Methods and dosage forms for the treatment of human cancers   

Abstract: Methods for the treatment of human cancers, daily dosage forms for cancer patients, and methods of formulating the dosage forms are provided wherein the daily dosage form contains from about 10-6,000 mg of each of β-sitosterol, isovanillin, and linolenic acid. Preferably, the dosage forms are formulated by first creating an aqueous decoction of Arum palaestinum Boiss, followed by fortification of the decoction with additional quantities of β-sitosterol, isovanillin, and linolenic acid.

This is a continuation of identically-titled U.S. patent application Ser. No. 12/905,847, filed Oct. 15, 2010, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to methods for the treatment of human cancers, daily dosage forms for administration to cancer patients, and methods of formulating such dosage forms. More particularly, the invention is concerned with the administration of daily dosage forms (e.g., aqueous mixtures, capsules, pills, or tablets) containing from about 10-6,000 mg of each of β-sitosterol, isovanillin, and linolenic acid. Such treatment provides a marked decline and/or elimination of cancerous tumors, particularly those of the bladder, breast, liver, and lung, and a corresponding enhancement of the wellness and lifestyles of the treated patients.

2. Description of the Prior Art

Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumours and neoplasms. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis. Metastases are the major cause of death from cancer.

Cancer is a leading cause of death worldwide. The disease accounted for 7.4 million deaths (or around 13% of all deaths worldwide) in 2004. The main types of cancer leading to overall cancer mortality each year are: lung (1.3 million deaths/year) stomach (803 000 deaths) colorectal (639 000 deaths) liver (610 000 deaths) breast (519 000 deaths). More than 70% of all cancer deaths occurred in low- and middle-income countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030.

The most frequent types of cancer worldwide (in order of the number of global deaths) are: Among men—lung, stomach, liver, colorectal, oesophagus and prostate Among women—breast, lung, stomach, colorectal and cervical.

Cancer arises from one single cell. The transformation from a normal cell into a tumour cell is a multistage process, typically a progression from a pre-cancerous lesion to malignant tumours. These changes are the result of the interaction between a person\'s genetic factors and three categories of external agents, including: physical carcinogens, such as ultraviolet and ionizing radiation chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxin (a food contaminant) and arsenic (a drinking water contaminant) biological carcinogens, such as infections from certain viruses, bacteria or parasites.

Some examples of infections associated with certain cancers: Viruses: hepatitis B and liver cancer, Human Papilloma Virus (HPV) and cervical cancer, and human immunodeficiency virus (HIV) and Kaposi sarcoma. Bacteria: Helicobacter pylori and stomach cancer. Parasites: schistosomiasis and bladder cancer.

Aging is another fundamental factor for the development of cancer. The incidence of cancer rises dramatically with age, most likely due to a buildup of risks for specific cancers that increase with age. The overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective as a person grows older.

Tobacco use, alcohol use, low fruit and vegetable intake, and chronic infections from hepatitis B (HBV), hepatitis C virus (HCV) and some types of Human Papilloma Virus (HPV) are leading risk factors for cancer in low- and middle-income countries. Cervical cancer, which is caused by HPV, is a leading cause of cancer death among women in low-income countries. In high-income countries, tobacco use, alcohol use, and being overweight or obese are major risk factors for cancer.

The most common cancer treatment modalities are surgery, chemotherapy, and radiation treatments. All of these techniques have significant drawbacks in terms of side effects and patient discomfort. For example, chemotherapy may result in significant decreases in white blood cell count (neutropenia), red blood cell count (anemia), and platelet count (thrombocytopenia). This can result in pain, diarrhea, constipation, mouth sores, hair loss, nausea, and vomiting.

Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) is a relatively new addition to the family of cancer treatments. Biological therapies use the body\'s immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments.

