DMG for inducing endothelium-derived no-dependent vasodilation

Abstract

The application relates to the use of a composition comprising N,N-dimethylglycine (DMG) and / or a salt thereof for inducing endothelium-derived NO-dependent vasodilation.

Description

[0001] DMG to induce endothelium-derived NO-dependent vasodilation

[0002] The application relates to the use of a composition comprising N,N-dimethylglycine (DMG) and / or a salt thereof for inducing endothelium-derived NO-dependent vasodilation.

[0003] Nitric oxide (NO) is known for its dilating effect on blood vessels. The protective effects of NO and its precursor L-arginine have now been well documented in healthy individuals as well as in patients with cardiovascular diseases such as arteriosclerosis, hypertension, and circulatory disorders.

[0004] The vasodilatory effect of nitric oxide is used in the treatment of a number of conditions, such as angina pectoris. Vasodilation is achieved through the use of NO-releasing substances.

[0005] However, the substances used for this purpose, such as nitroglycerin, molsidomine or isosorbide dinitrate (ISDN), are often limited in their application due to possible interactions, side effects or contraindications, so that there is always a great need for new NO-inducing approaches.

[0006] A first aspect of the invention relates to the use of a composition comprising N,N-dimethylglycine (dimethylglycine, DMG) and / or a salt thereof for inducing endothelium-derived NO-dependent vasodilation or a composition comprising N,N-dimethylglycine (dimethylglycine, DMG) and / or a salt for inducing endothelium-derived NO-dependent vasodilation.

[0007] Accordingly, the invention relates to a composition comprising N,N-dimethylglycine (dimethylglycine, DMG) and / or a salt thereof for use in inducing endothelium-derived NO-dependent vasodilation. The composition can find corresponding therapeutic and / or cosmetic applications.

[0008] A further aspect of the invention therefore relates to the cosmetic, non-therapeutic use of a composition as described herein comprising N,N-dimethylglycine (dimethylglycine, DMG) and / or a salt thereof.

[0009] According to the invention, it has now surprisingly been shown that DMG can also induce or initiate endothelium-derived NO-dependent vasodilation.

[0010] DMG is found in plants, animals, and humans, although it is only produced in very small amounts in humans. It is formed as an intermediate in a multi-step biosynthesis of glycine from choline through the transamination of betaine with betaine homocysteine ​​methylase. DMG and DMG-Na have also been shown to support tissue and cellular functions, for example, by improving antioxidant capacity and oxygen utilization, promoting tissue regeneration, and improving the immune response / defense.

[0011] N,N-Dimethylglycine, also (dimethylamino)acetic acid, is represented by the following chemical formula 1:

[0012] The invention relates not only to the use of dimethylglycine, but also to its salts, solvates, and hydrates. These are preferably pharmaceutically or cosmetically acceptable salts of dimethylglycine. The salt is particularly preferably a water-soluble salt with a solubility in water of at least 10 g / l at 20°C.

[0013] In a preferred embodiment, the salt of dimethylglycine is an alkali metal, alkaline earth metal, or ammonium salt of dimethylglycine. Examples are sodium, potassium, calcium, magnesium, and ammonium salts. In the ammonium salts, the ammonium cation carries one to four alkyl groups, each independently containing 1 to 4 carbon atoms. According to the invention, the sodium and potassium salts of dimethylglycine are preferred, in particular the sodium salt of dimethylglycine, namely sodium N,N-dimethylglycinate.

[0014] In an alternative preferred embodiment, the salt of dimethylglycine may be the salt of an inorganic and / or organic acid with dimethylglycine.

[0015] Examples of salts of dimethylglycine with an inorganic acid are the hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, sulfate, hydrogen sulfite, sulfite, hydrogen carbonate, carbonate, monophosphate, diphosphate, and triphosphate of dimethylglycine, as well as mixtures thereof. The hydrochloride of dimethylglycine is particularly preferred.

[0016] According to the invention, the described compositions comprising N,N-dimethylglycine (DMG) and / or a salt thereof are used to induce endothelium-derived NO-dependent vasodilation or vascular dilation. One aspect of the invention accordingly relates to a composition comprising N,N-dimethylglycine (DMG) and / or a salt thereof for use in the treatment and / or prevention of diseases that are NO-associated, caused by NO deficiency, and / or can be treated by NO induction and / or NO release with vasodilation or vascular dilation.

[0017] Vasodilation refers to the dilation or widening of blood vessels, in other words, the enlargement of their lumen. Vasodilation is a physiological reaction that leads to an increase in the vessel cross-section and thus the blood flow behind the affected vessel section. It is triggered by relaxation of the vascular smooth muscle. It is caused by visceromotor fibers of the autonomic nervous system. Various locally produced mediators, such as bradykinin, acetylcholine, and endothelin, can, among other things, cause increased NO production by stimulating their endothelial receptors (e.g., B2, M3, or ET-B receptor), thereby causing vasodilation or vascular dilation. Increased expression of endothelial NO synthase and the correspondingly induced NO production also leads to the same effect.

[0018] Nitric oxide (NO) itself is produced by the conversion of L-arginine to NO via NO synthases (NOS) in various parts of the body. Endothelial NOS (eNOS) produces NO, which explicitly acts as an endogenous vasodilator, diffuses into vascular cells, and mediates smooth muscle relaxation by binding to guanylyl cyclase. Guanylyl cyclase converts GTP to cGMP, which activates cGMP-dependent protein kinases. These protein kinases then phosphorylate various ion channels in the endoplasmic reticulum (ER), thereby sequestering calcium and preventing calcium mobilization within the cell. As a result, smooth muscle cells relax (Jennifer Witek; Anand D. Lakhkar, Treasure Island (FL): StatPearls Publishing; 2024 Jan). The present invention is not limited to this mechanism.

[0019] The induction of endothelium-derived NO-dependent vasodilation enables the prevention and / or treatment of conditions, indications, and / or diseases that can be avoided, improved, or treated by endothelium-derived NO-dependent vasodilation. Endothelium-derived NO-dependent vasodilation can be induced independently of other conditions and / or medical indications, such as inflammatory conditions. Preferably, the condition, indication, and / or disease to be treated is diagnosed prior to treatment.

[0020] In preferred embodiments, the composition according to the invention is used in combination with another active ingredient. The other active ingredient is generally selected depending on the indication being treated. Corresponding embodiments are described herein by way of example.

[0021] The indication to be treated according to the invention is preferably selected from the group consisting of skin aging, skin diseases, atrophy, acute and / or chronic wounds, and dermatitis. Examples of skin diseases include acne, microbial skin infections, skin inflammation, rough skin, dry skin, skin irritations, itching, pruritus, allergies, psoriasis, psoriatic arthritis, eczema, scleroderma, rosacea, systemic lupus erythematosus, acne, and susceptibility to contact allergies.

[0022] "Atrophy" describes the atrophy or shrinkage of a tissue, organ, or individual cell, accompanied by a reduction in function. Atrophy can be characterized by a decrease in cell volume or size, or by a decrease in cell number.

[0023] According to the invention, atrophy is preferably selected from age-related atrophy, inactivity atrophy, trophoneurotic / nerve atrophy, vascular atrophy, pressure atrophy, endocrine atrophy and / or atrophy of the skin.

[0024] “Age-related atrophy” is characterized by a decrease in the volume of all functional (parenchymal) cells, which can be particularly pronounced in the brain and heart.

[0025] “Inactivity atrophy” is induced by a lack of use of an organ, for example when a leg is in a cast.

