ]. The two most common adverse effects reported after l -glutamine consumption are nausea and vomiting see Table 2.

Interestingly, a recent study investigated the effect of glutamine on glucose metabolism in DMD boys [ 83 ]. Glutamine, in fact, is involved in gluconeogenesis as a source of carbon skeletons via the tricarboxylic acid cycle TCA cycle. After 5 h of glutamine infusion, a rapid and transient increase of insulin plasma levels, and a prompt return to normal values when blood glutamine concentration was maintained at basal level were observed.

For this reason, DMD patients under insulin therapy should avoid glutamine co-administration. Also, in glutamine supplements contaminations with anabolic steroids 4-estren3,dion, 4-androsten3,dion were found v. In the last decades, creatine Cr has become the most popular dietary supplementation among athletes, both professionals and amateurs.

The reason for this widespread popularity of Cr is attributable to the benefits on muscle performance globally observed in the sports field, not only at competitive level. Cr elicits various effects on muscle metabolism, managing energy resources in skeletal muscle cells. Cr and its phosphorylated form phosphocreatine PCr are responsible for the ATP shuttling between mitochondria and cytosol.

In this way, during physical activity, myofibres have access to a dynamic reserve of energetic substrates, which remains locked within the cell, also thanks to the negative charge of PCr. Moreover, Cr is involved in the increase of muscle fibre size that might be related to an improvement of protein synthesis or a decrease of protein breakdown [ 85 ].

The administration of creatine in animal models demonstrated an enhancement of muscle strength and oxidative capacity of skeletal muscle cells with a reduction of myofibres necrosis [ [86] , [87] , [88] , [89] ]. Importantly, it must be taken into account that the effects of Cr supplementation might be strictly related to the disease phase [ [90] , [91] , [92] , [93] ]. Despite these promising results, long-term studies would be necessary to assess benefits and potential side effects of Cr, particularly analysing interaction with corticosteroids.

Aside from anecdotal cases of gastrointestinal distress and muscle cramps, a side effect that potentially represents a serious hazard for DMD patients is the weight gain observed after Cr supplementation, becoming more significant with prolonged use of the compound [ 94 ].

The increase of body mass is mainly due to water retention and this effect might represent a relevant issue for patients with reduced mobility, and cardiac and hemodynamic sufferance, like DMD boys. In literature, high variability in responsiveness to creatine supplementation was described. This variance primarily depends on the muscular content of Cr, that is higher in fast-twitch type II fibres. In accordance with this evidence, muscles consisting mainly of type fibres II are more susceptible to Cr supplementation.

As is well known, in dystrophic muscles the fibre type mainly affected by pathology is the fast one and a progressive replacement of type II myofibres with fibrotic tissue is observed. Due to these reasons, a lack of responsiveness to Cr supplementation in DMD patients might be expected [ 95 ]. There are serious concerns about the renal safety of Cr.

In detail, literature review and adverse events reports see Table 2 mentioned cases of renal dysfunction in subjects with kidney disease history but also in healthy people taking Cr, even at the recommended dose [ 96 , 97 ]. Similarly, no clear evidence is available about the interaction of Cr with drugs potentially harmful for the kidney or mainly excreted via kidney, and possibly used on demand in DMD patients, including antibiotics, antivirals, hydroxychloroquine and other drugs of potential help in viral infections as COVID [ [98] , [99] , [] ].

It must be considered that Cr supplements most commonly traded in supermarkets, drugstores and also on internet, is a synthetic product derived from the reaction between sarcosine and cyanamide. Possible contaminants produced during this process are creatinine, arsenic, dicyandiamide and dihydrotrianzines; all compounds potentially hazardous for human health [ 85 ]. For this reason, careful attention should be paid to the source of the product, rather relying on brands prescribed by clinicians, which ensure the traceability of ingredients and which are subject to inspections that guarantee the respect of the good laboratory practices.

One of the supplements with the most multitasking potential is certainly taurine, an amino acid found free in mammalian tissues and particularly abundant in excitable ones. In the human body, taurine exerts various actions, ranging from the antioxidant and the anti-inflammatory effect to the regulation of ion channels functions. This plethora of actions explains the potential use of taurine in the adjuvant therapy of some disorders that affect the muscular system, like myotonia, sarcopenia and disuse muscle atrophy [ ].

This is particularly true in conditions characterized by altered tissue amount of taurine as it occurs at different extent in the various phases of dystrophic pathology [ 89 , ]. Preclinical studies in mdx mice showed amelioration of functional parameters and markers of necrosis, oxidative stress and inflammation, being more effective than creatine [ 89 , , , ].

Accordingly, taurine appears to be most effective in early phases of muscle and cardiac pathology, and synergic effect effects with glucocorticoids have been described [ ]. This profile may envisage the potential usefulness in chronic use. Taurine supplementation might interfere with hemodynamic: a study in male rats demonstrated that acute injection of taurine induced hypotension and vasodilatation whereas a long-term supplementation in drinking water had hypertensive effect [ ].

However, a possible interaction with drugs for blood pressure should be considered. For this reason, a possible interaction with CYP3A4 inducers such as glucocorticoids might decrease blood levels of steroids and other drugs in DMD patients v. Furthermore, taurine levels in the body are also controlled by its renal transport, a sodium and chloride dependent mechanism.

