TW202203900A - Diisopropylamine compounds and iodine for the treatment of cancer, endometriosis and pain in patients with cancer or endometriosis - Google Patents

Abstract

The present invention proposed that DADA is an alternative and safe PDK4 inhibitor, potentially suitable for the treatment of endometriosis and pain in endometriosis and cancer patients. To potentiate the efficacy of DADA, our invention proposed the use a combination of Diisopropylamine dichloroacetate and Iodine compounds.

Description

Diisopropylamine compounds and iodine for the treatment of cancer, endometriosis and pain in patients with cancer or endometriosis

The present invention describes the use of diisopropylamine compounds and iodine for the treatment of cancer, endometriosis, and pain in cancer or endometriosis patients.

Endometriosis (EM) is one of the common gynecological conditions causing menstrual and pelvic pain and affects 10% to 15% of women of reproductive age.

EM is a chronic condition when endometrial tissue grows abnormally and adheres to the outside of the uterus. EM has a high prevalence in women of reproductive age and is classified into ovarian EM, abdominal EM and deep infiltrating EM according to the implantation site. The most common site is the ovaries and the most common symptoms are chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. EM is associated with an increased risk of ovarian, breast, and other cancers, as well as autoimmune and atopic diseases.

Endometrial tissue contains estrogen and progesterone receptors that enable it to grow and differentiate in response to changes in hormonal levels during the menstrual cycle. Endometriosis is usually confined to the abdominal cavity and serosal surface of the abdominal organs, usually the ovaries, the posterior broad ligament, the posterior cul-de-sac, and the uterosacral ligament. Less common sites include the serosal surfaces of the small and large intestines, ureters, bladder, vagina, surgical scars, pleura, and pericardium. Endometriosis is clinically characterized by pelvic pain, pelvic mass, menstrual changes, and infertility, whereas bowel or bladder lesions can cause pain during defecation or urination, abdominal distension, and menstrual bleeding with rectum.

Intrinsic endometriosis includes adenomyosis or adenomyoma. Adenomyosis, also known as endometriosis intrinsic, is an invasion of the endometrial tissue of the uterus into the muscle tissue (myometrium). When the disease is generalized it is called adenomyosis and when the disease is in a smaller area of the uterus it is called adenomyosis.

Treatment of EM can be drugs and/or surgery. Hormone replacement therapy uses, for example, birth control pills, progestogenic hormones (progestogenic), gestrinone (gestrinone), danazol (androgen derivative), and gonadotropin-releasing hormone (GnRH) Agonists, progesterone receptor modulators, angiogenesis inhibitors, aromatase inhibitors, COX-2 (cyclooxygenase 2) inhibitors. However, long-term administration with these therapies remains problematic due to severe side effects such as heavy bleeding, premenopausal stage symptoms, virilizing traits, intestinal ulcers, kidney and liver damage.

Endometriosis and tumorigenesis share striking similarities. In tumorigenesis, TGF-β induces a shift in cellular metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis, known as the "Warburg effect". Overproduction of lactate increases cell invasion, angiogenesis, and immune suppression, all of which are critical steps in tumor development and are known regulators of endometriosis.

The prevalence of cancer pain is high in patients with endometriosis and cancer. Pain in cancer patients, considered primarily a secondary issue, results from tissue destruction, compression of nerves, inflammation, and secretion of biological mediators from necrotic tumor masses. As a result, opioids have remained the primary pharmacological treatment for cancer pain over the past century. Approximately 75-90% of patients with advanced or terminal cancer experience chronic pain associated with treatment failure and/or tumor progression or metastasis.

Endometriosis has a prevalence of 20-50% in infertile women, but can be as high as 71-87% in women with chronic pelvic pain. In a large series of studies involving adolescent women with chronic pelvic pain, endometriosis was observed in 45% by laparoscopy.

