TREATMENT OF BEDSORES AND ATONIC ULCERS THROUGH CELL

TISSUE DEGRADATION

This invention relates to a formulation comprising an extract of five tinctures originating from five herbs in the form of an alcoholic solution or in the form of external cream for there-epithelialization of granulation tissue-related wounds.

The most common method used in the treatment of such cases to date firstly requires the prognosis and subsequently a complex diagnostic and therapeutic process, since bed sores and ulcers comprise the consequence of a number of pathological changes in the body, causing reduced blood flow and tissue oxygenation.

More specifically, a patient’ shealth statusis of particular importance with respect to the treatment (coexisting conditionswith respect to the cardiovascular, respiratory, musculoskeletal systems and nutritional status) since the main causes are exertion of prolonged pressure, while tonic immobility (paralysis), decreased tissue oxygenation (such as hypoxia due to respiratory problems, vasculopathy due to atherosclerosis), and poor hygieneare consideredaggravating factors.

Healing a bedsore or ulcer is often a strenuous, painful, and long process of long duration (from a few weeks to several months) and is designed to provide basic instructions and tips, based on each case’s symptoms.

In particular, the following treatment options apply A) Care: is related to the following procedures

1. resection of theareas of necrosis and debridementof thesurgical margins

2. Use of patches (hydrocolloids, alginates, biological membranes) which differences relate to properties such as absorbency, permeability, preserving and controlling moisture, thereby replacing the classicsterile gauze which promotes healing, but also dehydrate the wound and cause injuries when removed. 3. Washings using various antiseptics such as iodine preparations and hydrogen peroxide, which, however, are cytotoxic and delay healing when frequently used in high concentrations.

B) Nutritional support

For example, albumin uptake that appears to accelerate healing through the absorption into the extracellular fluid compartment, B-group antioxidant supplements, i.e., vitamin E, Se, and b-carotenoids, and finally, the administration of various factors such as:

1. Polyphenols. For example, green tea or (-) epigallocatechin gallate, and grape seedsor procyanidin B 5 -3 '-gallate

2. A mixture of three flavonoidequivalents

3. Genistein, aphytoestrogen found in beans

4. Lycopene, unsaturated carotenoids found in tomatoes, watermelon, grapefruit

5. Curcumin or diferuloylmethane, and finally,

6. Vitamin A and retinoids

These comprise nutrients that have the ornithine decarboxylase (ORP)-related inhibitory effect, an enzyme that is responsible for converting ornithine to putrescine, which in turn is converted to spermidine and spermine.

The sequence of these reactions comprises the biosynthesis pathway of polyamines; thus, ornithine decarboxylase activity is a key step in oncogenesis.

They also affect growth factors, thus the proto-oncogenesindirectly, thus inhibiting the malignant processes.

They inhibit the induction of apoptosis by increasing P53 levels and DNA base oxidation. Indeed, a damage or loss in the p53 gene results in the production of a nonfunctional protein, thereby causing the cells to continue to proliferate, thereby leading to further mutation accumulation, which further promotes their carcinogenesis or degeneration. Finally, in edema-related conditions, they inhibit the levels of cyclooxygenase (adenylate cyclase) and lipoxygenase, glutathione-related content, and arachidonic acid levels.

However, they did not provide valid results in the experimental stage and are not indicated for high-risk patients, except for small doses in the initial stage, since they cause hepatotoxicity due to high cholesterol, triglycerides, and liver enzymes.

C) Administration of analgesics as non-steroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid, aspirin, mefenamic acid, ibuprofen, naproxen, indomethacin, or steroids (glucocorticoids), i.e., cortisol, cortisone, and corticosterone.

In particular, glucocorticoidsmodulate the anti-inflammatory response by acting on microcirculation through vasoconstriction, thereby reducing capillary permeability, thus inhibiting the effects of quinines and bacterial endotoxins, also reducing the amount of histamine released from basophils.

