WO2011005310A1 - Pharmaceutical composition - Google Patents

Abstract

Therapeutic and/or diagnostic formulations intended to improve glucose uptake and the oxidation of nutrients in warm-blooded animals, including humans, presenting with cancer, in a manner that diminishes toxic by-products generated by these metabolic events, may be administered either for single daily independent administration or a binary morning and nighttime administration which also promotes sleep. In a preferred embodiment of the present invention, effective amounts of derivatives of thiol-containing alkyl fatty acids, such as but not limited to those of lipoic acid and analogs thereof, are co-formulated with effective amounts of naturally-occurring or synthetic antioxidants, trace elements, botanical extracts, carbohydrates, and other substances. Pharmaceutically-acceptable carriers and excipients may be included in the formulation as necessary.

Description

Pharmaceutical Composition

Field of the Invention

This invention relates to pharmaceutical compositions, and more particularly to therapeutic and diagnostic compounds, compositions, and formulations prepared or formulated for single daily independent or binary use as a morning and/or nighttime medicament for cancer patients.

Background of the Invention

Nutrition plays a significant part in many aspects of cancer development and treatment, with knowledge regarding the precise role of nutrition's impact on cancer continually being cultivated. Malnutrition is a common problem in cancer patients that has been recognized as an important component of adverse outcomes, including increased morbidity and mortality and decreased quality of life (QoL). Significant weight loss, generally defined as at least a 10% loss of body weight in six months' time, has been identified as an indicator of poor prognosis in cancer patients. While good nutrition practices can help cancer patients maintain weight and the body's nutrition stores, offering relief from nutrition impact symptoms and improving QoL, poor nutrition practices, which can lead to undernutrition, can contribute to the incidence and severity of treatment side effects and increase the risk of infection, thereby reducing chances for survival.

Nutrition impact symptoms are those symptoms that impede oral intake, including but not limited to anorexia; nausea and vomiting; diarrhea or constipation; stomatitis; mucositis; dysphagia; alterations in taste and smell; pain; and anxiety and depression. Early recognition and detection of risk for malnutrition through nutrition screening followed by comprehensive assessments is increasingly recognized as imperative in the development of standards of quality of care in oncology practices. Consequently, the eating practices of individuals diagnosed with cancer should be assessed throughout the continuum of care to reflect the changing goals of nutritional therapy.

Nutritional status is often jeopardized by the natural progression of neoplastic disease. Alterations in nutritional status begin at diagnosis, when psychosocial issues may also adversely affect dietary intake, and proceed through treatment and recovery. Protein-calorie malnutrition (PCM) is the most common secondary diagnosis in individuals diagnosed with cancer, stemming from the inadequate intake of carbohydrate, protein, and fat to meet metabolic requirements and/or the reduced absorption of macronutrients. Most often associated with anorexia, the loss of appetite or desire to eat; cachexia, a progressive wasting syndrome evidenced by weakness and a marked and progressive loss of body weight, fat, and muscle which cannot be reversed nutritionally even with caloric supplements; and the early satiety sensation frequently experienced by individuals with cancer, PCM in cancer results from multiple factors. These factors range from altered tastes to a physical inability to ingest or digest food, leading to reduced nutrient intake. PCM incidence is also increased by cancer-induced abnormalities in the metabolism of major nutrients, including but not limited to glucose intolerance and insulin resistance; increased lipolysis; and increased whole-body protein turnover. If left untreated, PCM can lead to progressive wasting, weakness, and debilitation as protein synthesis is reduced and lean body mass is lost, possibly leading to death.

Anorexia is typically present in 15% to 25% of all cancer patients at diagnosis and may also occur as a side effect of treatments. Indeed, anorexia is an almost universal side effect in individuals with widely metastatic disease because of physiologic alterations in metabolism during carcinogenesis, chemotherapy and radiation therapy side effects, and gastrointestinal surgical procedures. Anxiety, depression, and other emotional components may be enough to cause anorexia and resultant PCM. Finally, other systemic or local effects associated with cancer that may affect nutritional status include pain, sepsis, malabsorption, and obstructions.

Anorexia can hasten the course of cachexia, which can develop in individuals who appear to be eating adequate calories and protein but have primary cachexia whereby tumor- related factors prevent maintenance of fat and muscle. Particularly at risk are patients with diseases of the gastrointestinal tract. Cachexia syndrome presents with loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite. Metabolic acidosis from decreased protein synthesis and increased protein catabolism is also frequently seen.

Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor. Thus, where a patient has cachexia, the chance of death from the underlying cancer is increased dramatically and is in fact estimated to be the immediate cause of death in 20% to 40% of cancer patients.

The basal metabolic rate in cachectic individuals is not adaptive; it may be increased, decreased, or normal. Also, cachexia can manifest in individuals with metastatic cancer as well as in individuals with localized disease, so some hypothesize that cachexia is caused by a complex mix of variables, including tumor-produced factors and metabolic abnormalities.

Consequently, the etiology of cancer cachexia is not entirely understood. While some patients do respond to nutrition therapy, most will not see a complete reversal of the syndrome, even with aggressive therapy. The most prudent and advantageous approach to cachexia is hence prevention of its initiation through nutrition monitoring and nutrition intervention.

Nutritional status can be compromised in direct response to tumor-induced alterations in metabolism. Tumor-induced weight loss occurs frequently in patients with solid tumors of the lung, pancreas, and upper gastrointestinal tract and less often in patients with breast cancer or lower gastrointestinal cancer. Although anorexia may also be present, the energy deficit alone does not explain the pathogenesis of cachexia. Several factors have thus been proposed, such as the effects of cytokines, neuropeptides, neurotransmitters, and other tumor- derived factors. Products of host tissues, such as tumor necrosis factor-α, interleukin-1, interleukin-6, interferon-γ, and leukemia inhibitor factor, as well as tumor products that have a direct catabolic effect on host tissues, such as lipid-mobilizing factor and proteolysis- inducing factor (not established as definite in humans), have all been identified as mediators of this complex syndrome. Altered metabolism of fats, proteins, and carbohydrates is evident in cancer patients with cachexia. Tumors may induce impaired glucose uptake and glucose oxidation, leading to an increased glycolysis. Weight loss can occur from a decrease in energy intake, an increase in energy expenditure, or a combination of the two. Although anorexia is a common symptom of cancer patients, studies have shown that increased caloric intake by the oral route has failed to counteract the wasting process. This supports the theory that the aberrant metabolic rate is the direct response by the tumor and the immune system to disrupt the pathways that regulate the homeostatic loop of body- weight regulation.

Current studies suggest that the basal metabolic rate serves as a possible prognostic indicator of survival. As cancer progresses, the basal metabolic rate declines and cachexia occurs, reducing long-term survival. Although alterations in overall basal metabolic rates have not been observed by some, increased basal metabolic rates have been reported in pediatric, breast, lung, and other cancer patient populations; however, the discrepancy may be related to the stage of cancer progression. Nutritional support therapies aimed at preserving lean muscle mass and subcutaneous adipose stores despite this altered metabolic rate may ultimately improve patients' QoL and impact overall survival.

Although an individual's nutritional status may be compromised initially by the diagnosis of cancer, thorough nutritional screening procedures and the timely implementation of nutritional therapies may markedly improve the patient's outcome. Symptoms and side effects may sometimes be managed by a combination of dietary and pharmacologic interventions.

Several approaches to the treatment of cancer cachexia have been reported, and a variety of agents have been studied for their effects on appetite and weight. The decision to use pharmacological treatment to improve a patient's appetite should be based on the patient's desires, current medical condition, and life expectancy. While several medications have been proposed to treat the symptoms of cancer cachexia, the management of cachexia remains a complex challenge, and integrated multimodal treatment targeting the different factors involved has been proposed. Hence, in one phase III study, patients were randomly assigned to receive megestrol acetate, eicosapentaenoic acid, L-carnitine, thalidomide, or megestrol acetate plus L-carnitine and thalidomide. Interim analysis of 125 patients suggested the most effective treatment would be a combination regimen. The optimal combination is the goal of ongoing research. (See Mantovani G, Macciό A, Madeddu C, Gramignano G, Serpe R, Massa E, Dessi M, Tanca FM, Sanna E, Deiana L, Panzone F, Contu P, and Floris C (2008). Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. Nutrition 24:305-13, herein incorporated by reference.)

Optimal nutritional status is an important goal in the management of individuals diagnosed with cancer. Although nutrition therapy recommendations may vary throughout the continuum of care, maintenance of adequate intake is important. Whether patients are undergoing active therapy, recovering from cancer therapy, or in remission and striving to avoid cancer recurrence, the benefit of both optimal caloric and nutrient intake is well documented. The goals of nutrition therapy are to prevent or reverse nutrient deficiencies; preserve lean body mass; help patients better tolerate treatments; minimize nutrition-related side effects and complications; maintain strength and energy; protect immune function to decrease the risk of infection; aid in recovery and healing; and maximize QoL. Patients with advanced cancer can receive nutritional support even when nutrition therapy can do little for weight gain, especially to improve their well-being and provide comfort and symptomatic relief. Indeed, nutrition continues to play an integral role both for individuals whose cancer has been cured or who are in remission, and good nutrition helps prevent or control comorbidities such as heart disease, diabetes, and hypertension.

