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WO2001003708A1 - Compositions contenant du cadmium - Google Patents

Compositions contenant du cadmium Download PDF

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Publication number
WO2001003708A1
WO2001003708A1 PCT/US2000/018580 US0018580W WO0103708A1 WO 2001003708 A1 WO2001003708 A1 WO 2001003708A1 US 0018580 W US0018580 W US 0018580W WO 0103708 A1 WO0103708 A1 WO 0103708A1
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Prior art keywords
cadmium
zinc
human
accordance
cadmium salt
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PCT/US2000/018580
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English (en)
Inventor
Gordon L. Woods
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CancEr2 Inc
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CancEr2 Inc
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Priority to CA002377920A priority Critical patent/CA2377920A1/fr
Priority to EP00947094A priority patent/EP1200104A1/fr
Publication of WO2001003708A1 publication Critical patent/WO2001003708A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors

Definitions

  • the present invention relates to methods for decreasing PGE2 : PGF2 ⁇ and zinc: cadmium ratios and for regulating the concentration of zinc-containing and PGE2-dependent matrix metalloproteinases in the body of mammals. More specifically, the present invention relates to the administration of bioavailable cadmium salt(s) to a mammal to decrease PGE2 : PGF2 ⁇ and zinc: cadmium ratios and to regulate the concentration of zinc-containing and PGE2-dependent matrix metalloproteinases in the body of the mammal. High or fluctuating levels of zinc and these matrix metalloproteinases have been shown to be associated with the onset of a number of diseases. The invention thus further relates to methods of preventing or treating disease. BACKGROUND OF THE INVENTION
  • MS multiple sclerosis
  • diabetes Other diseases which remain significant include multiple sclerosis (MS) and diabetes.
  • Present treatments for diabetes include the administration of insulin either orally or through an injection solution.
  • glucose may be administered either directly as through injection or indirectly, as through ingestion of certain foods or drinks.
  • Other methods of treating diabetes include the use of implantable glucose systems which have been designed to provide continuous measurement of the patient's glucose concentration.
  • implantable insulin pumps also can be used for the treatment of diabetes.
  • MS Multiple sclerosis
  • drugs which act in a non-specific fashion to suppress the immune response in a subject.
  • drugs are cyclophosphamide, imuran (azathioprine) and cyclosporin A.
  • Steroid compounds such as prednisone and methyl-prednisolone also are employed in many instances. These drugs have only limited efficacy against MS. The use of such drugs is limited by their toxicity and by the fact that they induce "global" immunosuppression upon prolonged use. Consequently, better and alternative methods and compositions for the treatment of MS have been sought.
  • Methods for inhibiting matrix metalloproteinases used in the past include the use of hydroxamic acid derivatives such as alpha-amino sulphonyl hydroxamic acids and carboxy-peptidyl compounds.
  • hydroxamic acid derivatives such as alpha-amino sulphonyl hydroxamic acids and carboxy-peptidyl compounds.
  • Natural products such as TIMP-1, TIMP-2 and alpha 2-macroglobulin also are known matrix metalloproteinase inhibitors. Although these inhibitors have been of interest, other easily manufactured compounds and compositions which can regulate the concentrations of matrix metalloproteinases and zinc in the body fluids and tissues of a patient are sought.
  • methods and compositions are provided for decreasing or regulating PGE2 : PGF2 ⁇ and zinc: cadmium ratios and regulating the concentration of zinc-containing and PGE2-dependent matrix metalloproteinases in the body of a mammal. Elevated or fluctuating levels of PGE2 and zinc and elevated concentrations of zinc-containing and PGE2-dependent matrix metalloproteinases have been found to be associated with the development of certain diseases, including prostate cancer, colon cancer, breast cancer, multiple sclerosis and diabetes. By regulating the concentration of zinc and PGE2 in the mammal's body, one can prevent the onset of, or treat the development of, these diseases.