Accordingly, administration of non-steroidal anti-inflammatory drugs inhibits the action of the cyclooxygenaseenzyme, thereby reducing the production of prostaglandins, which appear to act as elements controlling lipolysis, since their reduction leads to an increase in production of AMPc, thereby to increased lipolysis, according to a a feedback control system.

Prostaglandins E2 (PGE2) and PGI2 are vasodilators along with other mediators, such as leukotrienes TTP4 and LTC4, bradykinin, and histamine increase vascular permeability and contribute to granulocyte movement, followed by monocytes, from circulation into the tissues.

Increased vascular permeability can lead to erythema (edema) i.e., inhibition of production of platelets. Prostaglandins aggravate pain caused by bradykinin, histamine, and mechanical irritations. When the stimulus upon the immune system persists, constant cell migrationcauses the release of mediatorsand enzymes, which in turn cause the tissue destructionthat accompanies chronic inflammatory conditions.

D) Taking antibiotics

It is known that colonization of a bedsore or ulcer by germs is common, but does not necessarily comprise an infection, wherestench, purulent drainage, and recurrent fever coexist. Antibiotics are onlyindicated when deemed necessary, due to serious side effects they may cause during treatment.

We are talking aboutantimicrobials, such as:

1. Inducers of the P4503A4aisoenzyme (rifampicin) or cyclic esters (lactones). Which increase the conversion of pyrrolidine alkaloidsinto toxic metabolites (by-products) and have been implicated in toxic liver diseaseand pulmonary toxicity.

In particular, they cause hepatomegalyand metabolic disorders with functional fat loss and liver degeneration, such as sinusoidal obstruction syndrome or veno-occlusive disease.

2. Various chemotherapeutic agents

Acridines, anthracyclines, camptothecin, actinomycin, epipodophyllotoxins) which benefit from the normal function of topoisomerases (enzymes which are very good therapeutic targets) during DNA replication and fragmentation.

More specifically, during DNA origami, complementary DNA chains are synthesized toward two directions, forming two so-called folding “forks”.

For this process to begin, the double-stranded helixmust first be unwound and separated. To do this, the DNA chains form“supercoils” which twist the helical polymers as they rotate toward the direction of the double-stranded helix. “Supercoils” increase tension in the DNA“folds” and thus can participate more in unfolding.

In the absence of this process to relieve the pressure created by the “supercoils”, the entire chromosome would have to rotate. This process is energy-consuming and could involve the entire molecule.

When DNA origamiis complete, the two progenitor cells are wrapped around each other.

Topoisomerases play two roles:

They move excess DNA supercoils during DNA origami and separate the intertwined ancestral DNA strands.

Topoisomerases catalyze these activities by DNA strand breakingand rotating.

There are two types of topoisomerases:

Type (I) that reduces positive supercoiling and type (II) that serves the functions of ligases and nucleases in both DNA strands and moves excess DNA supercoils during DNA origami.

A common feature of the mechanism of action of the two topoisomerases is the use of tyrosine hydroxylase, by uptake of cellnucleophiles, into a phosphate backbone. Thus, apost-esterification “transesterification”, i.e., cleavage of the phosphodiester bond with the sugar in DNA.

The DNA-topoisomerase complex is stabilized by covalent bonds, forming a ternarycomplex:

The “DNA-enzyme-inhibitor drug”, which prevents the completion of the DNA replication, causing cell death (apoptosis), but we are talking aboutirreversible covalent bonds that lead to multiple DNA-related ruptures, hence the name “topoisomerase poisons”, as they convert the enzyme into a strong cell-related toxin.

The preparationrelated to this invention has an advantage over the foregoing ones due to its functional action as a suppressor of topoisomerase and not as a poison.

