WO2021151122A1

WO2021151122A1 - Therapeutic compositions comprising sodium diacetate for cancer pain and metabolic abnormalities

Info

Publication number: WO2021151122A1
Application number: PCT/VN2020/000008
Authority: WO
Inventors: Cuong Hoang; Quang Thai NGUYEN; Xuan Ba HOANG; Bo Han
Original assignee: Thai Minh Pharmaceutial Joint Stock Company
Priority date: 2020-01-21
Filing date: 2020-11-04
Publication date: 2021-07-29

Abstract

The present invention relates to compositions for cancer treatment and cancer pain relief, cancer cachexia, cancer metastasis, infection, burns and wounds, infection of bums, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis and related syndromes, wherein the composition comprises any anticancer therapeutics or methods with sodium diacetate or acetic acid/ sodium acetate or magnesium acetate ( or magnesium acetate) as active agents.

Description

[DESCRIPTION]

[Invention Title]

THERAPEUTIC COMPOSITIONS COMPRISING SODIUM DIACETATE FOR CANCER PAIN

AND METABOLIC ABNORMALITIES

[Technical Field]

The present invention relates to cancer treatment and pain relief, more specifically, the present invention relates to therapeutic compositions for pain and cellular metabolic abnormalities, particularly, for cancer treatment and pain relief in patients with cancer and other diseases.

[Background Art]

Generally, researchers found that when cancer cells appear, human cells system and body will have the following processes:

Metabolic reprogramming in cancer cells: A metabolic shift that increases aerobic glycolysis and reduces mitochondrial oxidative phosphorylation - often referred to as the Warburg effect -is considered a common feature of most cancers and rapid cell proliferation. This metabolic reprogramming confers cancer cells advantages by enhancing their resistance to hypoxia, thereby allowing for a fast conversion of nutrients into biomass for cell proliferation. Most cancers are confirmed to have increased glucose uptake and lactic acid production.

In normal cells, intracellular pH (pHi) is tightly regulated to near-neutral values by ion-transporting proteins reside in the plasma membrane. The activity of these transporters is regulated not only by changes in pH, as a homeostatic mechanism, but also by intra- or extra-cellular cues, such as oncogenes, growth factor signaling, metabolic burden, hypoxia and osmolarity. The pHi in cancer cells is typically higher than in normal cells (~7.3-7.6 versus — 7.2), while extracellular pH (pH_e) is lower (—6.8-7.0 versus —7.40). This reversed pH gradient in cancer cells is an early event in cancer development and neoplastic progression.

The higher pHi in cancer cells is paradoxical, considering that metabolic acids are generated through enhanced metabolism and cell proliferation; however, an increase in pHi is maintained in cancer cells through the an increase in expression or activity of plasma membrane ion transporters and pHi regulators, including the Na⁺-H⁺ exchanger 1 (NHE1), carbonic anhydrases (CAs), monocarboxylate transporter 1 and 4 (MCT1 and MCT4, respectively), and N a⁺ -driven HCO₃ exchangers and the H⁺/K⁺-ATPase proton pump. Additionally, pH-dependent proliferation has recently been confirmed in vivo.

Decreased pHi has been observed in both death-receptor-mediated and mitochondrial-mediated apoptosis. In death-receptor-mediated apoptosis, the decrease in pHi depends on Caspase and precedes DNA fragmentation. In mitochondrial apoptosis, pH decreases before cytochrome C is released from the mitochondria and occurs even when caspase inhibitors are used, which suggests that a lower pH; is an early signal for caspase activation in apoptosis. With this idea, it is apparent that cytochrome-C-mediated activation of caspases requires cytosolic acidification, with the highest caspase activity at pH 6.3-6.8. It has also been shown that constitutively increased pHi blocks apoptotic signaling as measured by downstream effects on DNA degradation.

Migration and Metastasis: Abundant evidence indicates that the increase in pH, plays a role in the direction of cell migration, including the remodeling of actin filaments and cell-substrate adhesions which is critical for motile cells. The decreased pH_e enables cell to migrate and invade, partly by increasing the activity of acid- activated matrix metalloproteinases (MMPs) that dissolve cell-substrate adhesions. Furthermore, the increased pHi due to a higher ion transporter activity is associated with the cell invasion phenotypes.

Tumorigenesis: Dysregulated pHi causes cancer cells to exhibit diverse behaviors and may be considered a distinguishing feature of cancer. This leads to a growing consensus in cancer research that approaches to increasing pHi have clinical potential, especially when other therapies have failed. Increasing pH_i in the absence of oncogenes is sufficient to induce hyperproliferation and dysplasia. Fatty acids accumulation and cancer: Tumor micro environment consists of low O₂, low pH, and high concentrations of fatty acids. Large amounts of fatty acids are produced by cancer cells as a metabolic by-product. Myeloid-derived suppressor cells thrive on these high fatty acid concentrations via fatty acid oxidation (FAO). Under these conditions, they support tumor growth by suppressing T cells that would normally attack the tumors.

