WO2021113938A1

WO2021113938A1 - Vitamin and mineral food supplement

Info

Publication number: WO2021113938A1
Application number: PCT/BR2020/050527
Authority: WO
Inventors: Paul Huber
Original assignee: Cellavit Representação De Produtos Naturais Ltda
Priority date: 2019-12-09
Filing date: 2020-12-09
Publication date: 2021-06-17
Also published as: BR102019025965A2; WO2021113938A9

Abstract

The food supplement is intended to reduce the side effects and toxicity related to chemotherapy in patients with breast cancer, prostate cancer, colon cancer and lung cancer and includes the following active substances: tryptophan [(R)-2-amino-3-indole-propionic acid], thymine [2,4-dihydroxy-5-methylpyrimidine, 5-methyluracil] and pyridoxine, and also a pharmaceutically acceptable excipient, such as cornstarch.

Description

"VITAMIN-MINERAL FOOD SUPPLEMENT"

Field of Invention

[001] The present invention refers to a food supplement, vitamin-mineral, whose composition aims to reduce the side effects and toxicity of chemotherapy treatments in patients with breast cancer, prostate cancer, colon cancer and cancer of the lung. Invention History

[002] It is known from the prior art a composition used in the treatment of malignant neoplasms and immunosuppressive deficiencies through the restoration of biochemical balance in cell intimacy, especially for cells in disordered reproduction, acting as a cell restorer. This composition, comprising an essential amino acid from benzoic genesis and a genetic derivative of pyrimidine nitrogen base, and its process for obtaining it, is described in patents PI9702557-7, EP 0956015 B1 and US 6,143,753.

[003] Experiments have shown, clinically, the efficiency of said composition on neoplastic cells, preventing their disordered reproduction and allowing the correction of various forms of DNA damage.

[004] This well-known composition has its pharmaceutical formula, biologically acceptable, with the following composition: DL-kinurenin, [2-amino-3-(2-aminobenzol)propionic acid] and thymine, [2,1 dihydroxy-5-methyl -pyrimidine;5-methyluracil].

[005] Despite the proven beneficial effects obtained with the use of said pharmaceutical composition, in the treatment of malignant neoplasms, the need to provide, to patients with breast cancer, prostate cancer, colon cancer and lung cancer and undergoing chemotherapy treatments, a food supplement capable of improving the quality of life and reducing risks occurrence of side effects and toxicity in patients with the above mentioned types of cancer and undergoing the usual and aggressive chemotherapy treatments.

Invention Summary

[006] In view of the above, it is an objective of the present invention to provide a vitamin-mineral food supplement that has qualities similar to those of the pharmaceutical composition containing DL-kinurenin (or even tryptophan) and thymine, but having its composition changed to operate as a food supplement capable of reducing the risk of side effects and toxicity in patients with breast, prostate, colon and lung cancer and undergoing chemotherapy, aiming to improve the quality of life of these patients.

[007] The food composition object of the present invention comprises, in addition to thymine and tryptophan, pyridoxine and an excipient such as, for example, corn starch.

Description of the invention

[008] The invention will be described below, from preliminary comments, related to factors, present in the daily life of modern life, harmful to the human body, particularly when associated with factors related to chemotherapy treatments in individuals with the types of cancers listed above. The purpose of the food supplement is to alleviate or even eliminate the side effects of harmful factors to those individuals.

[009] The quality of food has been compromised by the lack of nutrients (minerals) in the soil, leading to poorly nutritious foods that are further harmed by factors that include: a premature harvest of agricultural products, their storage for prolonged periods, the use of food additives and how they are prepared.

[010] In addition to the above factors, exposure to environmental pollutants, herbicides, pesticides, industrial chemicals, chemical products and waste from homes and offices, formaldehydes, hydrocarbon-based synthetic products, recirculation system, micro radiation should also be considered. - waves and other electromagnetic systems, including noise. All of these environmental stresses place severe demands on the human body's antioxidant reserves. The need for nutrients increases considerably due to exposure to the negative factors mentioned above, which can lead to certain diseases or deficiencies such as scurvy, beriberi, pellagra.