It targets the enzyme-linked receptor without directly interfering with the covalent complex, thereby excluding DNA bonds. This invention relates to an alcoholic solution containing an extract of tinctures originating from the following five herbs:

Per 100ml it contains alkanna tinctoria 30% w/w, capsela bursa pastoris 27% w/w, stachys sylvatica 15% w/w, solidago virgaurea 15% w/w, and chamomilla matricaria 13% w/w, in the form of an oral alcoholic solution, aiming at cytotoxic action, with a proposed dose: 3ml pre-food, three times daily or in the form of cream, for external use, based on arnica, in proportion: 75ml alcoholic solution per lOOgr of Arnica cream, which is intended to immunize on granular human cells and lymphocytes of arnica cream, which aims at immunoenhancement in human granulocytes and lymphocytes.

This formulation has been used in in vitro and in vivo studies, in experimental models in higher-ordermammals (rabbit), but also in Wister rats. It has also been receivedby a significant number of people who have voluntarily used the extract with bedsores and atonic ulcers of different etiology and at a different stage, through to conditions which were defined as irreversible, while healing of surface soft tissue traumahas been observed. More specifically, in the bark of the alkanna tinctoria plant root, significant amounts of a mixture of two enantiomeric naphthoquinoneswith strong healing and antimicrobial activities, which bear many similarities with the chemistry of naphthazarins, i.e., their parent compound. The chemical structure of the naphthazarinsystem, as noted below, exists in two main forms of tautomerization: Normal tautomer (NT), comprising the predominant form and double tautomer (DT), which is the least stable, and two intermediate forms of tautomerization (Ml, M2), created by proton transport.

The most stable tautomersare (NT) and (M2).

Consequently, the major quinone nucleus tautomerization form has been replaced by a group of electron donors, as described in forms 1 and 2.

The hydroxyl (-OH) group present in the chain of compounds 1 and 2 provides them with important properties, leading to the result that both alkannin and shikonin, as well as their derivatives, are more reactive than naphthazarin. According to the structure of naphthazarin, as described in the reaction below, in acidic conditions, a ring is formed on the side of the chain, where the hydroxyl group pre-exists at a rapid rate. Therefore, the following quinones: alkannin,shikonin, and hexanyl derivatives are not stable compounds, i.e., they are subject to racemization under strongly acidic conditions, resulting in cell tissuedegradation.

Plant pigments are responsible for their healing effect on wounds and ulcers; their bioactive components are the following alkannin esters:

1. B,P-dimethyl-acryl-(8)

2. Aggelylo -(10)-

3. Isovaleryl-alkannin-6-, and

4. B-Acetoxy-isovaleryl-alkannin-(12)-

We are talking about ester-related form fat-soluble pyrrolizidine alkaloids that lead a thin cell layer to a highly cellular one, with increased proliferation of the granulation tissue with many new blood vessels, thus leading to re-epithelialization of the wounds.

Alkannin, shikonin, and related derivatives also have antimicrobial and antibacterial activities, i.e., they are active for Gram (+), for example, Bacillus subtilis Escherichia coli, staphylococcus aureus,

Inactive for Gram (-) due to the naphthoquinone dyes and naphthazarin ring.

Alkylation of phenols of the constituents of the roots of the alkanna tinctoria plant leads to loss of antimicrobial activity, polymerization leads to reduced antimicrobial activity, provided that alkannin, shikonin, and their esters are active substances, the aliphatic compoundof the carbon chain can act as a transport systemon naphthazarins, further separation of ester derivatives may lead to more active products.

Finally, alkannin, shikonin, and its derivatives have antioxidant and anticoagulant activities.

These are powerful antioxidants against various active oxygen species (CReactive oxygen species), such as: elemental oxygen (10 ₂ ), superoxide anion(0 ² ), hydroxyl radical (-OH), and butyl peroxideradical (BuCO ), i.e., they act on various substrates and convert to hemiquinone radicals.

At the same time, shikonin has anti-inflammatory and analgesic effects on edemas and injuries, since it inhibits the biosynthesis of leucotriene B and 5-hydroxy-eicosa- tetranoic, therefore, it plays a major role in the mechanism ofanti-inflammatory actions, thus with respect to the treatment of wounds and healing of damaged cell tissue, as well as anti-cancer effect, as a strong enzyme inhibitor.