[0026] If a nerve is damaged, the muscle it no longer supplies atrophies; “trophoneurotic / nerve atrophy” occurs.

[0027] If the blood vessels don't deliver enough oxygen and nutrients to the cells, they can also atrophy. This is called "vascular atrophy." This requires that the inadequate supply develops slowly (for example, a renal artery that narrows over months).

[0028] "Pressure atrophy," for example, occurs when tumors press on surrounding tissue, causing neighboring cells to atrophy. "Endocrine atrophy" can occur due to endocrine signals, such as cortisone therapy.

[0029] A possible side effect of glucocorticoid treatment of atopic eczema is “skin atrophy” (“skin thinning”).

[0030] "Dermatitis" refers herein to an inflammatory skin reaction that primarily affects the dermis (leather skin). The term dermatitis also includes eczema. According to the invention, the dermatitis to be treated is preferably selected from eczema, bathing dermatitis, dermatitis herpetiformis Duhring, exfoliative dermatitis, dermatitis exfoliativa neonatorum, dermatitis factitia, dermatitis ulcerosa, perioral dermatitis, stasis dermatitis, light dermatoses, radiation dermatitis (especially dermatitis solaris), atopic dermatitis, diaper dermatitis, contact dermatitis, incontinence-associated dermatitis, psoriasis, and / or xeroderma.

[0031] The term "eczema" as used herein encompasses a group of inflammatory skin diseases that manifest as a non-infectious inflammatory reaction of the skin. Eczema can be triggered by various factors. It is characterized by a typical sequence of skin reactions (redness, blistering, oozing, crusting, scaling).

[0032] “Bath dermatitis” (cercarial dermatitis) is an infection caused by cercariae of various flukes.

[0033] “Dermatitis herpetiformis Dühring” is a chronic-recurrent autoimmune disease with subepidermal blistering,

[0034] "Dermatitis factitia" is a factitious disorder caused by self-harming behavior. "Ulcerative dermatitis" is characterized by vasculitis with isolated ulcers.

[0035] “Perioral dermatitis” (syn. rosacea-like dermatitis) is caused by inflammation of the facial skin due to excessive use of cosmetics.

[0036] “Stamina dermatitis” is usually initially caused by venous circulation disorders such as chronic venous insufficiency.

[0037] Atopic dermatitis is a chronic, non-contagious skin disease that belongs to the atopic group of diseases. Other common names include neurodermatitis or atopic eczema.

[0038] Psoriasis is a non-contagious, chronic autoimmune disease that primarily manifests as an inflammatory skin condition. This systemic disease often affects other organs, particularly joints and associated ligaments, as well as adjacent soft tissues (psoriatic arthritis), the eyes (uveitis), the vascular system, the heart, and the genitals. It can also be associated with diabetes mellitus and strokes.

[0039] Also included are skin diseases caused by radiation exposure, such as photodermatoses due to excessive sun exposure (sunburn: dermatitis solaris), photoallergic or photoxic reactions (e.g., Berloque dermatitis, meadow grass dermatitis), or radiation dermatitis (radiodermatitis) as a result of ionizing radiation, and / or an improvement in skin circulation in uremia and chronic kidney disease. Endothelial dysfunction

[0040] One aspect of the invention relates to the composition described herein for use in the treatment of endothelial dysfunction.

[0041] Endothelial dysfunction is generally defined as a dysfunction of the endothelium. This dysfunction encompasses all functional areas of the endothelium, such as vascular dilation regulation, vascular permeability, and the modulation of adhesive properties, as well as platelet aggregation inhibition.

[0042] Endothelial dysfunction is particularly important in the processes of atherosclerosis. Endothelial dysfunction is caused by a deficiency of dissolved nitric oxide, which is attributable to various biochemical pathomechanisms. These mechanisms are usually caused or promoted by risk factors for atherosclerosis, such as diabetes mellitus, hypertension, homocysteinemia, obesity, and smoking abuse.

[0043] Endothelial dysfunction promotes or causes the development of atherosclerosis. It can accelerate or trigger ischemia-related symptoms, such as angina pectoris.

[0044] In principle, both invasive and non-invasive diagnostic methods are available for diagnosis. Examples of non-invasive diagnostic methods for monitoring NO-induced vasodilation include analysis of the retinal microcirculation (dynamic vascular analysis or Doppler sonography). Using ADMA (asymmetric dimethylarginine), ADMA ELISA can be used to detect endothelial dysfunction in the laboratory. Atherosclerosis risk parameters such as glucose, blood lipids, and homocysteine ​​can also be used.

[0045] In preferred embodiments of the present application for the treatment of endothelial dysfunction, the minimization of atherosclerotic risk factors may also be a priority. This can be achieved, for example, by controlling diabetes mellitus, normalizing weight, abstaining from smoking, treating hypocholesterolemia, and drug therapy for hypertension.

[0046] Furthermore, in a preferred embodiment, the treatment according to the invention can be supplemented by additional drug therapy strategies. These additional therapy strategies preferably causally intervene in the development of endothelial dysfunction. One aspect of the invention therefore relates to the composition according to the invention for use in the treatment of endothelial dysfunction in combination with another active ingredient.

[0047] Exemplary additional active ingredients for the treatment of endothelial dysfunction, which can be administered in combination with the composition according to the invention, are ACE inhibitors, AT1 antagonists, statins, PDE5 inhibitors, diuretics such as thiazide diuretics, antioxidants, antidiabetics, prostacyclin analogues and NO donors such as L-arginine or nitroglycerin.

[0048] Regardless of the indication to be treated, when the composition according to the invention is combined with another active ingredient within the meaning of this invention, the other active ingredient can be contained in the composition according to the invention or administered as the active ingredient of another composition. If the composition according to the invention is administered in combination with another composition comprising another active ingredient, the two compositions are preferably administered independently of one another according to the respective dosage instructions of the two compositions. Simultaneous administration of the two compositions is of course also possible.

[0049] ACE inhibitors (angiotensin-converting enzyme inhibitors) also reduce AT1-mediated oxidative stress. ACE inhibitors are used to treat high blood pressure, heart failure, and other cardiovascular diseases. Examples of ACE inhibitors are ramipril (e.g., Tritace), lisinopril (e.g., Zestril), enalapril (e.g., Renitec), captopril (e.g., Capoten), perindopril (e.g., Preterax), or quinapril (e.g., Accupril). AT1 antagonists (ARBs) block the angiotensin II receptor. Angiotensin II is a hormone that plays an important role in regulating blood pressure and fluid balance in the body. When it binds to the AT1 receptor, it causes blood vessels to constrict and blood pressure to rise. By blocking this receptor, AT1 antagonists prevent the effects of angiotensin II, leading to a reduction in blood pressure.These medications are primarily used to treat high blood pressure (hypertension) and heart failure, but can also help treat kidney disease and prevent strokes. Examples of AT1 antagonists include losartan, valsartan, olmesartan, and irbesartan.

[0050] Statins lower cholesterol levels, especially LDL cholesterol. They also have a beneficial effect on endothelial function by promoting nitric oxide production and reducing inflammation in the endothelium. Examples of stanines include atorvastatin, simvastatin, and rosuvastatin.

[0051] Phosphodiesterase-5 inhibitors (PDE-5 inhibitors) enhance the action of nitric oxide by inhibiting the enzyme phosphodiesterase-5. This increases the availability of cGMP (a molecule activated by NO). This leads to relaxation of the vascular muscles and improved blood flow. Examples of PDE-5 inhibitors are sildenafil (Viagra) and tadalafil (Cialis).