Then taurine may influence diuresis; in turn, altered kidney function may alter taurine equilibrium in the body [ , ]. Then, the previous considerations raised for creatine about interaction with drugs at kidney level, also apply to taurine. Adolescent and children consumption of energy drinks with caffeine and taurine is raising globally. Some studies observed an increase in systolic blood pressure and heart rate after consumption. In Table 2 was also reported a case of a young subject who shown symptoms like diarrhoea, tremors and speech disorders after energy drinks consumption.

Green tea extract GTE , derived from Camellia sinensis leaves, contains flavonoids catechins epigallocatechingallate EGCG , epicatechin gallate, epicatechins, gallic acid that have claimed antioxidant properties. For this reason, GTE supplementation was tested in mdx mice to counteract the oxidative stress in dystrophic muscle cells. Preclinical studies demonstrated that GTE improved muscle function and reduced necrosis in muscle tissues of treated animals. Even though encouraging results are available, there is still a lack of consistency among different studies [ [] , [] , [] , [] ].

EGCG is the principal polyphenol antioxidant present in green tea and has main potency in preclinical tests. Protandim was firstly tested on healthy human subjects and a reduction of oxidative stress markers was observed. However, no relevant effects on muscle histology and functional parameters were described.

The most frequent side effects are due to the presence of caffeine in GTE extracts, and are headache, nervousness, sleep problems, vomiting, diarrhoea, irritability, irregular heartbeat, tremor, heartburn, dizziness, ringing in the ears, convulsions, and confusion [ ] see also Table 2.

Caffeine has also a diuretic effect [ ] and this may exacerbate the urinary calcium loss in DMD patients. High dose of GTE has hepatic adverse effects: in animal models, EGCG induced hepatotoxicity and several case reports showed hepatic adverse events in humans, associated with an increase of livers enzymes [ , ] see Table 2.

The concomitant administration of GTE and drugs metabolized by the aforementioned cytochromes should be avoided, including steroids v. Green tea intake could, therefore, interfere with the transport of folate across the small intestine and decrease the bioavailability of this essential vitamin [ ].

The lack of folate absorption alters cysteine metabolism, inducing hyperhomocysteinemia HHcy [ ]. HHcy is involved in skeletal muscle malfunction and could exacerbate the muscle degeneration in DMD. The number of GTE-cardiovascular drug interactions reported in humans increased in the last years and now include simvastatin, rosuvastatin, nadolol, sildenafil, tacrolimus and warfarin. However, the list might be longer, as suggested by the results of animal experiments with diltiazem, verapamil and nicardipine.

GTE may, on one hand, increase the exposure to some drugs simvastatin, tacrolimus , and, on the other hand, reduce the exposure to others rosuvastatin, nadolol [ ]. Green tea consumption might also impair the correct gastrointestinal absorption of antibiotics i. DMD patients treated with drugs or other phenol-based nutraceuticals metabolized by UGT may, therefore, incur in unwanted interactions with GTE [ ].

For instance, UGT1A9 is also the major enzyme that metabolizes ataluren, a novel drug recently approved for DMD to promote ribosomal read-through for patients with premature stop codon mutations [ 31 , ]. Its metabolism could be delayed or impaired by GTE, with potential toxic effects. Focusing on Protandim, most common adverse effects are related to allergic reactions to one or more herbal components of the product.

Thirty-two per cent of Chinese tea exceeded the national maximum permissible concentration for Pb [ ]. Sources of green tea contamination are: pesticides HCH and DDTs , environmental contaminants Polycyclic aromatic hydrocarbons PAHs , mycotoxins and microorganisms Aspergillum, Penicillium, Fusarium , toxic elements mercury Hg , lead Pb , arsenic As , cadmium Cd , aluminium Al , chromium Cr , and nickel Ni , radioactive contaminants in plantations near areas like Chernobyl and Fukushima , and plant growth regulators [ ].

Pb is more bioavailable to tea plants growing in highly acidic soils: Japanese tea had the highest Pb contamination whereas Indian teas had the highest percentage of Cd leaching [ ]. On , LifeVantage Corporation announces voluntary recall for lots of Protandim due to contamination with small metal fragments in final products. Supplementation with the omega-3 fatty acid eicosapentaenoic acid EPA in mdx mice induced a decrease of inflammation, creatine kinase and improved muscle regeneration [ , ].

In addition, PUFA can lead to several PD interactions with drugs acting as anticoagulants and modulating blood homeostasis. It is important to recall that heparins are used empirically in COVID and risk of bleeding in association with omega 3 should be considered. PUFA, in fact, might interfere with platelet aggregation, with an additive anticoagulant effect [ ]. UPS is a protein network responsible for inducing muscle atrophy and, if not inhibited, promotes protein breakdown. For this reason, the co-administration of omega fatty acids and GC might enhance the pro-atrophic effects of steroids in skeletal muscle.

The excessive consumption of fish oil may also cause hypervitaminosis vitamin D and A [ ]. A case report of shown an abnormal mercury blood level in a 38 years old man in Canada see Table 2. This issue suggests an inadequate purification of the product by the manufacturer [ ]. Fish oils taken as dietary supplements may contribute significantly to daily intakes of organochlorine contaminants due to the presence of pesticides in marine environments [ ].