Lactic acid in cancer Acidosis and hypoxia are hallmarks of tumors as well as tumor progression. In solid tumors such as malignant melanoma, brain tumor, sarcoma, breast cancer, squamous cell carcinoma and adenocarcinoma, the pH of the microenvironment is in the range of 5.8 to 7.4. The Warburg effect, identified by Otto Warburg in the 1920s, shows that even in the presence of oxygen, tumor cells have an increased rate of glucose uptake and are biased towards lactate production. DeBerardinis et al. showed that glutamic acid can be metabolized in cancer cells via the citric acid cycle and produce a major source of lactate. Furthermore, poor and chaotic tumor vascularity prevents efficient clearance of protons from the extracellular space, resulting in acidification of the extracellular space. Extracellular acidosis has been shown to facilitate cancer progression by promoting local tumor invasion as well as distant metastatic spread. Different strategies have been investigated to exploit the acidity of tumors relative to normal tissue to improve the efficacy of anti-tumor chemotherapy.

Elevated acidity in the cancer microenvironment not only activates some lysosomal enzymes, but also triggers the expression of genes involved in pro-transfer factors. When melanoma cells were pretreated with an acidic medium and injected into the tail vein of mice, the cancer cells had a tendency to metastasize to the lungs. High lactate levels indicate a high tendency for metastasis, tumor recurrence, immune suppression, pain, and poor prognosis in certain cancer patients. The acidic microenvironment acts as a trigger of pain in both inflammatory and cancer patients. Osteolytic cells can be activated by breast cancer-derived H ⁺ , resulting in osteolysis when cancer cells metastasize to bone. During this process, the patient experiences pain via acid-sensitive ion channels. - Hoang BX et all Acidosis and Formaldehyde Secretion as a Possible Pathway of Cancer Pain and Options for Improved Cancer Pain Control. - J Pain Palliat Care Pharmacother. 2015 Sep ; 29( 3): 276-80. doi: 10.3109/15360288.2015. 1063561. Epub 2015 Sep 14.

Lactic acid in the pathogenesis of endometriosis Endometriosis exhibits cancer-like features. For example, tumor cells are programmed by TGF-β1 to use aerobic glycolysis, resulting in increased secretion of lactate. Both TGF-β1 and lactate are elevated in the peritoneal fluid (PF) of women with endometriosis and, at the same time, switch from normal mitochondrial respiration in human peritoneal mesothelial cells lining the pelvic cavity for glycolysis. In tumors, lactate is thought to be a key factor driving cell invasion, angiogenesis, pain, and immune suppression, and its alterations have also been implicated in the development of endometriotic nodules and pain.

Among the known inhibitors of pyruvate dehydrogenase kinase (PDK) synthesis, the pyruvate analog, sodium dichloroacetate (DCA), is the most common typical inhibitor of PDK isoforms. Functional types include PDK4. DCA is known to have beneficial effects on congenital errors of mitochondrial metabolism, diabetes, lactic acidosis, myocardial ischemia, and the metabolism of cancer cells to increase mitochondrial-dependent apoptosis. However, DCA also has symptomatic adverse effects of peripheral neuropathy.

Diisopropylamine dichloroacetate (DADA) is a PDK4 inhibitor that inhibits PDK4 and PDK2 with a potency similar to DCA. DADA, originally derived from apricot kernels and known as pangamic acid or "vitamin B15", has been used as a safe treatment option for liver damage and nonalcoholic fatty liver disease, while asymptomatic peripheral neuropathy or other adverse effects. The present invention proposes that DADA is an alternative and safe PDK4 inhibitor, potentially suitable for the treatment of endometriosis and pain in patients with endometriosis and cancer, as well as for the prevention and treatment of diseases including COVID-19 Viral infection caused by coronavirus. To enhance the efficacy of DADA, our invention proposes the use of a combination of diisopropylamine dichloroacetate and an iodine compound.

Diisopropylamine (DIPA), molecular formula C ₆ H ₁₅ N Diisopropylamine (DIPA) is a secondary amine, which is used as a chemical intermediate, and as a catalyst for the synthesis of pesticides and drugs. DIPA is known as an antihypertensive agent when administered intravenously to hypertensive patients. DIPA exerts its effect by lowering arterial blood pressure and reducing cardiac output. DIPA reduces blood glucose concentrations in fasted mice and in glucose-loaded or streptozotocin-diabetic rats.