[0052] Diuretics, especially thiazide diuretics, are used to lower blood pressure and can also indirectly improve endothelial function by reducing vascular stress. Examples of thiazide diuretics include hydrochlorothiazide and chlorthalidone, or furosemide.

[0053] Antioxidants can reduce oxidative stressors that damage endothelial function, thus supporting blood vessel health. Examples of antioxidants include vitamin C, vitamin E, and coenzyme Q10.

[0054] Antidiabetics can stabilize blood sugar levels and improve endothelial function in diabetic endothelial dysfunction. Examples include metformin and SGLT-2 inhibitors (such as empagliflozin and canagliflozin). NO donors such as L-arginine and nitro derivatives (e.g., nitroglycerin) increase nitric oxide production, which can lead to vasodilation and improved blood flow.

[0055] L-arginine is an amino acid that plays a key role in regulating vascular function, particularly through the formation of nitric oxide (NO). Nitric oxide acts as a vasodilator, a substance that dilates blood vessels, thus lowering blood pressure and improving blood flow. Because it serves as a precursor for the synthesis of nitric oxide, L-arginine can be used as a supplement to promote endothelial function.

[0056] Prostacyclin analogues can influence blood coagulation and inflammatory processes in the endothelium and promote vasodilation. Iloprost is an example.

[0057] In addition to the described indications, a number of other indications can be treated according to the invention. These include, among others, diseases of the cardiovascular system, such as atherosclerosis, heart failure, peripheral arterial occlusive disease, chronic myocardial insufficiency, acute right heart failure, coronary heart disease or angina pectoris, hypertension, in particular arterial hypertension, pulmonary hypertension, and persistent pulmonary hypertension of newborns (PPHN), and diseases of the respiratory tract and / or lungs, such as acute respiratory distress syndrome (ARDS), bronchiolitis, in particular acute bronchiolitis, viral diseases of the respiratory tract and / or lungs, in particular COVID-19, cor pulmonale, chronic sinusitis, sickle cell anemia, erectile dysfunction, (benign) prostatic hyperplasia, glaucoma, and / or for the treatment of oxidative stress, in particular oxidative stress induced by hydroxyl radicals.

[0058] Pulmonary hypertension can occur especially after heart surgery.

[0059] In a preferred embodiment, the endothelial dysfunction is age-related endothelial dysfunction, in particular age-related endothelial dysfunction with effects on the skin. A combination with at least one other active ingredient may also be advantageous in the treatment of these indications according to the invention.

[0060] Heart failure

[0061] Heart failure (or heart weakness) is a chronic condition in which the heart is no longer able to pump enough blood to meet the body's needs.

[0062] The treatment of heart failure includes a combination of lifestyle changes, drug therapy, and, in some cases, interventional or surgical procedures. Medications play a key role in slowing the progression of the disease, alleviating symptoms, and reducing the risk of complications. In addition to ACE inhibitors and ARBs, other medications used include beta-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), vasodilators, SGLT-2 inhibitors, ivabradine, digitalis glycosides, and inotropic agents (for acute heart failure).

[0063] In the treatment of these indications according to the invention, a combination with at least one further active ingredient, preferably selected from the groups comprising ACE inhibitors, ARBs, beta-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), vasodilators, SGLT-2 inhibitors, ivabradine, digitalis glycosides or inotropic agents (for acute heart failure) may also be advantageous.

[0064] Beta-blockers reduce heart rate and blood pressure, thus relieving the strain on the heart. They also have a protective effect on heart tissue and improve quality of life in patients with heart failure. Examples of beta-blockers include bisoprolol, carvedilol, and metoprolol.

[0065] Diuretics help remove excess water and salt from the body, lowering blood pressure and relieving stress on the heart. They reduce symptoms such as shortness of breath and fluid retention (edema), which are common in heart failure. Examples of diuretics include furosemide, torasemide, and hydrochlorothiazide. MRAs block the action of aldosterone, a hormone that causes fluid retention in the body. They have a cardioprotective effect by reducing the risk of cardiac arrhythmias and the progression of heart failure. Examples of MRAs include spironolactone and eplerenone.

[0066] Vasodilators dilate blood vessels, which lowers blood pressure and relieves the strain on the heart. They are particularly useful in patients with heart failure who also suffer from high blood pressure. Examples of vasodilators include hydralazine and isosorbide dinitrate.

[0067] SGLT-2 inhibitors lower blood sugar and also have a cardioprotective effect by improving kidney function and reducing cardiac stress. They have been shown to be beneficial for patients with heart failure and diabetes in clinical trials. Examples of SGLT-2 inhibitors include empagliflozin and dapagliflozin.

[0068] Ivabradine lowers the heart rate without affecting blood pressure. This helps relieve the strain on the heart and reduce its energy consumption.

[0069] Digitalis glycosides such as digoxin strengthen the heart's contractile force and can relieve the symptoms of heart failure. They are also used to control certain types of irregular heart rhythms (such as atrial fibrillation).

[0070] Inotropic drugs increase the heart's contractile force and are used in acute episodes of decompensated heart failure to improve cardiac output. Examples of inotropic drugs include dobutamine and milrinone.

[0071] Coronary heart disease

[0072] Coronary artery disease (CAD) is a condition in which the coronary arteries (the arteries that supply blood to the heart) are narrowed or blocked by atherosclerosis. This can lead to symptoms such as angina pectoris (chest pain) and, in severe cases, a heart attack. Antithrombotic drugs (e.g. aspirin (acetylsalicylic acid), clopidogrel (Plavix), prasugrel, ticagrelor), beta-blockers (e.g. metoprolol, bisoprolol, carvedilol), nitrates (e.g. nitroglycerin, isosorbide dinitrate), statins (e.g. atorvastatin, rosuvastatin, simvastatin), calcium channel blockers (e.g. amlodipine, diltiazem, verapamil), ACE inhibitors (e.g. ramipril, lisinopril, enalapril), ARBs (e.g. losartan, valsartan, candesartan), PCSK9 inhibitors (e.g. evolocumab, alirocumab), ranolazine, fibrates and other lipid-lowering drugs (e.g. fenofibrate, ezetimibe) are used to treat coronary artery disease.

[0073] Calcium channel blockers dilate blood vessels and lower blood pressure. They also reduce the heart's oxygen demand and can help relieve the symptoms of angina pectoris, especially in patients who cannot tolerate beta-blockers.

[0074] PCSK9 inhibitors reduce LDL cholesterol levels to very low levels by promoting the uptake of LDL cholesterol into the liver. These drugs are used particularly in patients with high cardiovascular risk or familial hypercholesterolemia.

[0075] Ranolazine reduces the heart's oxygen demand by improving cellular energy production and increasing the metabolic efficiency of the heart muscle. It is used primarily as adjunctive therapy for the treatment of angina pectoris.

[0076] Fibrates lower triglycerides and increase “good” HDL cholesterol, while ezetimibe blocks the absorption of cholesterol in the intestine.

[0077] Angina pectoris

[0078] Angina pectoris is a symptom of coronary heart disease (CHD) that causes temporary chest pain or tightness caused by insufficient blood flow to the heart muscle.

[0079] Drug treatment for angina pectoris primarily includes nitrates, beta-blockers, calcium channel blockers, ACE inhibitors, ARBs, ranolazine, ivabradine, and antiplatelet agents, which help relieve symptoms, reduce the risk of heart attacks, and reduce the strain on the heart.