However, as no indication about the use and safety of these oils are spread from the food agencies, the consumption of OGM products should be careful [ ]. This is mainly due to the chronic corticosteroid use by DMD boys. In addition, reduced sun exposure due to little outdoor activities can play a role.

Lowered levels of 25 OH D contribute to reducing bone mineral density with an increasing probability of fractures of long bones and vertebrae. Vitamin D supplementation is a widespread strategy adopted in DMD boys to counteract corticosteroid-induced osteoporosis and is recommended by the standards of care [ 5 , ]. Considering that vitamin D insufficiency may have detrimental role in the immune system, its supplementation in DMD patients should not be interrupted during viral pandemic emergencies, such as COVID [ ].

However, caution should be taken according to what described in 5. Vitamin D is generally considered safe when taken in appropriate amounts but can cause side effects when taken chronically in high doses. Side effects of vitamin D include weakness, fatigue, dizziness, nausea, vomiting, headache, anorexia, and others. Vitamin D assumption can further increase hypercalcemia as frequently reported i.

Excess vitamin D is also associated with symptoms related to hypercalcemia, such as hypertension, anorexia, nausea, and possible kidney damage [ 30 ]. Literature reports occasional cases of drug-drug interactions with drugs metabolized by the same CYP e. Vitamin D intake is associated with improved absorption of essential inorganic elements calcium Ca , magnesium Mg , copper Cu , zinc Zn , iron Fe , and selenium Se but has also been linked to enhanced uptake of toxic elements such as aluminium Al , cadmium ca , cobalt Co , and lead Pb as well as radioactive isotopes including caesium Cs and radioactive strontium Sr.

In children, elevated 25 OH D 3 levels are associated with an increase in blood lead levels [ ]. Bioaccumulation of toxic metals, in turn, counteracts the renal synthesis of vitamin D active form. This bacterium causes severe respiratory infections, particularly resistant to antibiotics treatment. Accordingly, contamination with B. For this reason, this compound was tested in dystrophic animals and preclinical studies suggested that resveratrol supplementation may exert amelioration of muscle function and maturation of skeletal muscle cells by reducing oxidative stress [ , , ].

This curcuminoid, produced by Curcuma longa, was administered i. Treated mice showed an amelioration in muscle function and a mitigation of dystrophic symptoms. Nevertheless, a previous study [ ], demonstrated that NF-kappaB activity of mdx mice of three different ages 10 days; 4 and 8 weeks was resistant to inhibition by oral curcumin supplementation, suggesting that the route of administration might heavily influence the bioavailability of the compound. CYP3A4 activity is important for the metabolism of calcium channel antagonists e.

In addition, resveratrol is metabolized by liver and intestinal UGTs and may cause, like catechins, unwanted interactions with drugs metabolized by the same enzymes [ ]. Since glucocorticoids inhibit mTOR activity [ ], possible additive effects should be taken into account [ ] v. Curcumin is generally considered as safe [ ].

Studies in human subjects have shown only moderate adverse effects, like bloating, diarrhoea, headache and nausea [ , ]. None reported. However, careful attention of production chain for commercial resveratrol is advised, like pesticides, heavy metals and other contaminants can be present in grapes, soy, Polygonon cuspidatum and other resveratrol sources [ ].

Analyses on curcumin supplements revealed contamination with metanil yellow C18H14N3NaO3S , a toxic colorant used to adulterate Curcuma longa powder [ ]. Furthermore, other compounds commonly used as adulterants are pigments containing lead, with serious concerns about the safety of these products [ , ].

Because muscles in dystrophic individuals may produce more reactive oxygen species ROS and are thought to be more susceptible to oxidative damage, antioxidant supplementation may serve as an adjunct therapy that can be easily incorporated into treatment plans. N-acetylcysteine NAC is a potent antioxidant and has been studied as a potential DMD treatment in mdx mice [ [] , [] , [] ].

In detail, NAC is a precursor of the amino acid cysteine that can itself function directly as an antioxidant, and indirectly through glutathione synthesis. Cysteine is also a precursor of taurine synthesis and the increase in muscle taurine content contributes to the amelioration of strength and function of mdx muscle, both i n vivo and ex vivo [ , ].

Importantly, although it has no direct anti-viral actions, NAC has been claimed to have protective effects against pulmonary damages during viral infections in both pre-clinical and clinical studies due to its antioxidant and mucolytic activities [ [] , [] , [] ]. A clinical trial in cancer patients revealed mostly gastrointestinal side effects, including nausea, vomiting, bloating and diarrhoea [ ] Table 2. Paradoxically, long-term administration of NAC in humans increases oxidative stress after an acute muscle injury induced by eccentric exercise, with higher blood levels of markers of inflammation [ ].

A preclinical study in mdx mice showed that NAC significantly impaired body weight gain in young growing mice both mdx and wild type , and reduced liver weight in C57 mice and muscle weight in mdx mice [ ]. Coenzyme Q 10 CoQ 10 is a naturally occurring compound that plays a fundamental role in cell bioenergetics as a cofactor in the mitochondrial electron transport chain.