[011] A medical fact related to nutrition is that 50% of individuals over 50 years show a reduction in their stomach hydrochloric acid levels, which not only causes poor protein digestion, but also decreases the absorption of many essential minerals such as iron , calcium and manganese. With each decade of an individual's aging, the percentage of hydrochloric acid deficiency increases, increasing the malabsorption of nutrients.

tryptophan

[012] Tryptophan is an essential amino acid, obtained through dietary protein. However, it is not abundant in the diet, and consumption of 60 g of predominantly complete protein can be said to provide only 0.5 g of tryptophan. The plasma level varies according to food intake and time of day.

[013] This amino acid is a potent stimulator of smooth muscle contraction, a precursor of serotonin, a precursor of melatonin and is also a regulator of circadian rhythm.

[014] When absorbed, it can follow two routes: be transported to the central nervous system (CNS), where it will generate the neurotransmitter 5-hydroxytryptamine (serotonin) from tryptophan 5-hydroxylase, or remain in the periphery, where the formation of kynurenine derivatives and nicotinamide and adenine dinucleotides.

[015] In the first pathway, tryptophan is actively taken up by neurons, converted by tryptophan hydroxylase into 5-hydroxytryptophan and then decarboxylated by an enzyme nonspecific amino acid decarboxylase into 5-HT (serotonin). However, due to its poorly fat-soluble characteristics, tryptophan, at the beginning of this route, finds it difficult to cross the blood-brain barrier, thus requiring the aid of transporting proteins. These have low selectivity for the amino acids to be transported across the barrier, making them preferentially selected those amino acids whose concentrations serum levels are higher. This explains the paradoxical effect of diet on CSF tryptophan levels; on a high-protein diet, the transporter will be saturated by other amino acids that will have immediate access to the CNS, while tryptophan, which is one of the least abundant in the diet, will be used in peripheral metabolism.

[016] The second pathway has two routes of metabolization: the irreversible, which is initiated by tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO), and the reversible, through indoleamine 2,3-dioxygenase (IDO). ODD is located in liver cells and is responsible for opening the indole ring, incorporating molecular oxygen and forming N-formylkynurenine. Tryptophan-pyrrolase is an iron-porphyrin metalloprotein inducible in the liver by adrenal corticosteroids and tryptophan, and is inhibited by feedback by nicotinic acid derivatives, including NADPH. Hydrolytic removal of the formyl group of kynurenine-formylase produces kynurenine.

[017] IDO is expressed in a variety of cells, including macrophages derived from monocytes and dendritic cells, and is preferentially induced by Thl-type interferon-gamma cytokines. The decrease in tryptophan via IDO is part of the interferon-gamma-mediated antiproliferative and cytostatic activity in cells. This route is called reversible because these tryptophan deposits can be mobilized and later used by the.

[018] Low serum/plasma tryptophan concentration is observed in infections, autoimmune and malignant diseases and in disorders involving activation of cellular immunity (type 1) as well as during pregnancy, due to the accelerated conversion of tryptophan. Thus, in states of persistent immune activation, a low concentration of tryptophan may contribute to immunodeficiency.

[019] In activated immunocompetent cells, IDO-induced tryptophan degradation appears to be part of the defense mechanism to prevent growth of, for example, intracellular pathogens or malignant cells, through the removal of this essential amino acid from the microenvironment. Degradation of tryptophan by macrophages/monocytes can also reduce the T cell response. In patients with HIV and in adults with T cell leukemia/lymphon, low concentrations of tryptophan may be predictive of accelerating disease progression and precipitous death, as well as tryptophan degradation and low tryptophan levels in HIV patients are associated with impaired cognitive performance. [020] The decrease in serum tryptophan can also affect the biosynthesis of serotonin and thus contribute to the impairment of quality of life and depressive mood. Tryptophan has been tested as an antidepressant as a result of hypotheses linking reduced serotonin levels to the etiology of depression. However, other clinical studies carried out raise the hypothesis that tryptophan is more effective in patients with mild to moderate depression.

[021] In studies with schizophrenic patients, tryptophan given to aggressive patients reduced the number of episodes of aggression.