[0080] hypertension

[0081] The goal of drug treatment for hypertension (high blood pressure) is to lower blood pressure to a healthy level and reduce the risk of cardiovascular events such as stroke, heart attack, and kidney failure. There are different classes of medications used depending on the severity of hypertension and individual patient characteristics. Examples of drug classes used for treatment include diuretics, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, alpha-blockers (e.g., doxazosin, terazosin), renin inhibitors (e.g., aliskiren), centrally acting antihypertensives (e.g., clonidine, methyldopa), or direct vasodilators (e.g., hydralazine, minoxidil).

[0082] Alpha-blockers block the alpha receptors in the blood vessels, causing them to relax and dilate, thus lowering blood pressure.

[0083] Renin inhibitors block the action of renin, an enzyme that stimulates the production of angiotensin II. By inhibiting renin, the production of angiotensin II is reduced, thus reducing the increase in blood pressure.

[0084] Centrally acting antihypertensives act on the central nervous system and reduce the activity of the sympathetic nervous system, leading to a reduction in blood pressure. They are typically used for treatment-resistant hypertension.

[0085] Direct vasodilators dilate blood vessels directly without affecting the renal or sympathetic systems. They are usually used in combination with other antihypertensive drugs. Peripheral arterial disease

[0086] Peripheral arterial disease (PAD) is a condition in which the blood supply to the extremities is compromised due to narrowing or blockage of the arteries. It is often associated with atherosclerosis (hardening of the arteries) and leads to symptoms such as intermittent claudication, leg pain on exertion, and, in advanced cases, resting pain or impaired wound healing. Cilostazol is a PDE-3 inhibitor that improves vasodilation and blood circulation. It has a positive effect on endothelial function by dilating blood vessels and reducing the formation of blood clots and is used in peripheral arterial disease (PAD) to improve walking ability.

[0087] Atherosclerosis

[0088] Atherosclerosis is a chronic disease of the arteries that causes hardening and thickening of the artery walls, often due to deposits of fats, cholesterol, and other substances. These deposits (plaques) can narrow the arteries, impeding blood flow and increasing the risk of cardiovascular events such as heart attack, stroke, or peripheral arterial disease (PAD).

[0089] The treatment of atherosclerosis primarily involves controlling risk factors such as high cholesterol (e.g., ezetimibe), high blood pressure, and preventing blood clots. Medications such as statins or PCSK9 inhibitors to lower cholesterol, fibrates or nicotinic acid to lower triglyceride levels, and antiplatelet drugs to prevent blood clots are fundamental to treatment. Blood pressure medications such as ACE inhibitors, calcium channel blockers, vasodilators, or ARBs can also influence atherosclerosis and reduce the risk of cardiovascular events.

[0090] Erectile dysfunction

[0091] Erectile dysfunction (ED) is the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. It can be caused by various factors such as stress, anxiety, physical conditions (e.g., diabetes, high blood pressure, cardiovascular disease), or hormonal imbalances.

[0092] Drug treatment of erectile dysfunction includes a variety of approaches, from PDE-5 inhibitors (such as sildenafil and tadalafil), testosterone preparations, alprostadil (prostaglandin E1), dapoxetine or vasodilators (e.g. papaverine).

[0093] The compositions described herein can also be used according to the invention for immunomodulation. NO alters the balance of T helper 1 (TH1) and T helper 2 (TH2) cells. In particular, NO reduces the proliferation rate of TH1 cells and the synthesis of the cytokine IL-2, but increases the production of IL-4 cytokines from TH2 cells. In this way, NO can inhibit inflammatory responses to viral and bacterial pathogens. Furthermore, NO is thought to influence the adhesion and recruitment of leukocytes (Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001 Oct;2(10):907-16).

[0094] Any suitable form of administration may be chosen within the scope of the present invention. Exemplary forms of administration include oral, topical, intravenous, intramuscular, cutaneous, subcutaneous, nasal, inhalation, and / or rectal.

[0095] Topical application means external application, in particular local, external application.

[0096] Administration may produce local or systemic effects.

[0097] Cutaneous and especially topical application is particularly preferred.

[0098] For diseases of the respiratory tract and / or lungs, administration by inhalation is preferred. Another preferred method of administration is transdermal, particularly preferably using a patch. Transdermal patches are flexible and thin pharmaceutical preparations that are applied to the skin. They continuously release the active ingredients they contain across the skin barrier into the bloodstream. Accordingly, achieving a systemic effect is preferred in this embodiment.

[0099] The composition used according to the invention, especially for topical use, is preferably applied as a gel, cream, ointment, lotion, solution, suspension or milk.

[0100] Gels consist of gelled liquids and are produced with suitable swelling agents such as cellulose derivatives, starches, carbomers, gelatin, xanthan, bentonite, agar, tragacanth, carrageenan, alginates and / or pectin.

[0101] Creams are semi-solid preparations typically intended for application to the skin or mucous membranes. They are multiphase preparations consisting of a lipophilic and an aqueous phase.

[0102] Ointments are semi-solid preparations for external use. They consist of a single-phase base in which solid or liquid substances may be dispersed. This contrasts with creams, which are multi-phase and consist of a lipophilic and an aqueous phase.

[0103] Lotions are preparations for external application on the skin with a liquid to semi-solid consistency.

[0104] Solutions are liquid preparations in which the active ingredients and excipients are dissolved in water or any other suitable solvent (e.g., an oil). Solutions, especially for oral administration, can be freshly prepared shortly before use, for example, from a powder. Suspensions are heterogeneous mixtures consisting of a solid and liquid phase. The solid phase may settle to the bottom of the storage container over time. Therefore, suspensions should often be shaken immediately before use.

[0105] According to the invention, the pH of the topical composition is preferably 3.0 to 7.0, more preferably 3.0 to 5.9, even more preferably 3.5 to 5.4, and particularly preferably 4.0 to 5.0 (measured at 21°C using a Mettler-Toledo SevenCompact S220 pH meter). Within this range, the compositions according to the invention are not only particularly chemically, physically, and microbiologically stable, but also medically and cosmetically extremely well-tolerated for topical administration. Particularly suitable pH values ​​for the composition according to the invention are: 3.5; 3.6; 3.7; 3.8; 3.9; 4.0; 4.1; 4.2; 4.3; 4.4; 4.5; 4.6; 4.7; 4.8; 4.9; 5.0; 5.1; 5.2; 5.3; and 5.4. The pH of the composition is preferably adjusted using one or more pH modifiers. Suitable pH modifiers can be acids, bases, and / or buffer systems to stabilize or influence the pH of the composition.Typical pH modifiers according to the present invention are adipic, citric, malic, succinic, tartaric, ascorbic, phosphoric, lactic, and fumaric acid and the corresponding salts, as well as sodium alginate, polyacrylic acid, sodium carbonate, and sodium bicarbonate. In the context of pH modifiers, the term "salt" refers to alkali metal salts or alkaline earth metal salts, unless otherwise stated.

[0106] Another preferred application according to the invention is oral administration. Preferred oral administration forms include, for example, tablets, capsules, coated tablets, film-coated tablets, syrups, or liquid forms such as drops.

[0107] The composition according to the invention contains dimethylglycine and / or a salt of dimethylglycine preferably in a proportion of 0.00001 wt.% to 25.0 wt.%, based on the total weight of the composition.