[Disclosure]

From the above study results, with a significant investment of time and effort, the present inventors have proposed a solution in cancer treatment and pain relief in patients with malignant tumors and cancer metastases in human and animals, cancer pain, cancer cachexia, cancer metastasis, metabolic acidosis, infection, burns and wounds, infection of bums, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis, chronic and acute liver diseases such as hepatitis, fatty liver, liver cirrhosis, and liver failure of all causes.

In order to achieve the above objectives, the first aspect of the present invention provides therapeutic composition for cancer treatment and pain relief in patients with malignant tumors and cancer metastases in human and animals, cancer pain, cancer cachexia, cancer metastasis, infection, bums and wounds, infection of burns, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis and related syndromes, wherein the composition comprises sodium diacetate or acetic acid/sodium acetate buffer or magnesium acetate/acetic acid as active agents.

In the second aspect, the present invention provides the therapeutic composition of the first aspect, wherein, the composition further comprises other combined agents selected from a group consisting of zinc salts, fenbendazole or any benzimidazoles analogs, and/or chemotherapeutic agents, target drugs, immunotherapeutic agents or immunotherapeutic methods.

In another aspect, the present invention provides therapeutic composition of any of the above aspects, wherein, the zinc salt is Zinc Acetate, Zinc Chloride or Zinc Iodide.

In another aspect, the present invention provides the therapeutic composition of any of the above aspects, wherein, the benzimidazole is selected from a group consisting of albendazole, cambendazole, ciclobendazole, fenbendazole, flubendazole, luxabendazole, mebendazole, oxfendazole, triclabendazole, oxibendazole, parbendazole, ricobendazole, thiabendazole, and metabolites, derivatives, and prodrugs thereof.

In another aspect, the present invention provides the therapeutic composition of any of the above aspects, wherein, the composition is formulated into a solution for tablets, capsules, soft-gel, liquid, suspension, parenteral drugs, rectal drug, transdermal drug, aerosol for nebulization, vesical and oral instillation, Iontophoresis, intravenously used solution, topical application such as skin cancers, rectal cancers, mouth and throat cancer, vesical instillation, percutaneous hepatic perfusion, vaginal perfusion, soft tissue sarcomas, bone sarcomas and urine bladder cancer.

In another aspect, the present invention provides the therapeutic composition of any of the above aspects, wherein, sodium diacetate or acetic acid/sodium diacetate buffer is formulated into a 0.1% to 0.9% solution with sterile water or sodium chloride of 0.1% to 0.9% for an intravenous therapeutic product.

In another aspect, the present invention provides the therapeutic composition of any of the above aspects, wherein, the composition is formulated into a solution by mixing with dimethyl sulfoxide (DMSO) 1% to 90% and sodium chloride 0.9% or steril water 10% to 90%.

In another aspect, the present invention provides the therapeutic composition of any of the above aspects, wherein, the additional pharmaceutical solvent DMSO can be used from 1% to 25% to improve therapeutic efficacy and tolerance of the solution. [Description of Drawings]

The above objects, features and other advantages of this present invention will be better understood by a skilled person through the following detailed description combined with accompanying drawings, in which:

FIG. 1 shows the synergistic effect of a combination of sodium diacetate (A) and fenbendazole (B) on inhibiting the growth of Pancreatic cancer;

FIG. 2 shows the synergistic effect of a combination of sodium diacetate (A) and fenbendazole (B) on inhibiting the growth of Glioblastoma;

FIG. 3 shows combinational effects on intracellular and extracellular Lactate secretion;

FIG. 4 shows Live/Dead assay.

[Mode for Invention]

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purpose only and the scope of the present invention is not limited thereto.

As used herein, the term "sodium diacetate - SD" refers to sodium hydrogen acetate with chemical formula NaH (C₂H₃O₂)₂, which is a salt of acetic acid used in seasonings, food additives and antimicrobial agents.

The compositions of the present invention, which are used to treat all types of cancer and cancer metastases in human and animals, consist of sodium diacetate (SD) or a buffer system made from the combination of acetic acid (AA) with sodium acetate (SA) (or potassium acetate) or magnesium acetate (MA) with proportion ranged from 10% to 90% for AA and 10% to 90% for SA or MA

The ingredients of the compositions of the present invention have biological action, particularly, SD or AA, MA and SA in the proper ratio can create intracellular and extracellular buffer systems to normalize pHi and pHe, thereby restoring normal cellular functions such as cellular metabolism, cellular apoptosis, cellular regeneration and cellular proliferation, The compositions of the present invention comprise sodium diacetate or the mixture of AA and SA can also eliminate biofilm formation to treat refractory infection and sepsis.

The salt is formed upon half-neutralization of acetic acid, followed by the evaporation of the solution. It can be viewed as the result of homo-association, an effect that enhances the acidity of acetic acid in concentrated solution:

2 CH₃CO₂H + NaOH → Na⁺ [(CH₃CO₂)₂H] + H₂O

A mixture of a weak acid and its conjugate base is called a buffer solution, or a buffer system, Buffer solutions resist a change in pH when small amounts of a strong acid or a strong base are added. A solution of acetic acid and sodium acetate (CH₃COOH + CH₃COONa) is an example of a buffer that consists of a weak acid and its salt.

