WO2012019295A1 - Composés bioactifs dans l'urine et le lait de chameau - Google Patents

Composés bioactifs dans l'urine et le lait de chameau Download PDF

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WO2012019295A1
WO2012019295A1 PCT/CA2011/000953 CA2011000953W WO2012019295A1 WO 2012019295 A1 WO2012019295 A1 WO 2012019295A1 CA 2011000953 W CA2011000953 W CA 2011000953W WO 2012019295 A1 WO2012019295 A1 WO 2012019295A1
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acid
camel
disease
extract
urine
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Tony Antakly
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/145—Ultrafiltration
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/22—Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland

Definitions

  • the subject matter disclosed generally relates to extracts from camel urine and milk. More specifically, the subject matter relates to bioactive extracts from camel urine comprising benzoate; phenylacetate and several other molecular species.
  • HIP HCG-like Inhibitory Products
  • camels The physiology of camels is interesting. Arabian camels are called the desert ships because they can walk in the desert for days without drinking and can withstand extreme high temperature of 40°C. Camels not only survive the harsh hot weather but also resist many viral and other infections presumably due to the unique molecular composition of their immunoglobulins (Deschacht et al., 2010, J. Immunol. 184, 5696-5704). It is believed that the camel's peculiar natural antibodies display a wide antigen- recognizing repertoire may be responsible for infection resistance.
  • camels display very low rates of water excretion as compared to other animals who share the same habitat (donkeys, horses, sheep) Guthier-Pilters and Dagg, 1981 , University of Chicago Press, Chicago). This results in the concentration of solutes and metabolites in the urine. Since camels do not urinate for a long time, their urine represents a valuable source of metabolites.
  • an extract from camel urine comprising an NMR spectrum as set forth in figure 1.
  • an extract from camel urine comprising a HPLC fractionation spectrum as set forth in figure 8A.
  • the extract may comprise a fraction C of said HPLC fractionation spectrum as set forth in figure 8A.
  • extract from camel milk comprising at least one compound chosen from benzoate, lactate and citrate.
  • the extract may be further comprising at least one compound chosen from acetoacetic acid, fumaric acid, glyceric acid, homovanillic acid, oxalic acid, oxoprolic acid, phenylpyruvic acid, propionylglycinic acid, pyruvic acid, 2-hydroxyglutaric acid, 2-oxoadipic acid, 2-oxoglutaric, 3-hydroxybutiric acid, 3 hydroxypropionic acid, 4-hydroxyphenyllactic acid, and 4- hydroxyphenylpyruvic acid.
  • a pharmaceutical composition comprising an extract from camel urine, camel milk, or combination thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising at least one compound as identified by a peak of an NMR spectrum as set forth in figure 1 , a HPLC fractionation spectrum as set forth in figure 8A or a fraction C thereof; and a pharmaceutically acceptable carrier.
  • the at least one compound may be benzoate, phenylacetate or a combination thereof.
  • the at least one compound may be chosen from Butyrylglycinic acid, Citric acid, Ethylmalonic acid, Glyceric acid, Glycolic acid, Glutaric acid, Hexanoylglycenic acid, Hippuric acid, Homovanillic acid Homogentisic acid, Isobutyrylglycinic acid, Isovalerylglycinic acid, Lactic acid, Malonic acid, Methylcitric acid, Methylmalonic acid, Methylsuccinic acid, N- acetylaspartic acid, Oxalic acid, Oxoprolinic (pyroglutamic) acid, Phenylpropioniglycinic acid, Phenyllactic, Propionylglycinic acid, Pyruvic acid, Sebacic acid, Suberic acid, 2-hydroxyadipic acid, 2-hydroxyglutaric acid, 2- hydroxyis
  • the disease may be a cancer, a neoplasm including multidrug resistant tumors, various haematological malignancies, and the cancer may be chosen from a breast cancer, colon cancer, a prostate cancer, malignant gliomas, and a thyroid cancer .
  • the disease may be a metabolic defect in a urea-cycle enzyme.
  • the disease may be any metabolic disease such as diabetes or pathologic obesity that is regulated by the Peroxisome Proliferator-activiated Receptor (PPAR) which belongs to the steroid receptor superfamily
  • PPAR Peroxisome Proliferator-activiated Receptor
  • the disease may be any metabolic disease such as diabetes or pathologic obesity that is regulated or by the DNA binding partner of the Peroxisome Proliferator-activiated Receptor (PPAR) which is the retinoid X receptors (RXR),
  • PPAR Peroxisome Proliferator-activiated Receptor
  • RXR retinoid X receptors
  • the disease may be chosen from multiple sclerosis, sickle cell anaemia, amyotrophic lateral sclerosis, and Huntington's disease.