[0108] In a preferred embodiment, the composition according to the invention contains dimethylglycine and / or a salt of dimethylglycine in a proportion of 0.001 wt.% to 10.0 wt.%, more preferably from 0.01 wt.% to 8.0 wt.%, more preferably from 0.1 wt.% to 6.0 wt.%, even more preferably from 0.3 wt.% to 5.0 wt.%, in particular from 0.5 wt.% to 3.0 wt.%, in each case based on the total weight of the composition. In a preferred embodiment of the invention, the composition according to the invention can contain 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 1.1 wt.%, 1.2 wt.%, 1.3 wt.%, 1.4 wt.%, 1.5 wt.%, 2.0 wt.% or 2.5 wt.% of dimethylglycine and / or a salt of dimethylglycine, in each case based on the total weight of the composition.

[0109] The composition according to the invention preferably contains dimethylglycine and / or a salt of dimethylglycine as a pure chemical substance, including the respective solvates and hydrates (e.g. the dihydrate of sodium dimethylglycinate), since this can increase the purity of the composition and reduce the occurrence of undesirable side effects.

[0110] In a preferred embodiment, the composition according to the invention contains at least one further active ingredient. The at least one further active ingredient can be selected depending on the indication to be treated. In other embodiments, the further active ingredient is not contained in the composition according to the invention, but is administered in an appropriate combination. If the composition according to the invention is administered in combination with another composition comprising a further active ingredient, the two compositions are preferably administered independently of one another according to the respective dosage instructions of the two compositions. Simultaneous administration of the two compositions is of course also possible.

[0111] Preferably, at least one active ingredient is selected from the group comprising ACE inhibitors, AT1 antagonists, platelet aggregation inhibitors, NO donors, L-arginine, ARBs, beta-blockers, diuretics, calcium channel blockers, PDE-5 inhibitors, antibiotics, antimycotics (in case of superinfection by fungi), antihistamines (symptomatic in case of itching), glucocorticoids, retinoids (in case of psoriasis, acne, rosacea), immunosuppressants, menthol, biotin, zinc PCA, caffeine, niacinamide, panthenol, ectoin, ubiquinone-10, taurine, echinacea, tocopheryl acetate, NO-releasing agents and combinations thereof.

[0112] Antibiotics generally refer to drugs used to treat bacterial infectious diseases, regardless of whether they are high or low molecular weight, natural or synthetic in origin.

[0113] Antifungals are antimicrobial substances that act against diseases caused by fungi.

[0114] Antihistamines are active substances that weaken or eliminate the effect of the body's own messenger substance histamine by blocking histamine receptors or reducing their receptor activity below the basal level.

[0115] Glucocorticoids are hormones, particularly steroid hormones. Glucocorticoids have diverse physiological and therapeutic effects. They influence metabolism, water and electrolyte balance, the cardiovascular system, and the nervous system. They also inhibit inflammation and are immunosuppressive.

[0116] Retinoids are derivatives of vitamin A. Retinoids have sebostatic, antiproliferative, proapoptotic, and anti-inflammatory properties.

[0117] Immunosuppressants are generally substances that reduce the function of the immune system.

[0118] Menthol is a monocyclic monoterpene alcohol and can be added to the composition according to the invention as a circulation-stimulating agent. Menthol can also provide a refreshing sensory stimulation to the skin. Biotin, also known as vitamin B7 or vitamin H, is a water-soluble vitamin from the B complex. Biotin can strengthen the skin.

[0119] Zinc PCA is the zinc salt of L-pyrrolidone carboxylate and can be added to the composition according to the invention as a substance with antimicrobial activity.

[0120] Caffeine is a methylxanthine alkaloid belonging to the class of methylxanthines. It is a bitter crystalline substance, can be considered a purine derivative, and is chemically related to the adenine and guanine bases of deoxyribonucleic and ribonucleic acids. The IIIPAC name of caffeine is 1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione. Caffeine is known for various pharmacological effects. In particular, it is known for its stimulating effect on the central nervous system. There is a growing body of evidence supporting its beneficial effects on a number of different disorders.

[0121] Niacinamide (also known as nicotinamide) is the amide of nicotinic acid and is also known as vitamin B3. Niacinamide reduces oxidative stress.

[0122] Panthenol is a provitamin that is converted in the body into pantothenic acid (vitamin B5). The latter is part of coenzyme A and thus important for skin metabolism. According to the invention, when panthenol is applied, skin elasticity and moisture are further improved. Itching and inflammation are also relieved and wound healing is promoted.

[0123] Ectoine is a cyclic amino acid and exists in aqueous solution as a mesomeric-stabilized zwitterion. Ectoine has been shown to protect against UV radiation and may be helpful in the treatment of inflammatory diseases.

[0124] Ubiquinone-10 (Q10 or coenzyme Q10) is a quinone derivative. Q10, which belongs to the ubiquinone pool, is considered an antioxidant and, according to the invention, has a stabilizing effect on the skin. Taurine, or 2-aminoethanesulfonic acid, also has a further stabilizing effect on the skin as an antioxidant.

[0125] According to the invention, echinacea has a soothing effect on the skin and relieves itching and tightness. Echinacea can also stimulate blood circulation in the skin.

[0126] Tocopheryl acetate exhibits antioxidant properties and, according to the invention, has a further stabilizing effect on the skin.

[0127] Nitric oxide-releasing agents include nitroglycerin, isosorbide nitrate, or molsidomine for the treatment of angina pectoris, a typical symptom of coronary heart disease.

[0128] In a preferred embodiment of the invention, the composition according to the invention contains at least one further active ingredient selected from menthol, biotin, zinc PCA, niacinamide, panthenol, ectoine, caffeine, ubiquinone, taurine, echinacea, tocopheryl acetate and combinations thereof, each in a proportion of 0.001 wt.% to 10.0 wt.%, more preferably 0.005 wt.% to 7.50 wt.%, even more preferably 0.01 wt.% to 5.0 wt.%, in particular 0.1 wt.% to 3.0 wt.%, based on the total weight of the composition.

[0129] Furthermore, the composition according to the invention can be water-based. This means that it contains, for example, 45.0 to 85.0 wt.% water.

[0130] The composition used according to the invention may contain at least one additive, which is preferably selected from the group comprising refatting agents, preservatives, stabilizers, antioxidants, rheology modifiers, thickeners, conditioning agents, dyes, solvents, and any combination thereof. Refatting agents, also called refatting or superfatting agents, are lipophilic substances that can prevent a disruptive effect on the epidermal barrier function. Examples of refatting agents are wool wax, squalene, liquid paraffin, vegetable oils, silicones, and cetyl palmitate.

[0131] Preservatives are substances used for preservation by killing and / or inhibiting the growth of microorganisms that degrade the composition. Preferably, the preservatives can be selected from the group consisting of benzoic acid, benzoic acid derivatives, sorbic acid, sorbic acid derivatives, salicylic acid, salicylic acid derivatives, phenoxyethanol, parabens, and combinations thereof. In a preferred embodiment, sodium benzoate and / or potassium sorbate are used as preservatives in the composition according to the invention. In a slightly acidic environment, sodium benzoate releases benzoic acid, and potassium sorbate releases sorbic acid. Both acids are believed to have an antimicrobial effect.

[0132] Stabilizers can protect light-sensitive components against radiation and are preferably UV absorbers such as benzophenone derivatives.

[0133] The addition of fragrances can provide a pleasant smell to the composition. Examples include perfumes, which are familiar to those skilled in the art.

[0134] An antioxidant is a chemical compound that slows down or completely prevents the oxidation of other components in the composition according to the invention. Examples of suitable antioxidants include citric acid, ascorbic acid, and butylhydroxyanisole.

