WO2019035989A1 - Prévention de calculs rénaux d'oxalate de calcium par de l'hydroxycitrate de potassium - Google Patents

Prévention de calculs rénaux d'oxalate de calcium par de l'hydroxycitrate de potassium Download PDF

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WO2019035989A1
WO2019035989A1 PCT/US2018/000270 US2018000270W WO2019035989A1 WO 2019035989 A1 WO2019035989 A1 WO 2019035989A1 US 2018000270 W US2018000270 W US 2018000270W WO 2019035989 A1 WO2019035989 A1 WO 2019035989A1
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kohcit
hydroxycitrate
urinary
citrate
kcit
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PCT/US2018/000270
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Charles Pak
Orson Moe
Ming-Chang Hu
Naim MAALOUF
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The Board Of Regents Of The University Of Texas System
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Publication of WO2019035989A1 publication Critical patent/WO2019035989A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/285—Polyhydroxy dicarboxylic acids having five or more carbon atoms, e.g. saccharic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid

Definitions

  • the present invention relates generally to the fields of biology, chemistry, and medicine. More particularly, it concerns methods and compositions relating to treating or preventing the formation of calcium oxalate (CaOx) kidney stones by oral administration of potassium hydroxycitratc (KOHCit).
  • CaOx calcium oxalate
  • KHCit potassium hydroxycitratc
  • CaOx is the most common constituent of kidney stones. CaOx kidney stones are commonly associated with hypocitraturia (low urinary citrate), hypercalciuria (high urinary calcium) and hyperoxaluria (high urinary oxalate). Potassium citrate (KCit) is often used to prevent CaOx stone formation, since it increases urinary citrate, which is an inhibitor of stones, and reduces urinary saturation of CaOx by complexing calcium. (Pak, 1985).
  • Garcinia extract touted to contain HCA
  • HCA a food supplement
  • These preparations allegedly lead to weight loss by inhibiting the ability of citrate to provide acetyl groups to CoA in the cytoplasm (Heymsfield, 1998). While their value in weight control might be disputed, Garcinia HCA preparations are well tolerated with safety of usage at recommended doses.
  • HCA might be a stone- prevention drug that might be devoid of the complication of calcium phosphate stones (Chung, 2016).
  • HCA inhibited crystal growth and disrupted CaOx crystals in vitro. This inhibitory effect of HCA was greater than that of citric acid, especially at lower concentrations.
  • HCA In human subjects taking a commercial preparation of HCA, a sufficient amount of HCA appeared in urine to exert inhibitory action. Orally administered HCA should not increase urinary pH to cause calcium phosphate crystallization, since HCA does not confer an alkali load because it doesn't have an accompanying non-metabolizable cation. Although HCA would not increase urinary citrate without alkali load, HCA might enhance urinary citrate by inhibiting renal citrate lyase (Melnick, 1996). Thus, it was speculated that HCA might inhibit CaOx urolithiasis (by enhancing both urinary hydroxycitrate and citrate), without potential complication of calcium phosphate stones (in the absence of urinary alkalization).
  • HCA is not readily available in a pure form. It is not an ideal oral agent, since it is unstable and gradually converts to inactive HCA lactone (HCAL) in water.
  • HCAL HCA lactone
  • HCA has the potential for aggravation of stones in patients with very low urinary pH.
  • KOHCit meets the need for an agent that confers a modest alkali load to avoid abnormally high urinary pH or undue urinary acidity, produces an optimum rise in urinary citrate, and yields urinary excretion of another inhibitor - hydroxycitrate.
  • KOHCit is just as effective as KCit in increasing urinary citrate, a key inhibitor of CaOx stone formation.
  • KCit unlike KCit, KOHCit does not overly alkalinize the urine and thereby does not pose a risk of calcium phosphate stones.
  • KOHCit increases urinary hydroxycitrate, another inhibitor of CaOx crystallization.
  • HCA KOHCit is stable in water.
  • a method of preventing or treating calcium oxalate kidney stones in a subject comprising orally administrating a composition comprising an effective amount of potassium hydroxycitrate to treat or prevent calcium oxalate stones.
  • the term "effective,” as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result.
  • Effective amount or “therapeutically effective amount” or “pharmaceutically effective amount” means that amount which, when administered to a subject or patient to accomplish a desired, expected, or intended results, is sufficient to achieve the desired, expected, or intended result.
  • the effective amount raises urinary citrate, raises urinary hydroxycitrate, increases urinary excretion of both citrate and hydroxycitrate, and/or maintains normal urinary pH (5.5-6.9).
  • a concentration is raised if there is a measurable increase in concentration, or if there is a 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100%, or more, increase.
  • the subject for a 70 kg human being, is administered a dose of 5-80 meq per day.
  • the effective amount is the above said amounts given in divided doses.
  • the composition may be administered to (or taken by) the patient 1 , 2, 3, 4, 5, or 6 times, or any range derivable therein, and they may be administered every 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 18, or 24 hours, or 1 , 2, 3, 4, 5, 6, or 7 days. It is specifically contemplated that the composition may be administered once daily, twice daily, three times daily, four times daily, five times daily, or six times daily (or any range derivable therein) and/or as needed to the patient. In some embodiments, the composition is administered two, three, or four times per day.