The preferred method of nutrition support is via the oral route, with the use of dietary modifications to reduce the symptoms associated with cancer treatments. Appetite stimulants may be used to enhance the enjoyment of foods and to facilitate weight gain in the presence of significant anorexia. Recommendations during treatment may focus on eating foods that are high in energy, protein, and micronutrients to help maintain nutritional status. This may be especially true for individuals with early satiety, anorexia, and alteration in taste, xerostomia, mucositis, nausea, or diarrhea. Under most of these circumstances, eating frequently and including high-energy and high-protein snacks may help overall intake. However, as noted previously, simply increasing a patient's caloric intake is insufficient to counter cachexia. Thus, it is essential to provide other ingredients in any oral supplementation administered to cancer patients that influence those patients' aberrant metabolic processes and/or rates. It would thus be particularly beneficial to restore energy metabolism in patients presenting with cachexia due to cancer to normal levels through mechanisms of action which do not simply boost calorie intake in these patients.

Alpha lipoic acid (ALA) (l,2-dithione-3-pentanoic acid), known as dihydrolipoic acid (DHLA) in its reduced form, is a sulfur-containing saturated fatty acid found in small amounts in such foods as red meat, organ meats, spinach, broccoli, peas, Brussels sprouts, potatoes, yams, carrots, beets, and yeast. As a supplement, ALA is rapidly absorbed into the blood and the cells where it can prevent free-radical damage, being rapidly reduced to DHLA by NADH or NADPH in most tissues.. ALA is also synthesized de novo from octanoic acid in mitochondria.

ALA occurs naturally in every cell of the body and is an essential cofactor for the mitochondrial dehydrogenase complexes which both control the chemical reactions that allow cells to produce energy through the maintenance of mammalian glucose homoeostasis and influence the regulation of free radical metabolism. During conversion of unusable forms of energy contained in such nutrients as sugar, protein, fat, and amino acids into adenosine triphosphate (ATP) by oxidation reactions, mitochondria transport free electrons liberated from these reactions through the electron transport chain. An electrical potential develops across the inner mitochondrial membrane as a result of this electron movement, such that energy liberated from these oxidation reactions is used as the driving force for ATP synthesis. Mitochondrial pumps or uptake mechanisms, including binding and transport chaperones, may be important in transporting lipoic acid to mitochondria. The anti-glycation capacity of lipoic acid combined with its capacity for hydrophobic binding enables lipoic acid to prevent glycosylation of albumin in the bloodstream.

However, ATP production also increases the influx of lactate or pyruvate into mitochondria with corresponding increased H₂O₂, O₂ ^', OH^*, and other similar free radicals. This high flux of oxidants would not only be expected to damage the cell overall but also certainly would damage the mitochondria in which the oxidants are produced, thereby severely affect overall cellular metabolism and ultimately, energy levels and survival. To balance this oxidative stress on the cell, ALA possesses potent antioxidant activity, and it has been observed that ALA synergizes with other antioxidants, such as vitamin C, glutathione and vitamin E, as well. Unlike many antioxidants which are active only in either the lipid or the aqueous phase, ALA is active in both lipid and aqueous phases. ALA also enhances the efficiency of many different supplements and pharmaceuticals; for example, it enhances the absorption of creatine and glucose into muscle cells by upregulating transporter proteins through ALA's activation of the insulin receptor. Overall, ALA's effects on cellular metabolism make it an ideal nutritional supplement for the cancer patient presenting cachexia.

Supplementation of the cancer patient's diet with ALA can have additional treatment benefit as well. In one study, it was observed exposure of HT-29 human colon cancer cells to ALA or DHLA for 24 hours dose-dependently increased caspase-3-like activity and was associated with DNA-fragmentation, leading to apoptosis of these cells. Both compounds increased O₂ ^" generation inside mitochondria, preceded by the aforementioned increased influx of lactate or pyruvate into mitochondria which resulted in the down-regulation of the anti-apoptotic protein BcI-XL. By contrast, no apoptosis was observed in non-transformed human colonocytes in response to ALA or DHLA addition. (See alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O₂ ^'*-generation (2005). Wenzel U, Nickel A, Daniel H. Apoptosis 10:359-68, herein incorporated by reference.)

Derivatives of lipoic acid are exquisitely useful to target the aberrant energy metabolism found in cancer cells. For example, US Patent No. 6,117,902 to Quash et ah, herein incorporated by reference, discloses novel 6,8 dimercaptooctanoic acid derivatives as potential therapeutic agents useful in the treatment of cancer. US Patents 6,331,559 and 6,951,887 to Bingham et al, as well as US Patent Application No. 12/105,096 by Bingham et ah, all herein incorporated by reference, disclose a novel class of lipoic acid derivative therapeutic agents that selectively target and kill both tumor cells and certain other types of diseased cells. These teachings further disclose pharmaceutical compositions, and methods of use thereof, comprising an effective amount of such lipoic acid derivatives along with a pharmaceutically acceptable carrier. Furthermore, US Provisional Patent Application No. 61/193,427 to Shorr et ah, herein incorporated by reference, teaches a pharmaceutical composition constructed from a compound comprising a fatty acid, or analogue thereof, conjugated to at least one polymer, non-polymer, or lipid-based particle and/or at least one therapeutic, imaging, or diagnostic agent, which modulates the binding affinity of the compound to a carrier molecule in the blood of warm-blooded animals in such a way as to modulate the circulation time of the pharmaceutical composition, and consequently the penetration and distribution of the compound into a tumor mass, as well as to demonstrate selective uptake and transport into a specific organelle in a diseased cell. More specifically, increased depth of tumor cell layer penetration and more even distribution throughout a tumor mass, with a resulting active cellular uptake and transport into diseased-cell mitochondria, leading to enhanced therapeutic, imaging, or diagnostic benefit, is contemplated.

While the use of sugars other than glucose in nutritional supplements for cachexic patients has been taught in the prior art, the purpose of such use has been solely as a flavorant. Thus, for example, US Patent 7507425 to Rosenbloom, herein incorporated by reference, discloses a method for treating cachexia and/or alleviating one or more its symptoms by administering to a cachexic patient a composition including carbohydrates as sweeteners, such as fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, and honey solids. However, each of these sugars not only provides flavor but is also a carbon source which can ultimately feed into energy metabolism. It would thus be desirable to provide simple or complex sugars in a nutritional supplement for patients presenting with cachexia to implicate other sources of carbon to be used for metabolic purposes. Substances other than ALA and derivatives thereof have been demonstrated to have a similar effect on blood glucose levels and metabolism. For example, the quarternary ammonium compound N-acetyl-L-carnitine is involved in transporting fatty acids into mitochondria so that they can be used as a fuel for energy production. The acetyl group of N- acetyl-L-carnitine is used to form acetyl-CoA, an intermediary in the tricarboxylic acid (TCA) cycle used to ultimately generate energy from amino acids, fats, and carbohydrates. As N-acetyl-L-carnitine is used in the cellular energy production process, supplementation is reported to improve the symptoms of mental and physical fatigue. Consequently, in a recent study, adult patients with advanced cancer, carnitine deficiency, moderate to severe fatigue, and a Karnofsky Performance Status score of 50 or more, were randomly assigned to receive either L-carnitine (0.5 g/day for two days, then 1 g/day for two days, and finally 2 g/day for ten days) or placebo. This double-blind phase was followed by an open-label phase, during which all patients received L-carnitine supplementation for two weeks. From baseline to the end of the double-blind phase, serum total and free L-carnitine increased significantly in the L-carnitine-treated group and nonsignificantly in the placebo group. An intent-to-treat analysis revealed no significant improvement in any of the study's endpoints, and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated. However, upon excluding these violators and including outcome data from both the double-blind and open-label phases, fatigue and well-being analysis demonstrated significant improvement in the group that started with L-carnitine during the double-blind phase. It was concluded that these positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a subpopulation of cancer patients. (See Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud S, Lapin J, Portenoy RK, and Esteban-Cruciani N (2009). L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study. J. Pain Symptom Manage. 37:622-31, herein incorporated by reference.)

Derivatives of N-acetyl-L-carnitine demonstrate therapeutic benefit in non- mitochondrial disorders as well. For example, US Patent 5,043,355 to Cavazza, herein incorporated by reference, teaches the use of acyl derivatives of L-carnitine for the treatment of peripheral neuropathies of the motor neurons of the brain stem and spinal cord, primary sensory neurons, and/or the peripheral autonomic neurons, with involvement of the peripheral axons and their attendant supporting structures. Such neuropathies include but are not limited to atrophy and cerebral degeneration in normal aging and in pathological conditions (e.g., Alzheimer's disease; pre-senile and senile dementia; Creutzfeldt- Jakob disease; and Huntington's chorea); demyelinating diseases such as multiple sclerosis; and pathological degeneration of Purkinje cells and cholinergic neurons of Meynert nucleus. Additionally, it has been demonstrated that rats with compromised coronary arteries administered daily doses of 100 mg/kg propionyl L-carnitine for four weeks showed marked improvement in left ventricular function due to sarcolemmal Na⁺-dependent Ca⁺² uptake, indicating that metabolic therapy with propionyl L-carnitine may attenuate defects in the sarcolemmal membrane and thus may improve heart function in congestive heart failure due to myocardial infarction. (See Sethi R, Dhalla KS, Ganguly PK, Ferrari R, and Dhalla NS (1999). Beneficial effects of propionyl L-carnitine on sarcolemmal changes in congestive heart failure due to myocardial infarction. Cardiovasc Res 42:607-615, herein incorporated by reference.)

