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WO2011005311A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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WO2011005311A1
WO2011005311A1 PCT/US2010/001908 US2010001908W WO2011005311A1 WO 2011005311 A1 WO2011005311 A1 WO 2011005311A1 US 2010001908 W US2010001908 W US 2010001908W WO 2011005311 A1 WO2011005311 A1 WO 2011005311A1
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therapeutic
diagnostic formulation
formulation
diagnostic
mimetics
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Robert Shorr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/898—Orchidaceae (Orchid family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger

Definitions

  • 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.
  • 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.
  • 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.
  • anorexia nausea and vomiting
  • diarrhea or constipation 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.
  • PCM Protein-calorie malnutrition
  • 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.
  • 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.
  • Optimal nutritional status is an important goal in the management of individuals diagnosed with cancer.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • ATP production also increases the influx of lactate or pyruvate into mitochondria with corresponding increased H 2 C> 2 , O ⁇ , 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.
  • 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.
  • ALA or DHLA 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 O 2 " 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.
  • no apoptosis was observed in non-transformed human colonocytes in response to ALA or DHLA addition.
  • US Patent 7507425 to Rosenbloom 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.
  • carbohydrates as sweeteners such as fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, and honey solids.
  • sweeteners such as fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, and honey solids.
  • sweeteners such as fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, and
  • 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.
  • TCA tricarboxylic acid
  • N-acetyl-L-carnitine is used in the cellular energy production process, supplementation is reported to improve the symptoms of mental and physical fatigue.
  • N-acetyl-L-carnitine demonstrate therapeutic benefit in non-mitochondrial disorders as well.
  • 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.
  • 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
  • pathological degeneration of Purkinje cells and cholinergic neurons of Meynert nucleus e.g., Alzheimer's disease; pre-senile and senile dementia; Creutzfeldt-Jakob disease; and Huntington's chorea
  • 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 ⁇ -l,3-glucan or ⁇ -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.
  • beta- glucan 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.
  • white blood cells are mobilized to attack infections and disease and are guided by antibodies released by B-cells.
  • stem cells 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.
  • beta-glucans found in certain mushroom fungi are also thought to have anticancer properties, especially in combination with chemotherapeutic agents.
  • 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 ⁇ -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.
  • indium-11 1 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
  • eggplant ⁇ Solarium melongena) 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • quercetin an aglycone or aglucon polyphenolic flavone
  • Quercetin glycone conjugates include rutin (quercetin-3-rutinoside) and thujin.
  • rutin quercetin-3-rutinoside
  • 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.
  • quercetin 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.
  • quercitin also inhibits deregulation of inflammatory mast cells, basophiles and neutrophils, having an overall antihistamine effect in the body.
  • quercetin potentially also has immunomodulatory, anti- inflammatory, anti-allergy, antiviral, and gastroprotective activities and may be useful in preventing secondary complications of diabetes.
  • 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.
  • 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.
  • serratiopeptidase The proposed antiinflammatory 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.
  • 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.
  • 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.
  • 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.
  • THC delta-9-tetrahydrocannabinol
  • CE whole- plant cannabis extract
  • 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.
  • 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 GI 50 of 5.2 ⁇ M, 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.
  • 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 M, 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.
  • 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.
  • delayed sleep phase syndrome a circadian-rhythm sleep disorder characterized by abnormally late sleep and wake times.
  • 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.
  • 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).
  • EGFR epidermal growth factor receptor
  • MAPK mitogen-activated protein kinase
  • 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.
  • effective amounts of alkyl fatty acids such as but not limited to thiol-containing alkyl fatty acids
  • effective amounts of nutritional supplements such as but not limited to excipient mixtures of plant extracts, which may be purified.
  • thiol-containing alkyl fatty acids such as but not limited to 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.
  • the alkyl fatty acid is octanoic acid
  • 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 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
  • the beta-glucan is ⁇ -l,3-glucan or ⁇ - 1,6-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.
  • thiol-containing alkyl fatty acids to be used in the therapeutic and/or diagnostic formulations of the present invention have the general formula:
  • R3 is alkyl defined as C n H 2n + 2 , alkenyl defined as C n H 2n , and/or alkynyl defined as C n , where n is 1 to 18;
  • Ri and/or R 2 is aryl and/or aromatic
  • R 4 is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH 2 ;
  • Ri, R 2 , R 3 , and/or R 4 may be phosphorylated; and wherein R 1 , R 2 , R 3 , and/or R 4 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.
  • R is N or sulfonium
  • Ri is H; alkyl defined as C n H 2n+2 , alkenyl defined as C n H 2n , and/or alkynyl defined as C n , where n is 1 to 18; aryl; aromatic; -COOH; or -NH 2 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • FIGURE 1 is a graph illustrating the relative uptake of a fluorescent analog of glucose into L6 myoblasts upon administration of either ⁇ -lipoic acid or the therapeutic and/or diagnostic formulations of the present 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.
  • effective amounts 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.
  • thiol-containing alkyl fatty acids such as but not limited to 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.
  • 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).
  • direct effect e.g., direct enhancement of glucose uptake or glycolytic or TCA cycle activity
  • indirect effect e.g., regulation of energy metabolism-controlling hormones, appetite, or sleep-wake cycles.
  • thiol-containing alkyl fatty acids to be used in the therapeutic and/or diagnostic formulations of the present invention have the general formula: and derivatives, congeners, and salts thereof,
  • R 3 is alkyl defined as C n H 2n+2 , alkenyl defined as C n H 2n , and/or alkynyl defined as C n , where n is 1 to 18;
  • Ri and/or R 2 is aryl and/or aromatic
  • R 4 is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, or -NH 2 ;
  • Ri, R 2 , R 3 , and/or R4 may be phosphorylated
  • Ri, R 2 , R 3 , and/or R 4 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 alkyl fatty acid is octanoic acid, and in a more preferred embodiment of the present invention, the alkyl fatty acid is lipoic acid.
  • R is N or sulfonium
  • Ri is H; alkyl defined as C n H 2n+2 , alkenyl defined as C n H 2n , and/or alkynyl defined as C n , where n is 1 to 18; aryl; aromatic; -COOH; or -NH 2
  • the derivative is propionyl L-carnitine.
  • 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, 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,
  • the beta-glucan is ⁇ -l,3-glucan or ⁇ -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.
  • 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.
  • 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
  • decreasing the downregulation of these hormones, enzymes, and/or processes 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
  • 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.
  • 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.
  • a glucose tolerance test is the modality used, glucose is coadministered 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 acids 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.
  • 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.
  • 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, sulftiric, nitric, phosphoric, maleic, acetic, palicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic.
  • 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.
  • 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.
  • the tablet may be further constituted with an enteric coating to prevent gastrointestinal upset.
  • an 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.
  • 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.
  • 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/m 2 to 2000 mg/m 2 , preferably about 60 mg/m 2 .
  • each individual ingredient may be present in an amount ranging from 0.5 mg to 1000 mg per dose.
  • the formulation of the therapeutic and/or diagnostic formulation contains 300 mg ALA; 5 mg indium sulfate; 10 mg eggplant extract; 7 mg whole-plant cannabis extract; 200 mg N-acetyl-L-carnitine and/or 200 mg propionyl L-carnitine; 50 mg beta-glucan; 50 mg quercetin; 37.5 mg guarana; 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.
  • the therapeutic and/or diagnostic formulation may be prepared for binary use as a co-administered morning and nighttime medicament regimen.
  • the formulation of the therapeutic and/or diagnostic morning formulation again contains 300 mg ALA; 5 mg indium sulfate; 10 mg eggplant extract; 7 mg whole-plant cannabis 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; and 50 mg serratiopeptidase and/or analogs, congeners, and mimetics thereof, each per dose, to markedly increase metabolism and appetite during the consumer's waking period.
  • the formulation of the therapeutic and/or diagnostic nighttime formulation thus contains 300 mg ALA; 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.
  • 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 objective of this investigation was to assess the impact of lipoic acid and the therapeutic and/or diagnostic formulation (Cellimmune) on stimulation of glucose uptake in L6 skeletal myoblast cells.
  • L6 rat skeletal muscle myoblast cells were used in this investigation.
  • the L6 cells were maintained at 37°C in a humidified 5% CO 2 atmosphere in T75 tissue culture flasks containing 20 mL of DMEM medium, 10% FBS, and 1% penicillin and streptomycin (100 IU/mL penicillin and 100 ⁇ g/mL streptomycin).
  • the L6 cells were split at a ratio of 1 :5 every 4-5 days by trypsinization and resuspended in fresh medium in a new flask. Cells were harvested for experiments at 70% confluency.
  • the 2-NBDG glucose analog was prepared by dissolving the solid in IX PBS to give a 10 rnM stock solution. This solution was further diluted in IX PBS to give a 500 ⁇ M working solution of 2-NBDG glucose.
  • 2.5 mM of lipoic acid was prepared by dissolving ( ⁇ )- ⁇ -lipoic acid in IM TEA and diluting in 10% FBS containing DMEM media.
  • the amount of lipoic acid present per tablet of this particular batch of Cell immune was 300mg; therefore the Cellimmune solution was prepared to contain 2.5mM of lipoic acid. The Cellimmune tablet was crushed to get a fine powder, which was dissolved in IM TEA and 10% FBS containing DMEM media.
  • Results are the mean ⁇ of 3 independent experiments each having 6 replicates