Diisopropylamine dichloroacetate (DADA) is the active ingredient of pine gluconate and has been marketed for over 50 years for the treatment of chronic liver disease. DADA has previously been reported to be a safe inhibitor of pyruvate dehydrogenase kinase 4 (PDK4), a subtype of PDK. DADA is a vasodilator of peripheral and cerebral arterioles. DADA is also thought to aid in the detoxification of chemical and metal metabolites, possibly through the formation of chelate-like compounds whose excretion through the kidneys is facilitated and increased. DADA increases oxygen utilization and cortical glucose uptake.

Other names: dichloroacetic acid diisopropylammonium salt; diisopropylammonium dichloroacetate; diisopropylamine dichloroethanoate; DADA; DIPA-DCA; DIEDI

Molecular formula: C ₈ H ₁₇ Cl ₂ NO ₂

references: Preparation: GB 862248 (1961 to Italseber). Pharmacology: V. A. E. Kraushaar et al., Arzneim.-Forsch. 13, 109 (1963). Angel's Mutation Test M. D. Gelernt, V. Herbert, Nutr. Cancer 3, 129 (1982). Determination of Pharmacokinetics and Thin Layer Chromatography in Race Horses: J.-M. Yang et al., Gen. Pharmacol. 19, 683 (1988). Pharmacological Review: P. W. Stacpoole, J. Clin. Pharmacol. J. New Drugs 9, 282-291 (1969).

Toxicity data: Oral mouse lethal dose (LD ₅₀ ): 1700 mg/kg (Kraushaar)

purposes (Therap-Cat): vasodilators, hypotensive drugs.

Iodine is an essential element in human physiology. There is epidemiological evidence supporting its role in cancer prevention through immunomodulatory, hormonal balance, antioxidant, anti-inflammatory, pro-differentiation and pro-apoptotic effects. In the medical literature, the term iodine represents any form of the molecule, including molecular iodine (I ₂ ), iodide salts (ZnI ₂ , CuI ₂ , NaI or KI), iodate (NaIO) and/or iodine-containing (iodine-based) ) moiety of lipids or proteins such as iodotyrosine or iodolactone or methionine-iodine, providone-iodine, iodoacetate.

Ongoing epidemiological data have demonstrated an association between goiter origin and cancer morbidity/mortality, especially gastric cancer morbidity/mortality. Epidemiological evidence also suggests that thyroid disorders, especially goiter, may be associated with breast cancer morbidity and/or mortality. Other cancers associated with goitreogenic status include prostate cancer, endometrial cancer, ovarian cancer, colorectal cancer, and thyroid cancer.

Venturi S, Venturi A, Cimini D, Arduini C, Venturi M, Guidi A. A new hypothesis: iodine and gastric cancer. Eur J Cancer Prev. 1993 ; 2( 1): 17-23. - Abnet CC, Fan JH, Kamangar F, et al. Self-reported goiter is associated with a significantly increased risk of gastric noncardia adenocarcinoma in a large population-based Chinese cohort. Int J Cancer. 2006 ; 119( 6): 1508-10. - Eskin BA. Iodine metabolism and breast cancer. Trans N Y Acad Sci. 1970 ; 32( 8): 911-47. - Kalache A, Vessey MP, McPherson K. Thyroid disease and breast cancer: findings in a large case-control study. Br J Surg. 1982 ; 69:434-5 - Smyth PP, Smith DF, McDermott EW, Murray MJ, Geraghty JG, O'Higgins NJ. A direct relationship between thyroid enlargement and breast cancer. J Clin Endocrinol Metab. 1996 ; 81:937-41. - Vassilopoulou-Sellin R, Palmer L, Taylor S, Cooksley CS. Incidence of breast carcinoma in women with thyroid carcinoma. Cancer. 1999 ; 85:696-705.