[0135] Rheology modifiers and thickeners can help improve the application properties of the composition according to the invention. The addition of table salt (sodium chloride) can be considered as a rheology modifier and thickener. By adding table salt, the flowability of the composition according to the invention can be influenced within certain limits and adjusted to the required level. Cellulose derivatives or polyacrylates can also be used as thickeners.

[0136] For the purposes of the application, care products are understood to be substances that care for the skin, especially the scalp. Hydrolyzed wheat protein and allantoin have a caring effect on the skin. Hydrolyzed wheat protein has primarily moisturizing properties.

[0137] Dyes are optionally used to impart a characteristic color to the composition according to the invention so that it can be easily distinguished from other products.

[0138] A solvent or solvent mixture commonly known to those skilled in the art can be used as the solvent. Preferred solvents are ethanol or butylene glycol, especially 1,4-butylene glycol, propylene glycol, and isopropyl alcohol. Ethanol is preferred. These solvents can preferably be present in the composition according to the invention in an amount of 0.1 to 70 wt.%. Their use can lead to a feeling of freshness and, due to the rapid drying, has a very minimal impact on the hairstyle. Solvents also aid the penetration of the active ingredients, thus enhancing their effectiveness.

[0139] The dosage of the composition used according to the invention depends on the indication to be treated and the patient to be treated. Factors that may play a role here include age, weight, height, gender, other medications, especially those taken regularly, pregnancy, and / or pre-existing conditions. Based on such parameters, the dosage can be determined by a person skilled in the art. The compositions can be administered for the treatment and / or prevention of acute and / or chronic conditions. Long-term treatment is particularly suitable for the treatment of chronic conditions. For example, chronic myocardial insufficiency can be treated with the compositions according to the invention alone or in combination with cardiac glycosides and / or diuretics as long-term treatment.

[0140] Figure 1 : Effects of DMG-Na on various biological functions of HDMECs in vitro

[0141] (a) Representative immunofluorescence labeling of eNOS (red) in HDMECs treated with various concentrations of DMG-Na. The cell nuclei were counterstained with DAPI (blue). Scale bar = 50 μm. (b) Representative Western blot immunolabeling of eNOS and β-tubulin in HDMECs treated with various concentrations of DMG-Na. (c) Statistical analysis of optical density measurements on immunoblots. Relative eNOS / β-tubulin values ​​(mean ± SEM, n = 4 independent experiments) are presented as fold change, normalized to the respective controls. The P values ​​are also given, where * marks the statistical difference compared to the control (determined by Kruskal-Wallis with Dunn's post-hoc test (* p < 0.05)). (d) Statistical analysis of the microfluorimetric measurement of NO synthesis.Values ​​(mean ± SEM, n = 4 independent experiments) are expressed as fold change, normalized to the respective controls. P values ​​are also given, where * indicates the statistical difference compared to the control using one-way ANOVA with Dunnett's post-hoc test (*** p < 0.001).

[0142] Figure 2: Effects of DMG-Na on human skin microcirculation in vivo

[0143] (a, b) Dermal microcirculation measured by blood flow at 1 mm (a) and 8 mm (b) skin depth after the indicated treatments (untreated control, placebo, or verum). (c, d) Dermal microcirculation measured by blood velocity at 1 mm (c) and 8 mm (d) skin depth after the indicated treatments (untreated control, placebo, or verum). Box and whisker plots (Tukey method) showing the median, quartiles, and extreme values ​​for the differences between T90 and TO (delta T90) of blood flow in arbitrary units [AU]. P values ​​calculated using the Wilcoxon Signed Rank Test are presented as follows: *p<0.05 and **p<0.01 significant difference compared to placebo; #p<0.05 and ##p<0.01 significant difference compared to the untreated control.

[0144] Example

[0145] 1. In vitro cell culture studies

[0146] Cell culture

[0147] Adult human skin microvascular endothelial cells (HDMECs) were purchased from Lonza Ltd (Basel, Switzerland) in 2023 and cultured in EBM™-2 Endothelial Cell Growth Basal Medium supplemented with EGM™-2 MV Microvascular Endothelial SingleQuots™ Kit (both from Lonza Ltd, Basel, Switzerland) containing human epidermal growth factor, vascular endothelial growth factor, R 3 Insulin-like Growth Factor-1, ascorbic acid, hydrocortisone, human fibroblast growth factor-beta, fetal bovine serum, and gentamicin / amphotericin B, and cultured according to the manufacturer's guidelines. HDMECs were initiated from two different female donors, and passages 4 to 8 were used for the experiments.

[0148] Immunocytochemistry

[0149] HDMECs (5,000 cells per 10 mm round glass coverslips) treated with DMG-Na (0.005%, 0.02%, and 0.05%) were fixed in 1% paraformaldehyde (PFA, Merck KGaA, Darmstadt) for 10 minutes at room temperature. After washing with phosphate-buffered saline (PBS, Merck KGaA), they were postfixed with -20°C ethanol-acetic acid (2:1) for 5 minutes. Cells were permeabilized with 0.25% Triton X-100 in PBS for 10 minutes, blocked with antibody diluent (Thermo Fisher Scientific, Waltham, MA) for 30 minutes at room temperature, and then incubated with primary anti-human eNOS antibody at a dilution of 1:100 (Abeam, Cambridge, UK; #ab76198) at 4°C overnight. After the appropriate washing step with PBS, the coverslips were incubated for 45 minutes at room temperature for fluorescent staining with Alexa Flour-568 goat anti-mouse IgG antibody (Thermo Fisher Scientific, Waltham, MA; #A-11004) at a dilution of 1:500.The coverslips were washed with PBS, and nuclear counterstaining was performed with 4',6-diamidine-2-phenylindole (DAPI, Merck KGaA) for 1 minute. After another wash, the cells on the coverslips were mounted with Fluoromount-G® (Southern Biotech, Birmingham, AL). Images were acquired with a Nikon A1 confocal microscope (Nikon, Tokyo, Japan) and analyzed using Image J Fiji software, version 2.9.0 (National Institutes of Health, Bethesda, MD).

[0150] Western blot

[0151] HDMECs were seeded in 6-well plates and treated with DMG-Na (0.005% and 0.05%) for 24 hours. After treatment, the cells were harvested in lysis buffer (30 mM TRIS, pH 7.6, 140 mM NaCl, 5 mM EDTA, 50 mM NaF, 1 mM NasVCL) supplemented with protease inhibitors. After vigorous vortexing and centrifugation, the protein content of the samples was determined using the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific, Waltham, MA). Equal amounts of protein samples were subjected to 7.5% SDS-PAGE and transferred to nitrocellulose membranes (Bio-Rad Laboratories, Hercules, CA). The protein-binding nitrocellulose membranes were blocked with 5% skim milk in 1 xTBST for 1 hour at room temperature and then treated with primary mouse monoclonal [M221] anti-eNOS antibody (Abeam, Cambridge, UK, #ab76198) at a dilution of 1:1000 in 2.5% skim milk / 1 xTBST overnight at 4 °C.The membranes were washed three times for 7 minutes with 1×TBST and then incubated with horseradish peroxidase-labeled anti-mouse IgG antibody (GE Healthcare, Amersham, UK; #NA931V) at a dilution of 1:5000 in 1.5% skim milk / 1×TBST for 45 minutes at room temperature. Bands were visualized with SuperSignal West enhanced chemiluminescence systems (Thermo Fisher Scientific, Waltham, MA) using the CCD camera-based Azure c300 Gel Imaging System (Azure Biosystems, Dublin, CA). Densitometric analysis was performed using Azure Spot image analysis software version 2.0.062. To assess equal loading, the membranes were treated with a primary anti-beta-tubulin antibody (Thermo Fisher Scientific, Waltham, MA; #PA5-86071) at a dilution of 1:10.000 in 2.5% skimmed milk / 1 xTBST and anti-rabbit IgG-HRP (GE Healthcare, Amersham, UK; #NA934V) was applied as a secondary antibody at a dilution of 1:10,000 in 1.5% skimmed milk / 1 xTBST.