More specifically, shikonin and its derivatives can strongly interact with DNA- topoisomerases, enzymes that have been identified as targeted therapies, as they are involved in many important processessuch as replication, transcription, and recombinant DNAand control the topological properties of DNA by total cleavage and reunification of its strands.

Shikoninis a potent inhibitor of protein-protein interactions, with multiple targets in the intracellular and extracellular segments.

It acts against drug-resistant cell lines. As a result, drug-resistant cell linescarry p- glycoproteins, which are responsible for most antineoplastic and chemotherapeutic drug-resistant types of cancer.

It reduces the rate of azomethane decomposition, (which is) responsible for digestive system tumors.

Finally, a correlation of functional activity with reference to the biological activity of malonic aldehyde, (which is) an indicator of oxidativestress, has been observed.

Namely, during oxidative stress, methyl aldehyde (MDA) and other aldehydes formed in various biological systems have the property of reacting with various amino acids as well as DNA, and thus leading tochanges in the replication and transcription of genetic material, resulting in tumor formation. Increased MDA values liver cancer skin cancer

In fact, it has been observed that, in skin cancer with elevated levels of peroxides and lipids which decreased after administration of flavonoids and epipodophyllotoxin, administration of low-doses shikonin showed a decrease in MDA by more than twice the dose.

Therefore, the reduction of malonic aldehyde after administration of shikoninis indicative of reduced oxidation, i.e., reduced lipid peroxidation; therefore, shikonin has a dose-dependent chemoprotective action by reducing oxidizing propertiesand through anti-inflammatory properties.

This protective effect can be attributed to an increase in glutathione (GSH) and antioxidant enzymes, which are catalase (CAT) and superoxide dismutase (SOD).

In addition to the above with respect to the biological activity of the alkanna tinctoria plant, regarding the preservation and stability of the genomic composition, some other interventions regarding the regulation in modifications of genetic and biochemical processes, which are as follows, should be noted:

Changes in cell size and shape, as well as factors that control the gene for expression, replication, and repair, protein synthesis and regulatory signal exchange, called signaling transduction, a process that ensures communication between cellstheir response toward the extracellular environment, through transmembrane receptors.

Defects in one or more steps of the signaling process alter cell growth control, hence the elements of the signaling steps that are modified are the target of treatment.

Indeed, the second combinatorial herb of the therapeutic regimen, to which this invention is directed, refers to the Capsela Bursa Pastoris plant. It is a weed, an angiosperm of the Brassicaceae family, which chemical composition is as follows:

A: flavonoids and phenols: (quercetin-6-s-glucoside, kaempferol

B: Amino acids: glutamic acid, asparagine, serine, glycine, ompine, histidine, tryptophan, threonine, alanine, valine, arginine)

C: Organic and fatty acids: oxalic acid, palmitic acid, oleic acid, and stearic acid)

C: Sterols (campesterol. beta-sitosterol, stigmasterol) high concentrations of flavonoid phenols and amino acids, as well as organic and fatty acids of the extract from the Capsela Bursa Pastorisplant tincture gives it a strong competitive effect of growth factor and signal transduction-relatedreceptors, by inhibiting specific enzymes, since the four main types of receptors are shown below:

I) receptor tyrosine kinases

II) tyrosine kinase-associated receptors

III) serine/threonine kinase receptors

IV) receptors that bind to trimeric G-proteins.

In particular, the abovementioned components act as differentiating factors with respect to the function of the endocrine system, inhibiting the tyrosinase-kinase (TK), an enzyme that contains copper and catalyzes theoxidation of L-tyrosineto dopamine (neurotransmitter) and subsequently its polymerization to melanin, responsible for skin pigmentation disorders as a result of genetic and environmental factors. Accumulation of high levels of skin pigmentation can lead to (malignant) melanoma. In essence, we are talking about an inhibition of the hydroxylation of L-tyrosine toward levodopa (L-3,4-dihydroxyphenylalanine). More specifically, they act as competitive phosphorylation-relatedinhibitors due to intracellular tyrosine kinase (TK)-related ATP, which is located at the epidermal growth factor receptor (EGFR)-TK.