Investigational studies report that _I2 exerts synergistic efficacy when used in combination with doxorubicin (DOX) anticancer therapy in both rodent and canine models. In a rodent model of methylnitrosourea _- induced mammary tumors, I therapy increased tumor sensitivity to DOX, resulting in a four-fold reduction in the therapeutic dose of this drug. Furthermore, _I2 supplementation resulted in marked cardioprotective effects as indicated by reductions in cardiac lipid peroxidation and circulating cardiac creatine kinase (CK-MB) levels. The molecular efficacy of _I2 therapy also includes reduced proliferation of DOX-resistant cells, reduced acquisition of epithelial-mesenchymal transition (EMT) markers, induction of tumor cell redifferentiation, and increased anti-tumor immune responses. In the canine study, iodine supplementation produced a significant reduction in adverse effects and a 33% increase in disease-free survival compared to DOX monotherapy after 10 months.

Alfaro, Y. ; Delgado, G. ; Cárabez, A. ; Anguiano, B. ; Aceves, C. Iodine and doxorubicin, a good combination for mammary cancer treatment: Antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection. Mol. Cancer 2013, 12, 45–55. - Zambrano-Estrada, X. ; Landaverde-Quiroz, B. ; Dueñas-Bocanegra, A.A. ; De Paz-Campos, M.A. ; Hernández-Alberto, G. ; Solorio-Perusquia, B. ; Trejo-Mandujano, M. ; Pérez-Guerrero, L. ; Delgado-González, E. ; Anguiano, B. ; et al. Molecular iodine/doxorubicin neoadjuvant treatment impair invasive capacity and attenuate side effec tin canine mammary Cancer. BMCVet. Res. 2018,14,87–100. -Bontempo, A. ; Ugalde-Villanueva, B. ; Delgado-González, E. ; Rodríguez, A.L. ; Aceves, C. Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of CD44+/CD24+ and E-Cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin. Oncol. Rep. 2017, 38, 867–876 .

Diisopropylamine dichloroacetate and iodine for the treatment of endometriosis, cancer, and pain in patients with cancer and endometriosis, and for the prevention and treatment of viruses caused by coronaviruses including COVID-19 Infect

10% to 99% of diisopropylamine dichloroacetate and 1% to 90% of molecular iodine I ₂ , iodide salts (such as zinc iodide, sodium iodide, potassium iodide), iodate (NaIO) and/or Therapeutic combinations of lipids or proteins containing iodine (iodine-based) moieties such as iodotyrosine or iodolactone or methionine-iodine or providone-iodine or iodoacetate. Therapeutic compounds of DADA and iodine may be formulated orally, suspensions, liquids, solutions, aerosols with acceptable pharmaceutical excipients or by known techniques for the treatment of endometriosis and intrauterine cancer patients Membrane, cancer, and pain. The therapeutic compounds of the present invention may be administered orally, rectally, by infusion, by nebulization, transdermally or parenterally.

Examples of therapeutic compounds for use in human trials are formulated as follows:

180 grams of diisopropylamine dichloroacetate, 5 grams of molecular I ₂ (Iodine crystals) and 15 grams of potassium iodide. The mixture is mixed in gelatin capsules with 100 mg or 200 mg of active substance and pharmaceutically acceptable excipients. (DADA-I)

The dose range of DADA-I for human use is 1 mg/kg to 40 mg/kg body weight (preferably: 5 mg/kg body weight to 20 mg/kg body weight in 3 divided daily doses, 1- within 4 hours).