Beta-glucans are natural gum polysaccharides, found in mushrooms, barley, oats, rye, and wheat, which are thought to have extensive use or potential in many medical and human nutritional applications. The sugars are branched from a protein backbone molecule which has myriad configurations and may be both soluble and insoluble; edible mushrooms contain insoluble β-l,3-glucan or β-l,6-glucan. Insoluble beta-glucan has the unusual ability to enter the bloodstream via intestinal Peyer's patches and activate the immune system's complement component regardless of whether or not the body is invaded by germs or viruses. When beta- glucan activates such complement components as, without limitation, CR3 receptors on stem cells, they are upregulated to bind with certain growth factors released by injured tissue. These factors act as powerful signals to recruit dormant progenitor stem cells, thereby causing these cells to mobilize and migrate to certain disease or injured tissues in order to repair and/or replenish the injured or dysfunctional cell population. In one example, white blood cells are mobilized to attack infections and disease and are guided by antibodies released by B-cells. In a second example, once stem cells become resident in a tissue system or organ, they quickly multiply and replace old tissue with new juvenile cells which are able to mature in a matter of hours or days into the same tissue type that was once dysfunctional. If the genetic component of the tissue is normal, the new cells continue replicating indefinitely, potentially completely and permanently eradicating the problem.

Additionally, besides beta-glucan being a potent immune system stimulant similar to such other natural products as echinacea and/or apitoxin, beta-glucans found in certain mushroom fungi are also thought to have anticancer properties, especially in combination with chemotherapeutic agents. In one study, liver metastases were established by inoculation of C-26 colon carcinoma cells into syngeneic mice. Treatment of mice started 24 hours after inoculation of tumor cells by daily intravenous injections of either aminated β-l,3-d-glucan, interferon-gamma, or a combination of both for six days. The resultant liver metastases were then quantified after an additional eleven days. While the beta-glucan alone did not exert any significant antitumor effect, the combination dose inhibited the growth of liver metastases almost entirely, indicating that activation and recruitment of liver macrophages may be a part of the mechanism responsible for the inhibition of metastatic growth observed in this study. (See Sveinbjømsson, B; Rushfeldt C, Seljelid R, and Smedsrød B (1998). Inhibition of establishment and growth of mouse liver metastases after treatment with interferon gamma and beta-l,3-D-glucan. Hepatology 27:1241-1248, herein incorporated by reference.) It would thus be desirable to provide an immune system stimulant as an ingredient in a nutritional supplement to be used by cachexic cancer patients.

While radioactive indium-I l l has been used as both an imaging agent and a radiochemotherapeutic agent to diagnose and/or treat cancer, the trace element indium, physiologically active as indium sulfate, also appears to have an effect on metabolism. Indium appears to work via the hypothalamus/pituitary/adrenal feedback loop complex, a homeostatic mechanism which regulates parasympathetic functions such as breathing, body temperature, blood pressure, sleep, food and water intake, and stimulation of the gastrointestinal tract; growth hormone release; regulation of the sexual glands; production of sterols such as adrenalin, epinephrine, and Cortisol; and overall synchronization of the function and production of at least thirty-one hormones which downregulate the effects of inflammation as well as the perception of pain, fatigue, and mental alertness. Indium also hastens the removal of the glycolytic metabolite lactate, which can demonstrate buildup in muscle mass. In this manner, then, indium sulfate is also useful as a nutritional supplement for cancer patients.

Next, eggplant (Solarium melongenά) extract contains the active ingredient solamargine, a glycoalkaloid which also possesses metabolic regulatory activity. Solamargine binds to the nicotinic acetylcholine receptor, a specific agonist and receptor for signal transduction influencing the growth and development of adult stem cells and which has been demonstrated to be part of a mechanism of action for de novo angiogenesis in hypoxic tissue such as that found within a tumor mass. Additionally, solamargine exhibits anticancer activity. In one study, Hep3B human hepatoma cells were treated with solamargine to determine whether there would be changes of cell morphology, DNA content, and gene expression of cells. The appearance in solamargine-treated cells of chromatin condensation, DNA fragmentation, and a sub-Gl peak in a DNA histogram suggests that solamargine induces cell death by apoptosis. The maximum number of dead Hep3B cells was detected within 2 hr of incubation with constant concentrations of solamargine, and no further cell death was observed after an extended incubation with solamargine, indicating that the action of solamargine was irreversible. Further analysis implied that cells in the G2/M phases are relatively susceptible to solamargine-mediated apoptosis. In addition, a parallel up-regulation of tumor necrosis factor receptor-I and -II on Hep3B cells was detected after solamargine treatment, and the solamargine-mediated cytotoxicity could be neutralized with either TNFR- I or -II specific antibody. Therefore, these results reveal that the actions of TNFR-I and -II on Hep3B cells may be independent, and both are involved in the mechanism of solamargine- mediated apoptosis. (See Kuo KW, Hsu SH, Li YP, Lin WL, Liu LF, Chang LC, Lin CC, Lin CN, and Sheu HM (2000). Anticancer activity evaluation of the solanum glycoalkaloid solamargine: Triggering apoptosis in human hepatoma cells. Biochem. Pharmacol. 60:1865- 73, herein incorporated by reference.)

Guarana (Paullinia cupana Mart.) is a natural substance, purported to aid fat and lipid metabolism, which is rich in caffeine and the xanthine alkaloids theophylline and theobromine. In one study, mice treated with the hepatocarcinogen N-nitrosodiethylamine received three different doses of guarana added to commercial food, and euthanized after 25 weeks. Gross lesions were quantified, and preneoplastic lesions were histologically measured. Cellular proliferation was evaluated by immunobloting for the proliferating cell nuclear antigen. The incidence and multiplicity of macroscopic lesions were reduced. The number of preneoplastic lesions and expression of proliferating cell nuclear antigen were reduced in the highest guarana dose. According to these results, guarana presented inhibitory effects on hepatocarcinogenesis in mice. (See Fukumasu H, da Silva TC, Avanzo JL, de Lima CE, Mackowiak II, Atroch A, de Souza Spinosa H, Moreno FS, and Dagli ML (2006). Chemopreventive effects of Paullinia cupana Mart var. sorbilis, the guarana, on mouse hepatocarcinogenesis. Cancer Lett. 233:158-64, herein incorporated by reference.) Guarana is hence another example of a medicament which also possesses anticancer properties.

Finally, quercetin, an aglycone or aglucon polyphenols flavone, is widely distributed in the plant kingdom in rinds and barks as glycone or carbohydrate conjugates. Quercetin glycone conjugates include rutin (quercetin-3-rutinoside) and thujin. Especially rich sources of quercetin include red wine; green tea; St. John's wort; and onions, which contain conjugates of quercetin and the carbohydrate isorhamnetin, including quercetin-3,4'-di-O- beta glucoside, isorhamnetin-4'-0-beta-glucoside and quercetin-4'-0-beta-glucoside. While quercetin itself is practically insoluble in water, quercetin carbohydrate conjugates have much greater water solubility, such that daily quercetin conjugation with other carbohydrates in the body may produce mild diuretic effects. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are therefore found in circulating blood. Although metabolic conversion attenuates its biological effects, active aglycone may be generated from the glucuronide conjugates by enhanced beta-glucuronidase activity during inflammation. Quercetin is an antioxidant and has been shown to inhibit lipid peroxidation, with the phenolic hydroxyl groups at the B-ring and the 3-position responsible for its free radical-scavenging activity. In vitro and animal studies have shown that quercetin also inhibits deregulation of inflammatory mast cells, basophiles and neutrophils, having an overall antihistamine effect in the body. Hence, quercetin potentially also has immunomodulatory, anti-inflammatory, anti-allergy, antiviral, and gastroprotective activities and may be useful in preventing secondary complications of diabetes. Additionally, quercetin aglycone has been shown to interact with some receptors, particularly an aryl hydrocarbon receptor, which is involved in the development of cancers induced by certain chemicals. Quercetin aglycone has also been shown to modulate several signal transduction pathways involving MEK/ERK and Nrf2/keapl, which are associated with the processes of inflammation and carcinogenesis. Rodent studies have demonstrated that dietary administration of this flavonol prevents chemically-induced carcinogenesis, especially in the colon, and epidemiological studies have indicated that an intake of quercetin may be associated with the prevention of lung cancer. {See Murakami A, Ashida H, and Terao J (2008). Multitargeted cancer prevention by quercetin. Cancer Lett. 269:315-25, herein incorporated by reference.) Given such metabolic and anticancer activity, then, it would be desirable to include quercetin in a nutritional supplement to be administered to cancer patients.