  • a method of decreasing the PGE2 : PGF2 ⁇ ratio in the body fluids and tissues of a mammal which comprises administering to the mammal one or more cadmium salts in an amount sufficient to lower the concentration of PGE2 in the body of the mammal.
  • a method for decreasing the zinc: cadmium ratio in the body fluid and tissues of a mammal which comprises decreasing the concentration and activity of zinc in the body fluid of the mammal by administering to the mammal one or more cadmium salts.
  • a method of regulating the concentrations of zinc and zinc-containing and PGE2-dependent matrix metalloproteinases in a mammal by administering one or more cadmium salts is provided.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more cadmium salts, said composition being in oral dosage form.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more cadmium salts in combination with an estrogen, a protease inhibitor or a combination thereof.
  • a method for treatment or prevention of cancer which comprises decreasing the PGE2:PGF2 ⁇ and zinc: cadmium ratios in the body of a mammal suffering from, or at risk of developing, cancer by administering an amount of one or more cadmium salts effective to inhibit or prevent the growth, division or metastasis of cancer cells.
  • a method for the prevention or treatment of a disease in a mammal which comprises administering one or more cadmium salts at dose levels effective to regulate the concentration of zinc in the body fluids and tissue of a patient suffering from or at risk of developing such a disease.
  • stallions have low fertility (e.g. unsuccessful equine in vi tro fertilization (1)) and approximately 1/3 the incidence of cancer mortality compared to humans or dogs (8% versus 24% or 23%, respectively (2, 3, 4, 5)).
  • prostate cancer has never been reported in the stallion.
  • Stallions have high levels of unique estrogens (6, 7, 8, 9) paralleling the high levels of unique estrogens of pregnant mares.
  • Stallions in comparison to man, have a low testosterone: estrogen ratio (stallions 1:13, (10), men 9:1, (10)) which may regulate their postulated low seminal plasma PGE2 : PGF2 ⁇ concentrations and ratio (11, 12, 13, 14, 15, 16, 17) .
  • stallion urine comprises cadmium in the form of cadmium sulfate, as well as protease inhibitors and other chemicals.
  • bioavailable salts of cadmium can be administered to mammals, particularly humans, as therapeutic agents.
  • cadmium salt(s) can be administered to humans as an effective therapy for a number of diseases which are associated with high or fluctuating levels of zinc in body fluids and tissues.
  • Such tissues include multiple sclerosis, diabetes and cancers, such as prostate cancer, colon cancer and breast cancer.
  • Prostaglandin E2 increases sperm quality (26, 27, 28, 29, 30, 31) and increases cancer cell division (32).
  • the high PGE2 levels in man's seminal plasma also impair the immune systems of individuals who receive this semen (33, 34, 35, 36, 37, 38).
  • zinc increases sperm quality (39) and enhances cancer cell metastasis (40, 41, 42) .
  • Zinc is a key component of proteases that function in cancer cell metastasis (40, 41, 42). Zinc is not retained in tissues (18). In general, zinc is regarded as an essential metal.
  • Zinc has a negative relationship with cadmium. Zinc decreases the amount of cadmium absorbed from the gut (18) and decreases the physiological effects of cadmium (43, 44, 45, 46, 47, 48, 49, 50, 51) .
  • PGE2 has opposing physiologic actions to PGE2.
  • compositions of the present invention When mammals, particularly humans, are administered compositions of the present invention the levels of zinc and PGE2 in the mammal's body fluids and tissues are regulated.
  • Matrix metalloproteinases are regulated by zinc and PGE2. Therefore, the systemic decrease in zinc and PGE2 levels inhibit these matrix metalloproteinases.
  • the level of matrix metalloproteinases By regulating the level of matrix metalloproteinases, the onset of diseases which have been shown to be associated with high or fluctuating levels of zinc and matrix metalloproteinases in the body can be prevented or delayed and the presence of the disease in one who has already contracted it can be treated.