  • a method of treating a disease in a subject in need thereof by administering to the subject a therapeutically effective amount of an extract camel urine, camel milk, or combination thereof.
  • a method of treating a disease in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound as identified by a peak of an NMR spectrum as set forth in figure 1 , a HPLC fractionation spectrum as set forth in figure 8A or a fraction C thereof.
  • the compound may be benzoate, phenylacetate or a combination thereof.
  • the at least one compound may be chosen from Butyrylglycinic acid, Citric acid, Ethylmalonic acid, Glyceric acid, Glycolic acid, Glutaric acid, Hexanoylglycenic acid, Hippuric acid, Homovanillic acid Homogentisic acid, Isobutyrylglycinic acid, Isovalerylglycinic acid, Lactic acid, Malonic acid, Methylcitric acid, Methylmalonic acid, Methylsuccinic acid, N- acetylaspartic acid, Oxalic acid, Oxoprolinic (pyroglutamic) acid, Phenylpropioniglycinic acid, Phenyllactic, Propionylglycinic acid, Pyruvic acid, Sebacic acid, Suberic acid, 2-hydroxyadipic acid, 2-hydroxyglutaric acid, 2- hydroxyisovaleric acid
  • the disease may be a cancer, a neoplasm, a multidrug resistant tumors, a haematological malignancy, and the cancer may be a breast cancer, a colon cancer, a prostate cancer, a malignant glyoma, and a thyroid cancer.
  • the disease may be a metabolic defect in a urea-cycle enzyme.
  • the disease may be chosen from multiple sclerosis, sickle cell anemia, amyotrophic lateral sclerosis, and Huntington's disease.
  • a method of producing an extract from camel urine comprising an NMR spectrum as defined in figure 1 by removing a fraction of at least 10 kDa from a camel urine sample to produce an extract having at least one molecule of molecular weight lower than 10 kDa.
  • the removal of the molecules may be done by filtration of said camel urine sample.
  • the filtration may be with a filter membrane.
  • the filter membrane may have pores preventing passage of molecules having at least 10 kDa or more.
  • the filter membrane may be treated with water prior to filtration of said camel urine sample.
  • molecular weight cut-off' or cut-off value is defined as the molecular weight at which a where the membrane or filter will reject, or prevent the passage of 90% of the solutes. Hence, a filter with a molecular weight cut-off of about 10 kDa will prevent the passage of molecules having molecular weight of at least 10 kDa.
  • compositions of the present invention are intended to mean a preservative solution, a saline solution, an isotonic (about 0.9%) saline solution, or about a 5% albumin solution, suspension, sterile water, phosphate buffered saline, and the like.
  • Other buffering agents, dispersing agents, and inert non-toxic substances suitable for delivery to a patient may be included in the compositions of the present invention.
  • the compositions may be solutions, suspensions or any appropriate formulation suitable for administration, and are typically sterile and free of undesirable particulate matter.
  • the compositions may be sterilized by conventional sterilization techniques.
  • the term "nutraceutical” is intended to mean a food or food product that provides health and medical benefits, including the prevention and treatment of disease.
  • a non-food ingredient is intended to mean an ingredient that may be added to food but that may not be a food ingredient contributing to the caloric content of the food per se.
  • Fig. 1 illustrates the 1 H NMR spectra of camel urine compared to human urine.
  • the full spectra are shown in the lower part of the figure.
  • the expanded spectra of the region 7.1-7.9 (boxed area) are shown on the top.
  • the phenylacetate and benzoate NMR peaks are more intense in camel than human.
  • the numbers 1a, 1 b, 1c and 2b, 2c, 2d refer to the characteristic peaks emanating from the carbons identified by the same numbers on the chemical atomic structures shown. Other compounds labeled by the indicated numbers correspond to the chemicals shown in the boxed area. Creatinine, which constitutes a standard reference in urine analysis, is also shown.
  • the star (*) identified peak is present only in camel but not human.
  • Figs. 2A and 2B illustrate the GS-MS spectra of benzoic acid and phenylacetic acid identified in camel urine using GS-MS.