[022] Studies demonstrating the effect of tryptophan on sleep reveal that it is more effective in mild and moderate insomnia, and less effective in severe or chronic insomnia. A lack of tryptophan can also manifest itself as increased sensitivity to pain and a tendency to be frightened.

timina

[023] Thymine is a nitrogenous base that belongs to the class of pyrimidines (along with adenine) . Nitrogen bases are one of the components of the formation of nucleotides which, in turn, are the constituents of the nucleic acids DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Thymine is predominantly present in the DNA. [024] The free pyrimidine nitrogen bases are constantly being formed inside cells, but are not recovered in sufficient amounts in mammals. Human cells have the ability to save purines and pyrimidines for the synthesis of deoxyribonucleotides that are used for DNA synthesis.

[025] Nucleotides also have a variety of functions in cell metabolism; they are the energy currency in metabolic transactions, the essential chemical intermediary in the cell's response to hormones and other extracellular stimuli, and the structural components of a set of enzymatic cofactors and metabolic intermediates.

[026] Thymine is a planar, aromatic molecule and has a heterocyclic ring. This molecule exists in two alternative tautomeric states, which are in balance with each other. The balance is quite shifted to the side of the conventional structure, which represents the predominant and important state for base pairing. The nitrogen atom attached to the thymine ring is in the amino form in the predominant state. Thus, the oxygen atom attached to thymine is usually in the keto form and rarely takes on the enol configuration.

Thymine Thymine

(keto or lactam form) (enol or lactim form)

[027] The above formulas define two possible tautomeric forms of thymine residues. The other nitrogenous bases can also present this proton shift.

[028] Although abundant in the diet, the intake of purine and pyrimidine bases is usually not necessary due to the fact that the body produces these nitrogenous bases, therefore not considered essential. Animal studies show that ingestion of nitrogenous bases has health, function, and survival benefits with the supplementation of nucleic acid elements generally with the ingestion of nitrogenous bases. From the perspective of longevity studies it is one of the biggest benefits.

[029] In studies on the use of pyrimidines and purines, rats were fed dietary components of the nucleic acid, [14C] uracil, [RNA14C] cytosine-labelled, [DNA 14C] thymine-labelled, or [RNA14C] adenine-labelled. The absorption and catabolism of each radioactive material ingested was rapid; 80% or more of the ingested radioactivity was excreted as products of catabolism within an 8-hour period. The use of ingested radioactive materials for the synthesis of nucleic acids was limited to 2-5%, 4h after feeding. Such radioactivity was mainly located in the gastrointestinal and liver tissue. This demonstrates that the gastrointestinal tissue and the liver utilize and degrade most of the exogenous bases before their entry into the systemic circulation.

[030] It was observed that the activity of the antitumor agent 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on Sarcoma was improved by oral co-administration of thymine, uracil and thymine. Thymine and uracil caused a decrease in body weight. Furthermore, in vitro drug degradation was inhibited more by thymine than by uracil.

[031] Cancer is a complex disease that has marked features such as proliferation and resistance to cell death (including apoptosis), which are often caused by changes in the genome. An increased rate of cell proliferation is frequent, but not exclusively found in cancer cells. Most cancer cells divide more than normal cells. The objective of directing cell proliferation is to stop the cell cycle and/or cause the death of cancer cells using cytotoxic compounds (chemotherapy) or ionizing radiation (radiotherapy). DNA is one of the main targets of these therapies because its replication is essential for the cell cycle phase.

[032] Most cytotoxic agents, often used in cancer treatment, cause high levels of DNA damage, which initiates cell cycle "checkpoints", leading to cell cycle arrest and/or cell death.

[033] When cells undergo checkpoint adaptation, they go into mitosis with damaged DNA. Most cells undergo cell death, but some can survive related to changes in their genome.

[034] Knowing the important role of thymine as a constituent of DNA and that therapy with antitumor agents (anticancers) leads to damage both in cancer cells and normal cells, it can be assumed that thymine supplementation could help in the repair of damage to the DNA from normal cells caused by the drugs used in cancer therapy and, furthermore, reduce the adverse effects caused by these drugs.