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Abstract

L'invention porte sur des préparations thérapeutiques ou diagnostiques visant à améliorer le captage du glucose et l’oxydation des nutriments chez les animaux à sang chaud dont l’homme, atteints d’un cancer, en diminuant les sous-produits toxiques produits par ces événements métaboliques, et qui peuvent s’administrer soit en une seule dose quotidienne, soit le matin et le soir favorisant ainsi le sommeil. Dans une exécution préférée, la préparation comprend une dose efficace d’acides gras alkyliques à teneur en thiol tels que non exclusivement des dérivés de l’acide lipoïque et de ses analogues, associés à une dose efficace d’oxydants naturels ou de synthèse, à des éléments traces, à des extraits de plantes, à des hydrates de carbone ou à d’autres substances. Des excipients pharmacocompatibles peuvent être ajoutés si nécessaire à la préparation.
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HK1216619A1 (zh) * 2012-12-19 2016-11-25 Robert Shorr 藥物化合物
RU2016117205A (ru) * 2013-11-08 2017-12-11 Легаси Хелскеар Лтд Способ ведения пациентов, больных раком и сопутствующими заболеваниями, связанными с лечением рака
CA2965671A1 (fr) * 2014-10-24 2016-04-28 Robert Shorr Procedes et compositions permettant le traitement de pre-diabete, de diabete et de syndrome metabolique
AU2017357164A1 (en) 2016-11-14 2019-05-30 Farm To Farma, Inc. Cannabinoid formulations and method of making the same

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