  • Fig. 2A shows the entire spectrum of camel urine.
  • Fig. 2B shows spectra identified in camel urine.
  • Fig. 3 illustrates the mechanisms of ammonia diversion from the urea cycle with the administration of phenylacetate and benzoate.
  • Figs. 4A and 4B illustrates (A) the fractionation of camel urine using reversed phase-HPLC and (B) the bioassay of the collected fractions following HPLC separation.
  • Panel A shows the elution profile of camel urine from the HPLC column.
  • Y axis indicates absorbency at 220 nm.
  • x-axis indicated time of elution in minutes.
  • the contents of the indicated elution tubes are pooled into five fractions named A, B, C, D, E, then lyophilized.
  • Panel B shows the bioactivity of the five fractions as tested in vitro for cell proliferation using the MCF7 cells.
  • Y-axis shows % cell proliferation of the test material as compared to the Vehicle (Veh), i.e a control consisting of culture media alone.
  • an extract from camel urine comprising the NMR spectrum as defined in Fig. 1.
  • Fig. 1 a 1 H NMR spectra of camel urine showing significant differences as compared to human urine. The most striking finding in the camel urine is marked, high levels of both benzoate and phenylacetate (Fig. 1 ). In contrast, human, rat, elephant and dromedary urines display very little expression of these two compounds as shown in Table 1.
  • the number of NMR signals in camel urines is much less than the corresponding signal numbers in human urines.
  • the spectra show that the camel urine has lower level of sugar compared to human samples. More notable is the presence of peaks that are only present in camel urine. For example, an intense peak around 5.3 ppm is always present in the camel urine spectra and it is absent from any human urine spectra, indicating that some metabolites are unique to camel. Other intense peaks appear at 1.85 ppm, 2.255 ppm, 2.93 ppm, 3.205 and 3.91 ppm repeatedly demonstrated in camel spectra.
  • PA phenylacetate
  • benzoate in lowering plasma ammonium levels in patients with hyperammonemia represent the hallmark of their therapeutic action (Enns et a/. , 2007, N. Engl. J. Med. 356, 2282-2292).
  • ammonium which cannot be converted to urea accumulates to a toxic level that can be lethal.
  • This drug combination of PA and benzoate, marketed as Ammonul® is useful to treat patients with inborn errors of metabolism of the urea-cycle enzyme and prevents several complications such as encephalopathy and death (Enns et a/., 2007, N. Engl. J. Med. 356, 2282-2292).
  • both phenylacetate and benzoate are found to be potentially useful for the treatment of multiple sclerosis, as disease characterized by demyelination presumably due to a T-cell auto-immune response.
  • both compounds exert immunomodulatory and anti-inflammatory effects which are mediated by immune T-cells and involve among others, suppression of NF- ⁇ and nitric oxide synthetase; these actions ultimately result in the alleviation of the disease.
  • Phenylacetate is originally discovered as a plant hormone that regulates cell growth it has been studied in the past two decades as anticancer arid cellular differentiating compounds. PA inhibits the growth of several cancer cell types of different lineages and, in some instances, it promotes their differentiation to a non-cancerous phenotype. Of interest are the effects of PA and PB on gliomas and neuroblastomas, originally thought to be mediated by inhibition of protein prenylation cholesterol and fatty acid biosynthesis. Subsequent studies have demonstrated that PA and PB inhibits the growth of several neoplastic cell types including breast cancer (Liu et a/., 2007, Cancer Chemother. Pharmacol. 59, 217-225), prostate cancer, colon cancer and thyroid carcinoma.
  • PA and PB can potentiate the action of other hormones such as estrogens and retinoids in regulating cancer cell growth.
  • Other hormones such as estrogens and retinoids
  • These anti-cancer actions of PA and PB have prompted clinical trials especially that these compounds display little toxicity (Lin et a/., 2009, Clin. Cancer Res. 15, 6241-6249; Cudkowicz et al., 2009, Amyotroph. Lateral. Scler. 10, 99-106).
  • the overall picture that emerges is that PA and PB act as mild agents that synergize or cooperate with other bioactive agents, some of which may be endogenous.
  • PA and PB can act alone or in synergy with differentiating agents such as retinoid to down-regulate key cell-cycle genes as well as angiogenic and growth factors and that promote tumor cell growth.