The immune system is a complex network of cells and organs that work together to defend the body against attacks by “foreign” or “non-self” invaders. This network is one of the body\'s main defenses against infection and disease. The immune system works against diseases, including cancer, in a variety of ways. For example, the immune system may recognize the difference between healthy cells and cancer cells in the body and works to eliminate cancerous cells. However, the immune system does not always recognize cancer cells as “foreign.” Also, cancer may develop when the immune system breaks down or does not function adequately. Biological therapies are designed to repair, stimulate, or enhance the immune system\'s responses.

Some antibodies, cytokines, and other immune system substances can be produced in the laboratory for use in cancer treatment. These substances are often called biological response modifiers (BRMs). They alter the interaction between the body\'s immune defenses and cancer cells to boost, direct, or restore the body\'s ability to fight the disease. BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines, gene therapy, and nonspecific immunomodulating agents.

Researchers continue to discover new BRMs, to learn more about how they function, and to develop ways to use them in cancer therapy. Biological therapies may be used to: Stop, control, or suppress processes that permit cancer growth. Make cancer cells more recognizable and, therefore, more susceptible to destruction by the immune system. Boost the killing power of immune system cells, such as T cells, NK cells, and macrophages. Alter the growth patterns of cancer cells to promote behavior like that of healthy cells. Block or reverse the process that changes a normal cell or a precancerous cell into a cancerous cell. Enhance the body\'s ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation. Prevent cancer cells from spreading to other parts of the body.

A variety of medicinal plants have also been employed in the treatment of human cancers. For example, plants from the hills and mountains of Israel, Palestine, and the Golan Heights have been used for many years for the treatment of many human diseases, including cancers. Among these are extracts of Arum palaestinum Boiss. See, for example, Said et al. Ethnopharmacological Survey of Medicinal Herbs in Israel, the Golan Heights and the West Bank Region. J. Ethnopharmacology. 83 (2002): 251-265.

The National Institutes of Health estimated that the total cost of cancer care in the United States in 2005 was $209.9 billion. Direct medical costs including inpatient and outpatient care, drugs, and devices accounted for $74 billion of this total, $17.5 billion was attributed to indirect morbidity costs (ie, lost productivity), and indirect mortality costs (i.e, lost productivity due to premature death) accounted for $118.4 billion. Given that cancer is largely a disease of older individuals, cancer expenditures will be of even greater concern in the future as the so-called baby boomer population swells the ranks of the US Medicare program from 42.5 million in 2005 to almost 70 million by 2030. As evidence of this demographic trend (and as evidence of unmet clinical need in oncology relative to other disease contexts), cancer recently surpassed heart disease as the number one killer of Americans younger than 85 years.

Despite the immense amount of worldwide research and efforts to stem the tide of cancer and its side effects, the disease in its many manifestations continues to be a huge problem. Therefore, any new cancer treatment having a curative affect and/or the ability to ameliorate cancer symptoms and improve the lifestyle of patients is highly significant and important.

SUMMARY

The present invention provides an improved method for the treatment of a variety of human cancers, most especially female breast and lung cancers, by the administration to a cancer patient of a dosage form containing from about 10-6,000 mg (more preferably from about 1,000-4,000 mg, still more preferably from about 2,500-,3500 mg, and most preferably about 3,000 mg) of each of β-sitosterol, isovanillin, and linolenic acid. The administration is preferably carried out on a daily basis for a period of time of at least about 21 days, and more preferably until elimination of the patient\'s cancer, or at least the amelioration of the patient\'s cancer symptoms. The products of the invention can be in any dosage form, such as an aqueous dispersion, capsule, pill, and tablet. The most preferred dosage form is an aqueous dispersion.

In preferred practice, the dosage forms of the invention are prepared employing a decoction or tea using plant parts (preferably leaves and/or roots) of Arum palaestinum Boiss, or any other suitable plant parts of the genus Arum. However, such decoctions, standing alone, do not have the requisite amounts of β-sitosterol, isovanillin, and linolenic acid required in the invention. Accordingly, it is necessary to supplement or fortify the plant decoctions using amounts of β-sitosterol, isovanillin, and linolenic acid not derived from the plant decoctions. Advantageously, amounts of essentially pure β-sitosterol, isovanillin, and linolenic acid are added to the plant decoctions to achieve the foregoing amounts of these ingredients. The linolenic acid may be added in the acid form or as a salt (e.g., sodium or potassium salt).