  • the composition may be administered every 2 to 24 hours (or any range derivable therein) to or by the patient. It is specifically contemplated that the composition may be administered daily over the course of multiple months or years, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 months or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 years (or any derivable range therein) or for an indefinite period of time.
  • the compositions may be administered one or more times in such daily administration. In some embodiments, the compositions are administered 1 to 10 times or more.
  • the term "subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dogs, cat, mouse, rat, guinea pig, or transgenic species thereof.
  • the subject is a primate.
  • the subject is a human.
  • Non-limiting examples of human subjects are adults and juveniles.
  • the subject has calcium oxalate kidney stones.
  • the subject is at risk for developing calcium oxalate kidney stones.
  • the composition may be administered in any suitable manner.
  • administration comprises oral administration.
  • the composition is in the form of a tablet, a solution, or a powder.
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease e.g., arresting further development of the pathology and/or symptomatology
  • ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease e.g., reversing the pathology and/or symptomatology
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.
  • “and/or” operates as an inclusive or.
  • compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed invention.
  • FIG. 1 illustrates structural formula of tripotassium hydroxycitrate (KOHCit).
  • KOHCit has three potassiums for each hydroxycitrate molecule.
  • FIG. 2 illustrates examination of analytical grade KOHCit, KCit, and HCAL by capillary electrophoresis. Peak 1 is HCAL, peak 2 citrate, and peak 3 is hydroxycitrate.
  • FIG. 3 is a schematic illustration for the calculation of formation product (FP) and crystal growth (CG) of CaOx in human urine in vitro. Precipitation of CaOx occurring from addition of increasing amounts of oxalate was detected by optical density (absorbance). The arrow indicates the FP, or the minimum amount of additional oxalate needed to elicit precipitation. The CG of CaOx is shown by the shaded area.
  • FIG. 4 compares FP of CaOx upon addition of KOHCit, KCit or KC1 6 meq/L each to human urine in vitro. Dots represent data obtained from urine samples collected from 12 separate human subjects. ** p ⁇ 0.01 and ⁇ p ⁇ 0.001 from KC1, (**) p ⁇ 0.01 between KCit and KOHCit. Since chloride is physicochemically inactive, KC1 served as the control.
  • FIG. 5 illustrates CG of CaOx upon addition of KOHCit, KCit or KC1 6 meq/L each to human urine in vitro, p ⁇ 0.05 and ⁇ p ⁇ 0.001 from KC1, (**) p ⁇ 0.01 between KCit and KOHCit.
  • FIG. 6 reveals the FP and CG of CaOx when HCAL is added to human urine in vitro. Studies in 6 human urine samples are depicted.
  • FIGS. 7A-7D shows the results of ex vivo experiments in rat liver slices examining hepatic uptake and presumed oxidation of hydroxycitrate (lower panels, FIGS. 7C and 7D) and citrate (upper panels, FIGS. 7A and 7B). Concentration (left panels, FIGS. 7A and 7C) and percent change (right panels, FIGS. 7B and 7D) in hydroxycitrate or citrate in culture media are depicted. Open circles on the left corner of the slide pointed by arrows represent original hydroxycitrate or citrate concentration at time zero. Each line represents separate experiments.
  • FIGS. 8A-8F demonstrates the change in urinary pH (FIG. 8A), ammonium (FIG. 8B), net acid excretion (NAE) (FIG. 8C), citrate (FIG. 8D), FP (FIG. 8E), and CG (FIG. 8F) of CaOx in rats from before treatment to treatment with KOHCit or KCit.
  • the vertical line above or below the bars indicates plus or minus SD.
  • FIG. 9 demonstrates the relationship between urinary citrate and corresponding NAE during KOHCit and KCit treatments.
  • a 24-hour urine was collected during two days before treatment and on days 6 and 7 of treatment. Each dot represents result from separate urine sample.
  • FIG. 10 illustrates the effect of four commercial Garcinia products on the FP and CG of calcium oxalate when added to human urine in vitro. Studies in 8 human urine samples are shown.
  • KOHCit demonstrates: (a) a greater inhibition of CaOx crystallization by KOHCit versus KCit when added to human urine in vitro, (b) incomplete hepatic uptake and presumed oxidation of hydroxycitrate from ex vivo experiments with liver slices, and (c) partial alkali load and urinary alkalization but optimum citraturic response by KOHCit from in vivo studies in rats. Additional in vivo studies in rats are planned to further clarify the action of KOHCit in the prevention of CaOx stones.
  • an ideal agent is one that increases urinary pH mild-modestly (avoiding over-alkalization or undue urinary acidity) but increases the inhibitor activity (by raising both urinary citrate and HCA).
  • KOHCit is such an agent.
  • KOHCit is a tripotassium salt of hydroxycitrate. Its structural formula is shown in FIG. 1. The third dissociation constant (pKa 3 ) of hydroxycitrate is 5.1 1 (Chung, 2017). Thus, in normal urinary pH, hydroxycitrate is mostly present as a trivalent anion. KOHCit is readily soluble in water. Once KOHCit is dissolved, the released hydroxycitrate is stable.
  • compositions described herein may be administered to a subject in need of treatment by a variety of routes of administration, including orally and parenterally, (e.g., intravenously), as a suppository or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water, topically, and/or administration via mucosal routes in liquid or solid form.