A mixture of acetic acid and sodium acetate is acidic because the K_a of acetic acid is greater than the Kb of its conjugate base acetate. It is a buffer because it contains both the weak acid and its salt. Hence, it acts to keep the hydronium ion concentration (and the pH) almost constant when either a small amount of a strong acid or a strong base is added. If we add a base like sodium hydroxide, hydroxide ions will react with the few hydronium ions present. Then more of the acetic acid react with water, restoring the hydronium ion concentration almost to its original value.

If we add an acid such as hydrochloric acid, most of the hydronium ions from the hydrochloric acid will combine with acetate ions, forming acetic acid molecules. Thus, there is very little increase in the concentration of the hydronium ion and and the pH remains practically unchanged.

To. increase or optimize the therapeutic activity of the compositions of the present invention, the following potential therapeutic agents can be combined:

Preferably, the combined therapeutic agent is zinc salts selected in a group of zinc diacetate, zinc acetate, zinc iodide, zinc salicylate, zinc sulfate, zinc picolinate, zinc chloride, zinc thiocyanate.

In another preferable embodiment of the present invention, other therapeutic agents that can be combined with sodium di acetate for treatment of cancer and cancer pain, cancer metastasis are selected in a group of fenbendazole, triclabendazole (or benzimidazole analogs), ascorbic acid or ascorbate salts, chemotherapeutic agents, target drugs, immunotherapeutic agents or methods.

In another preferable embodiment of the present invention, the compositions of the present invention can be effectively used to treat infection, burns and wounds, infection of burns, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis, chronic and acute liver diseases such as: hepatitis, fatty liver, liver cirrhosis, liver failure of all causes.

Furthermore, the combination of therapeutic agents or therapeutic methods for cancer and cancer metastasis would generally provide optimal synergetic therapeutic effects.

In another embodiment of the present invention, the ratio of the therapeutic composition of zinc acetate or zinc iodide is 0.1% - 20% and sodium diacetate is 80% - 99.9%, or ideally, zinc acetate or zinc iodide is 0.5% - 10% and sodium diacetate is 90% - 99.5%.

In another embodiment of the present invention, the ratio of components in the composition of the present invention is 45% to 90% of sodium acetate (anhydrous) and 10% to 55% of glacial acetic acid. Sodium acetate can be replaced by magnesium acetate (MA)to form the same therapeutic composition in the current invention.

Zinc acetate and sodium diacetate are approved as Generally Recognized as Safe (GRAS) substances for miscellaneous and all-purposes.

This composition has good solubility in water and acceptable physiological pH value of aqueous solutions (pH ranges: 4.0 - 6.5). For example, the composition that can be formulated into solution for- oral and intravenous uses in human and animals in our toxicological and clinical trials is composed of 99.5% sodium dictate and 0.5% zinc acetate (ZD A).

The composition of the present invention is suitable for oral use and can be formulated into pharmaceutical formulas for oral, intravenous, intramuscular, intravesical instillation, rectal application, wash the bladder, pleura, colon, abdomen and vagina, vesical and oral instillation, combined with pharmaceutical solvent and excipients for topical application or transdermal use.

The doses of the composition of the present invention for oral, injection and intravenous injection range from 2 mg/kg to 300 mg/kg body weight, or more preferably, from 10 mg/kg to 200 mg/kg body weight.

In another embodiment of the present invention, sodium diacetate or buffer system of acetic acid/sodium diacetate can be formulated into intravenous solution (Solution - SD) to treat primary cancers or cancer metastases from cancer of all origins.

Furthermore, the compositions of the present invention can be effectively used to treat and relieve pain caused by infection, burns and wounds, infection of burns, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis, chronic and acute liver diseases such as hepatitis, fatty liver, liver cirrhosis, and liver failure of all causes.

In another embodiment of the present invention, the therapeutic composition comprises 1% to 50% fenbendazole and 50% to 99% sodium diacetate (hereinafter referred to as composition FDA). An example of formulas for oral application in human is a composition FDA consisting of 100 grams of fenbendazole and 900 grams sodium diacetate.

The doses of FDA for human and animal use range from 5 mg/kg body weight to 100 mg/kg body weight, or preferably 20 mg/kg body weight to 60 mg/kg body weight in

2-3 devided doses daily in 1-3 hours after meals.

Benzimidazoles are heterocyclic aromatic organic compositions consisting of a fusion of benzene and imidazole. Examples of benzimidazoles include triclabendazole, albendazole, flubendazole and fenbendazole. Methyl N-(6-phenylsulfanyl-lH- bensoimidazoI-2-yl) carbonate - Fenbendazole (FBDZ) is a compound used as a veterinary anthelmintic in some animals, including poultry, swine and cattle. Compounds used to control nematodes such as acarida, heterakis and capillaria in poultry and in swine are often administered in feed or in drinking water. The term "benzimidazole" as used herein is a chemical compound that contains a bicyclic ring structure in which benzene is fused to the 4- and 5- positions of an imidazole and includes benzimidazole derivatives

The preferred benzimidazole compound is Fenbendazole which is used for treating helminthiasis in animals. Fenbendazole is non-terato genic, non-carcinogenic, has no adverse effect on fertility, and has no toxic or teratogenic effects on embryos or developing fetuses. Therefore, it can be used at the time of conception in female and breeding male mammals. Besides, in avian species, fenbendazole does not depress egg production or hatchability indices. Fenbendazole is also known to have a very high safety margin and is non-toxic to animal breeders who are administering drugs to animals.