EGFR is a single transcription receptor, which is dimerized when it binds to the substrate, resulting in the activation of tyrosine kinase.

The activated receptor of tyrosine kinase is aphosphorylated dimer.

The system activationeffect is autophosphorylation of tyrosine kinase by ATP, which in turn leads to signal transductionby growth factors.

We are talking about a biochemical pathway from the cell surface toward the nucleus, which requires energy.

Transduction of these signals leads to increased angiogenesis, proliferation, and cancer cell migration, as well as decreased apoptosis (programmed cell death).

Inhibition of phosphorylation leads to the cessation of these effects, resulting in cancer cells to undergo apoptosis.

However, the tincture extract of the capsela bursa pastoris plant also shows a strong antioxidant activity due to flavonoids and phenols, which are effective against 02, preventing the formation of harmful radicals such as superoxide nitrates, as well as due tounsaturated fatty acids which are involved in inhibiting lipid peroxidation and promoting antioxidant enzymes such as peroxidase dismutase and catalase, thus reducing the risk of coronary heart disease and biliary cholesterol, i.e., decreased sensitivity of LDL, to oxidation.

Additionally, a strong antibacterial effect due to the ability of phenols to increase cell membranepermeability is observed, making them active against Gram+ bacteria - such as: 1. Micrococcus luteus

2. Pseudomonas

3. Salmonella

4. Bacillus cereus

5. Proteus mirabilis, and finally

6. Escherichia coli

While glycine and histidine demonstrated High Antibacterial Activityagainst Gram- bacteria.

Finally phytosterols such as campesterol, b-sitosterol, and stigmasterol, isolated from the plant extract, are potent acetylcholinesterase (AchE) inhibitors, thus leading to high levels of acetylcholine (Ach) (neuro transmitter).

We are talking about compounds that belong to the family of triterpenes in a free or esterifiedform.

Their chemical structure and composition are equivalentto those ofcholesterol, hence they compete with it in the intestine, reducing its rate of absorption in a dose- dependent manner.

They are subsequently transported to the liver via plasma chylomicrons such as cholesterol, and reduce its hepatic uptakethrough this mechanism, thereby forcing the liver cell to increase its LDLuptake through its receptors.

In particular, the percentage of phytosterols absorbed by the liver cells is oxidized by the enzyme catalyst found in the mitochondria: P450cc, producing acidic liquids which are secreted in the duodenum through the bile, to facilitate the process of digestion and lipid absorption, as well as fat-soluble vitamins.

Namely, they are concentrated throughsulfur-containing aminesor polysaccharides to form sodium (Na+) or (K+) potassium sulfides which are finally excreted through the urinary tract, thus allowing lipolysis, while exerting their antimicrobial propertiesas antagonists of the Gram- bacterial flora. The remainder of the unabsorbed phytosterols returns through the carriers which are cell membranetransporters, back to the intestinal lumen, where it is excreted, passes into the colon through it, and finally ends in the rectum, where it is excreted through the feces.

In addition, phytosterols do not connect tothe microtubules and finally activate the dynamicM3 receptor ion channel of in the hepatocytes and pancreatic islets, thereby causing the entry of calcium ions (Ca++) and insulin release.

The final conclusion is that the decreased absorption of intestinal or liver cholesterol (of animal origin) indicates decreased endogenous catecholamine release, consequently decreased concentration of neurosteroids, which, through the formation of carbon bonds, form compounds that can be excreted through the urinary tract.

Therefore, in terms of their pharmacodynamics, phytosterols act as hormone-blocking inhibitors, without affecting the hypothalamic-pituitary-adrenal axis.

However, a normal excretory system such as the kidneys, is deficient or blocked when another vital organ system is deficient, or when a treatment option intended for that person, according to the patient’s history, fails to provide the desired results, conversely leading to aggravation and development of a new problem, due to metabolic food disorders.