[0152] Microfluorimetric measurements of NO

[0153] HDMECs were seeded at a density of 15,000 cells per well in a black, clear-bottom 96-well plate (Greiner Bio-One, Kremsmünster, Austria) and cultured in growth medium at 37°C for 24 hours. Subsequently, the cells were incubated with 5 pM DAF-FM DA (4-amino-5-methylamine-2',7'-difluororescein diacetate) in phenol red-free DMEM (both from Thermo Fisher Scientific, Waltham, MA) supplemented with 0.5% FBS (Serana Europe GmbH, Brandenburg, Germany) for 1 hour at 37°C. The HDMECs were washed to remove excess sample, replaced with fresh medium, and then incubated for another 30 minutes at 37°C to allow complete deesterification of the intracellular diacetates.After incubation, cells were treated with DMG-Na (0.01%, 0.02%, and 0.05%) and fluorescence was measured at 490 / 510 nm excitation / emission using a FlexStation II (Molecular Devices, Sunnyvale, CA) fluorescence microplate reader (Nagy et al., 2003 and 2004).

[0154] Statistical analysis

[0155] The graphs were generated using OriginPro 8.6 software (OriginLab Corporation, Northampton, MA), and the data were analyzed using GraphPad Prism version 8.0.1 for Windows (GraphPad Software, San Diego, CA). For normally distributed data, a one-way ANOVA followed by Dunnett's post-hoc test was performed. For non-normal data distributions, the Kruskal-Wallis test with Dunnett's multiple comparison test was used. For intracellular calcium measurements, the data were analyzed using a two-way ANOVA followed by Tukey's post-hoc test.

[0156] 2. In vivo studies in humans

[0157] Study design, subjects

[0158] A total of 20 subjects (16 women and 4 men) aged 18–30 years (0=24.90 years) with healthy, normal skin participated in this single-center, single-group, randomized, placebo-controlled study to investigate the efficacy on skin microcirculation. Exclusion criteria included pregnancy and breastfeeding, use of topical or systemic treatments in the past few weeks that could interfere with the assessment of skin tolerability of the study product, subjects who had undergone surgery under general anesthesia within the past month, excessive exposure to sunlight or UV radiation within the past month, and participation in another clinical trial during the study period that could interfere with the current study.Participants were also instructed not to apply any other similar product to the test areas for 24 hours prior to study entry, not to start or change their usual hormone treatment, and not to make any lifestyle changes such as diet, smoking, or exercise.

[0159] The following gel formulations were used in the in-human in-vitro study: Active ingredient: N,N-Dimethylglycine sodium salt (1%), water, poloxamer 407, alcohol, citric acid. Placebo: Sodium hydroxide, water, poloxamer 407, alcohol, citric acid. Both formulations contained the same concentrations of ingredients (except DMG-Na and NaOH) and were adjusted to pH 4.5.

[0160] Efficacy study

[0161] The O2C system (LEA Medizintechnik GmbH, Gießen) was used to measure the short-term effects of the active ingredient sodium dimethylglycine (DMG-Na) on dermal blood flow and velocity between 0 and 90 minutes after a single application at two depths, 1 mm and 8 mm. The measurement of blood flow and velocity (arbitrary units) was determined by the frequency of the light shifted by moving erythrocytes (Doppler effect).

[0162] The subjects were asked to sit down. The forearm remained in the same position throughout the experiment. The subjects were not allowed to engage in any physical activity during the experiment. All measurements were taken after an acclimatization period of 15 to 20 minutes at 22°C under the same conditions. The measurements were taken on the inner surface of the forearm.

[0163] First, baseline values ​​were determined on the forearm before application of the active drug and placebo. Subsequently, the active drug or placebo was applied, and capillary blood flow and capillary blood velocity were measured 30 minutes, 60 minutes, and 90 minutes after application. An untreated area served as a control. The test areas on the inner forearm were randomly selected (left or right arm), with the control always being measured on the inner upper arm to exclude the effects of the active drug. Microcirculation data were recorded over 60 seconds (measured every second) for each measurement time point.

[0164] Statistical analysis

[0165] Descriptive summary statistics were calculated for each parameter separately for three groups and for all four time points. These statistics include mean and median, standard deviation, minimum, and maximum. In addition, individual differences from baseline (pre-post difference) were determined to capture development over time and presented as summary statistics.

[0166] To investigate the treatment effect, group comparisons were conducted for placebo vs. actual treatment and untreated control vs. actual treatment. The nonparametric Wilcoxon signed-rank test was applied two-sidedly at a 5% alpha level to analyze pre-post differences from baseline. The analysis was applied to the observed values, i.e., taking individual differences from baseline into account for all calculations. All differences were considered significant at p<0.05. All statistical analyses were performed using SAS (SAS Institute, Gary, NC) version 9.3. Graphs were generated using Prism version 7.05 (GraphPad Software, San Diego, CA).

[0167] 3. Summary

[0168] The current study investigated the effects of DMG on microcirculation and endothelial functions of human skin.

[0169] In the / nv / tro studies conducted, it was surprisingly found that DMG-Na increased the expression of endothelial nitric oxide synthase and induces the production of nitric oxide (NO).

[0170] Furthermore, a single-center, single-group, randomized, placebo-controlled in vivo human study surprisingly demonstrated that topically applied 1% DMG-Na gel statistically significantly increased dermal blood flow and dermal blood flow velocity compared to placebo and / or untreated control.

[0171] These data represent the first demonstration in humans that topical DMG increases the intensity of dermal microcirculation by penetrating deeper skin layers, which can be attributed to its effect on HDMECs, where it induces endothelium-derived, NO-dependent vasodilation.

[0172] In detail

[0173] The experiments investigated whether DMG-Na could induce NO release from the endothelium. Therefore, in the first part of the study, various cellular and molecular techniques were used to measure the effects of DMG-Na in vitro on primary HDMECs. First, we investigated whether DMG-Na affected eNOS expression in HDMECs. As shown by semiquantitative immunocytochemistry, DMG-Na appeared to increase eNOS expression after 24 hours of treatment (Figure 1a). This was quantitatively verified by Western blotting, suggesting that DMG-Na does indeed increase eNOS protein levels in a dose-dependent manner and, in the case of 0.05% DMG-Na, statistically significantly (p=0.0189) compared to the control (Figures 1b and 1c).

[0174] Finally, the effect of DMG-NA on NO synthesis in HDMECs was investigated. Using DAF-FM-DA-based microfluorimetry, it was surprisingly found that 0.02% and 0.05% DMG-NA statistically significantly increased cellular NO production compared to the control (p=0.0002 and p=0.0001, respectively) (Figure 1d).

[0175] These / nv / tro data clearly showed that DMG-Na promotes eNOS activation and NO synthesis, which in turn can induce endothelium-dependent vasodilation and improve skin microcirculation, e.g., when applied topically.