  • differentiating agents such as retinoid to down-regulate key cell-cycle genes as well as angiogenic and growth factors and that promote tumor cell growth.
  • PA and PB can bind and activate the Peroxisome Proliferator-activiated Receptor ⁇ (PPAR) which belongs to the steroid receptor superfamily of ligand-activated transcription factors (Samid et al., 2000, Clin. Cancer Res. 6, 933-941).
  • PPAR Peroxisome Proliferator-activiated Receptor ⁇
  • the latter finding would suggest that these compounds act similar to steroidal hormonal drugs and would explain the pleotropic action of PA and PB compounds in different diseases and different physiological settings to regulate metabolism, inflammation, cancer growth and cell differentiation.
  • the extracts may be prepared through the fractionation of camel urine samples using techniques well known in the art.
  • the sample may be fractionated using exclusion chromatography techniques or any other method known in the art for the separation of molecules based on their size, shape, hydrophilicity, hydrophobicity, charge, polarity, or any other inherent physical characteristics which may be employed for the isolation (or exclusion) of molecules from the urine sample of interest.
  • the preferred method for the preparation of extracts according to the present invention is by using size exclusion filtering membranes excluding a fraction of molecules having a molecular weight larger than a set weight (i.e. having a predetermined molecular weight cut-off).
  • the urine samples are filtered with the filtering membrane to fractionate the sample in a filtrate comprising smaller molecules and a retentate of larger molecules.
  • Suitable molecular weight for exclusion are from at least 100 kDa, or from at least 50, or from at least 30 kDa, or from at least 10 kDa, or from at least 3 kDa.
  • the preferred molecular weight for exclusion i.e. the preferred molecular weight cut-off) is from at least 0 kDa.
  • an extract from camel urine which comprises an NMR spectrum as set forth in Fig. 1.
  • the extract may be used for the preparation of medicaments and/or for the treatment of various diseases such as cancer, including but not limited to breast cancer, prostate cancer, and thyroid cancer; metabolic diseases such as defects in the urea- cycle enzymes; multiple sclerosis, sickle cell anaemia, amyotrophic lateral sclerosis and Huntington's disease.
  • an extract from camel urine which comprises a HPLC fractionation spectrum as set forth in Fig. 8A, and preferably comprising fraction C of said HPLC fractionation spectrum as set forth in Fig. 8A.
  • the extract may be used for the preparation of medicaments and/or for the treatment of various diseases such as cancer, including but not limited to breast cancer, prostate cancer, and thyroid cancer; metabolic diseases such as defects in the urea-cycle enzymes; multiple sclerosis, sickle cell anaemia, amyotrophic lateral sclerosis and Huntington's disease.
  • camel milk prepared according to the method described above. Desert Bedouins and even ordinary people living in Saudi Arabia today are also known to mix camel urine and milk to get therapeutic effects. We therefore examined whether camel milk contains any hub molecules. Indeed, the milk from adult camels contains significant amounts of benzoate (table 5) albeit in lower amounts than in camel urine. However, camel milk is devoid of phenyl acetate.
  • the extracts of the present invention may be used alone, or combined to each other for any therapeutic use for which they may be useful.
  • the extracts of the present invention may also be used in food composition, such as for example nutraceutical compositions.
  • Nutraceuticals are food or food product that provides health and medical benefits, including the prevention and treatment of disease.
  • Products according to the present invention may range from isolated nutrients, dietary supplements, prebiotic, specific diets and herbal product supplement, and processed foods such as cereals, soups, and beverages.
  • the compositions of the present invention may also be used as a functional food, a food ingredient, a food additive, a natural food additive, a non-food ingredient, a cosmeto-food, a pharmaceutical, and a food supplement.”
  • Urine are collected from 15 male and 5 female adult camels (Camelus dromedarius) raised in separate geographic areas in Saudi Arabia, Jordan, Egypt, andoane. In addition, urines are obtained from 2 adult dromedaries, 2 alpaca, and one llama and two elephants from a zoo near Montreal, Canada. Furthermore, urines are obtained from two adult male Sprague-Dawley laboratory rats. The urine samples are transported to the laboratory either on ice or after freezing.
  • a urine sample (0.5 ml) is centrifuge-filtered at 2,000 g and 4°C for 15 minutes by using 10 kDa centrifugal filter tubes (Millipore, Billerica, MA, USA) to remove molecules and particles in the sample that have molecular weights of at least 10 kDa.