Thymine and Tryptophan Association

[035] The association of thymine with tryptophan is known as food supplement "TK3". Studies carried out in the past showed that thymine was the best nitrogenous base in association with tryptophan, having also compared and determined doses of the two substances.

[036] In laboratory experiments with rats having malignant tumors, the formulation prepared from TK3 and the disappearance of the tumor mass in the animals was observed. The biochemical reactions found showed that the enzyme tryptophan 2,3 dioxygenase, opens the five-carbon ring of tryptophan, during its catabolism, initiating the Quinurenine-Anthranilate pathway.

[037] It was observed that tryptophan, when transforming into oxyformylkynurenine, removes the N2 and 02 existing in cellular toxicosis, during catacholase, through a dual action biochemical reaction - deoxidase and detoxose - which disarm the catacolase, leaving the aromatic ring of Uracil, where, in the presence of the enzymes thymidylate synthase and dihydrofolatorreductase, the only cellular pathway for thymine synthesis in nucleotide biosynthesis, receives the methyl group (CH3), by hydroxymethyl oxidation. Then, 5-methyluracil is formed, which reestablishes the bond with the deoxyribonucleic, through the hydrogen bonds of the nitrogenous bases, in the paired bonds of the nucleic acids, T=A (Thymine-Adenine) in the DNA and U=A (Uracil -Adenine) in RNA. Cancer cells thus lose their abnormal cycle, become amitotic, and go into apoptosis (programmed cell death). [038] Thymine (5-methyluracil) is a derivative of pyrimidine, a constituent of acids. Studies have already shown the benefit of the association of the two substances, which protects the body from the effects of gastric ulcers, a benefit that is not achieved when tryptophan and thymine are used separately.

Pyridoxine

[039] Pyridoxine (vitamin B6) is the food supplement vitamin that participates in more organic functions than any other single nutrient. It affects both physical and mental health, being a coenzyme that interferes with the metabolism of proteins, fats and tryptophan. It acts in the production of hormones and stimulates the defensive functions of cells, having as main sources: cereals, meats, fruits and vegetables. Cooking reduces the pyridoxine content in food.

[040] Deficiency manifestations: are very rare and include seborrheic lesions around the eyes, nose and mouth, accompanied by glossitis and stomatitis. As for the nervous system, the lack of pyridoxine (vitamin B6) can cause seizures and edema of the peripheral nerves, with suspicion that it can cause carpal tunnel syndrome. Growth disorders and anemia are attributed to vitamin B6 deficiency. [041] Pyridoxine has molecular formula: C8 Hll N 03, HCl

(Pyridoxine Hydrochloride), molecular weight: 205.6 g/mol, presenting itself as a white or almost white crystalline powder, soluble in the proportion 1:5 in water and 1:115 in alcohol; practically insoluble in chloroform and ether and indicated in the following cases:

[042] Pyridoxine deficiency can occur as a result of an inadequate diet or intestinal malabsorption, requiring a balanced diet and even vitamin supplementation. Pyridoxine supplementation is necessary in cases of alcoholism, congenital metabolic dysfunction, congestive heart failure, chronic fever, gastrectomy, hemodialysis, hyperthyroidism, infections, intestinal diseases, malabsorption syndrome associated with diseases of the hepatobiliary tract caused by alcoholism or cirrhosis and prolonged stress. It can also be used, as an antidote, in cases of intoxication by Isoniazid - for the prevention of neuropathies associated with intoxication.

[043] Women use vitamin B6 (pyridoxine) for premenstrual syndrome (PMS) and other problems related to menstruation, for "morning nausea" (nausea and vomiting) in early pregnancy, to stop the flow of milk after childbirth, for pregnancy-related depression, the use of birth control pills, and for other effects of menopause. [044] Pyridoxine is converted in erythrocytes to pyridoxal phosphate (pyridoxal phosphate), which acts as a coenzyme in various metabolic processes that affect proteins, carbohydrates, and lipids. It is also involved in the conversion of tryptophan to nicotinic acid or serotonin and also in the deamination, decarboxylation, transamination and transsulfuration of amino acids. In carbohydrate metabolism, it is responsible for the breakdown of glycogen to glucose-1-phosphate. It also participates in the synthesis of gamma-aminobutyric acid (GABA) within the central nervous system (CNS) and heme synthesis, as well as in the conversion of oxalate to glycine.