CoQ 10 is also a potent antioxidant and may counteract the excessive ROS production in dystrophic myofibres. The compound was tested in different clinical trials in DMD patients with encouraging results: CoQ 10 supplementation ameliorated the impaired myocardial function and physical performance [ [] , [] , [] ], although no significant improvement in echocardiographic parameters was revealed [ ].

Interestingly, idebenone, a synthetic analogue of CoQ10 sharing its antioxidant profile, is at an advanced stage of development for treating cardiorespiratory dysfunction of DMD patients [ [] , [] , [] ]. There are no serious adverse events reported. One patient developed a headache of moderate intensity associated with high blood levels of CoQ The event resolved with a decrease of the dose [ ]. CoQ 10 supplementation may result in a reduction of diastolic blood pressure and might increase the effect of medication with antihypertensive activity [ ].

None described. Sources animal tissues and extracts and whole grains have to be ensured for quality and purity. Several studies corroborate the view that melatonin might protect many tissues, including skeletal muscle, from oxidative stress, due to the antioxidant properties of this compound and its metabolites. In mdx mice, muscle of treated animals showed an amelioration of the contractile function of dystrophic myofibres, accompanied by a decrease of CK plasma levels [ ].

Recently, interest has been raised around melatonin for its anti-inflammatory, immunomodulatory and sedative actions, that may foresee the use of melatonin as adjuvant to contrast the exaggerated immune response finally leading to acute lung injury and acute respiratory distress syndrome in critical care patients with COVID [ ].

These may further increase the use of melatonin as supplements by DMD patients as adjuvant in seasonal viral pandemics. Oral melatonin reduces blood coagulation activity with a dose-response relationship [ ]. It has been reported that the evening administration of melatonin in hypertensive patients taking the calcium antagonist nifedipine, interfered with the mechanism of cardiovascular regulation, inducing an increase in blood pressure [ ].

Melatonin seems to interfere with calcium signalling via calmodulin. This suggests caution should be taken in uncontrolled use of melatonin in hypertensive patients as well as possible interference with antihypertensive drugs. Lastly, it should be underlined that the actual safety of melatonin was not properly assessed, in paediatric population. Doubts were raised over the potential harmful effect of melatonin supplementation on endocrine and reproductive systems in children and adolescents [ ].

Further enquiries are needed to evaluate the effects of melatonin in young subjects. A recent study demonstrated that a quarter of melatonin products sold in one city in Canada contained serotonin, some at potentially significant doses [ , ]. An increment of serotonin levels might cause symptoms like tachycardia, palpitations and hypertension as observed in some cases reported in Table 2.

Reports indicated that the eosinophilia-myalgia syndrome EMS was triggered by the consumption of a contaminated batch of the dietary supplement l -tryptophan l -Trp. Because melatonin is structurally like to l -Trp both compounds contain the indole ring functionality , a study investigated the nature of the contaminants in commercial preparations of melatonin. Several contaminants in commercial preparations of melatonin were found formaldehyde-melatonin condensation product and two structural isomers of hydroxymelatonin.

Of interest, an EMS-related contaminant in l -Trp referred to as "peak C" has been proposed as a 5hydroxytryptophan isomer. These findings should raise serious questions about the consequences of long-term ingestion of melatonin preparations containing such impurities [ ].

Two ASOs, eteplirsen and golodirsen, have been recently approved by FDA and others are currently in clinical trials, as well as gene and cell therapies. Little or no data are present about the possible interaction of those innovative therapies with classical drugs and even more with dietary supplements. Below an attempt to underline the main points of interaction susceptibility of these innovative approaches.

ASOs approved for DMD are phosphorodiamidate morpholino oligomers PMO , very stable molecules in biological systems, administered in weekly regimens and mostly eliminated as such by renal excretion. Then approved ASOs do not undergo main metabolism via hepatic microsomes nor are they substrates of main transporters in the body. So, it is generally believed that the level of interaction with drug, food and dietary supplements is low.

Both eteplirsen and golodirsen have little if any activity as inhibitor or inducer of cytochromes [ , ], golodirsen being a weak inducer of CYP1A2. This cytochrome is involved in the metabolism of various commonly used drugs and also involved in the biotransformation of PUFA; then interaction cannot be excluded. Although the available information does not support major harmful interactions, these compounds have potential toxicity at kidney and liver level, suggesting that these tissues could be a possible site of harmful interactions.

Moreover, since they are not very well absorbed at cellular level and they are excreted very fast via the kidney, supplements increasing renal clearance could interfere with their efficacy. Other ASOs under development may have different profiles and specific interaction can occur.

Patients in clinical trials should then avoid using dietary supplements without medical control. Cell therapy represents another innovative approach for many diseases, including DMD. Various muscle progenitor cells have attracted interest, with some of them, such as mesangioblasts, tested in clinical settings, due to their ability to cross vessel wall in order to reach the site of the damage [ , ].

Although very little is known about possible interaction with drugs or with dietary supplements, it is intuitive to predict they may occur at various stages of cell therapy. In fact, muscle precursors are highly proliferating cells which are known to critically depend, for proliferation, fusion and adhesion, on nutrients, such as glucose and amino acids, via high expression of specific transporters such as CD98hc [ , ].