Experiment 1: This is an open-label, non-randomized trial in inpatient and outpatient settings to investigate the efficacy of 2 capsules 3 times a day of DADA-I in 8 patients with pain from hormone-refractory prostate cancer with bone metastases . We used a verbal descriptor scale (VDS) to measure pain levels: "no pain" = 0; "mild pain" = 1; "moderate pain" = 2; "severe pain" = 3; Pain" = 4. To assess pain control according to the guidelines, the analgesic intake scale (AIS) was used according to the World Health Organization (WHO) (0 = no analgesics; 1 = nonsteroidal anti-inflammatory drugs (NSAIDs) ); 2 = weak opioid; 3 = morphine). Eight patients with hormone-refractory prostate cancer were diagnosed by clinical symptoms in a specific oncology hospital or department and by other standard biochemical/imaging methods.

patient characteristics Number of patients N = 8 Median age: 67 (range: 61 to 80) Median weight: 46 kg (range: 41 to 63) Major Associated Diseases: Diabetes: 4, Chronic Hepatitis: 1, Hypertension: 5, Chronic Obstructive Pulmonary Disease (COPD): 1, Congestive Heart Disease: 2, Gastritis: 2, Osteoarthritis: 4 All 8 patients were treated with DADA-1: 200 mg 3 times a day 2 hours after meals for 90 days. result:

[Table 1] Results of pain control by VAS disease AIS pain score baseline 5 days 10 days 20th 30 days 50 days 70 days 90 days Pain Score VAS 4 2 1 0 0 0 0 0 Pain Control Score AIS 2 2 1 0 0 0 0 0

[Table 2] Kinetics of prostate-specific antigen (PSA) levels in patient serum during the course of treatment parameter baseline 10 days 20th 30 days 50 days 70 days 90 days PSA ng/ml 942 868 761 583 462 359 286

After 90 days of treatment with DADA-I, the median patient weight increased from 46 kg to 49 kg.

All patients tolerated the treatment well. No toxicity was observed clinically and in monthly monitoring of blood analysis and biochemical parameters.

Clinical Example Embodiment 1: An 81-year-old man diagnosed with metastatic prostate cancer had a serum PSA level of 976 ng/ml. Bone scan showed diffuse bone metastases. Prostate biopsy showed alkaline phosphatase level of 1654 IU/L in Gleason 8/10 adenocarcinoma. The patient additionally experienced significant bone pain with a VAS score of 4 and an AIS score of 3.

The patient started treatment with 200 mg of DADA-I (2 capsules) and 100 mL of water, 2 hours after meals, 3 times a day. Ten days after treatment with DADA-I, the patient reported a reduction in bone pain with a VAS score of 2 and an AIS pain control score of 1, and a reduction in serum PSA levels to 689 ng/ml. After 20 days of treatment with DADA-I, the patient's pain level decreased to a VAS score of 1 and an AIS pain control score of 0. After 30 days of treatment with DADA-I, the patient had no bone pain and regained 1 kg of body weight, and the PSA decreased to 219 ng/ml. Within 90 days of therapy with DADA-I, the pain was asymptomatic, the PSA level was 92 ng/ml and the alkaline phosphatase level was 345 IU/L. Within 90 days of treatment with DADA-I, the patient regained 2 kg of body weight.

Embodiment 2: A 61-year-old woman presented with severe headache and nausea. In the past 15 months, the patient has undergone surgery, hormone therapy, and chemotherapy for the treatment of stage II breast cancer.

An MRI scan of the head showed 2 brain metastases with signs of cerebral edema. The patient had been prescribed Dexamethasone lozenge and Phenytoin to relieve symptoms, and the patient refused further anticancer therapy.

Patients started treatment with 200 mg of DADA-I (2 capsules) and 150 mL of water, 2 hours after meals, 3 times a day. The patient reduced dexamethasone and eventually stopped taking dexamethasone within 10 days. The patient's headache and nausea were controlled within 10 days. The patient continued to take DADA-I 200 mg three times daily for 85 days, and the patient experienced no symptoms and no pain treatment during the treatment period. MRI scans within 92 days from the start of DADA-I treatment showed a 60% reduction in the size of brain metastases and no evidence of cerebral edema.