[045] As an antidote, pyridoxine increases the excretion of certain drugs, such as isoniazid, which act as its antagonists.

[046] As a nutritional supplement and pyridoxine dependence, the dosage is 30 to 600mg/day; with maintenance maintenance of 50mg/day, throughout life; [047] As a dietary supplement, the dosage is 10 to 20mg/day for 3 weeks, followed by 2 to 5mg/day for several weeks.

[048] To treat drug-induced deficiency, the dosage is 10 to 50mg/day for that caused by penicillamine, or 100 to 300mg/day for that caused by cycloserine, hydralazine or isoniazid;

[049] In cases of alcoholism the dosage is 50mg/day for 2 to 4 weeks; if there is a response to anemia, one should continue to administer Pyridoxine indefinitely.

[050] In cases of hereditary sideroblastic anemia, the dosage is 200 to 600mg/day, for 1 to 2 months, followed by 30 to 50mg/day, throughout life, if effective.

[051] In cases of pregnancy, lactation and in children the same defined doses for deficiencies are used.

[052] Pyridoxine is rapidly absorbed from the gastrointestinal tract (mainly in the fasting state), except in malabsorption syndromes. Does not bind to plasma proteins; pyridoxal phosphate is fully bound. It is stored mainly in the liver, with smaller amounts in the muscles and brain. It undergoes hepatic biotransformation, degrading to 4-pyridoxic acid. Half-life is 15 to 20 days. It is eliminated in urine almost entirely as metabolites; the excess, which is not used, is excreted in the urine, largely in its entirety. It is removable by hemodialysis.

[053] Pyridoxine works in synergism with vitamins Bl, B2, B5, B12, C, A, E, and with the elements linoleic acid, magnesium, potassium, sodium, zinc, chromium, phosphorus, manganese and selenium.

Benefits of food supplementation

[054] The food supplement object of the invention strengthens the organism and activates cellular functions, complementing the diet of malnourished people, aiming to provide a longer and quality life, that is, maintain health, energy and vitality, through the replacement of essential nutrients. Currently, vitamins, minerals and amino acids are the most recommended components by nutritionists around the world, due to the benefits they bring to the body. The nutritional supplement of the invention meets this need, offering nutrients for a rich and healthy diet, being indicated to reduce the risks of occurrence of side effects and toxicity in patients with breast, prostate, colon and lung cancer and undergoing chemotherapy treatments, aiming to improve the quality of life of these patients, in addition to being used by sportsmen, intellectuals, executives and all people who, as a result of the attributions of modern life, end up neglecting good nutrition.

[055] The food supplement of the invention comprises tryptophan, thymine, pyridoxine and an excipient that can be defined, for example, by corn starch, elements that have high absorption by the body and do not produce undesirable side effects in individuals.

[056] Pyridoxine acts on protein metabolism, being related to the prevention and treatment of cancer. It also has an antioxidant action in the body. [057] The nutritional supplement of the invention, formed by tryptophan, thymine, pyridoxine and an excipient, has the following composition:

47.50% to 52.50% tryptophan, preferably 50.00%;

41.50% to 46.50% thymine, preferably 44.00%;

5.00% to 7.00% pyridoxine, preferably 6.00%; and an excipient in sufficient quantity, for example corn starch.

[058] The nutritional supplement of the invention can be presented in the form of 500mg capsules, for oral use by adults, having the following composition:

-80.0 mg of tryptophan;

-70.0 mg of thymine;

-10.0 mg of pyridoxine; and

-340.0 mg of pharmaceutically acceptable excipient (eg corn starch). pharmaceutical

[059] Pyridoxine (vitamin B6) acts on protein metabolism, being related to the prevention and treatment of cancer. It also has an antioxidant action in the body.

[060] The nutritional needs of people with cancer vary from person to person. The use of nutrients is related to improving the quality of life in people who use chemotherapy for cancer treatment.