Other substances which do not affect metabolism or nutrition nevertheless may be of benefit in a nutritional supplement to be used by cancer patients. For example, serratiopeptidase is a protease produced by enterobacterium Serratia sp. E- 15, a microorganism isolated in the late 1960s from the intestine of the Japanese silkworm (Bombyx mori L.), and purified therefrom. US Patent 3,792, 160 to Isono et al., herein incorporated by reference, claims both the purified serratiopeptidase molecule combined with a pharmaceutically-acceptable carrier therefor and a method of use of this pharmaceutical agent in the treatment of inflammation. The proposed anti-inflammatory action of serratiopeptidase is the protease's ability to flush off extraneous fibrin, mucus, and other inflammatory compounds, thereby naturally easing pain and inflammation, as well as its blockage of the release of pain-inducing amines from inflamed tissues. To evaluate the usefulness of serratiopeptidase as an analgesic, twenty-four healthy individuals with symmetrically impacted mandibular third molars underwent surgical removal of one third molar each in two sessions under local anaesthesia via a buccal osteotomy by the same surgeon. All patients received a combination of either serratiopeptidase 5mg or placebo tablets and 1000 mg paracetamol tablets at either the 1st or 2nd operation in accordance with the randomization plan. A significant reduction in the extent of cheek swelling and pain intensity in the serratiopeptidase group at the 2nd, 3rd and 7th postoperative days was found. (See Al-Khateeb TH and Nusair Y (2008). Effect of the proteolytic enzyme serrapeptase on swelling, pain and trismus after surgical extraction of mandibular third molars. Int. J. Oral Maxillofac. Surg. 37:264-8, herein incorporated by reference.) Given the effects of pain on anorexia in cancer patients, it would be desirable to include an ingredient with analgesic properties in a nutritional supplement for cancer patients.

Cannabis sativa is a natural plant family containing approximately sixty cannabinoids, compounds for which a number of receptors exist in both cerebral neurons and other cells that are involved in the regulation and/or propagation of appetite and nausea, two qualities which affect a cachexic patient's QoL. In one study, European researchers attempted to determine the most effective cannabis ingredients and the proper dosages for treating loss of appetite in 243 advanced-stage adult patients with cancer-related anorexia- cachexia syndrome by testing administration of two forms and dosages of cannabinoids: 5 mg of delta-9-tetrahydrocannabinol (THC) alone, and a combination of 5 mg of THC mixed with 2 mg of cannabidiol in a whole-plant cannabis extract (CE), both versus placebo. Patients were assessed both for subjective feelings on QoL as well as nausea, appetite and weight loss, toxic effects known to be associated with cannabinoids, and other QoL issues. The researchers concluded that CE did no worse in either stimulating appetite or improving QoL specifically related to symptoms of anorexia and cachexia than did placebo. (See Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko Y, Schnelle M, Reif M, and Cerny T (2006). Comparison of orally administered cannabis extract and delta-9- tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A multicenter, Phase III, randomized, double-blind, placebo-controlled clinical trial from the cannabis-in-cachexia-study-group. J. Clin. Oncol. 24:3394-3400, herein incorporated by reference.) Given the importance of the stimulation of appetite in cachexic cancer patients, it would thus also be desirable to include an appetite stimulant in a nutritional supplement for such patients.

Protease inhibitors, such as but not limited to cysteine protease inhibitors, serine protease inhibitors, threonine protease inhibitors, aspartic protease inhibitors, and/or metalloprotease inhibitors, are effective for blocking or reducing enhanced activity of the ubiquitin-proteasome system; specific examples include but are not limited to soybean trypsin inhibitor, pepstatin, and leupeptin. Protease inhibitors have also been identified as useful in the management of cachexia. Preventing muscle wasting is crucial, as sustained skeletal muscle wasting exceeding 70%, which corresponds to a body weight loss between 30 to 40%, becomes rapidly deleterious and ultimately results in increased morbidity and mortality. Protease inhibitors also possess anticancer activity. In one study, six HIV protease inhibitors were screened in vitro in non-small cell lung carcinoma (NSCLC) xenografts for anticancer efficacy. The HIV protease inhibitors nelfinavir, ritonavir, and saquinavir inhibited NSCLC cell proliferation, with nelfinavir being the most potent agent with a mean GI₅₀ of 5.2 μM, a physiologically-tolerable concentration. It was also found that nelfinavir caused two types of cell death, caspase-dependent apoptosis and autophagy, and that nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Finally, nelfinavir also decreased the viability of a panel of drug-resistant breast cancer cell lines. (See Gills JJ, Lopiccolo J, Tsurutani J, Shoemaker RH, Best CJ, Abu-Asab MS, Borojerdi J, Warfel NA, Gardner ER, Danish M₅ Hollander MC, Kawabata S, Tsokos M, Figg WD, Steeg PS, and Dennis PA (2007). Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res. 13:5183-5194, herein incorporated by reference.)

Finally, the hormone melatonin, produced, among other tissue, by the pineal gland, advances sleep and circadian phase upon exogenous administration to patients presenting delayed sleep phase syndrome, a circadian-rhythm sleep disorder characterized by abnormally late sleep and wake times. (See Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, and Zee PC (2005). Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep 28:1271-1278, herein incorporated by reference.) Significantly, it has also been well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments, consistent with melatonin's role in the protection of lipids, proteins, cellular membranes, and both nuclear and mitochondrial DNA, by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. (See Reiter RJ, Acuna-Castroviejo D, Tan DX, and Burkhardt S (2001). Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann NY Acad Sci 939:200-215, herein incorporated by reference.)

One researcher has noted that melatonin has also been identified as a new member of an expanding group of regulatory factors that control cell proliferation and loss and is the only known chronobiotic hormonal regulator of neoplastic cell growth. At physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status by altering adhesion molecules and maintaining gap junction intercellular communication. In other cancer cell types, melatonin, alone or with other agents, induces programmed cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cell structure and function, intracellular oxidation-reduction status, melatonin-receptor-mediated signal transduction cascades, and fatty acid transport and metabolism. One of the main ways melatonin inhibits tumor growth at certain stages in the circadian cycle is by suppressing the activity of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK). This effect occurs via melatonin-receptor-mediated blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE), which normally activates EGFR/MAPK mitogenic signalling. The researcher concluded that not only is this is a potentially unifying model for melatonin's chronobiological inhibitory regulation of cancer growth in maintaining host-cancer balance but also the first biological explanation of how melatonin enhances the efficacy and reduces the toxicity of chemotherapy and radiotherapy in cancer patients. (See Blask D (2003). Melatonin: an integrative chronobiotic anticancer therapy whose time has come. [Electronic version]. In The NCl Office of Cancer Complementary and Alternative Medicine Invited Speaker Series: Melatonin, Chronobiology, and Cancer. Retrieved May 28, 2009 from http://www.cancer.gov/CAM/attachments/MelatoninSummary.pdf, herein incorporated by reference.)

Given the severity of the effects of mitochondrial dysfunction seen in cancer, where aberrant energy metabolism is seen not only in cancer cells but also in healthy cells, and the potential to counteract these effects through the administration of various substances in the form of medicaments, it would hence be desirable to incorporate such medicaments with derivatives of lipoic acid into therapeutic and/or diagnostic formulations intended to improve glucose uptake and the oxidation of nutrients in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells. Furthermore, it would also be desirable to use additional substances that may enhance the body's own ability to adjust hormone levels and growth and repair functions during sleep in combination with those substances that establish healthy oxidative metabolism. It would be even more desirable that most, if not all, of these medicaments also have demonstrated anticancer activity. It would also be even more desirable to have medicaments in a novel combination with lipoic acid wherein the combination demonstrates synergistic effects in both mechanism of action and clinical efficacy, such effects not having been demonstrated in the prior art. Optimally, then, it would be desirable to prepare therapeutic and/or diagnostic formulations which improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells, for either single daily independent use or binary use as a morning and/or nighttime medicament.

Objects of the Invention and Industrial Applicability

Consequently, it is an object of the present invention to provide therapeutic and/or diagnostic formulations that improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells, which are acceptably chemically pure and stable.

It is a further object of the present invention to provide therapeutic and/or diagnostic formulations that improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells, which are of reasonable cost and commercial availability.

It is a still further object of the present invention to provide therapeutic and/or diagnostic formulations that improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells, which may be administered either as a single daily independent medicament or as a binary morning and nighttime medicament for ease of use. It is a still further object of the present invention to provide therapeutic and/or diagnostic formulations that improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products in normal cells while nevertheless impairing energy metabolism in cancer cells, which demonstrates synergistic effects in both mechanisms of action and clinical efficacy.