Also, extravasation may need a concerted action of cytokines and molecules involved in oxidative stress signalling and endothelial permeability, which may also be modulated by either drug or supplements. Another point of interaction can be related to a massive immune response that may be induced by the administration of high amounts of cells, which can also be influenced by supplements such as BCAA [ ].

Then, although not easy to decipher, interaction with complex outcome may occur between cell therapies and dietary supplements. The idea behind gene therapy is to treat the pathology by substituting the defective gene s or at least one copy of it. For what it concerns muscular dystrophy, considering the size of dystrophin protein usually not fitting in an adeno-associated virus AAV -vector , the transfer of microdystrophin is under clinical assessment [ ].

One of the main points of interaction relates to the need to control the immune reaction to viral vectors and the new protein, then immunosuppressive drugs can be required. Accordingly, supplements able to modulate PD or PK profile of immunosuppressive drugs should be used with caution.

For this approach, important concern can be raised for off-target actions and gene mismatch [ , ], which can modify key organ functions for drug and supplement mechanism and clearance. For this reason, it will be pivotal to fully understand and not rule out possible interactions with supplements. During the last years, the interest in natural, dietary supplements is increasing in the DMD field as adjuvant approaches in controlling both dietary requirement and pathological events.

The recent emergency due to the outbreak of SARS-CoV-2 further increased the interest toward dietary supplements, among the population worldwide. It is therefore understandable, and even more justified by the fragility of the population, that such interest also arises from DMD community. They think that if a supplement will not be beneficial then it will also not be harmful, so it does not hurt to try. This can be amplified by media and internet, also in relation to economic interests.

Consequently, the risks of dietary supplements are seriously underestimated and often their use is not discussed with experts either medical specialists, practitioners or pharmacists , nor related to any proven nutritional deficits. In fact, most of the dietary supplements discussed herein and even those with claimed effect on the immune system, such as vitamin C, are present in food, especially fresh fruits and vegetables. Then, a proper diet, healthy and varied, is the first aid to supply necessary essential elements, amino acids and vitamins.

Supplements can, on the other hand, exert unwanted effects related to the use of excessive doses or interact with other medicines patients are using, either inhibiting or enhancing their efficiency and cause serious health risks. There is often no solid proof of dietary supplements effectiveness, while many side effects have been reported, including the complication or the ineffectiveness of outcome of other therapies see Table 2.

Then, prolonged use of supplements may cause several adverse effects, that often lead to emergency department visits and, in severe cases, hospitalization. In United States alone, approximately 23 emergency department visits and hospitalizations are connected every year to side effects related to dietary supplement [ ].

For DMD and also for BMD patients these interactions can be of particular relevance as they can occur with drugs used for standard care or with innovative therapies during clinical trials. A similar situation also applies in emergency cases, as in the current pandemic by Sars-CoV In fact the treatment of symptomatic COVID patients is still a largely empirical approach with a wide variety of drugs according to the phase of the disease and ranging from antiviral and antibiotics, repurposed old drugs, such as chloroquine and hydroxychloroquine, to immunosuppressants, monoclonal antibodies and low-molecular weight-heparins.

All these class of therapeutics have either a low therapeutic index or can per se at high risk of ADR events which may increase with uncontrolled D-D and D-S associations. In addition, more than clinical trials are currently ongoing on COVID worldwide clinicaltrial. Another issue is that the quality check of these supplements is not always as rigid as it should be and they can be contaminated, certainly when they are retrieved from less controlled sources, like via the internet.

Awareness of the risks of uncontrolled use should be raised amongst caregivers and patients. They should be encouraged to always first discuss with their clinicians and pharmacists before starting supplement use and only retrieve them from certified sources, like their pharmacy. Supplement use can also be a confounder in clinical studies and thereby influence the results. Unexplored interactions may reduce the efficacy of innovative therapies in clinical trials or cause unexpected toxicity.

A database about the use of food supplements in DMD and BMD population, also in relation to geographical distribution, would be important, also with the aim to carry on properly conducted clinical studies. In parallel, it is important to consider that there is an increasing awareness to focus on dietary requirement in DMD patients.

Accordingly, it is pivotal to reinforce translational research in the field of supplements, considering the different nutritional requirements in different species used for preclinical studies [ 28 , 29 ]. This review underlines that supplements may represent an important support in nutritional deficit occurring in DMD patients, although dosage and efficacy need to be better established with controlled studies [ 28 ]. Caution has to be taken in properly discussing with experts before deciding to start using supplements.

Also, supplements from unknown sources or acquired via the web or outside pharmacy or other authorized retailers should always be avoided. In this respect, the active role by regulators and health professionals helps to provide correct information, in order to avoid direct use of products that escape the normal paths of distribution or do not provide the possibility to check quality control or surveillance [ 37 ]. The uncontrolled use of dietary supplements may, in fact, represent an important confounding factor during the development of new therapies or during studies aimed at repurposing drugs in DMD.

The pandemic emergency of COVID provided further evidence of this critical issue, as seen by the greater demand for dietary supplements. Patients and caregivers aim to be protected, especially for the evident difficulties to put in place effective social distance for proper assistance of fragile patients. Although specifically focused on DMD, the considerations raised in the present review can also apply to BMD and to other neuromuscular and non-neuromuscular rare patients, that share similar fragility, complexity and uncertainties.