It is therefore necessary to stimulate these organs of the excretory functional system (in particular, the kidneys) using medication without any organic tropisms or normal interactions.

This technique mirrors the dynamism of the pharmaceutical method, which consists in stimulating the secretory function-related organs.

This, in a sense, leads to the opening of channels that will cause the release of toxins to be excreted from the body. Therefore, the therapeutic regimen aimed at administering this specificsolution related to this invention comprises the combined action of two more herbs:

Stachys sylvatica and solidago virgaurea, similar in chemical composition and complementarity as antioxidants, antimicrobials, anti-inflammatory drugs, andanalgesics, mainly as styptic agents, in particular as non-osmotic electrolyte- related diuretics.

Stachys sylvatica is an angiosperm, dicotyledon of the Lamiaceae family, in which essential oils were the following compounds identified:

A: manoyloxide

B: caryophyllene oxide and Cel- caryoplhyllene (bicyclic sesquiterpene)

C: epi-alpha- muurolol

D: horminone (taxoquinone or a-hydroxyquinone) and finally,

E: glycosidic flavonoids such as apigenin and hydroxy-antigenin (isoscutellarein)

Solidago viagea or Verga d’orobelongs to the Asteraceaeplant family and the chemical composition of the extract reproduced from their tinctureof the plant flowers is the following, containing:

A: triterpenoid saponins

B: Phenolic glycosidesand phenolic acids such as acid virgureside, acidoleiocarposide, and chlorogenic acid.

C: Acetylene

D: catechin-related tannins E: anthocyanins F: flavonoids G: hydroxybenzoates H: inulin

I: bis-desmosic acid-related esters J: soluble polysaccharides K: diterpenes and,

L: essential oil. As stated above. Based on the chemical compositions of stachys sylvatica and solidago virgaurea, we are talking two herbs of similar and complementary action.

High diterpene, triterpene, and sesquiterpene quinine concentrations provide them with strong antimicrobial and chemoprotective effects.

More specifically, they increase serum of alanineaminotransferase (ALT), aspartate aminotransferase, and cytochrome bscytochrome (cieBs), while they reduce cytochrome P450 concentration, and finally inhibitbacterial protein synthesis.

Indeed, in an in vitro tube, inhibition of protozoan growth was observed: trypanosomes and total suppression of the absorption and integration of thymidine, uridine, and L-leucine in this particular parasitic macromolecule, due to the interaction of Horminone with its DNA, holding HM-Mg +2(horminone resonance (PM) with hydrated magnesium ions) responsible for this complex.

In particular, the eight-sided Horminone complex can transfer two units of water molecules from a hexahydric complex, thus creating a very high energy metal- substrate bonding (ligando). Therefore, it becomes able to penetrate the bacterial cell membrane, within which it binds to rRNA phosphate groups, thus suppressing theearly stages of protein synthesis.

Another category of active ingredients which are responsible for the characteristic properties of the two herbs, are the glycosidic flavonoids, namely apigenin and its derivatives, where in position 7 of its chain, joins, through a glycosidic bond, with a b-D glucopyranosidic group:

[Apigenin-7 -0- (6”-E-p- coumaroyl)- a- D- glucopiranoside]

[isoscutellarein-7-0 (6”’-o- acetil-a-D allopiranosile- (l->2)-a-D-glucopiranoside]

They are non-steroidal anti-inflammatory drug with analgesic, antipyretic and platelet-related properties.

They neutralize or slow down bacterial growth, i.e., they inhibit the synthesis of prostaglandins, acting as inhibitors of cyclooxygenase, an enzyme that catalyzes the conversion of arachidonic acid into cyclic endoperoxides, which areprostaglandin precursors.

They also enhance liver function by lowering cholesterol and triglyceride levels, lowering albumin and protein levels, while, at the same time, increasing serum aspartateaminotransferase (AST), and alanine-aminotransferase (ALT) levels.