Summary of the Invention

In accordance with the aforementioned aims, the present invention broadly provides therapeutic and/or diagnostic formulations intended to improve glucose uptake and the oxidation of nutrients in warm-blooded animals, including humans, presenting with cancer, in a manner that diminishes toxic by-products generated by these metabolic events. In a general embodiment of the therapeutic and/or diagnostic formulations of the present invention, effective amounts of derivatives of alkyl fatty acids are formulated or co-formulated with effective amounts of nutritional supplements such as but not limited to excipient mixtures of plant extracts, which may be purified. In a preferred embodiment of the present invention, effective amounts of derivatives of thiol-containing alkyl fatty acids, such as but not limited to derivatives of lipoic acid and analogs thereof, are co-formulated with effective amounts of naturally-occurring or synthetic antioxidants, amino acids, peptides, protease inhibitors, trace elements, vitamins, botanical extracts, and carbohydrates. In a more preferred embodiment of the present invention, the alkyl fatty acid is octanoic acid, and in a more preferred embodiment of the present invention, the thiol-containing alkyl fatty acid is lipoic acid; the antioxidant, without limitation, is quercetin; the amino acids include those amino acids considered "essential" to human health, and precursors, analogs, and metabolites thereof, including but not limited to tryptophan, its metabolite 5-hydroxytryptamine, and N-acetyl-L- carnitine and/or derivatives thereof, including but not limited to propionyl L-carnitine; the proteins and peptides include but are not limited to melatonin and serratiopeptidase and/or analogs, congeners, and mimetics of each thereof; the trace elements include but are not limited to indium sulfate; the plant extracts include but are not limited to eggplant extract, resveratrol-containing extracts such as but not limited to grape and grape seed extracts, guarana extract, purified or synthetic whole-plant cannabis extract, vanilla extract, cinnamon, nutmeg, cloves, and turmeric; the protease inhibitor is soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; and the carbohydrates and analogs thereof include but are not limited to beta-glucans, fiber extracts, pulps, and simple and complex sugars and analogs thereof. More preferably, the beta-glucan is β-l,3-glucan or β-l,6-glucan. The additional plant extracts also possess energy metabolism-regulating and antioxidant capacity. Suitable mimetics for melatonin to promote sleep during the consumer's resting period include chamomile extract, valerian extract, and 5-hydroxytryptamine. Specific amounts of each ingredient to be added to the formulation are herein provided. Furthermore, pharmaceutically-acceptable carriers and excipients may be included in the formulation as necessary.

The thiol-containing alkyl fatty acid derivatives to be used in the therapeutic and/or diagnostic formulations of the present invention have the general formula:

and derivatives, congeners, and salts thereof,

wherein R₃ is alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18;

wherein Ri and/or R₂ is aryl and/or aromatic;

wherein R₄, is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH₂;

wherein Ri, R₂, R₃, and/or R₄ may be phosphorylated; and wherein R₁, R₂, R₃, and/or R₄ may be so modified as to modulate the binding affinity of the compound to carrier molecules in vivo so as to regulate the amount of circulating time the compound spends in the blood.

The derivatives of N-acetyl-L-carnitine used in the therapeutic and/or diagnostic formulations of the present invention have the general structure:

and derivatives, congeners, and salts thereof,

wherein R is N or sulfonium;

and wherein R₁ is H; alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18; aryl; aromatic; -COOH; or -NH₂. In a preferred embodiment, the derivative is propionyl L-carnitine.

Each of the ingredients to be used in the formulation of the present invention shall have either a direct or an indirect effect on the consumer's metabolism by normalizing glucose uptake and the oxidation of nutrients in normal cells while nevertheless impairing energy metabolism in cancer cells. The therapeutic benefits of these ingredients are expected to be produced, activated, inactivated, or altered by in vivo metabolic events in a consumer presenting a diseased and/or metabolically-inefficient state. Such metabolic events may occur in specific cellular organelles, such as but not limited to endosomes or mitochondria, or throughout any tissue, such as but not limited to heart, kidney, lung, and liver. The therapeutic beneficial effects are achieved in various ways, including but not limited to the upregulation of glucose transporters; upregulation of enzymes which are used in glycloysis and/or the TCA cycle; imparting greater efficiency to glycolytic, dehydrogenase, and/or TCA cycle enzymes; and/or decreasing the downregulation of these enzymes and processes. Significantly, due to the properties of the ingredients to be used in the therapeutic and/or diagnostic formulations of the present invention, it is expected that these effects shall not cause increased accretion of toxic by-products in the target cell, tissue, or organ.

In a preferred embodiment of the present invention, the therapeutic and/or diagnostic formulation is administered as a single daily independent medicament. Consequently, melatonin is deleted from the formulation to prevent drowsiness during the consumer's waking period. However, in a still more preferred embodiment of the present invention, to promote not only increased metabolic activity during the consumer's waking period but also the adjustment of hormone levels and the promotion of growth and repair functions during sleep, the therapeutic and/or diagnostic formulation may be prepared for binary use as a co- administered morning and nighttime medicament regimen, in which both N-acetyl-L- carnitine and/or derivatives thereof, guarana, and whole-plant cannabis extract are present in the morning administration to markedly increase metabolism and appetite during the consumer's waking period but replaced with melatonin to promote sleep during the consumer's resting period.

Brief Description of the Figures

FIGURE 1 is a graph showing median tumor volume over time in a human H460 NSCLC murine xenograft treated with either a thiol-containing alkyl fatty acid derivative alone or in combination with the therapeutic and/or diagnostic formulations of the present invention, as compared to non-treated tumor bearing mice.

FIGURE 2 is a graph depicting average tumor volume over time in a human H460 NSCLC murine xenograft treated with either a thiol-containing alkyl fatty acid derivative alone or in combination with the therapeutic and/or diagnostic formulations of the present invention, as compared to non-treated tumor bearing mice.

FIGURE 3 is a graph illustrating median tumor volume over time in a human H460

NSCLC murine xenograft treated with either paclitaxel alone or in combination with the therapeutic and/or diagnostic formulations of the present invention, as compared to non- treated tumor bearing mice.

FIGURE 4 is a graph showing average tumor volume over time in a human H460 NSCLC murine xenograft treated with either paclitaxel alone or in combination with the therapeutic and/or diagnostic formulations of the present invention, as compared to non- treated tumor bearing mice.

FIGURE 5 is a graph showing average tumor volume over time in a human BXPC3 pancreatic cancer murine xenograft treated with either one concentration of gemcitabine or with the therapeutic and/or diagnostic formulations of the present invention, as compared to non-treated tumor bearing mice.

FIGURE 6 is a graph showing average tumor volume over time in a human BXPC3 pancreatic cancer murine xenograft treated with either a second concentration of gemcitabine or with the therapeutic and/or diagnostic formulations of the present invention, as compared to non-treated tumor bearing mice.

FIGURE 7 is a graph showing survival rates over time in a human BXPC3 pancreatic cancer murine xenograft treated with either gemcitabine or with the therapeutic and/or diagnostic formulations of the present invention, as compared to non-treated tumor bearing mice. Detailed Description of the Invention

The present invention broadly provides therapeutic and/or diagnostic formulations intended to improve glucose uptake and the oxidation of nutrients, in a manner that diminishes toxic by-products generated by these metabolic events in normal cells while nevertheless impairing energy metabolism in cancer cells, in warm-blooded animals, including those of the mammalian class, such as humans, domestic animals including dogs and cats, horses, cattle, etc. In a general embodiment of the therapeutic and/or diagnostic formulations of the present invention, effective amounts of derivatives of alkyl fatty acids are formulated or co-formulated with effective amounts of nutritional supplements such as but not limited to excipient mixtures of plant extracts, which may be purified.

In a preferred embodiment of the present invention, effective amounts of derivatives of thiol-containing alkyl fatty acids, such as but not limited to derivatives of lipoic acid and analogs thereof, are co-formulated with effective amounts of naturally-occurring or synthetic antioxidants, amino acids, peptides, protease inhibitors, trace elements, botanical extracts, and carbohydrates. As a cofactor of various dehydrogenase complexes which affect glycolysis and the TCA cycle, lipoic acid will increase both glucose uptake due to the upregulation of glucose transporters on the plasma membrane and ultimate enhanced glycolytic capacity and enhanced cellular energy metabolism. Each of the additional ingredients to the therapeutic and/or diagnostic formulation of the present invention is also expected to contribute to this enhanced cellular energy metabolism caused by increased levels of lipoic acid, either through direct effect (e.g., direct enhancement of glucose uptake or glycolytic or TCA cycle activity) or through indirect effect (e.g., regulation of energy metabolism-controlling hormones, appetite, or sleep-wake cycles). It is expected that the lipoic acid derivatives used in the present invention should have the same effect in cancer cells.

The thiol-containing alkyl fatty acid derivatives to be used in the therapeutic and/or diagnostic formulations of the present invention have the general formula:

and derivatives, congeners, and salts thereof,

wherein R₃ is alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18; wherein R] and/or R₂ is aryl and/or aromatic;

wherein R₄, is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH₂;

wherein R], R₂, R₃, and/or R₄ may be phosphorylated;

and wherein R], R₂, R₃, and/or R₄ may be so modified as to modulate the binding affinity of the compound to carrier molecules in vivo so as to regulate the amount of circulating time the compound spends in the blood.

In a more preferred embodiment of the present invention, the alkyl fatty acid is octanoic acid, and in a more preferred embodiment of the present invention, the alkyl fatty acid is lipoic acid.

The derivatives of N-acetyl-L-carnitine used in the therapeutic and/or diagnostic formulations of the present invention have the general structure:

and derivatives, congeners, and salts thereof,

wherein R is N or sulfonium;

and wherein Ri is H; alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18; aryl; aromatic; -COOH; or -NH_2. In a preferred embodiment, the derivative is propionyl L-carnitine.

In a more preferred embodiment of the present invention, then, the alkyl fatty acid is lipoic acid; the antioxidant is quercetin, without limitation; the amino acids include those amino acids considered "essential" to human health, and precursors, analogs, and metabolites thereof, including but not limited to N-acetyl-L-carnitine and/or derivatives thereof, including but not limited to propionyl L-carnitine; the proteins and peptides include but are not limited to melatonin and serratiopeptidase; the trace elements include but are not limited to indium sulfate; the plant extracts include but are not limited to eggplant extract, resveratrol- containing extracts such as but not limited to grape and grape seed extracts, guarana extract, purified or synthetic whole-plant cannabis extract, vanilla extract, cinnamon, nutmeg, cloves, and turmeric; the protease inhibitor is soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; and the carbohydrates and analogs thereof include but are not limited to beta-glucans, fiber extracts, pulps, and simple and complex sugars and analogs thereof. More preferably, the beta-glucan is β-l,3-glucan or β-l,6-glucan. These additional botanical extracts also possess energy metabolism-regulating and antioxidant capacity. Suitable mimetics for melatonin to promote sleep during the consumer's resting period include chamomile extract, valerian extract, and 5- hydroxytryptamine .