  • treatment includes halting or slowing the progress of a disease.
  • regulating means to lower abnormally high levels of, or to minimize abnormal fluctuations in the levels of, zinc (and, therefore, zinc-containing and PGE2-dependent matrix metalloproteinases) in body fluids and tissues.
  • Diseases which are influenced by zinc and matrix metalloproteinase levels and, therefore, can be prevented or treated by the present invention include diabetes and multiple sclerosis and cancers, such as prostate, colon and breast cancer.
  • cadmium is relatively high in stallion semen in contrast to man's semen because cadmium is retained at high levels in horse kidneys.
  • PGE2 or zinc cadmium decreases fertility in man (52, 53, 54, 55) and, in an animal study, suppresses tumors in the B6C3F1 mouse liver and lung (56) .
  • Cadmium has a contraceptive action (52) and is in high levels in infertile men (53, 54, 55).
  • zinc which is generally viewed as an essential metal
  • cadmium is regarded as a toxic metal. Because of cadmium's classification as a toxin, it has been overlooked as a beneficial treatment for humans. In fact, although cadmium is highly toxic and potentially carcinogenic when inhaled, it is relatively innocuous when ingested (57).
  • the concentration of zinc in human serum normally is within the range of about 0.5 - 1.5 ⁇ g/ml and in human semen normally is within the range of about 140 - 202 ⁇ g/ml.
  • researchers have found elevated levels of zinc and, therefore, elevated levels of zinc-containing and PGE2-dependent matrix metalloproteinases, in patients suffering from certain diseases.
  • one or more bioavailable cadmium salts can be administered to a mammal, preferably a human, to decrease elevated ratios of PGE2 : PGF2 ⁇ and zinc: cadmium in the mammal's body so as to effect a treatment for, or to prevent or delay the onset of, a disease associated with elevated levels of zinc or zinc- containing or PGE2-dependent matrix metalloproteinases.
  • a mammal preferably a human
  • high levels of these proteinases have been shown to be associated with the metastasis of at least certain types of cancer cells.
  • bioavailable cadmium salts can be administered to effect a treatment for, or to prevent or delay the onset of, certain types of cancer, such as prostate cancer, colon cancer or breast cancer.
  • concentration of zinc in the mammal's body fluids and tissues By lowering the concentration of zinc in the mammal's body fluids and tissues, the concentration of zinc- containing and PGE2-dependent matrix metalloproteinases can be decreased and stabilized.
  • Cadmium salts are administered to a patient so as to regulate the PGE2 : PGF2 and zinc: cadmium ratios in the patient's blood and other body fluid, thereby regulating the patient's systemic levels of zinc and PGE2.
  • the cadmium salts are administered in a series of daily doses and can be administered at a dose of about 1 ⁇ g to about 100 ⁇ g per day.
  • the cadmium salts are administered at a daily dose of about 10 to about 100 ⁇ g per day, and most preferably within the range of about 10 to about 50 ⁇ g per day.
  • Suitable salts are bioavailable cadmium salts. Such salts include the sulfate, nitrate, chloride and acetate salts. A single salt can be administered or a combination of salts can be used.
  • the one or more cadmium salts can be administered in combination with at least one further therapeutic agent.
  • the cadium salts are administered in combination with at least one estrogenic compound.
  • This combined administration of cadmium salt and estrogen can be beneficial in the treatment or prevention of prostate cancer.
  • the estrogenic compound (s) act synergistically with the cadmium salt(s) to directly prohibit PGE2 production in semen, blood and other bodily fluids.
  • a single estrogen can be administered or a mixture of estrogens can be used.
  • Suitable conjugated estrogenic compounds include those found in commercially available estrogen preparations, such as Premarin®, sold by Wyeth Ayerst .
  • the principal estrogen in Premarin® is sodium estrone sulfate.
  • the estrogenic compound (s) can be administered at a daily dose of about 0.1 mg to about 0.5 mg, preferably about 0.3 mg per day.