They are effective natural nutritional antioxidants, as they protect the cellular environment from lipid peroxidation.

For example, apigenin repairs possible damages or possible cumulative mutations in the lymphocytes of the hematopoietic system when they are subject to the oxidative activity of the photoproducts produced after exposure of the body to gamma radiation

(r)·

In addition, they improve kidney function by lowering urea and creatinine levels and increasing glutathione peroxidase and superoxide dismutaselevels. Therefore, stachys sylvatica and solidago virgaurea are diuretic herbs with similar actions. They increase urine production without causing an increase in electrolyte production. Namely, they dilate looped capillariesby increasing their filtration rate and, consequently, increasing the excretion of sodium ions (Na+) (natriuresis) and water through the kidneys.

They therefore cause a reduction in the volume of extracellular fluid, which is responsible for the presence of peripheral edema or hypertension, thus ensuring balance and homeostasis.

Increased serum production (increased diuresis) also helps to increase the elimination of metabolic wasteproducts, mainly nitrogen-related ones, from the breakdown of protein substances such as urea, uric acid, orcreatinine, as well as foreign substances such as drugs or their metabolites, which enter the body voluntarily or without the consent of the patient.

Pharmacokinetic activity of the two herbs is related to diuretics or electrolytes of reduced potassiuresis, i.e.,we are talking about anti-aldosterones (hydrophilic steroid hormones and sulfate derivatives) which are negative allosteric regulators of g- aminobutyric acid (GABA inhibitors).

Therefore, there is no risk of potassium deficiency (K+) in cases of heart failure or renal insufficiency, since they contain saccharides, which, during their filtration by the coils, do not exist, due toosmosis, remarkable re-absorption by cell lumens. Finally, the presence of phenolic glycosides, of which approximately 65% is eliminated through the urine, regardless of the form of the drug in which they are contained, contributes to the excellent diuresis-related effect of both herbs. More specifically, phenolic glycoside consists of:

A: organic matter (saccharide) and,

B: an inorganic, non-saccharide, called aglycone, joined together by hydrophilic or water-soluble bonds.

Phenolic glycoside is hydrolyzed in the intestinal lumen resulting in the production of a diphenol compound (polyphenols). Which undergoes direct oxidation to hydroquinone via the cytochrome P450.

Subsequently, hydroquinone, through bloodplasma, is converted, by liver cells, into a conjugated compound of sulfideglucuronide (glucosinolates) in the form of a digestive oil, which, through enzymatic hydrolysis in urine (pH >8), releases hydroquinone again.

Free hydroquinone exerts strong antiseptic and antimicrobial activities.

Biosynthesis of free hydroquinone is described according to the following reaction: Therefore, herbs containing sulfide glucuronideslower plasma cholesterol levels and accelerates the elimination of toxins.

Hydrolysis-related products of conjugates of the herbs exert great antiseptic and antimicrobial activities against bacteria such as: staphylococcus aureus and epidermidis, enterococcus faecalis, and bacillus subtilis.

Pharmacodynamically, stachys sylvatica and solidago virgaureacan provide the maximum therapeutic effect when urine-related environmental conditions have an acidic pH, so it is necessary to administer it with simultaneous water intake, to keep the urine-related alkaline environment values stable.

However, to complete the therapeutic regimen which the formulation of this invention refers to, one more herb is required, which, in addition to its antimicrobial, antiinflammatory, and diuretic action, has shown very good results after investigating animals, in terms of its antihypertensive, anxiolytic, anti-inflammatory, and alleviatingeffects.

It is also used in phytotherapy as an analgesicfor stomachache, irritable bowel syndrome and as a mild hypnotic drug.

We are talking about chamomilla matricaria or recutita, an angiosperm of the Asteraceaefamily.

Possible side effects that this herb may cause are uterine contractions, which is why it is not recommended for it to beadministered during pregnancy.

It can also cause allergy symptoms such as skin rashes oranaphylaxisand finally, due to its coumarin content; care must be taken in its use to avoid intense pharmacological interactions such as, for example, being administeredalong with anticoagulants, simultaneously.