The therapeutic benefits of these ingredients are expected to be produced, activated, inactivated, or altered by in vivo metabolic events in a consumer presenting a diseased and/or metabolically-inefficient state. Such metabolic events may occur in specific cellular organelles, such as but not limited to endosomes or mitochondria, and/or throughout any tissue, such as but not limited to skeletal muscle, heart, kidney, and liver. The therapeutic beneficial effects are achieved in various ways, including but not limited to the upregulation of glucose transporters; upregulation of enzymes which are used in glycloysis and/or the TCA cycle; imparting greater efficiency to glycolytic, dehydrogenase, and/or TCA cycle enzymes; upregulation of hormones which regulate cellular energy metabolism; and/or decreasing the downregulation of these hormones, enzymes, and/or processes. Significantly, due to the properties of the ingredients to be used in the therapeutic and/or diagnostic formulations of the present invention, it is expected that these effects shall not cause increased accretion of toxic by-products in the target cell, tissue, or organ. Furthermore, it is expressly contemplated the ingredients of the therapeutic and/or diagnostic formulations of the present invention may be metabolized in vivo but the metabolites retain the beneficial capacity of the original non-metabolized ingredient

The therapeutic and/or diagnostic formulations of the present invention are also expected to be useful in such general cancer types as carcinoma, sarcoma, lymphoma and leukemia, germ cell tumor, and blastoma. More specifically, these formulations are expected to be useful in primary or metastatic melanoma, lung cancer, liver cancer, Hodgkin's and non- Hodgkin's lymphoma, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, and pancreatic cancer, without limitation.

The therapeutic and/or diagnostic formulations of the present invention are expected to be of diagnostic benefit as well. Where a patient is suspected of having one of the aforementioned conditions, the formulation may be administered before, after, or both before and after a diagnostic examination modality (e.g., MRI, CT, SPECT, PET, or a glucose tolerance test, without limitation) is administered. Comparing the patient's results upon such administration to his own baseline or to a metabolically-efficient standard will aid the examiner to determine and/or confirm the incidence of a mitochondrial pathology or other underlying energy metabolism disorder. Where a glucose tolerance test is the modality used, glucose is co-administered with the therapeutic and/or diagnostic formulations of the present invention to ascertain both blood glucose and blood insulin levels to assure more accurate energy metabolism analysis.

The thiol-containing alkyl fatty acid derivatives to be used to synthesize the therapeutic and/or diagnostic formulations of the present invention described herein may have asymmetric centers, and the R-isomer of a particular active compound may possess greater physiological activity than does the S-isomer. Consequently, all chiral, diastereomeric, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated, and the active compound should be present either solely in its R- or S-isomer form or in a mixture of the R- and S-isomers. Additionally, where carbohydrates are co-formulated, both D and L isomers of the carbohydrates are contemplated as being within the range of the present invention.

The therapeutic and/or diagnostic formulations of the present invention may further include a pharmaceutically-acceptable carrier or excipients. Examples of pharmaceutically- acceptable carriers are well known in the art and include those conventionally used in pharmaceutical compositions, such as, but not limited to, salts, antioxidants, buffers, chelating agents, flavorants, colorants, preservatives, absorption promoters to enhance bioavailability, antimicrobial agents, and combinations thereof, optionally in combination with other therapeutic ingredients. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically-acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically- and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, palicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

The methods of the present invention may be practiced using any mode of administration that is medically acceptable, and produces effective levels of the compounds without causing clinically unacceptable adverse effects. It is intended that the therapeutic and/or diagnostic formulations of the present invention be ingested orally, such as in a drink or food; a drink may be prepared from a powder. Although formulations specifically suited for oral administration are preferred, the compositions of the present invention can also be formulated for inhalational, parenteral, topical, transdermal, nasal, ocular, pulmonary, rectal, transmucosal, intravenous, intramuscular, subcutaneous, intraperitoneal, intrathoracic, intrapleural, intrauterine, intratumoral, or infusion methodologies or administration, in the form of aerosols, sprays, powders, gels, lotions, creams, suppositories, ointments, and the like. Additionally, where the ingredients of the formulation are to be pressed into a tablet, the tablet may be further constituted with an enteric coating to prevent gastrointestinal upset. If such other formulations are desired, other additives well-known in the art may be included to impart the desired consistency and other properties to the formulation, such as but not limited to the ability of the ingredients to be released over time. Those skilled in the art will recognize that the particular mode of administering the therapeutic and/or diagnostic formulation depends on the particular agent selected; the severity of the consumer's inefficiency of energy metabolism; and the dosage required for imaging efficacy.

As used herein, "effective amount" refers to the dosage or multiple dosages of the therapeutic and/or diagnostic formulation at which a particular desired metabolic or physiological effect is achieved. Generally, an effective amount of the therapeutic and/or diagnostic formulation may vary with the activity of the specific agent employed; the metabolic stability and length of action of that agent; the species, age, body weight, general health, dietary status, sex and diet of the subject; the mode and time of administration; rate of excretion; drug combination, if any; and extent of presentation and/or severity of the particular condition being treated. The precise dosage can be determined by an artisan of ordinary skill in the art without undue experimentation, in one or several administrations per day, to yield the desired results, and the dosage may be adjusted to achieve a desired therapeutic effect or in the event of any complication.

Generally, the therapeutic and/or diagnostic formulations of the present invention will be delivered in a manner sufficient to administer to the consumer an amount effective to deliver a particular agent to its intended molecular target and can be prepared in any amount desired up to the maximum amount that can be administered safely to a consumer. The amount of the therapeutic and/or diagnostic formulation may range from less than 0.01 mg/mL to greater than 1000 mg/mL, preferably about 50 mg/mL. The dosage amount may thus range from about 0.3 mg/m² to 2000 mg/m², preferably about 60 mg/m².

As for the ingredients used in the therapeutic and/or diagnostic formulations of the present invention, each individual ingredient may be present in an amount ranging from 0.5 mg to 1000 mg per dose. In a preferred embodiment of the present invention, the formulation of the therapeutic and/or diagnostic formulation contains 300 mg lipoic acid derivative; 5 mg indium sulfate; 10 mg eggplant extract; 7 mg whole-plant cannabis extract; 37.5 mg guarana; 200 mg N-acetyl-L-carnitine and/or 200 mg propionyl L-carnitine; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof; and 2 mg melatonin and/or analogs, congeners, and mimetics thereof, each per dose. This is intended for daily use as a single independent medicament.

However, in a second preferred embodiment of the present invention, to promote not only increased cellular energy metabolic activity during the consumer's waking period but also the adjustment of hormone levels and the promotion of growth and repair functions during sleep, the therapeutic and/or diagnostic formulation may be prepared for binary use as a co-administered morning and nighttime medicament regimen. In this embodiment, the formulation of the therapeutic and/or diagnostic morning formulation again contains 300 mg lipoic acid derivative; 5 mg indium sulfate; 10 mg eggplant extract; 200 mg N-acetyl-L- carnitine and/or 200 mg propionyl L-carnitine; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 37.5 mg guarana; 7 mg whole-plant cannabis extract; and 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof, each per dose, to markedly increase metabolism during the consumer's waking period. In the therapeutic and/or diagnostic nighttime formulation, on the other hand, to promote sleep during the consumer's resting period, the carnitine, guarana, and whole-plant cannabis extracts are removed, and the formulation of the therapeutic and/or diagnostic nighttime formulation thus contains 300 mg lipoic acid derivative; 5 mg indium sulfate; 10 mg eggplant extract; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 50 mg serratiopeptidase; and 2 mg melatonin and/or analogs, congeners, and mimetics thereof, each per dose.

The dosage amount may be administered in a single daily dose or in the form of individual divided doses, such as from one to four or more times per day. In the event that the response in a subject is insufficient at a certain dose, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent of consumer tolerance.

The following non-limiting examples are provided both to facilitate understanding of the therapeutic and/or diagnostic formulations of the present invention and to exemplify the invention and are not to be construed as limiting the invention's scope.

Example 1 ^'

Assessment of the Effect of Cellimmune Administered Alone or in Combination with 6,8-6/5-benzylthio-octanoic Acid or Paclitaxel on Tumor Growth Inhibition in a Human

NSCLC Murine Xenograft Model The objective of this study was to assess the effects of the therapeutic and/or diagnostic formulation of the present invention (Cellimmune) alone or in combination with 6,8-fos-benzylthio-octanoic acid (CPI-613) or paclitaxel on tumor growth inhibition in a NSCLC murine xenograft model.

Study Design. Materials, and Methods

Materials

Animals

CDl-Nu/Nu female mice, approximately 28 days old, from Charles River Laboratories were housed five to a cage in a micro-isolator room in the Stony Brook University (SUNY) Department of Animal Laboratory Research. Animals were provided food (Purina Rodent Chow) and sterile distilled water ad libitum. Protocols and procedures were according to the rules of and approved by the SUNY Institutional Animal Care and Use Committee.