  • the actual amount of estrogen (s) used will depend upon the particular estrogen selected and its relative potency.
  • Another embodiment of the present invention comprises the administration of cadmium salt(s) in combination with one or more protease inhibitors to synergistically decrease levels of PGE2 concentration in blood, and other body fluids.
  • Proteases play pivotal roles in sperm function (58, 59, 60, 61, 62) and cancer cell metastasis (64, 65, 66, 67, 68, 69, 70, 71, 72, 73) .
  • protease inhibitors can block these proteases and thereby decrease sperm and cancer cell function.
  • a number of protease inhibitors are known and have been proposed or used as therapeutic agents. For example, several studies have described the negative effects of protease inhibitors on fertility.
  • Protease inhibitors can decrease the penetration rate of human sperm into oocytes (58) and, in seminal plasma, can act as decapacitation factors (61, 62).
  • protease inhibitors as anti-HIV therapeutics.
  • a number of protease inhibitors e.g., invirase, ritonavir, indinavir sulfate, and nelfinavir mesylate have been found to prevent reverse transcription of HIV (63).
  • U.S. Patent 4,906,457 reports the use of protease inhibitors for cancer protection.
  • a serine protease inhibitor, FOY-305 inhibits the invasion of tumor cells through interference with the u-PA activity of tumor cells (64).
  • Selective protease inhibitors at 10 nM concentration in the culture medium inhibit the migration of tumor cells in a Matrigel assay (65).
  • Dietary phytochemicals have protease inhibitory activity, and also inhibit cancer (66).
  • the recognized relationship between protease inhibitors and cancer is demonstrated by a second conference on ⁇ Proteases and Protease Inhibitors in Cancer' that was held in 1998 (68) .
  • Useful protease inhibitors in accordance with the present invention include those found in stallion urine.
  • Patent 3,912,704 incorporated herein by reference, describes protease inhibitors from stallion urine.
  • the molecular weight of the protease inhibitors from stallion urine are 26,000-28,000 by gel filtration, 17,000 by polyacrylamide gel electrophoresis, and 20,400 by ultracentrifuge .
  • protease inhibitors include those described in the patents cited above, including indinavir sulfate, commercially available as Crixivan® (Merck) ; ritonavir, commercially available as Norvir® (Abbott) ; invirase, commercially available under the name Saquinavir® (Immunet) ; and nelfinavir mesylate, commercially available as Viracept® (Agouron) .
  • the dose of the protease inhibitor varies depending upon the particular inhibitor or inhibitors chosen, but typically is in the range of from about 600 mg to about 2400 mg per day, depending upon the strength of the particular compound (s) of interest.
  • a preferred daily dose of indinavir sulfate typically is about 800 mg orally every eight hours
  • a preferred daily dose of ritonavir is within the range of about 300 mg to about 600 mg twice a day
  • a preferred daily dose of invirase is about 200 mg three times a day
  • a preferred daily dose of nelfinavir mesylate is about 750 mg three times per day.
  • the protease inhibitor can be administered in combination with an estrogenic compound in addition to a cadmium salt.
  • the cadmium salts are administered in a series of doses in an amount sufficient to prevent or inhibit the growth, division, or metastasis of cancer cells.
  • the cadmium salt(s) are administered in a series of doses in an amount sufficient to regulate fluctuations in the levels of zinc and the zinc-containing and PGE2- dependent matrix metalloproteinases in the patient's body which have been found to be associated with these diseases .
  • Cadmium salt(s) and optional estrogenic compound (s) and/or protease inhibitor (s) can be administered orally, parenterally or by inhalation. Oral administration, such as capsules, tablets, suspensions or solutions, is preferred. Cadmium salt(s) conveniently are administered in the form of tablets.