For these reasons, the quantitative proportion of the herbal extract in the total formulation is lower than the rest.

In particular, the main active substances identified in the extract of the chamomilla matricaria plant are terpene, a-bisabolol in the form of an essential oil, as well as chamazulene, coumarin, and flavonoids such as apigenin, quercetin, and luteolin.

The chemical components of the herb are classified into the following two categories, based on their lipophilicity: I) thelipophilic fraction which contains:

A: specific components of the essential oil B: cymarins

C: methoxyisoflavone aglycones

D: phytosterols

E: lipid and waxy substances

And II) the hydrophilic fraction which contains:

A: flavonoids

B: mucus-related substances (glycoproteins)

C: phenylcarboxylic acids D: amino acids E: choline

Sedative and anxiolytic effects of the herb may be due to the presence of the following triterpenes: apigenin and its glycosidic flavonoid derivatives (~8% by weight) chamazulene (-15% by weight), a-bisabolol and the corresponding sesquiterpenes (150% by weight).

Apigenin is a flavonoid with a similar chemical structure to benzodiazepines contained in the flower of the chamomilla matricaria plant; it is not recommended for patients using a medication, to administer the herb together with anticoagulants or antipyretic drugs, such as aspirin or ibuprofen, to avoid side effects.

Anxiolytic effect of the plant is due to the fact that apigenin binds to benzodiazepine receptors throughligands, thus activating g-aminobutyric acid (GABA) receptors, thereby increasing serotonin concentration, therefore displaying a mild anxiolyticand hypnotic effect, yet not an antiepileptic effect.

Apigenin acts as an inhibitor of cytochrome P430 and monoamine oxidase (MAO), facilitating the absorption of tyrosine, thus increasing the content of monoamines.

The active ingredients of the herb which provide it with antibacterial properties against staphylococcus aureus, bacillus subtilis, and streptococci mutans and salivarius, as well as fungicidal action against Candida albicans, trychophyton rubrum, and mentagin apigenin, area-bisabolol, luteolin, quercetin, and apigenin.

They increase bacterial cell membranepermeability through the depolarization of the mitochondria by the opening of ion channels, thus allowing the additional penetration of exogenous solvents, such as antibiotics, into the intracellular environment.

Anti-inflammatory activity of the essential oil from the extract of the Chamoilla matricaria plant is due to the inhibition of cyclooxygenase and lipoxygenase, therefore in the inhibition of the production of prostaglandins and leukotrienes B4.

Analgesic effect of the herb is due to the presence of organic acids: salicylic, oleic, and stearic, as well as lactones that provide the herb with anti-inflammatory and antierythema properties, similar to those of cortisone.

High concentration of polyphenols and their derivatives, such as coumarins and flavonoids do not allow the occurrence of indomethacin-, ethanol-, or oxidative stress- induced peptic ulcer.

The azulene effect (chamazulene) on the pituitary and endocrine glands causes an increase in the release of cortisone and, conversely, a decrease in the release of histamine.

They have a hypoglycemic effect in patients with diabetes mellitus because they lower blood sugar levels by inhibiting the conversion of glucose into sorbitol.

In addition, high concentration of a-bisabolol contributes to the epithelialization of the granulation tissue and its restoration.

It is a sympathomimetic type a2 drug that provides the herb with antihypertensive and vasoconstrictive activities, thus enhancing its diuretic and styptic functions.

Finally, it should be noted that high serum concentration of hippuric acidlevels (products of phenol metabolism) and glycine (amino acid) content in urine, which were identified after patients were administered the Chamomilla matricaria plant extract, showed a decrease in the incidence of inflammatory diseases such as influenza or inflammatory bowel disease, due to the action of hippurine, as well as the antispasmodic effect, thanks to the presence of glycine, for example in menstrual cramps orintestinal spasms.

It is important to note that elevated hippurine and glycine levels remained the same for the following two weeks.