Embodiment 3: An 82-year-old woman diagnosed with breast cancer and bone metastases. The patient was not on specific anticancer therapy, and was only treated for symptomatic relief with oral dexamethasone morphine tincture, Ultraheat, antidepressants, and sleeping pills. The patient had a large tumor in the left breast, lymphatic metastases, and metastases to the ribs and spine. The patient had high levels of pain with a VAS score of 4 and an AIS score of 3. The patient also presented with a diagnosis of heart failure, renal failure, and rheumatoid arthritis. The patient has been taking tamoxifen and anastrozole for the last 7 months. These drugs were discontinued due to side effects and progression of the patient's disease and symptoms.

The patient started DADA-I treatment at 200 mg, 2 hours after meals, 3 times a day with 100 mL of water. Within 2 days of treatment with DADA-I, the patient experienced significant pain relief and the patient was free of tinctures of morphine, dexamethasone and Ultraret for 10 days. The patient continued DADA-I treatment for the next 90 days. During 20 days of treatment, the patient's pain level decreased to a VAS score of 1 and an AIS score of 1. After 90 days of treatment with DADA-I, the patient showed no pain and no medication for pain. The size and number of breast tumors recorded by ultrasonography were reduced by 50%, and the size and number of lymphatic metastases were reduced by 60%.

Embodiment 4: A 47-year-old man presented with epigastric pain and nausea, extreme fatigue, and weight loss of 6 kg for 3 months. Blood test results showed carbohydrate antigen 19-9 (CA 19-9) of 298 U/ml and serum amylase level of 1219 U/l, among other current abnormalities. A CT scan revealed a mass in the head of the pancreas ranging from 3.4 cm to 4.2 cm, with 4 liver lesions ranging from 2.5 cm to 4.8 cm in diameter. The patient was diagnosed with metastatic pancreatic cancer and refused chemotherapy for his disease. The patient started treatment with DADA-I 300 mg orally with 150 mL of water, 3 times a day, 2 hours after meals. During 5 days of treatment with DADA-I, the patient's abdominal pain and fatigue improved rapidly. After 10 days of treatment, patients can eat twice as much food as before treatment. From day 11, the patient reduced the dose of DADA-1 to 200 mg three times a day and continued to take the compound for the next 85 days. Throughout the treatment period, the patient's general health and symptoms related to the current disease improved. After 90 days of treatment with DADA-I, the patient gained 3 kg of body weight, and the patient was pain-free. Control blood tests reported 67 U/L for CA 19-9 and 412 U/L for serum amylase. On the 94th day of treatment with DADA-I, an ultrasound examination showed that the tumor size in the head of the pancreas decreased from 2.2 cm to 3.1 cm and the size of the liver mass decreased from 1.6 to 2.5 cm without new metastases.

Embodiment 5: A 34-year-old woman was diagnosed with grade 4 endometriosis and a history of severe pelvic pain who was proven to have recurrent ovarian endometriosis. The patient was also unsuccessfully treated for infertility. The patient was treated with danazol for his pain and anemia with very limited efficacy and developed numerous side effects, which caused the patient to discontinue the drug. Ultrasonography confirmed the presence of endometritis cysts measuring 3 cm on the right and 4 cm on the left in both ovaries. The patient started DADA-I: 200 mg in 100 mL of water, 2 hours after meals, 3 times a day.

Patients were regularly monitored by a pain score (VAS), which showed a sharp reduction in pain levels from 4 to 1 within 5 days of treatment with DADA-1 and to 0 within 10 days. After 10 days from the start of treatment, the patient continued to take DADA-1 100 mg with 100 mL of water, 3 times a day, 2 hours after meals, for 80 days. The patient was pain free for 90 days from the start of treatment with DADA-I. The patient's anemia resolved, and ultrasonography revealed a reduction in the size of ovarian endometriosis cysts to less than 1 cm.

Embodiment 6: A 38-year-old woman was diagnosed with endometriosis in the last 7 years. Laparotomy 6 months ago revealed grade 4 endometriosis with a small amount of ascites. The patient has been treated with oral contraceptives, danazol, and a COX-2 inhibitor. The patient has developed serious side effects and must discontinue all medications other than COX-2 inhibitors. The patient had severe pelvic pain and back pain with a VAS score of 3. Ultrasound showed that the patient's bilateral ovarian endometrial dimensions were 4 cm and 5 cm, and the size of the adenomyosis nodules was 2 to 4 cm.