If it is desired to administer an aqueous dispersion dosage form, the above-described fortified decoctions can be used directly without further additions or modifications. On the other hand, it is equally possible to provide solid dosage forms by the lypholization of the fortified decoctions to yield solid extracts. In any case, the goal of administration is to provide to the patient the above-noted milligram amounts of each of β-sitosterol, isovanillin, and linolenic acid on a daily basis.

DETAILED DESCRIPTION

In preferred forms, the invention involves the administration of a dosage form prepared using plant parts of Arum palaestinum Boiss, which grows naturally in the Middle East, and particularly in Palestine and adjoining regions. This plant is of the genus Arum, family Araceae, subfamily Aroideae, and tribe Areae, and has a Nomen No. of 4357. The name was verified on Nov. 5, 1985 by ARS Systematic Botanists. The species priority site is the Ornamental Plant Germplasm Center. The plant is also known by common names, including Black Calla and Solomon\'s-Lily.

Analysis of Arum palaestinum Boiss

A detailed examination designed to determine the identity of the chemical components of Arum palaestinum Boiss was undertaken using Gas Chromatography-Mass Spectroscopy (GC-MS). In particular, one gram of dried plant leaf was boiled in 100 ml of dichloromethane for approximately 30 minutes. After cooling, the liquid was filtered, followed by solvent evaporation under nitrogen to a final volume of 8 ml. This liquid extract was then analyzed using GC-MS. conducted at North Carolina State University. The instrument used was an Agilent Technologies 5975 GC-MS equipped with a DB-5 column. Sample volumes injected were typically 1 μL with spitless injection. The GC inlet was maintained at 300° C. with the initial oven temperature set at 60° C. Three minutes after injection, the oven temperature was increased at a rate of 5° per minute to a final temperature of 325° C., which was held for five minutes.

Background samples were collected and analyzed throughout the entire sample preparation procedure. Retention time comparison, EI mass spectrum interpretation, accurate mass analysis, and known standard comparisons were used in the qualitative analysis. Quantitation was accomplished by comparing the unknown concentrations to a set of standards of known concentrations. The following table sets forth the results of this study, wherein the relative amounts of chemical ingredients were normalized to the amount of hexadecanoic acid:

GCMS RESULTS Relative Molecule Formula Amount hexadecanoic acid C16H32O2 1 linolenic acid C18H30O2 0.48 linoleic acid C18H32O2 0.44 oleamide C18H35NO 0.12 2-monopalmitin C19H38O4 0.17 phytol C20H40O 0.49 campesterol C28H48O 0.79 sitostenone C29H48O 0.085 stigmasterol C29H48O 0.29 isofucosterol C29H48O 0.13 5a-stigmastane-3,6-dione C29H48O2 0.038 beta-sitosterol C29H50O 1.9 cycloartenol C30H50O 0.19 dl-a-tocopherol C29H50O2 0.050 heneicosane C21H44 0.028 tricosane C23H48 0.093 pentacosane C25H52 0.29 heptacosane C27H56 0.88 nonacosane C29H60 2.1 hentriacontane C31H64 0.39 5,5,8a-Trimethyl-3,5,6,7,8,8a-hexahydro-2H-chromene C12H20O 0.15 6-(3,3-Dimethyl-oxiran-2-ylidene)-5,5-dimethyl-hex-3-en-2-one C12H18O2 0.029 2-butanone, 4(2,6,6-trimethyl-1,3 cyclohexadien-1-yl) C13H20O 0.070 2-cyclohexen-1-one, 4-(3-hydroxy-1-butenyl)-3,5,5-trimethyl

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