Acute Toxicity and Tolerance of Fenbendazole:

• LD50 acute, rats, p.o > 10000 mg/kg

• LD50 acute, cattle, p.o 750 mg/kg

• Livestock, pets and poultry usually tolerate fenbendazole very well.

• Margin (usual therapeutic dose in cattle & sheep: 5 to 10 mg/kg; in dogs and cats 20 to 50 mg/kg)

Fenbendazole is very poorly soluble in water and is poorly absorbed into the bloodstream when used orally. Therefore, it is very important that it remains as long as possible in the rumen to form a reservoir from which it is progressively dissolved and absorbed.

Absorbed fenbendazole is metabolized in the liver to its sulfoxide derivative, which is identical with oxfendazole, another veterinary anthelmintic benzimidazole. Interestingly, the oxfendazole produced through metabolism is released back into the rumen, where the bacterial flora reduces it back to fenbendazole. This increases the bioavailability of fenbendazole in ruminants.

The study of the acute toxicity of the FDA The experiments were performed on 20 white outbred rats of both sexes. To determine the rates of acute toxicity, the test solution was administered intravenously in accordance with the method intended for use in clinical trials of rats of both sexes by doses. Control animals received 0.9% sodium chloride solution in a volume of 20 ml/kg. The study of acute toxicity of the FDA revealed that no animal death was observed at the highest possible dose of 5,000 mg/kg.

Experience 1 : Paracetamol induced liver damage models

Sprague Dawley rats were divided into 4 groups

Group 1 Control - n 10 Saline (0.9% NaCl)

Group 2 Affected - n 10 Saline + Paracetamol

Group 3 Treated A - n 10 FDA 100 mg/kg + Paracetamol

Group 4 Treated B - n 10 FDA 200 mg /kg + Paracetamol

Rats were orally poisoned with paracetamol 500 mg/kg, 2 hours later, the rats were orally administered FDA with 100 mg/ lkg (group 3) and 200 mg/ lkg (group 4) for 10 days.

On the 11^th day, the rats were sacrificed and tested for: Blood biochemistry: AST and ALT, liver weight, histopathology (macroscopic, microscopic)

Liver protective effect of FDA

Effect of the composition of the present invention on liver weight according to the rate of toxicity by paracetamol.

Liver weight loss by more than lg in group 2 was significantly increased in comparison with the loss in the control group (group 1).

Liver weight loss by more than lg in group 3 was significantly decreased in comparison with the loss in group 2.

Liver weight loss by more than lg in group 4 was significantly lower than in group 2 and 3.

Liver weight loss in group 3 and 4 was higher than in group 1 , but the differences were not statistically significant.

Effect of FDA on AST and ALT levels

The activity of ALT and AST in group 2 was increased significantly compared to control group 1.

The levels of ALT and AST in group treated with the inventive solution (group 3 and 4) were significantly reduced compared to group 2 and were higher than group 1 but the differences were not statistically significant.

Effect of FDA on liver histopathology

Histopathology: results of macroscopic and microscopic examination of rat liver showed that group 2 of the tested rats without FDA treatment had more severe structural liver damages than the control group with the sign of necrosis and inflammation. FDA solution of both doses: lOOmg/kg and 200mg/kg showed a strong protective effect on the liver, with no virtual damages of structural liver but minor inflammation.

Immunoprotective property of the composition of the present invention

Research subjects: Swiss mice, purebred, both sexes, weighing 26 ± 2 gram

The experiment was conducted on the model of immunodeficiency induced cyclophosphamide (CPM). CPM was injected intraperitoneally with a single dose of 200 mg/kg body weight to induce immunosuppressed condition.

The tested mice were divided into 3 groups:

Group 1 (n = 10): Mice without intervention

Group 2 (n=10): Mice with CPM and treated with saline (NaCl 0.9%)

Group 3 (n=10): Mice with CPM and treated with 100 mg/ lkg of FDA orally in 2 divided doses.

On the 11^th day, the mice were sacrificed, and their blood and lymphatic organs were collected for examination.

Mice in all groups were assessed through the following parameters:

The number of leukocytes, neutrophils, lymphocytes, monocytes, NK cells

Evaluate IgG, cytokine IL2 and TNF - a in blood serum by ELISA.

Table 1 : Effect of FDA on the number of leukocytes

The results showed that the inventive solution significantly restored the decrease of leukocytes in peripheral blood induced by CPM.

Table 2: Effect of FDA on IgG concentration in blood serum

The results showed that the inventive solution significantly restored the humeral immunity of the CPM-induced immunosuppressed mice.

Table 3: Effect of FDA on IL - 2 concentrations (pg/ml)

The results showed that LRO was effective in restoring the IL-2 level of CPM- induced immunosuppressed mice.

Table 4: Effect of FDA on TNF - a Concentration (pg/ml)

The results showed the FDA’s strong efficacy in reducing the inflammatory reaction induced by CPM by suppressing TNF - a formation.