  • the cadmium salt(s) can be mixed with one or more lubricants, such as stearic acid or magnesium stearate, flavor ameliorating agents, disintegrating elements, including potato starch and alginic acid, binders, such as gelatin and corn starch, and/or tablet bases, such as lactose, corn starch and sucrose, and then pressed into tablets.
  • the cadmium salt(s) can be given in the form of capsules, prepared by mixing the salt(s) with a pharmaceutically acceptable excipient and then filling gelatin capsules with the mixture in accordance with conventional procedures .
  • cadmium salt(s) can be administered parenterally, provided in injectable doses of a solution or suspension in a physiologically acceptable diluent with a pharmaceutical carrier.
  • the carrier can comprise water or an oil and also optionally can comprise a surfactant or other pharmaceutically acceptable adjuvant.
  • the cadmium salt(s) can be administered by inhalation.
  • the salt(s) are provided in an aerosol spray and administered via an inhaler.
  • Example 1 PGE2, PGF2 , and zinc occur at higher concentrations in man's than in stallion' s semen and cadmium occurs at a lower concentration in man's than in stallion's semen, and 2) the ratio of PGE2 : PGF2 is higher in man's semen than in stallion's semen and the ratio of zinc: cadmium is higher in man's semen than in stallion's semen.
  • Example 2 observed sperm motility in
  • SEMEN COLLECTION Sperm-rich fractions of semen were collected from 8, healthy Morgan stallions aged 2-15 years old. The collected semen was immediately diluted 1:1 with 20 mg/ml aspirin in ultra-pure water and transported on ice to the laboratory. The stallion semen samples were frozen until analysis. Just prior to assay, samples were thawed and purified by centrifugation and then assayed for PGE2, PGF2, zinc and cadmium.
  • Centrifugation of both stallion and man' s semen samples consisted of a primary centrifugation to remove cells and debris (at 500 x g for 10 minutes at 4°C) and then a secondary centrifugation to remove large proteins (at 80,000 x g for 90 minutes at 4°C).
  • the stallion semen and all human semen samples were assayed for PGE2 and PGF2 by radioimmunoassay or enzyme immunoassay .
  • PGE2, PGF2 ⁇ , ZINC, AND CADMIUM ASSAYS Concentrations of PGE2 in human semen were quantified using acetylcholinesterase competitive enzyme immunoassay kits (Cayman Chemical Company, Ann Arbor, MI) . The assay uses 96-well microtiter plates, with goat anti-mouse polyclonal antibody previously bound to each well, and pure acetylcholinesterase from the electric eel ⁇ Electrophorus electricus) that is covalently coupled to PGE2 as the enzymatic tracer. The human semen PGE2 assays were performed according to manufacturer's directions.
  • semen samples were thawed and further purified by chromatography (using Waters Sep-Pak cartridges (Millipore Corp. Milford, MA) ) . Purified samples then were reconstituted with 450 ⁇ l of EIA buffer, and diluted to final concentrations of 1/10,000 to 1/100,000. Fifty microliters of each sample (from each dilution) were added to each well, followed by 50 ⁇ l of PGE2 acetylcholinesterase tracer and 50 ⁇ l of PGE2 monoclonal, anti-PGE2 antibody per well. Each dilution from each of the 9 semen samples was assayed in duplicate.
  • Plates were incubated for 18 hours at 4°C, were then rinsed thoroughly with wash buffer, and 200 ⁇ l of Ellman' s reagent was added to each well. Development occurred after 60-90 minutes in darkness. Plates were read at 405-420 nm with a spectrophotometer . Simultaneously incubated were wells with 50 ⁇ l of PGE2 standard with 50 ⁇ l of tracer and 50 ⁇ l of anti-PGE2 antibody. Nonspecific binding was determined by incubating 100 ⁇ l of EIA buffer and 50 ⁇ l of tracer, and maximum binding (B 0 ) was determined by incubating 50 ⁇ l EIA buffer, 50 ⁇ l of tracer, and 50 ⁇ l of anti-PGE2 antibody.