The fellowship of DPP-NL to OC for a project on artificial muscle as a new platform for testing the efficacy of novel compounds is also gratefully acknowledged. Pharmacol Res. Published online May Brigida Boccanegra , a, 1 Ingrid E. Ingrid E. Author information Article notes Copyright and License information Disclaimer. Annamaria De Luca: ti.

All rights reserved. Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Graphical abstract. Open in a separate window. Introduction Duchenne muscular dystrophy DMD is a severe, progressive muscle wasting disorders affecting around 1 in 5 newborn boys. Complex therapeutic regimens and risk of adverse drug reactions ADR Complex and chronic pathologies in the paediatric population, such as DMD, are at high risk of adverse drug reactions ADR , due to the combination of factors.

Phases of ADME and primary mechanisms involved in drug-to-supplement interactions. General aspects in safety control by law of dietary supplements Dietary supplements include one or more ingredients labelled to enrich diet, including vitamins, minerals, herbs, amino acids, whey protein, essential fatty acids and other components, formulated for oral use as pills, tablets, syrups, etc.

The reason for attention to supplements and nutraceuticals in DMD A great interest has been raised toward dietary supplements in DMD [ 42 ]. Effects of the most used dietary supplements in DMD: side effects, mechanisms of toxicity and interactions A wide range of dietary supplements is used by DMD patients. Table 2 Adverse events reports. Side effects, mechanism of toxicity and interactions The most common side effects revealed during the aforementioned trials were gastrointestinal: decreased appetite, anorexia, nausea, and general stomach discomfort [ 51 ].

Side effects, mechanism of toxicity and interactions The absence of serious adverse effects related to l -arginine or l -citrulline administration in human trials confirms the safety profile of these amino acids. Contaminants No relevant contaminations have been reported for l -arginine. Side effects, mechanism of toxicity and interactions A vast number of studies in human subjects that investigated the safety profile of glutamine have been published. Contaminants Also, in glutamine supplements contaminations with anabolic steroids 4-estren3,dion, 4-androsten3,dion were found v.

Creatine In the last decades, creatine Cr has become the most popular dietary supplementation among athletes, both professionals and amateurs. Side effects, mechanism of toxicity and interactions Aside from anecdotal cases of gastrointestinal distress and muscle cramps, a side effect that potentially represents a serious hazard for DMD patients is the weight gain observed after Cr supplementation, becoming more significant with prolonged use of the compound [ 94 ].

Contaminants It must be considered that Cr supplements most commonly traded in supermarkets, drugstores and also on internet, is a synthetic product derived from the reaction between sarcosine and cyanamide. Taurine One of the supplements with the most multitasking potential is certainly taurine, an amino acid found free in mammalian tissues and particularly abundant in excitable ones.

Side effects, mechanism of toxicity and interactions Taurine supplementation might interfere with hemodynamic: a study in male rats demonstrated that acute injection of taurine induced hypotension and vasodilatation whereas a long-term supplementation in drinking water had hypertensive effect [ ]. Contaminants None described. Green tea extract Green tea extract GTE , derived from Camellia sinensis leaves, contains flavonoids catechins epigallocatechingallate EGCG , epicatechin gallate, epicatechins, gallic acid that have claimed antioxidant properties.

Side effects, mechanism of toxicity and interactions The most frequent side effects are due to the presence of caffeine in GTE extracts, and are headache, nervousness, sleep problems, vomiting, diarrhoea, irritability, irregular heartbeat, tremor, heartburn, dizziness, ringing in the ears, convulsions, and confusion [ ] see also Table 2. Contaminants Thirty-two per cent of Chinese tea exceeded the national maximum permissible concentration for Pb [ ].

Side effects, mechanism of toxicity and interactions Vitamin D is generally considered safe when taken in appropriate amounts but can cause side effects when taken chronically in high doses. Side effects, mechanism of toxicity and interactions In vitro studies, [ ] showed that resveratrol is an irreversible inhibitor for CYP3A4 and a non-competitive reversible inhibitor for CYP2E1. Contaminants None reported. N-Acetylcysteine Because muscles in dystrophic individuals may produce more reactive oxygen species ROS and are thought to be more susceptible to oxidative damage, antioxidant supplementation may serve as an adjunct therapy that can be easily incorporated into treatment plans.

Side effects, mechanism of toxicity and interactions A clinical trial in cancer patients revealed mostly gastrointestinal side effects, including nausea, vomiting, bloating and diarrhoea [ ] Table 2. Coenzyme Q 10 Coenzyme Q 10 CoQ 10 is a naturally occurring compound that plays a fundamental role in cell bioenergetics as a cofactor in the mitochondrial electron transport chain.

Side effects, mechanism of toxicity and interactions There are no serious adverse events reported. Melatonin Several studies corroborate the view that melatonin might protect many tissues, including skeletal muscle, from oxidative stress, due to the antioxidant properties of this compound and its metabolites. Side effects, mechanism of toxicity and interactions Oral melatonin reduces blood coagulation activity with a dose-response relationship [ ]. Contaminations A recent study demonstrated that a quarter of melatonin products sold in one city in Canada contained serotonin, some at potentially significant doses [ , ].