Study of the effect on mortality of the ZDA in a model of acute endotoxemia induced by endotoxin from Salmonella enterica

The test was conducted on 20 standard Wistar rats aged 18-20 weeks and weighing 180-300 g. All animals received standard food and water.

Lethal endotoxin is modeled by the introduction of bacterial endotoxins, namely, lipopolysaccharide of Salmonella enterica serotype enteritidis (SIGMA-ALDRICH). Endotoxin was injected intravenously (tail vein) once with 0.2 ml water. Experimentally matched doses of endotoxin causing pyrogenic reaction and 50 and 100% mortality of animals due to toxic shock was 5 μg/kg and 25 μg/kg of endotoxin, respectively.

The efficacy of the ZDA intrap eritoneal treatment was assessed by the mortality rate in each group seven days after endotoxin administration.

Rats in the control groups for the first seven days after the administration of endotoxin at doses of 5 and 25 mg/kg experienced hyperthermia due to toxic shock, decreased motor activity, decreased muscle tone, food refusal, diarrhea, and death.

Maintenance of endotoxin at a dose of 5 mg/kg resulted in 60% mortality. Conducting the standard therapy for the formation of toxic shock with 0.9% solution of sodium chloride reduced mortality of animals from 60% to 50%. By using the ZDA 100 mg per 1 kg body weight, the mortality was decreased from 60% to 10% compared with the control within seven days of the experiment.

An increase in the administration of a single dose of endotoxin to 25 μg/kg to laboratory animals resulted in a weighting flow of toxic shock and 100% mortality within seven days of observation.

When conducting the standard therapy with 0.9% solution of sodium chloride at a dose of 20 ml/kg, the mortality of animals in group was reduced from 100% to 80%.

The use of the ZDA 100 mg per 1 kg body weight showed a more significant reduction in mortality within seven days of the experiment compared with the control from 100% to 40%.

Hereafter, the clinical trials that determine the effects of the composition of the present invention on patients will be described in more detail.

Clinical trial 1 :

A 64-year-old woman was diagnosed with stage 4 stomach cancer. She presented 5 kg weight loss within 3 months, severe fatigue, abdominal pain, vomiting water and foods, anemia (Hb of 93.4 g/dL). Upper gastric endoscopy revealed 6.5 ulcerative lesion in the pyloric region. Endoscopic ultrasound showed multiple abdominal lymphatic enlargements which suggested metastasis and ascites. Biopsy of the lesion confirmed poorly differentiated gastric adebocarcinoma. CT scan showed diffuse invasion of the gastric wall and multiple lymphatic nodes enlargement and 2 liver metastases. The patient has been recommended symptomatic and palliative treatment.

The patient started to take 2000 mg of ZDA mixed with 200 ml of water 4 times daily after meals.

After 3 days of the treatment, her symptoms of fatigue, abdominal pain and vomiting remarkably improved. These symptoms completely disappear after 9 days of treatment with ZD A. The patient continued to take ZDA 2000 mg, 3 times daily for the next 60 days. She continued to improve physically and symptomatically. After 30 days of treatment, the patient could eat three times as much as she could before the treatment with ZDA. Her Hb was improved to 10.3 g/dL.

After 70 days of the treatment the upper gastric endoscopy revealed dramatical reduce of pyloric lesion to less than 1 cm in sizes and no open ulceration. The abodominal ultrasound showed no hepatic metastasis, ascites and no lymphatic enlargement. The patient gained 3 kg of weight during the course of treatment with ZD A. Her Hb was 11.6 g/DL.

Clinical trial 2:

A 67-year-old man was admitted for dysphagia, repeated vomiting and 6 kg of weight loss in 4 months. The patient had a 6-year history of gastro-esophageal reflux disease and has been treated with multiple courses of proton pump inhibitor and antibiotics for Helicobacter pylori. An upper endoscopy confirmed a 5.5 cm long esophageal tumor and biopsy showed that it was a poorly differentiated carcinoma. The tumor was unresectable, and he was recommended radiotherapy. CT scan showed a large circumferential midthoracic esophageal tumor (5.6 cm) with multiple regionally lymphatic metastasis.

The patient refused radiotherapy and started using ZDA at a dose of 1000 mg mixed with 100 ml of water, 6 times daily and began intravenous nutrient infusion. After 4 days of treatment, the patient could eat and drink better, and his dysphagia and vomiting symptoms , completely disappeared after 10 days of treatment with ZDA. The patient continued to take ZDA 2000 mg mixed with 200 ml of water 3 times daily for 60 days.

He could eat and drink water normally after 30 days of treatment. An upper endoscopy after 70 days of treatment with ZDA showed the reduction of esophageal tumor to less than 1 cm in sizes. The patient gained 3 kg of weight during the course of treatment with ZDA.

Clinical trial 3 :

A 57-year-old woman presented with symptoms of severe headache and nausea. The patient has been treated for Stage III breast cancer for the past 16 months with surgery, hormonal therapy and chemotherapy.

An MRI scan of the head showed multiple brain metastases. The patient has been given Dexamethasone tablets and Phenytoin for symptomatic relief; and the patient refused to undergo further anticancer therapy.