[061] The food supplement in question, comprising tryptophan, thymine and pyridoxine, is an adjunct in the treatment of cancer, aiming to reduce the risk in the occurrence of effects resulting from the specific cancer treatment. [062] Chemotherapy-induced toxicity has important consequences for the physician and the patient. Issues related to risk and quality of life can prevent patients from accepting the treatment plan or seeking more aggressive regimens. Proper management of toxicities is of vital importance so that goals are not delayed.

[063] Nutritional status is of significant importance in the treatment of cancer patients and produces important benefits to patients, enabling the reduction of risk in the occurrence of side effects caused by chemotherapy, by reducing the dose administered, without prejudice to the therapeutic effects, contributing to the success of the treatment.

[064] The concept of food supplementation currently implies its ability, given the body's functions, to benefit the metabolism, with the objective of improving well-being and health and reducing the risk of different pathologies.

[065] The joint action of the nutrients considered here promotes efficient protection against the deleterious action of free and formyl radicals and against oxidation from oxygen metabolism, which arise during the degenerative processes of cells and tissues and within a recommended daily intake (RDI), nutrients represent a nutritional arsenal that forms a complex with therapeutic value with no toxicity and great efficiency in combating chronic diseases.

[066] Certain nutrients or even drugs that reduce the toxicity of chemotherapy, contribute to the development of better therapeutic options for cancer patients.

[067] Some amino acids, such as glutamine, have already demonstrated renal protection against nephrotoxicity induced by a single dose of the chemotherapy drug cisplatin. Other effects presented were: a protective role against some toxic effects of chemotherapeutics such as: radiation-induced mucositis and 5-FU; lower prevalence and severity of mucositis in patients with head and neck cancer during radiotherapy and/or chemotherapy treatment who used glutamine, when compared to the control group (without glutamine intake) and glutamine supplementation also significantly reduces the duration of mucositis during chemotherapy treatment. The use of an oral supplement of glutamine (amino acid) during and after chemotherapy significantly reduced the duration and severity of treatment-induced stomatitis, with similar results being observed in studies with doxorubicin in which a reduction in intestinal aggression was observed.

[068] The food supplement is effective in reducing the intensity of adverse effects of chemotherapy, and may even prevent its onset. This fact not only contributes to the patient's quality of life but also favors their adherence to treatment, increasing their chances of success. The supplement, comprising tryptophan + thymine + pyridoxine, has an action that goes beyond the dietary characteristics of tryptophan, thymine and pyridoxine and its good tolerability, allowing for its eventual association with other vitamins. [069] No general toxicity was noted neither in human cells nor in exposed animals, only a high white blood cell count was noted after oral administration, suggesting greater immunological activity and that the said association may be a food supplement safe, confirming the existence of antioxidant properties of that food supplement and demonstrating good tolerability when administered in maximum doses to healthy volunteers, as well as an improvement in the quality of life, in the psychological domain, of patients with head and neck cancer.

[070] The observations carried out indicate that the food supplement in question can be indicated as a dietary factor supporting cancer treatment, considering the relationship between its use and the reduction in the risk of occurrence of effects resulting from the specific cancer chemotherapy treatment.

Claims

1- Vitamin-mineral food supplement, to reduce the intensity of symptoms and toxicity of chemotherapy treatments in patients with breast cancer, prostate cancer, colon cancer and lung cancer, characterized by the fact that it comprises tryptophan [(R)- 2-amino-3-indole-propionic acid], thymine [2,4 dihydroxy-5-methyl-pyrimidine 5-methyluracil], pyridoxine, and a pharmaceutically acceptable excipient.

2- Food supplement, according to claim 1, characterized in that it comprises, as active components, 47.50% to 52.50% of tryptophan; 41.50% to 46.50% thymine; and 5.00% to 7.00% pyridoxine; and yet an excipient.

3- Food supplement, according to claim 2, characterized in that it comprises, as active components: 50.00% tryptophan; 44.00% thymine; and 6.00% pyridoxine.

4- Food supplement, according to claim 3, characterized in that it presents the active components in powder form in 500mg capsules, for oral use by adults, having the following composition: 80.0mg of tryptophan; 70.0mg of thymine; 10.0 mg of pyridoxine; and 340.0 mg of a pharmaceutically acceptable excipient.