  • routes of administration including orally and parenterally, (e.g., intravenously), as a suppository or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water, topically, and/or administration via mucosal routes in liquid or solid form.
  • the composition can be formulated into a variety of dosage forms, e.g., extract, pills, tablets, microparticles, capsules, powder in sachet or packets, or oral liquid.
  • compositions may also be included as part of the composition pharmaceutically compatible binding agents, and/or adjuvant materials.
  • compositions can also be mixed with other active materials including antibiotics, antifungals, other virucidals and immunostimulants which do not impair the desired action and/or supplement the desired action.
  • the mode of administration of the pharmaceutical composition described herein is oral.
  • Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the aforesaid compounds or agents may be incorporated with excipients and used in the form of tablets, powder in sachet or packets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Some variation in dosage will necessarily occur, however, depending on the condition of the subject being treated. However, the concentration of active ingredient in the composition itself depends on bioavailability and other factors known to those of skill in the art.
  • the mode of administration of the pharmaceutical compositions described herein is topical or mucosal administration.
  • polymeric and/or non-polymeric materials can be used as adjuvants for enhancing mucoadhesiveness of the pharmaceutical composition disclosed herein.
  • the polymeric material suitable as adjuvants can be natural or synthetic polymers.
  • Representative natural polymers include, for example, starch, chitosan, collagen, sugar, gelatin, pectin, alginate, karya gum, methylcellulose, carboxymethylcellulose, methylethylcellulose, and hydroxypropylcellulose.
  • Representative synthetic polymers include, for example, poly(acrylic acid), tragacanth, poly(methyl vinylether-co-maleic anhydride), poly( ethylene oxide), carbopol, poly(vinyl pyrrolidine), poly( ethylene glycol), poly(vinyl alcohol), poly(hydroxyethylmethylacrylate), and polycarbophil.
  • Other bioadhesive materials available in the art of drug formulation can also be used (see, for example, Bioadhesion— Possibilities and Future Trends, Gurny and Junginger, eds., 1990).
  • dosage values also vary with the specific severity of the disease condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compositions. It is to be further understood that the concentration ranges set forth herein are exemplary only and they do not limit the scope or practice of the disclosure.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the formulation may contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose, sucralose, or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose, sucralose, or
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methylparabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such as
  • compositions can be prepared as formulations with pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers Preferred are those carriers that will protect the composition against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as polyanhydrides, polyglycolic acid, collagen, and polylactic acid. Methods for preparation of such formulations can be readily performed by one skilled in the art.
  • Liposomal suspensions may also be used as pharmaceutically acceptable carriers.
  • Methods for encapsulation or incorporation of compounds into liposomes are described by Cozzani, I.; Jori, G.; Bertoloni, G.; Milanesi, C; Sicuro, T. Chem. Biol. Interact. 53, 131 -143 (1985) and by Jori, G.; Tomio, L.; Reddi, E.; Rossi, E. Br. J. Cancer 48, 307-309 (1983), for example.
  • These may also be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,81 1 (which is incorporated herein by reference in its entirety).
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • composition described herein may be administered in single (e.g., once daily) or multiple doses or via constant infusion.
  • the compounds may also be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compounds of this disclosure and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like according to a specific dosage form.
  • excipients such as calcium carbonate
  • disintegrants such as starch, alginic acid and/or certain complex silicates
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules.
  • Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
  • solutions of the compounds of this disclosure in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • These particular aqueous solutions are especially suitable for intravenous, and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • composition provided herein can also be used with another pharmaceutically active agent effective for a disease such as a metabolic disturbance as described herein.
  • compositions described herein can be formulated alone or together with the other agent in a single dosage form or in a separate dosage form.
  • Methods of preparing various pharmaceutical fonnulations with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art.
  • For examples of methods of preparing pharmaceutical formulations see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
  • the compositions described herein further comprise a carrier.
  • the carrier may be comprised of sequestering agents such as, but not limited to, collagen, gelatin, hyaluronic acid, alginate, poly(ethylenc glycol), alkylcellulose (including hydroxyalkylcellulose), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl- methylcellulose, and carboxymethylcellulose, blood, fibrin, polyoxyethylene oxide, calcium sulfate hemihydrate, apatites, carboxyvinyl polymer, and poly(vinyl alcohol). See for example, U.S. Pat. No. 6,620,406, herein incorporated by reference.