The patient started treatment with 2000 mg of ZDA dissolved in 150 ml of water 3 times daily in 2 hours after meals. She reduced and eventually stopped taking Dexamethasone in 8 days. Her headache and nausea were controlled within 5 days. The patient continued to take the inventive therapeutic composition for 20 days and generally experienced no symptoms. The patient continued to take 2000 mg of ZDA of the invention solution 3 times daily for the next 40 days.

An MRI scan taken 61 days after starting treatment with ZDA showed a 50% to 90% reduction in brain metastasis size.

Clinical trials 4:

A 49-year-old female patient was diagnosed with breast cancer with Stage IV invasive ductal carcinoma metastasized to multiple organs (including multiple lung spots and 2 brain metastasis). She refused chemotherapy and radiation therapy. She was treated with the infusion of 2000 mg of ZDA mixed with 200 ml of water 4 times daily on an empty stomach for 20 days.

The patient’s symptoms including coughing, headache, and nausea gradually improved. After 10 days of treatment, the patient’s general health status sufficiently improved. The patients continued to take ZDA2000 mg mixed with 200 ml of water, 3 times daily daily for the next 42 days.

A chest X-ray after 62 days of treatment showed a 50% reduction of the lung metastases in size; and a brain MRI scan showed that 2 brain metastases were reduced by 50% in size.

Clinical trial 5: A 54-year old male smoker was suffering with a long-term cough and pain in the chest. He has been experiencing headache, nausea, difficulty in speech and movement, and blurred vision for 3 weeks. When examing the chest X-ray, a mass was detected. Computed tomography (CT) scans of the chest and the head confirmed the lung cancer and multiple brain metastases with significant brain edema. The patient was prescribed Dexamethasone and Phenytoin tablets as symptomatic relief, and was given no specific cancer treatment per his own request.

The patient started to take 1000 mg of FDA mixed with 150 ml of water 3 times daily. Within 10 days of the treatment, the patient’s headache was markedly alleviated, and the patient’s nausea and blurred vision were reduced. Within 20 days of the treatment, the patient had no symptoms in his lungs and brain. The patient continued to take 1000 mg of FDA mixed with 150 ml of water 3 times daily for the next 43 days.

CT scans of chest and. head after 63 days of the treatment showed that the tumor in the lung shrank by more than 50% and the brain metastases decreased dramatically in number and size.

Clinical trial 6:

A 12-year-old boy patient was diagnosed as inoperable through MRI and experienced symptoms of headache, nausea, paralysis in the left side of his face and left hand, and weakness in his left leg. Although no biopsy was performed, the MRI suggested a diagnosis of astrocytoma. The patient was treated with steroids and chemotherapy for 1 month. However, his symptoms worsen after a short period of improvement.

The patient stopped chemotherapy and started to treat with 1000 mg of ZDA mixed with 100 ml of water 4 times daily for 20 days. He gradually reduced the doses of Dexamethasone and Depakine, and completely stopped taking these drugs 14 days after he began ZDA treatment.

The patient’s symptoms related to brain tumors gradually improved and completely disappeared within about 20 days of therapy with ZDA treatment. The patient continued to take 1000 mg of ZDA, 3 times daily for 45 days. An MRI after 52 days following the treatment with inventive combination of the inventive agents showed a 60% reduction in brain tumor size and elimination of brain edema.

Clinical trial 7:

A 75 -year-old man suffered from abdominal pain and significant weight loss over the preceding 2 months. His initial blood tests results were: total bilirubin: 128 mmol/L, GGT 241 U/L, ALT 286 U/L, AST 214 U/L, CA19-9 : 385 U/L (normal ranges < 37 U/ml).

Ultrasound examination and computed tomography (CT) have suggested adenocarcinoma of the pancreatic head with multiple metastases in the liver. There was a 33 x 38 mm mass in the head of the pancreas; his intrahepatic and extra hepatic biliary tree was dilated. The patient was offered a bile duct stent to relieve the j aundice and pain, but he refused.

The patient was treated with FDA 1000 mg mixed with 150 ml of water 4 times daily for 20 days. His abdominal pain was reduced after 10 days of treatment and completely disappeared after 15 days of treatment. After 10 days of the treatment, the patients’ blood test showed: total bilirubin: 96 mmol/L, GGT: 154 U/L. ALT: 145 U/L, AST: 103 U/L, CA 19-9: 184 U/ml,

The patient continued treatment with oral application of FDA at a dose of 1000 mg, 3 times daily. On the 21st day of treatment, his bilirubin level was 62 minol/L and CA 19-9 was 106 U/ml. The patient continued treatment with oral application of FDA with at a dose of 1000 mg, 3 times daily for 43 days. He gained 3 kg of body weight. By the end of 63 days of treatment, the control CT-scan showed a reduction of tumor in the head of pancreas to 22 mm ^χ 25 mm and there were no traces of liver metastasis and CA 19-9 level were 65 U/ml. The patient was freed from symptoms and complaints of his current disease. His total bilirubin: 46 mrnol/L, GGT: 74 U/L. ALT: 65 U/L, AST: 73 U/L.