[0176] To test this hypothesis, a monocentric, single-blind, randomized, placebo-controlled (nv / o) human study was designed to investigate the effects of topically applied 1% DMG-Na gel on microcirculation parameters, dermal blood flow (the volume of blood movement over time) and dermal blood flow velocity in the skin (the rate of blood movement over a distance).

[0177] As measured with the Doppler-based O2C system, at 1 mm skin depth, DMG-Na slightly increased blood flow as early as T30 min after topical application, resulting in a statistically significant increase in flow rate at T60 min (p=0.0073) and T90 min (p=0.0027) compared to the untreated control area (Figure 2a and Table 1). At 8 mm skin depth, the effect of DMG-Na was even stronger. A statistically significant increase in blood flow at T90 min (p=0.0083) was observed after treatment compared to the placebo-treated test area, while statistical significance was achieved at all time points (T30 min: p=0.0014, T60 min: p=0.0032, T90 min: p=0.0002) in favor of the DMG-Na-treated test area compared to the untreated control area (Figure 2). In addition to the blood flow rate, topically applied 1% DMG-Na also increased the dermal blood flow velocity at both measured skin depths.At 1 mm, statistical significance was reached at T90 min (p=0.0266) compared to the placebo-tested area, while statistical significance was observed at T60 min (p=0.0215) and T90 min (p=0.0023) compared to the untreated control (Figure 2c and Table 3). Furthermore, at 8 mm skin depth, the rate-enhancing effect of topical DMG-Na application was statistically significant at T30 min (p=0.0362) and T90 min (p=0.0042) compared to placebo, while statistical significance was reached at all time points (T30 min: p=0.0289, T60 min: p=0.0152, T90 min: p=0.0024) compared to the untreated area (Figure 2d and Table 4).

[0178] It is noteworthy that during this / nv / o study, an increase in microcirculation was observed in all subjects (one subject even showed slight, temporary red blotchiness of the skin approximately 60 minutes after application of the active product), which correlates with the increase in microcirculation. However, no adverse effects such as itching, burning, tightness, or any other discomfort were observed.

[0179] In summary, the data provide the first evidence in humans that topical DMG strongly increases the intensity of dermal blood flow by penetrating the deeper skin layers. Furthermore, the in vitro experiments clearly demonstrate that the above-mentioned effects of DMG are most likely due to its action on HDMECs, which in turn induces endothelium-derived, NO-dependent vasodilation.

[0180] The in vivo and / nv / fro results demonstrate that DMG, and in particular DMG-Na, is a novel active ingredient, e.g., in skin aging, atrophy, acute or chronic wounds, and various dermatitis, where the beneficial effects of DMG promote epidermal proliferation, regeneration, and repair, increase dermal blood flow and velocity, and / or exert protective functions. Table 1. Dermal blood flow between 0 and 90 min after administration of verum, placebo, and untreated control at 1 mm skin depth. compared to placebo; #p<0.05 and ##p<0.01 significant difference compared to the untreated control.

[0181] Table 2. Dermal blood flow between 0 and 90 min after administration of verum, placebo, and untreated control at 8 mm skin depth.

[0182] Values ​​are mean ± SD (n = 20). *p<0.05 and **p<0.01 indicate a significant difference compared to placebo; #p<0.05 and ##p<0.01, ###p<0.001 indicate a significant difference compared to the untreated control. Table 3. Dermal blood velocity between 0 and 90 min after administration of the active drug, placebo, and untreated control at a skin depth of 1 mm.

[0183] Values ​​are mean ± SD (n = 20). *p<0.05 and **p<0.01 indicate significant difference compared to placebo; #p<0.05 and ##p<0.01 indicate significant difference compared to the untreated control.

[0184] Table 4. Dermal blood velocity between 0 and 90 min after administration of verum, placebo, and untreated control at 8 mm skin depth. Values ​​are mean ± SD (n = 20). *p<0.05 and **p<0.01 indicate significant difference compared to placebo; #p<0.05 and ##p<0.01 indicate significant difference compared to the untreated control.

Claims

Claims 1. A composition comprising N,N-dimethylglycine (DMG) and / or a salt thereof for use in inducing endothelium-derived NO-dependent vasodilation.

2. Composition for use according to claim 1, for the treatment of an indication selected from the group consisting of skin aging, skin diseases, atrophy, acute and / or chronic wounds and dermatitis.

3. Composition for use according to claim 2, wherein the atrophy is selected from age-related atrophy, disuse atrophy, trophoneurotic / nerve atrophy, vascular atrophy, pressure atrophy, endocrine atrophy and / or skin atrophy.

4. Composition for use according to claim 3, wherein the dermatitis is selected from bathing dermatitis, dermatitis herpetiformis Duhring, exfoliative dermatitis, dermatitis exfoliativa neonatorum, dermatitis factitia, dermatitis ulcerosa, perioral dermatitis, stasis dermatitis, light dermatoses, atopic dermatitis, diaper dermatitis, contact dermatitis, incontinence-associated dermatitis, radiation dermatitis, psoriasis and / or xeroderma.

5. Composition for use according to one of the preceding claims for the treatment of endothelial dysfunction, diseases of the cardiovascular system, such as atherosclerosis, heart failure, peripheral arterial occlusive disease, chronic myocardial insufficiency, acute right heart failure, coronary heart disease or angina pectoris, hypertension, in particular arterial hypertension, pulmonary hypertension and persistent pulmonary hypertension of newborns (PPHN), and diseases of the respiratory tract and / or lungs such as acute respiratory distress syndrome (ARDS), bronchiolitis, in particular acute bronchiolitis, viral diseases of the respiratory tract and / or lungs, in particular COVID-19, cor pulmonale, chronic sinusitis, sickle cell anemia, erectile dysfunction, (benign) enlargement of the prostate and / or glaucoma.

6. Composition for use according to any one of the preceding claims, wherein the composition contains a salt of DMG and in particular is the sodium salt of DMG (DMG-Na).

7. A composition for use according to any one of the preceding claims, wherein the composition is for topical or oral application.

8. A composition for use according to any one of the preceding claims, wherein the composition is a gel, cream, ointment, lotion, solution, suspension or milk.

9. A composition for use according to any one of the preceding claims, wherein the composition is administered by means of a patch.

10. Composition for use according to any one of the preceding claims, wherein the composition has a pH in the range of 3.0 to 7.0, in particular 4.5-5.

0.

11. Composition for use according to any one of the preceding claims, wherein the composition contains 0.00001 to 25.0% by weight, in particular 0.1 to 10.0% by weight, of N,N-dimethylglycine (DMG) and / or a salt thereof.

12. Composition for use according to any one of the preceding claims, wherein the composition contains at least one further active ingredient.

13. The composition for use according to claim 4, wherein the at least one active ingredient is selected from antibiotics, antifungals, antihistamines, glucocorticoids, retinoids, immunosuppressants, menthol, biotin, zinc PCA, caffeine, niacinamide, panthenol, ectoine, ubiquinone-10; taurine, echinacea, tocopheryl acetate, and combinations thereof.

14. Use according to any one of the preceding claims, wherein the composition contains at least one additive selected from refatting agents, preservatives, stabilizers, antioxidants, Rheology modifiers, thickeners, conditioning agents, dyes, solvents and combinations thereof.

15. Cosmetic use of a composition comprising N,N-dimethylglycine (DMG) and / or a salt thereof for use in the induction of endothelium-derived NO-dependent vasodilation.

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