  • sequestering agents such as, but not limited to, collagen, gelatin, hyaluronic acid, alginate, poly(ethylenc glycol), alkylcellulose (including hydroxyalkylcellulose), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
  • the carrier may include buffering agents such as, but not limited to glycine, glutamic acid hydrochloride, guanidine, heparin, glutamic acid hydrochloride, acetic acid, succinic acid, polysorbate, dextran sulfate, sucrose, and amino acids. See for example, U.S. Pat. No. 5,385,887, herein incorporated by reference.
  • the carrier may include a combination of materials such as those listed above.
  • the carrier may be a PLGA/collagen carrier membrane.
  • the composition according to this disclosure may be contained within a time release tablet.
  • a bioactive agent described herein can be formulated with an acceptable carrier to form a pharmacological composition.
  • Acceptable carriers can contain a physiologically acceptable compound that acts, for example, to stabilize the composition or to increase or decrease the absorption of the agent.
  • Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, further antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, compositions that reduce the clearance or hydrolysis of the anti-mitotic agents, or excipients or other stabilizers and/or buffers.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • phenol and ascorbic acid include, for example, phenol and ascorbic acid.
  • the composition can have a dosage of about 1 g to about 10 kg, for example, the dose may be at least, at most, or exactly 1 , 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600,
  • Embodiments of the composition can be administered in a variety of unit dosage forms depending upon the method of administration.
  • unit dosage forms suitable may include powder, tablets, pills, capsules.
  • the composition is in the form of a tablet, a solution, or a powder.
  • KOHCit and KCit were used in ex vivo experiments with rat liver slices and in in vivo rat experiments.
  • the increment in oxalate at the inflection point estimated the FP or limit of metastability.
  • CG of CaOx reflected the growth of crystals formed following nucleation.
  • AUC area under the curve
  • a rise in FP indicated greater inhibition of CaOx nucleation, and reduced CG meant inhibition of further growth.
  • Twelve 24-hour urine samples collected from different human subjects were tested. To each urine sample, KC1, KOHCit, or KCit was added to yield three test urine specimens, containing 6 meq KC1, 6 meq K and 6 meq citrate, and 6 meq K and 6 meq hydroxycitrate, respectively.
  • FIG. 4 shows FP of CaOx in 12 human urine samples. FP was significantly higher on KCit and KOHCit than on KC1. FP was higher with KOHCit than with KCit.
  • FIG. 5 shows CG of CaOx in 12 human urine samples. Compared to KC1 control, CG was significantly lower upon adding KCit or KOHCit. CG was lower with KOHCit than with KCit.
  • FP of CaOx decreased slightly or did not change after addition of HCAL (FIG. 6).
  • CG of CaOx increased slightly.
  • HCAL is devoid of direct inhibitor activity against CaOx crystallization. Instead, it seems to have a slight promoter activity.
  • the opposing action of HCAL over KOHCit emphasizes the importance of KOHCit in the prevention of CaOx stones.
  • Materials used were: (a) a solution containing KOHCit 2.5 g/dL in sterile distilled water; (2) a solution containing 5 g/dL of KCit in sterile distilled water.
  • liver was harvested from normal Sprague-Dawley rats. While kept in ice, ⁇ 40 mg liver mass was weighed, cut into ⁇ 1 mm thick slices in high glucose DMEM culture media. A solution of KOHCit was added to a high glucose DMEM culture medium to reach a concentration of 500 mg/dL. A solution of KCit was added to a high glucose DMEM culture medium to reach a concentration of 250 mg/dL.
  • Liver slices were incubated in culture media containing KOHCit or KCit at 37°C in a standard C0 2 incubator (95% air and 5% carbon dioxide). At 15 and 120 minutes, 10 ⁇ ⁇ of cultured medium was taken for the measurement of hydroxycitrate and citrate by capillary electrophoresis. After 120 minutes, the hydroxycitrate concentration in the culture media was reduced by 18% from the value at 15 minutes (FIG. 7B). The citrate concentration in the culture media was reduced by 37% (FIG. 7D). This reduction of hydroxycitrate and citrate indicates uptake and presumed oxidation of hydroxycitrate and citrate by liver slices.
  • FIG. 8 plots the above data in another way by displaying the changes in various urinary parameters from baseline to treatment with KOHCit or KCit.
  • the line above or below the bars indicate plus or minus SD. The same directional changes were shown.
  • KOHCit produced a less prominent increment in urinary pH, and less decrement in urinary ammonium and NAE.
  • KOHCit produced an optimum rise in urinary citrate, without over-alkalinizing the urine.
  • KCit produced alkaline urine conducive to calcium phosphate stone formation.
  • Urinary hydroxycitrate was measured in urine by capillary electrophoresis. A distinct peak of hydroxycitrate was found in urine of rats treated with KOHCit but not with KCit. Thus, some hydroxycitrate was absorbed and excreted in urine following KOHCit treatment. Hydroxycitrate can potentially increase urinary citrate by inhibiting renal citrate lyase (Melnick, 1996).
  • FP of calcium oxalate was not different or slightly lower in urine samples containing Garcinia products compared with control.
  • Vertical bars indicate mean ⁇ SD. P values from control are shown.
  • CG of calcium oxalate was not different or slightly higher in urine samples with added Garcinia products compared with control (Fig. 10, bottom).