Clinical trial 8:

A 78-year-old male patient was diagnosed with prostate cancer with diffuse bone metastases and tremendous pain in his legs confirmed by X-ray scan. This patient was diagnosed with prostate cancer by a prostate needle biopsy 1.5 years earlier and the patient underwent continuous hormonal therapy until he developed bone pain and he decided to stop hormonal therapy. The patient was very anemic with a Red Blood Cell count of 2.8 million/cu mm, hemoglobin of 8.5 g/dL, and his serum prostate specific antigen (PSA) was 360 mg/ml. The patient could not function due to bone pain that was poorly controlled by ketorolac injection, and dexamethasone oral. He felt weak and loss 7 kg of weight during a 2 -month period,

The patient started treatment with 1000 mg of FDA mixed with 150 ml of apple juice 3 times daily. His pain improved by more than 50% after 10 days of therapy. After that, he continued to be treated with the same FDA for 20 days. His energy, quality of life and pain continued to improve with FDA therapy. In his blood test after 20 days of treatment with ZD A, the Red Blood Cell count increased to 3.2 million per microliter and hemoglobin to 9.5g/dL. His PSA was down to 120 ng/ml.

After 30 days of FDA infusion therapy, the patient continued to take 1000 mg of FDA mixed with apple juice 3 times daily for another 40 days. After 70 days of therapy with FDA, the patient gained 4 kg of body weight. His blood and biochemical examination showed a normal level of blood count, hemoglobin, and his PSA was 62 ng/ml.

Clinical trial 9 :

A 64 -year old male was diagnosed with stage IV non-small-cell lung cancer (NSCLC) with bone metastasis and brain metastasis confirmed by CT-scan and lung biopsy. The patient refused any specific anticancer therapy and took only tramadol, Dexamethasone tablets, and depakine. Despite the pain treatment, he still experienced severe headache, bone pain mainly in the chest and lumbar parts of his spine.

The patient was administered 1000 mg of FDA mixed with 150 ml of water 4 times daily for 20 days. After 5 days of treatment, his headaches began to reduce and his bone pain disappeared in 10 days. The patient continued to reduce the dose of tramadol and dexamethasone. On the 20th day of therapy he no longer had pain even without analgesic drugs. After 20 days of infusion therapy the patient continued to take 2000 mg of ZD A orally, 3 times daily for 45 days.

After one month of treatment, the patient’s general health, performance, and quality of life improved remarkably. After 65 days of therapy, the control CT-scan showed that lung tumor size decreased from 44mm x 43 mm to 24mm x 21mm, and brain metastasis size decreased from 34mm x 26mm to 18 mm x 15 mm compared to before treatment, and there was no sign of brain edema.

Clinical trial 10:

A 59-year-old man presented a diagnosis of metastasized small cell lung carcinoma with a 4-month history of chest pain, severe blood coughing, significant weight loss and extreme fatigue. A Bronchoscopic biopsy was performed, and the pathological examination confirmed the presence of small cell carcinoma based on immunostaining. The result was consistent with small cell lung carcinoma. CT scan also revealed a significant lymphatic metastasis, pleural effusion and some suspected bone metastasis in the ribs and spine.

The patient refused conventional treatment and only received symptomatic therapy with oral dexamethasone, pain killers, nebulization with bronchodilators, 24-hour oxygen treatment and intravenous nutrient infusion.

The patient started to take FDA 1000 mg mixed with 150 ml of water 4 times daily for 10 days. After 3 days of treatment, the level of bone and chest pain were remarkably improved. Dry cough with blood stopped completely after 6 days of treatment. The patient continued to take 1000 mg of FDA with 150 ml of water 3 times daily for another 54 days. The chest pain and bone pain were resolved completely within 16 days of treatment and the patient did not need oxygen therapy from the 15th day of treatment. The CT scan after 64 days of treatment with FDA showed that the bronchial tumor and lymphatic metastases were completely disappeared and there was no sign of pleural effusion. There was also a significant reduction in ribs and spine lesions. The patient gained 4 kg of body weight during the course of treatment with FDA.

Clinical trial 11 : A 53 -year-old man was diagnosed with small-cell lung carcinoma 6 months earlier. The patient has undergone 4 cycles of chemotherapy. The patient refused further chemotherapy because of severe side effects and poor health status. The patient had severe headaches, vomiting and blurred vision and was treated with mannitol and solumedrol infusion after MRI scan detected 3 brain metastases and significant sign of brain edema. The patient refused radiotherapy.

He started to take ZD A 1000 mg and FDA 1000 mg mixed with 200 ml of water, 4 times daily for 10 days.

His headache and vomiting have remarkably improved after 3 days of treatment. After 5 days, he did not need additional mannitol and solmnedrol infusion without episodes of headache.

The patient continued to take 1000 mg of ZDA and 1000 mg of FDA 3 times daily for the next 70 days.

After 71 days since the beginning of treatment, the CT-scan of the chest and MRI of the head showed that tumor size has decreased by more than 60%, lymphatic metastases and brain metastases with brain edema were completely resolved.

Clinical trial 12:

A 69 -year old male patient suffered from end-stage of cholangiocarcinoma. He developed malaise, chills and abdominal pain 2 months after bile duct stenting for palliative treatment of hyperbilirubinemia.