Antisense oligonucleotides ASOs approved for DMD are phosphorodiamidate morpholino oligomers PMO , very stable molecules in biological systems, administered in weekly regimens and mostly eliminated as such by renal excretion. Cell therapy Cell therapy represents another innovative approach for many diseases, including DMD. Gene therapy The idea behind gene therapy is to treat the pathology by substituting the defective gene s or at least one copy of it.

Discussion During the last years, the interest in natural, dietary supplements is increasing in the DMD field as adjuvant approaches in controlling both dietary requirement and pathological events. Conclusions This review underlines that supplements may represent an important support in nutritional deficit occurring in DMD patients, although dosage and efficacy need to be better established with controlled studies [ 28 ].

Declaration of Competing Interest The authors disclose non-conflict of interest. Acknowledgements None. References 1. Mercuri E. Muscular dystrophies. Lancet London, England ; — Hoffman E. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Koenig M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein.

Blake D. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Birnkrant D. Lancet Neurol. Haas M. European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. Neuromuscular Disorders: NMD. Aartsma-Rus A. FDA approves eteplirsen for duchenne muscular dystrophy: the next chapter in the eteplirsen Saga.

Nucleic Acid Ther. Frank D. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy [published online ahead of print, Mar 5] Neurology. Verhaart I. Therapeutic developments for Duchenne muscular dystrophy. Straub V. Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy.

Heydemann A. Skeletal muscle metabolism in Duchenne and Becker muscular dystrophy-implications for therapies. Rodriguez-Cruz M. Evidence of insulin resistance and other metabolic alterations in boys with duchenne or becker muscular dystrophy. Kuznetsov A. Impaired mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mdx mouse. Camerino G. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.

Gamberi T. Proteome analysis in dystrophic mdx mouse muscle reveals a drastic alteration of key metabolic and contractile proteins after chronic exercise and the potential modulation by anti-oxidant compounds. Rybalka E. Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency. PLoS One. Hogan S. Body composition and resting energy expenditure of individuals with Duchenne and Becker muscular dystrophy. Saure C. Energy expenditure, body composition, and prevalence of metabolic disorders in patients with Duchenne muscular dystrophy.

Diabetes Metab. Shimizu-Fujiwara M. Decreased resting energy expenditure in patients with Duchenne muscular dystrophy. Brain Dev-Jpn. Martigne L. Natural evolution of weight status in Duchenne muscular dystrophy: a retrospective audit. West N. Patterns of growth in ambulatory males with Duchenne muscular dystrophy. J Pediatr-Us. Bernabe-Garcia M.

Body composition and body mass index in Duchenne muscular dystrophy: role of dietary intake. Muscle Nerve. Davidson Z. Observations of body mass index in Duchenne muscular dystrophy: a longitudinal study. Matthews E. Corticosteroids for the treatment of Duchenne muscular dystrophy. Cochrane Database Syst.

Pane M. Feeding problems and weight gain in Duchenne muscular dystrophy. Nutrition in Duchenne muscular dystrophy March , Zaandam, the Netherlands. Salera S. Nutritional challenges in Duchenne muscular dystrophy. The national academies collection: reports funded by national institutes of health. In: Ross A. Muntoni F. Patadia V. Expert Rev. Petitet F. Development of an ADME and drug-drug interactions knowledge database for the acceleration of drug discovery and development.

Expert Opin. Drug Discov. Ryu J. Deep learning improves prediction of drug-drug and drug-food interactions. Dwyer J. Dietary supplements: regulatory challenges and research resources. Ronis M. Adverse effects of nutraceuticals and dietary supplements. American Cancer Society. Gupta R. Toxicity potential of nutraceuticals. Methods Mol. Nabukera S. Use of complementary and alternative medicine by males with Duchenne or Becker muscular dystrophy. Child Neurol. Samdup D. The use of complementary and alternative medicine in children with chronic medical conditions.

Woodman K. Nutraceuticals and their potential to treat duchenne muscular dystrophy: separating the credible from the conjecture. Willmann R. Mammalian animal models for Duchenne muscular dystrophy. Neuromuscular disorders: NMD. Blomstrand E. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise.

Moberg M. Activation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise. Wolfe R. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Sports Nutr. Stewart P. Branched-chain ketoacids reduce muscle protein degradation in Duchenne muscular dystrophy. Mendell J. Clinical investigation in Duchenne muscular dystrophy: IV. Double-blind controlled trial of leucine.

Gannon N. BCAA metabolism and insulin sensitivity - dysregulated by metabolic status? Food Res. Doi M. Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. Flores-Guerrero J. Carunchio I. Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture. Manuel M. Stronger is not always better: could a bodybuilding dietary supplement lead to ALS?

Holecek M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab Lond. Van der Merwe P. Inadvertent doping through nutritional supplements is a reality. South Afr. Di Luigi L. Supplements and the endocrine system in athletes. Sports Med. Hafner P. Improved muscle function in duchenne muscular dystrophy through L-arginine and metformin: an investigator-initiated, open-label, single-center, proof-of-concept-study.

Hanff E. Effects of single and combined metformin and L-citrulline supplementation on L-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications. Amino Acids. Chaubourt E. Nitric oxide and l-arginine cause an accumulation of utrophin at the sarcolemma: a possible compensation for dystrophin loss in Duchenne muscular dystrophy. Voisin V. L-arginine improves dystrophic phenotype in mdx mice. Mantuano P.