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Abstract

L'invention concerne des méthodes de prévention ou de traitement de calculs rénaux d'oxalate de calcium chez un sujet par l'administration d'une composition comprenant une quantité efficace d'hydroxycitrate de potassium (KOHCit). Le KOHCit augmente légèrement à modérément le pH urinaire mais augmente l'activité inhibitrice.
PCT/US2018/000270 2017-08-17 2018-08-17 Prévention de calculs rénaux d'oxalate de calcium par de l'hydroxycitrate de potassium WO2019035989A1 (fr)

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CN111418558A (zh) * 2019-09-22 2020-07-17 山西大学 一种消融代谢性泌尿结石动物模型的构建方法
CN115475156A (zh) * 2022-09-15 2022-12-16 广州医科大学附属第一医院（广州呼吸中心） 羟基柠檬酸在制备防治兰德尔斑药物中的应用
WO2024046340A1 (fr) * 2022-08-30 2024-03-07 安徽汤谷医药科技有限公司 Composition pharmaceutique et son utilisation

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111418558A (zh) * 2019-09-22 2020-07-17 山西大学 一种消融代谢性泌尿结石动物模型的构建方法
WO2024046340A1 (fr) * 2022-08-30 2024-03-07 安徽汤谷医药科技有限公司 Composition pharmaceutique et son utilisation
CN115475156A (zh) * 2022-09-15 2022-12-16 广州医科大学附属第一医院（广州呼吸中心） 羟基柠檬酸在制备防治兰德尔斑药物中的应用

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