  • Concentrations of PGF2 in stallion semen samples and in human semen samples were quantified by radioimmunoassay, with [5, 6, 8, 9, 11, 12, 14, 15 (n)- 3 H]-PGF2 ⁇ (sa 200 Ci/mmol; New England Nuclear, Boston, MA), rabbit anti-PGF2 ⁇ antibody (1:20,000 final dilution; supplied by D.H. Dubois & F.W. Bazer) and Lutalyse (Upjohn Co., Kalamazoo, MI) for standards (94). Briefly, just prior to assaying, diluted, previously frozen stallion semen samples were thawed and purified by centrifugation (as described above) .
  • Free PGF2 ⁇ was then separated from antibody-bound PGF2 ⁇ by addition of 0.5 ml of 0.25% Norit A charcoal and 0.025% dextran (in assay buffer) for 4 min at 4°C, followed by centrifugation for 10 min at 1,800 x g and at 4°C.
  • the amount of antibody-bound [3H]-PGF2 in 0.5 ml of supernatant was determined by liquid scintillation spectrometry .
  • a log-logit regression program was used to calculate concentrations of PGF2 (95). Assay sensitivity is 2.5 pg/tube (p ⁇ 0.01).
  • Cross-reactivity of the antisera is 63.0% for PGFl , 0.3% for PGE2, and ⁇ 0.1% each for 6-keto-PGFl , PGFM and arachidonic acid (94).
  • concentrations of PGE2 were quantified similarly using the same radioimmunoassay techniques as for PGF2 ⁇ , except with [5, 6, 8, 11, 12, 14, 15 (n) - 3 H] -PGE2 (sa 200 Ci/mmol; New England Nuclear, Boston, MA) , rabbit anti- PGE2 (1:20,000 final dilution; supplied by D.H. Dubois & F.W. Bazer) and PGE2 (Sigma Chemical Co., St. Louis, MO) for standards.
  • STATISTICS The mean concentrations of PGE2, PGF2 ⁇ , zinc, and cadmium, and the mean ratios of PGE2:PGF2 and zinc: cadmium were contrasted by the Student T test between stallion semen and human semen (control samples) and among human samples.
  • PGE2 is 4,556 (368,570.0/80.9) times greater (p ⁇ 0.01) in concentration (ng/ml) in man's than in stallion semen.
  • PGF2 ⁇ is 116 (231.6/2.0) times greater (p ⁇ 0.01) in concentration (ng/ml) in man's than in stallion semen.
  • the PGE2:PGF2 ⁇ ratio is 1597:1
  • cadmium was below detectable levels ( ⁇ 0.2 ng/ml) in all of the man's control semen samples, but was detected (1,6 to 11.4 ng/ml) in 5 of the 8 stallion semen samples. Therefore, cadmium is at least 13 (2.6/0.2 ng/ml) times greater (p ⁇ 0.01) in concentration (ng/ml) in stallion than in man's semen.
  • the zinc: cadmium ratio is 301 (343,200/1,139) times greater (p ⁇ 0.05) in man's than in stallion semen.
  • PGE2 Prostaglandin E2
  • PPF2 ⁇ prostaglandin F2 alpha
  • zinc zinc
  • cadmium concentrations mg/ml
  • the concentration of PGE2 is 4,556 times greater and the concentration of PGF2 is 116 times greater in man's than in stallion's semen. Also, the PGE2 : PGF2 ratio is 41 times greater in man's than in stallion's semen. Therefore, the stallion has regulatory mechanisms that maintain a 4,000 fold lower concentration of PGE2 and a 100 fold lower concentration of PGF2 ⁇ than in the semen of man. Because the PGF2 concentration is only 100 fold lower in stallions than in man, the ratio of PGE2 : PGF2 is 41 times lower in stallion's semen than in man's semen.