Effect of a long-term treatment with metformin in dystrophic mdx mice: a reconsideration of its potential clinical interest in Duchenne muscular dystrophy. Alvares T. L-Arginine as a potential ergogenic aid in healthy subjects. Auckland, NZ ; 41 3 — Deveaux A. L-arginine supplementation alleviates postprandial endothelial dysfunction when baseline fasting plasma arginine concentration is low: a randomized controlled trial in healthy overweight adults with cardiometabolic risk factors.

Shao A. Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Oketch-Rabah H. The importance of quality specifications in safety assessments of amino acids: the cases of l-tryptophan and l-citrulline. Grimble G. Adverse gastrointestinal effects of arginine and related amino acids. Guridi J. Arginine NO-dependent and NO-independent effects on hemodynamics. Nakaki T. L-arginine-induced hypotension. Lancet London, England ; Vasdev S.

The antihypertensive effect of arginine. Massara F. The hypophosphatemic and hyperkalemic effect of arginine in man. Cremades A. Tissue-specific regulation of potassium homeostasis by high doses of cationic amino acids. Martin S. The effects of oral arginine on its metabolic pathways in Sprague-Dawley rats.

Thomas G. Functional muscle ischemia in Duchenne and Becker muscular dystrophy. Prosser J. Adverse effects associated with arginine alpha-ketoglutarate containing supplements. Hankard R. Edinburgh, Scotland ; 18 6 — Cruzat V. Glutamine: metabolism and immune function, supplementation and clinical translation.

Escolar D. Mok E. Lack of functional benefit with glutamine versus placebo in Duchenne muscular dystrophy: a randomized crossover trial. Published online Jun 2. Nathan P. Ward a Department of Cancer Physiology, H. Gina M. Author information Article notes Copyright and License information Disclaimer. Chang Jiang: gro. DeNicola: gro. Associated Data Supplementary Materials Multimedia component 1.

Abstract The redox regulator NRF2 is hyperactivated in a large percentage of non-small cell lung cancer NSCLC cases, which is associated with chemotherapy and radiation resistance. Introduction Lung cancer is the second most common cancer and the leading cause of cancer death worldwide.

Results 2. Open in a separate window. Materials and methods 4. Redox Western blotting Redox Western blotting was performed as previously described [ 25 ]. Seahorse analysis of mitochondrial function Measures of oxygen consumption was determined with a Seahorse XFe96 Analyzer Agilent. Aconitase assay Aconitase activity was determined according to a previously established protocol [ 33 ]. Author contributions Conceptualization, C.

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data The following is the Supplementary data to this article: Multimedia component 1: Click here to view. References 1. Herbst R.

The biology and management of non-small cell lung cancer. Campbell J. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. DeNicola G. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Kankia I. Oxid Med Cell Longev; Karathedath S. PLoS One. Krall E. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Wang T.

Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: an in vivo and in vitro study. OncoTargets Ther. Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells. Bao L. ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells. Robledinos-Anton N. Torrente L. Targeting NRF2 and its downstream processes: opportunities and challenges.

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Los padres, sumamente confiados en la honestidad de su hijo, acceden. Y poco a poco surge un bonito romance al estilo de Cyrano de Bergerac. Sarah Ashburn, una arrogante detective del FBI esta obligada a trabajar junto a Shannon Mullins, un agente de policia de la ciudad de Boston de caracter impulsivo.

Ambas chicas tendran que aprender a resolver sus diferencias para trabajar juntas y conseguir el objetivo que tienen en comun; terminar con un terrorista ruso extremadamente peligroso. Diciembre de , Frente Noroeste. Para evitar otro desastre nuclear, Jae-Hyeok y sus colaboradores regresan a la central nuclear.

Segunda Guerra Mundial. En el planeta Baab, Scorch Supernova Brendan Fraser es toda una leyenda, un admirado y respetado astronauta del pueblo baabariano. Director Santiago Segura. Santiago Segura. Top credits Director Santiago Segura. See more at IMDbPro. Trailer Torrente 4: Lethal Crisis. The Torrente Package. Add photo. Top cast Edit. Santiago Segura Torrente as Torrente. Ernesto Sevilla Camarero boda as Camarero boda. Fernando Esteso Cuadrado as Cuadrado. Carmen de Mairena Vieja de las bolsas as Vieja de las bolsas.

Clever Rangeel Dieguito as Dieguito. More like this. Storyline Edit. Did you know Edit. Trivia Santiago Segura wanted Mario Conde to play the role of the villain, but did not manage to hire him. Quotes [subtitled version] [in a car, during a surveillance operation] Torrente : This is the worst part of surveillance, kid.

Connections Followed by Torrente 5 User reviews 5 Review. Top review. Torrente is in crisis for reboot. What worked in 1st part excellent movie BTW and held throughout second movie, failed in 3rd and now 4th part. Reason is simple. Torrente relied on same things that made it good in first two parts but now it is getting nowhere. Script and story are thin as air. Acting is good but keep repeating same jokes all over again and it is boring.

Torrente was in need of refreshment but it's author failed to see that. There are some funny moments in this movie but that is all there is to it. Not to mention it had so much scenes where things could get better but they were not used in innovative way.

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