Cell Line Origin and Culture

Human H460 NSCLC cells were used in this investigation. These tumor cells were originally obtained from American Type Cell Culture (ATCC) (Manassas, VA) and tested negative for viral contamination using the Mouse Antibody Production (MAP) test, performed by Charles River Labs Molecular Division, upon receipt from ATCC. The tumor cells were maintained at 37°C in a humidified 5% CO₂ atmosphere in T225 tissue culture flasks containing 50 mL of Roswell Park Memorial Institute (RPMI)- 1640 solution with 10% Fetal Bovine Serum (FBS) and 2 mM L-glutamine. Cells were split at a ratio of 1:10 every 2-3 days by trypsinization and resuspended in fresh medium in a new flask. Cells were harvested for experiments in the same way at 70-90% confluency.

Test articles, and preparation of and route of administration thereof The test articles are listed in Table 1. Specifically, the test articles will be paclitaxel for injection, CPI-613, and Cellimmune.

CPI-613 (50 mg/mL):

Immediately prior to dosing, the CPI-613 solution was diluted with 5% dextrose to an appropriate concentration, such that the dose volume per injection is 2.0 mL, to be administered via bolus IP injection three times a week for four weeks. Mice were to be dosed with either CPI-613 alone or in combination with Cellimmune at 1.0 and 10 mg/kg.

Paclitaxel (6mg/mL):

Immediately prior to dosing, paclitaxel was diluted with 5% dextrose to the appropriate concentration, such that the dose volume is 2mL, to be administered via bolus IP injection three times a week for four weeks. Mice were to be dosed with either paclitaxel alone or in combination with Cellimmune at 5.0 and 20 mg/kg.

Cellimmune (1 gram tablet):

Immediately prior to dosing, one tablet of Cellimmune was crushed with a mortar and pestle to a fine powder and divided into 1 mg equivalents. Each 1 mg aliquot was suspended in 5% dextrose (pH adjusted to 7.0 with 0.05M sodium phosphate), such that the dose volume is 0.2 mL, to be orally administered to the mice. Cellimmune was to be orally administered through a gavage needle, once daily for a total of five doses per week for four weeks either alone or with either CPI-613 or paclitaxel. On the days that either CPI-613 or paclitaxel is administered, Cellimmune will be administered immediately by p.o. administration. Table 1: Test Articles

Treatment Groups, Doses and Routes of Administration

As seen in Table 2, there were a total often groups of mice studied with ten animals per group: nine tumor-bearing treatment groups and one tumor-bearing group which was not treated with any of the test agents or 5% dextrose.

Table 2: Treatment Groups

Methods

An acclimation period of 7 days was allowed between the arrival of the animals at the study site before tumor inoculation and experimentation. Mice were inoculated subcutaneously (SC) in the right flank with 2 xlθ^δ human H460 NSCLC cells that were suspended in 0.1 mL of Dulbeco's Phosphate Buffered Salt (PBS) solution using a 1 cc syringe with a 27-5/8 gauge needle. Tumor dimensions (length and width) were measured three times weekly (using Vernier calipers), and the tumor volume was calculated using the prolate ellipsoid formula: (length x width²)/2. The mice were monitored daily for physical condition and mortality. Body weight was determined immediately prior to administration of test article or control article. Treatment with test or control articles began when the tumor was approximately 150mm³. Results

As seen in FIGURES 1 and 2, the median and average tumor volumes for those mice treated with Cellimmune in combination with CPI-613 at both tested concentrations or with either agent alone are significantly lower over time than those mice not treated with any agent. It is noteworthy, however, that the combination of Cellimmune and CPI-613 demonstrated marginal but noticeable decreased tumor volume over time versus that seen with CPI-613 alone. Indeed, the combination of 1.0 mg/kg CPI-613 with Cellimmune appears at least as effective as Cellimmune alone in decreasing tumor volume over time, with both treatments being marginally more effective than the combination of 10 mg/kg CPI-613 with Cellimmune.

Turning to FIGURES 3 and 4, it is evident that the combination of Cellimmune with paclitaxel at either tested concentration decreases median and average tumor volume over time significantly versus those volumes observed in both non-treated animals and those animals administered paclitaxel alone. While, as with CPI-613, the lower concentration of paclitaxel (5.0 mg/kg) in combination with Cellimmune was the more efficacious of the two concentrations in decreasing median and average tumor volume over time, it is remarkable that Cellimmune administration alone displays the most efficacy in doing so.

Overall, then, in vivo studies of Cellimmune administered either alone or in combination with other compounds to tumor-bearing animals demonstrates significant tumor growth inhibition properties in NSCLC.

Example 2

Assessment of the Effect of Cellimmune Administered Alone or in Combination with Gemcitabine on Tumor Growth Inhibition and Survival Rates in a Human Pancreatic

Murine Xenograft Model The objective of this study is to assess the effects of Cellimmune administered alone or in combination with gemcitabine on tumor growth inhibition and survival rates in a human pancreatic cancer murine xenograft model. Study Design, Materials, and Methods

Materials

Animals

Mice were provided and treated as per Example 1. Cell Line Origin and Culture

Human BxPC3 pancreatic cancer cells originally obtained from ATCC (Manassas, VA) were used in this investigation as per Example 1.

Test articles, and preparation of and route of administration thereof

The test articles are listed in Table 3. Specifically, the test articles will be gemcitabine and Cellimmune.

Gemcitabine (38 mg/mL):

Immediately prior to dosing, the gemcitabine solution will be diluted with 0.9% NaCl to an appropriate concentration, such that the dose volume per injection is 2.0 niL, and administered via bolus IP injection once per week for four weeks. Mice will be dosed with either gemcitabine alone or in combination with Cellimmune. The dosing concentrations for gemcitabine are 8.0 and 80 mg/kg. Cellimmune (1 gram tablet):

Immediately prior to dosing, one tablet of Cellimmune was crushed with a mortar and pestle to a fine powder and divided into 1 mg equivalents. Each 1 mg aliquot was suspended in 5% dextrose (pH adjusted to 7.0 with 0.05M sodium phosphate), such that the dose volume is 0.2 mL, to be orally administered to the mice. Cellimmune was to be orally administered through a gavage needle, once daily for a total of five doses per week for four weeks either alone or with gemcitabine. On the days that gemcitabine is administered, Cellimmune will be administered immediately by p.o. administration.

Table 3: Test Articles

Treatment Groups. Doses and Routes of Administration

As seen in Table 4, there were a total of six groups of mice studied with nine animals per group: five tumor-bearing treatment groups and one tumor-bearing group which was not treated with any of the test agents, 5% dextrose, or 0.9% NaCl.

Table 4: Treatment Groups

Methods

The implantation of the BXPC3 cells and all subsequent analysis was performed as per Example 1.

Results

As seen in FIGURES 5 and 6, Cellimmune significantly decreases average tumor volume over time compared to either 8.0 or 80 mg/kg of gemcitabine versus non-treated animals. Turning to FIGURE 7, this ultimately translates into an approximately 10% improvement in overall survival rate when using Cellimmune versus using either concentration of gemcitabine alone; significantly, however, overall survival rates are improved by approximately 40% when administering Cellimmune versus those rates observed in non-treated animals. Overall, then, these experiments demonstrate that Cellimmune displays significant tumor growth inhibition properties in pancreatic cancer.

The foregoing discussion discloses and describes merely specific exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion, and from the accompanying claims, that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the inventive concept as defined in the following claims. Furthermore, while exemplary embodiments have been expressed herein, others practiced in the art may be aware of other designs or uses of the present invention. Also, all patent applications, patents, and other publications cited herein are incorporated by reference in their entirety. Thus, while the present invention has been described in connection with exemplary embodiments thereof, it will be understood that many modifications in both design and use will be apparent to those of ordinary skill in the art, and this application is intended to cover any changes, modifications, adaptations, or variations thereof. It is therefore manifestly intended that this invention be limited only by the claims and the equivalents thereof.

Claims

The invention to be claimed is:

1. A therapeutic and/or diagnostic formulation intended for single daily independent administration to warm-blooded animals, including humans, presenting with cancer, comprising a derivative of an alkyl fatty acid co-formulated with excipient mixtures of plant extracts, antioxidants, and trace minerals.

2. The therapeutic and/or diagnostic formulation of claim 1, wherein the alkyl fatty acid contains from three to twenty carbons.

3. The therapeutic and/or diagnostic formulation of claim 1, wherein the alkyl fatty acid has eight carbons.

4. The therapeutic and/or diagnostic formulation of claim 1, wherein the alkyl fatty acid is a thiol-containing fatty acid.

5. The therapeutic and/or diagnostic formulation of claim 4, wherein the thiol- containing fatty acid is lipoic acid.

6. The therapeutic and/or diagnostic formulation of claim 4, wherein the thiol- containing fatty acid derivative has the general formula:

and derivatives, congeners, and salts thereof,

wherein R₃ is alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18;

wherein Ri and/or R₂ is aryl and/or aromatic;

wherein R₄, is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH₂;

wherein Ri, R₂, R₃, and/or R₄ may be phosphorylated; and wherein Ri, R₂, R₃, and/or R₄ may be so modified as to modulate the binding affinity of the compound to carrier molecules in vivo so as to regulate the amount of circulating time the compound spends in the blood.