The general health status of the patient worsened rapidly within 2 hours of administration. He developed leukopenia (2.1 GZL), his platelet levels were low (63 G/L), and his temperature increased to 39.5 degrees Celsius.

The patient was treated with intravenous injection of 80 mg of solumedrol and 1000 mg of paracetamol, followed by antibiotic therapy with Vancomycin and Meropenem. The patient developed hemodynamic problems (systolic blood pressure: 60-70 mmHg). Despite catecholaminergic therapy, the patient's condition deteriorated. He developed metabolic acidosis with a lactate level of blood raised to 8 mmol/L. The clinical diagnosis of sepsis was established.

The patient started an infusion of 1000 ml of Solution SD at a rate of 60 drops per 1 minute. Under this treatment, the patient's condition has gradually improved, and the body temperature dropped to 37.6 degrees Celsius within 90 minutes of starting treatment with sodium diacetate and sodium chloride infusion.

His systolic blood pressure raised to 98 mmHg and lactate level of blood reduced to 3 mmol /L when he received 500 ml of Solution SD. The patient’s general condition and symptoms of fever, low blood pressure and metabolic acidosis were completely resolved when he finished infusion of 1000 ml of Solution SD. His systolic blood pressure was 108 mmHg, and his blood lactate level was 1 mmol/L.

The patient continued treatment with 1000 ml of solution SD for the next 19 days without antibiotic, solumedrol or other symptomatic treatments. His general condition steadily improved and he was discharged after 20 days from the administration without symptoms and complaints. His platelet was raised to 212 G/L, his white blood cell count was 6.7 G/L and blood lactate level was 0,8 mmol/L.

The present specification omits the details that those skilled in the art of the present invention can fully recognize and infer, and various modifications can be made within a scope that does not change the technical spirit or essential constitution of the present invention in addition to the specific examples described herein. Thus, the present invention may be implemented in a different manner from those specifically described and exemplified in the present specification, which may be understood by those skilled in the technical field of the present invention.

Claims

[CLAIMS]

[Claim 1]

A composition for cancer treatment and cancer pain relief, cancer cachexia, cancer metastasis, infection, burns and wounds, infection of bums, antibiotic refractory infections, fungal infection, viral infection, metabolic imbalance, metabolic acidosis, diabetes and diabetes-related diseases, sepsis, endometriosis and related syndromes, wherein the composition comprises sodium diacetate or acetic acid/sodium diacetate buffer as active agents.

[Claim 2]

The composition according to claim 1, wherein the composition further comprises other combined agents selected from a group consisting of zinc salts, fenbendazole or any benzimidazoles analogs, and/or chemotherapeutic agents, target drugs, hormonal agent, immunotherapeutic agents or immunotherapeutic methods.

[Claim 3]

The composition according to claim 1 or 2, wherein the zinc salt is Zinc Acetate,

[Claim 4]

The composition according to any of the above claims, wherein, the ratio of the therapeutic composition is zinc acetate 0,1% - 20% and sodium diacetate 80% - 99.9%. Sodium diacetate in the composition can be replaced by Magnesium acetate or Magnesium Diacetate.

[Claim 5]

The composition according to any of the above claims, wherein the ratio of the therapeutic composition is zinc acetate 0,5% - 10% and sodium diacetate 90% - 99.5%

[Claim 6]

The composition according to any of the above claims, wherein the ratio of the therapeutic components is 45% to 90% of sodium acetate (anhydrous) and 10% to 55% of glacial acetic acid. Sodium acetate in the composition can be replaced by magnesium acetate.

[Claim 7]

The composition according to any of the above claims, wherein the benzimidazole is selected from the group consisting of albendazole, cambendazole, ciclobendazole, fenbendazole, flubendazole, luxabendazole, mebendazole, oxfendazole, triclabendazole, oxibendazole, parbendazole, ricobendazole, thiabendazole.

[Claim 8]

The composition according to any of the above claims, wherein the composition is formulated into any acceptable pharmaceutical and therapeutic products selected in a group consisting of tablets, capsules, soft-gel, liquid, suspension, parenteral drugs, rectal drug, transdennal drug, aerosol for nebulization, vesical and oral instillation, iontophoresis, solution for intravenous use and topical application (instillation) for skin cancers, rectal cancers, mouth and throat cancer, vesical instillation, percutaneous hepatic perfusion, vaginal perfusion, soft tissue sarcomas, bone sarcomas and urine bladder cancer.

[Claim 9]

The composition according to any of the above claims, wherein sodium diacetate or acetic acid/sodium diacetate buffer is formulated into a 0.1% to 1.5% solution with sterile water or sodium chloride of 0.1% to 0.9% for an intravenous therapeutic product.

[Claim 10]

The composition according to any of the above claims, wherein the composition is formulated into a solution by mixing with dimethyl sulfoxide (DMSO) 1% to 90% and sodium chloride 0.9% or steril water 10% to 90%.

[Claim 11]

The composition according to any of the above claims, wherein the additional pharmaceutical solvent DMSO 1% to 25% is used to improve the therapeutic efficacy and tolerance of the solution.