  • the concentration of zinc is 76 times greater and the concentration of cadmium is at least 13 times lower in man's than in stallion's semen. Also, the zinc: cadmium ratio is at least 301 times greater in man's than in stallion's semen. Therefore, the stallion has regulatory mechanisms that maintain a 76 fold lower concentration of zinc and a 13 fold higher concentration of cadmium than in the semen of man.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes et des compositions destinées à réduire ou à réguler les coefficients de zinc:cadmium et de PGE2:PGF2alpha, et à réguler la concentration de métalloprotéinases matricielles contenant du zinc et dépendantes de PGE2 dans les liquides et tissus organiques d'un mammifère, en administrant au mammifère une quantité de sel de cadmium acceptable d'un point de vue pharmaceutique et biodisponible. On a découvert que des niveaux élevés ou fluctuants de PGE2 et de zinc, ainsi que des concentrations élevées de métalloprotéinases matricielles contenant du zinc et dépendantes de PGE2, sont associés au développement de certaines maladies.
PCT/US2000/018580 1999-07-09 2000-07-07 Compositions contenant du cadmium Ceased WO2001003708A1 (fr)

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CA002377920A CA2377920A1 (fr) 1999-07-09 2000-07-07 Compositions contenant du cadmium
EP00947094A EP1200104A1 (fr) 1999-07-09 2000-07-07 Compositions contenant du cadmium

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US14292699P 1999-07-09 1999-07-09
US60/142,926 1999-07-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045404A3 (fr) * 2001-11-21 2003-10-30 Cancer2 Inc Procedes de regulation de taux de zinc, de cadmium et de calcium chez l'homme et de diagnostic, ou de criblage concernant le risque de developpement de maladies associees a des taux anormaux de zinc, de zinc et de calcium dans les tissus et fluides corporels

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WO1988003805A1 (fr) * 1986-11-19 1988-06-02 Chemex Pharmaceuticals, Inc. Composes pharmacologiquement actifs et leurs melanges, compositions organiques et sels metalliques
DE4431176A1 (de) * 1994-09-01 1996-03-07 Medico Pharma Vertriebs Gmbh Chelatkomplexe und diese enthaltende Arzneimittel

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1988003805A1 (fr) * 1986-11-19 1988-06-02 Chemex Pharmaceuticals, Inc. Composes pharmacologiquement actifs et leurs melanges, compositions organiques et sels metalliques
DE4431176A1 (de) * 1994-09-01 1996-03-07 Medico Pharma Vertriebs Gmbh Chelatkomplexe und diese enthaltende Arzneimittel

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Title
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WAALKES, MICHAEL P. ET AL: "Down-regulation of metallothionein expression in human and murine hepatocellular tumors: association with the tumor-necrotizing and antineoplastic effects of cadmium in mice", J. PHARMACOL. EXP. THER. (1996), 277(2), 1026-1033, 1996, XP000964817 *
WAALKES, MICHAEL P. ET AL: "Further evidence of the tumor-suppressive effects of cadmium in the B6C3F mouse liver and lung: Late stage vulnerability of tumors to cadmium and the role of metallothionein", J. PHARMACOL. EXP. THER. (1993), 266(3), 1656-63, 1993, XP000964816 *
WAALKES, MICHAEL P.: "Anticarcinogenic effects of cadmium in review", MET. IONS BIOL. MED., PROC. INT. SYMP., 3RD (1994), 137-42. EDITOR(S): COLLERY, PHILIPPE. PUBLISHER: LIBBEY, MONTROUGE, FR., 1994, XP000964978 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045404A3 (fr) * 2001-11-21 2003-10-30 Cancer2 Inc Procedes de regulation de taux de zinc, de cadmium et de calcium chez l'homme et de diagnostic, ou de criblage concernant le risque de developpement de maladies associees a des taux anormaux de zinc, de zinc et de calcium dans les tissus et fluides corporels

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CA2377920A1 (fr) 2001-01-18
EP1200104A1 (fr) 2002-05-02

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