7. The therapeutic and/or diagnostic formulation of claim 6, wherein the derivative is present as the R-isomer thereof.

8. The therapeutic and/or diagnostic formulation of claim 6, wherein the derivative is present as a racemic mixture thereof.

9. The therapeutic and/or diagnostic formulation of claim 1, wherein the plant extract comprises eggplant extract and whole-plant cannabis extract.

10. The therapeutic and/or diagnostic formulation of claim 7, wherein the plant extracts further comprise resveratrol-containing extracts, such as but not limited to grape and grape seed extracts; guarana extract; vanilla extract; cinnamon; nutmeg; cloves; and/or turmeric.

11. The therapeutic and/or diagnostic formulation of claim 1, wherein the trace element is indium sulfate.

12. The therapeutic and/or diagnostic formulation of claim 1, wherein the antioxidant is quercetin.

13. The therapeutic and/or diagnostic formulation of claim 1, further comprising N-acetyl-L-carnitine and/or derivatives thereof.

14. The therapeutic and/or diagnostic formulation of claim 13, wherein the derivatives of N-acetyl-L-carnitine have the general structure:

and derivatives, congeners, and salts thereof,

wherein R is N or sulfonium; and wherein Ri is H; alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18; aryl; aromatic; -COOH; or -NH_2.

15. The therapeutic and/or diagnostic formulation of claim 14, wherein the derivative is propionyl L-carnitine.

16. The therapeutic and/or diagnostic formulation of claim 1, further comprising carbohydrates.

17. The therapeutic and/or diagnostic formulation of claim 16, wherein the carbohydrates are beta-glucans, fiber extracts, pulps, and simple and complex sugars and analogs thereof.

18. The therapeutic and/or diagnostic formulation of claim 17, wherein the beta- glucan is β-l,3-glucan.

19. The therapeutic and/or diagnostic formulation of claim 17, wherein the beta- glucan is β-l,6-glucan.

20. The therapeutic and/or diagnostic formulation of claim 1 , further comprising serratiopeptidase and/or analogs, congeners, and mimetics thereof.

21. The therapeutic and/or diagnostic formulation of claim 1, further comprising melatonin and/or analogs, congeners, and mimetics thereof.

22. The therapeutic and/or diagnostic formulation of claim 1, further comprising at least one protease inhibitor, such as but not limited to a cysteine protease inhibitor, a serine protease inhibitor, a threonine protease inhibitors, an aspartic protease inhibitors, and/or a metalloprotease inhibitor.

23. The therapeutic and/or diagnostic formulation of claim 22, wherein the protease inhibitor is soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof.

24. The therapeutic and/or diagnostic formulation of claim 1, wherein the ingredients of the formulation are present in an amount effective to improve glucose uptake and the oxidation of nutrients in the consumer while diminishing the amount of toxic byproducts generated by these metabolic events in normal cells and impairing energy metabolism in cancer cells.

25. The therapeutic and/or diagnostic formulation of claim 1, wherein the ingredients of the formulation are individually present in amounts ranging from 0.5 mg to 1000 mg per dose.

26. The therapeutic and/or diagnostic formulation of claim 25, wherein the ingredients are present in amounts of 300 mg lipoic acid derivative; 5 mg indium sulfate; 10 mg eggplant extract; 200 mg N-acetyl-L-carnitine and/or 200 mg propionyl L-carnitine; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof; 37.5 mg guarana; and 2 mg melatonin and/or analogs, congeners, and mimetics thereof, each per dose.

27. The therapeutic and/or diagnostic formulation of claim 1, further comprising a pharmaceutically-acceptable carrier therefor.

28. A therapeutic and/or diagnostic formulation intended for binary morning and nighttime administration to warm-blooded animals, including humans, presenting with cancer, comprising a derivative of an alkyl fatty acid co-formulated with excipient mixtures of plant extracts, antioxidants, and trace minerals.

29. The therapeutic and/or diagnostic formulation of claim 28, wherein the alkyl fatty acid has three to twenty carbons.

30. The therapeutic and/or diagnostic formulation of claim 29, wherein the alkyl fatty acid has eight carbons.

31. The therapeutic and/or diagnostic formulation of claim 28, wherein the alkyl fatty acid is a thiol-containing fatty acid.

32. The therapeutic and/or diagnostic formulation of claim 31, wherein the thiol- containing fatty acid is lipoic acid.

33. The therapeutic and/or diagnostic formulation of claim 31, wherein the thiol- containing fatty acid derivative has the general formula:

and derivatives, congeners, and salts thereof,

wherein R₃ is alkyl defined as C_nH2_n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18;

wherein Ri and/or R₂ is aryl and/or aromatic;

wherein R₄, is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH₂;

wherein Ri, R₂, R₃, and/or R₄ may be phosphorylated;

and wherein Ri, R₂, R₃, and/or R₄ may be so modified as to modulate the binding affinity of the compound to carrier molecules in vivo so as to regulate the amount of circulating time the compound spends in the blood.

34. The therapeutic and/or diagnostic formulation of claim 28, wherein the derivative is present as the R-isomer thereof.

35. The therapeutic and/or diagnostic formulation of claim 28, wherein the derivative is present as a racemic mixture thereof.

36. The therapeutic and/or diagnostic formulation of claim 28, wherein the plant extract comprises eggplant extract.

37. The therapeutic and/or diagnostic formulation of claim 36, wherein the plant extracts further comprise whole-plant cannabis extract; resveratrol-containing extracts, such as but not limited to grape and grape seed extracts; guarana extract; vanilla extract; cinnamon; nutmeg; cloves; and/or turmeric.

38. The therapeutic and/or diagnostic formulation of claim 28, wherein the trace element is indium sulfate.

39. The therapeutic and/or diagnostic formulation of claim 28, wherein the antioxidant is quercetin.

40. The therapeutic and/or diagnostic formulation of claim 28, further comprising serratiopeptidase and/or analogs, congeners, and mimetics thereof.

41. The therapeutic and/or diagnostic formulation of claim 28, further comprising at least one protease inhibitor, such as but not limited to a cysteine protease inhibitor, a serine protease inhibitor, a threonine protease inhibitors, an aspartic protease inhibitors, and/or a metalloprotease inhibitor.

42. The therapeutic and/or diagnostic formulation of claim 41, wherein the protease inhibitor is soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof.

43. The therapeutic and/or diagnostic formulation of claim 28, further comprising N-acetyl-L-carnitine and/or derivatives thereof for the morning administration.

44. The therapeutic and/or diagnostic formulation of claim 39, wherein the derivatives of N-acetyl-L-carnitine have the general structure:

and derivatives, congeners, and salts thereof,

wherein R is N or sulfonium;

and wherein Ri is H; alkyl defined as C_nH_2n+2, alkenyl defined as C_nH_2n, and/or alkynyl defined as C_n, where n is 1 to 18; aryl; aromatic; -COOH; or -NH₂.

45. The therapeutic and/or diagnostic formulation of claim 44, wherein the derivative is propionyl L-carnitine.

46. The therapeutic and/or diagnostic formulation of claim 28, further comprising melatonin and/or analogs, congeners, and mimetics thereof for the evening administration.

47. The therapeutic and/or diagnostic formulation of claim 28, further comprising carbohydrates.

48. The therapeutic and/or diagnostic formulation of claim 47, wherein the carbohydrates are beta-glucans, fiber extracts, pulps, and simple and complex sugars and their analogs.

49. The therapeutic and/or diagnostic formulation of claim 48, wherein the beta- glucan is β-l,3-glucan.

50. The therapeutic and/or diagnostic formulation of claim 48, wherein the beta- glucan is β-l,6-glucan.

51. The therapeutic and/or diagnostic formulation of claim 28, wherein the ingredients of the formulation are present in an amount effective to improve glucose uptake and the oxidation of nutrients in the consumer while diminishing the amount of toxic byproducts generated by these metabolic events in normal cells and impairing energy metabolism in cancer cells for the morning administration and in an amount effective to improve glucose uptake and the oxidation of nutrients in the consumer while diminishing the amount of toxic by-products generated by these metabolic events in normal cells, impairing energy metabolism in cancer cells, and promoting sleep in the nighttime formulation.

52. The therapeutic and/or diagnostic formulation of claim 51, wherein the ingredients of the formulation are individually present in amounts ranging from 0.5 mg to 1000 mg per dose.

53. The therapeutic and/or diagnostic formulation of claim 52, wherein the ingredients are present in amounts of 300 mg alpha lipoic acid; 5 mg indium sulfate; 10 mg eggplant extract; 200 mg N-acetyl-L-camitine and/or 200 mg propionyl L-carnitine; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 37.5 mg guarana; and 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof, each per dose, for the morning administration, and 300 mg alpha lipoic acid; 5 mg indium sulfate; 10 mg eggplant extract; 50 mg beta-glucan; 50 mg quercetin; 100 mg soybean trypsin inhibitor, leupeptin, and/or pepstatin, and/or analogues, derivatives, and mimetics thereof, and/or combinations thereof; 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof; and 2 mg melatonin and/or analogs, congeners, and mimetics thereof, each per dose, for the nighttime administration.

54. The therapeutic and/or diagnostic formulation of claim 28, further comprising a pharmaceutically-acceptable carrier therefor.