The patient started treatment with DADA-I 200 mg in 100 mL of water, 3 times a day, 2 hours after meals for 10 days. After 5 days, the patient's pain score improved significantly, with the VAS decreasing to 1 within 5 days and to 0 within 10 days. Patients continued to take DADA-I 200 mg in 100 mL of water 2 hours after meals for 80 days. Within 90 days from the start of treatment with DADA-I, the patient had no complaints of pain and ultrasound examination showed a reduction in the size of ovarian endometrial and adenomyotic segments of less than 1.5 cm.

The pharmaceutical composition of the present invention can be prepared by methods known in the art. For example, when the medicament of the present invention is a tablet, capsule, softgel, suspension, solution, aerosol, liquid, it is used via oral, transdermal, parenteral, instillation, rectal administration and nebulization. Excipients including: binders, lubricants, coating agents, preservatives, colorants, stabilizers, pH adjusters, solubilizers, cooling agents, fragrances, pigments/colorants, etc. may be admixed.

without.

without.

Claims (12)

A pharmaceutical composition formulated for all modes of administration, comprising or consisting of diisopropylamine dichloroacetate (DADA) and an iodine compound, and used for the treatment of endometriosis and/or Or endometriosis, cancer, and pain in cancer patients. The pharmaceutical composition of claim 1, wherein the content of DADA is 50 mg to 1500 mg per day for adult patients. The pharmaceutical composition of claim 1, wherein the content of DADA is 1 mg to 30 mg per kilogram of body weight per day for adult patients. The pharmaceutical composition of 2 or 3, wherein DADA is combined with the iodine compounds to increase the therapeutic effect of DADA. The term iodine represents any form of molecule including iodine molecule (I ₂ ), iodide salts (ZnI ₂ , CuI ₂ , NaI or KI), iodate (NaIO) and/or lipids containing iodine (iodine) moieties or Proteins, the iodine (iodine-based) moiety such as iodotyrosine, iodolactone, methionine-iodine, povidone-iodine or iodoacetic acid Salt (iodoacetate). The pharmaceutical composition of claim 4, wherein the content of the iodine compounds is equivalent to 1 mg to 100 mg of elemental iodine per day for adult patients. The pharmaceutical composition of any one of claims 1 to 5, wherein the patients suffer from extreme endometriosis, endometrium, adenomyosis, adenomyoma, Uterosacral ligament nodules of uterine adenomyosis, and/or endometritis nodules outside the uterosacral ligament. The pharmaceutical composition of any one of claims 1 to 6, which is administered orally, parenterally, rectally, transdermally, or by instillation or aerosol spray in a pharmaceutically acceptable formulation for the treatment of cancer and endometriosis endometriosis, cancer, and pain in patients with The pharmaceutical composition according to any one of claims 1 to 6, which can be used in combination with endometriosis, cancer and endometriosis in patients with cancer and/or endometriosis at any stage of the disease. Combinations of other medications and treatments for pain. The pharmaceutical composition according to any one of claims 1 to 3, which can be used as a single therapeutic agent, or in combination with endometriosis, cancer in patients with cancer or endometriosis and other drug and method combinations for pain. The pharmaceutical composition of any one of claims 1 to 6, wherein the possible therapeutic agent to replace DADA is: diisopropylamine hydrochloride (diisopropylamine HCl) having the chemical formula C ₆ H ₁₆ ClN or having the chemical formula CHCl ₂ COOH in sodium dichloroacetate. The pharmaceutical composition of any one of claims 1 to 6, which can be used as a single therapeutic agent or with other drugs and/or methods for the treatment of cachexia (wasting syndrome) in cancer patients combination. The pharmaceutical or medical nutritional composition of any one of claims 1 to 6, which can be used to improve all types of cancer therapy including surgery, chemotherapy, radiation therapy, targeted drugs, hormone therapy, biological therapy and immunotherapy effect.