  • the centrifugal filters are washed several times with 0.5 ml water, then centrifuged at 12000 x g at 4°C to remove glycerol from the filter membrane until no NMR signal is observed in the filtrate.
  • Four hundred microliters of the filtrate are transferred to a 5 mm NMR tube and 100 ⁇ of D 2 0 (Cambridge Isotope Laboratories, Inc.) are added to the NMR tube.
  • the NMR spectra are obtained using a Varian Inova 600 MHz instrument (Palo Alto, California). All NMR experiments are obtained using a one-dimensional presaturation sequence with gradients pulse sequence (zgpr in the standard Bruker pulse sequence library).
  • the 1 H NMR spectra are recorded by collecting 64 and 128 free induction decays (FIDs) and digitized into 64 K complex data points over a spectral width of 12 ppm.
  • the recycle delay time is set to 5 sec and the receiver gain is kept at a constant value of 32.
  • the FID values are multiplied by an exponential function equivalent to 1.0 Hz line broadening factor. All spectra are then visually phased and adjusted manually where necessary.
  • Target chemicals are determined using an Agilent 7890 A GC (or equivalent) with 5975C MSD equipped with an Agilent 7683B automatic liquid sampler and an HP-5MS GC (or equivalent) column (30 m, 0.25mm i.d., 0.25 Mm film thickness). Helium is used as the carrier gas, with a column flow rate of 1.0 ml/min in constant flow mode. Injector temperature is 280°C. The GC-MSD interface quadruple and the ion source temperatures are set at 280, 170 and 230°C, respectively.
  • the GC oven temperature is kept at 50°C for 0.5 min, followed by the first ramp at 5°C / min to 225°C, second ramp at 3°C / min to 280°C, and holding for 1 min.
  • mass spectra and GC retention times of each compound from mlz 50 to 550 are obtained in full scan mode.
  • the mass spectrometer used is operating in electron impact with an ionization voltage of 70 EV.
  • the sample is injected in pulsed splitless mode.
  • PROPIONYLGLYCINE 0.67 0.17 0.09 0.02
  • ote means undetectable.
  • Fig. 4A the gradient is shown with the x- axis indicating time, in minutes.
  • the absorbency at 220 nm is recorded on the y-axis.
  • fractions (peaks) indicated by arrows on Fig. 4B. are lyophilized and each is reconstituted in one (1) ml of RPMI culture medium (without serum) and tested for biological activity using MCF7 cells.
  • the biological activity is tested in absence (Vehicle control, i.e. RPMI medium alone) or presence of 10 microliters of the reconstituted fractions. It can be seen from Fig. 4B that fraction C display an inhibitory activity.
  • MCF7 The breast cancer cell line called MCF7 is obtained from the American Type Tissue Culture Collection.
  • the KS cells are passaged and the culture medium is changed every other day in presence or in absence of any of the samples mentioned above for the indicated periods ranging from 24-96 hrs.
  • 3 H-thymidine incorporation is measured as described (Guo WX et al., 1996, Am J Pathol 148: 1999-2008). In most experiments, data are reported as means ⁇ SEM of sextuplet determinations. Statistical analysis is determined by student t-test.
  • VMA 35 VANILLYMANDEUQUE (VMA) 0

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Abstract

La présente invention concerne des extraits d'urine et/ou de lait de chameau comprenant du benzoate, du phénylacétate et d'autres espèces moléculaires. L'invention porte en outre sur des procédés d'utilisation desdits extraits, sur les composés identifiés pour le traitement de maladies, et sur des procédés d'isolation de ces extraits.
PCT/CA2011/000953 2010-08-13 2011-08-12 Composés bioactifs dans l'urine et le lait de chameau Ceased WO2012019295A1 (fr)

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CN102621262A (zh) * 2012-02-28 2012-08-01 杭州博圣生物技术有限公司 气相色谱－质谱检测尿有机酸的方法
WO2015036656A3 (fr) * 2013-09-13 2015-05-14 Replicon Health Oy Procédé d'amélioration de la production d'énergie et du métabolisme dans des cellules
WO2017091895A1 (fr) * 2015-12-01 2017-06-08 Theriac Biomedicale Inc. Activateurs ppar-gamma et leurs utilisations thérapeutiques
CN107290445A (zh) * 2017-05-24 2017-10-24 浙江圣兆药物科技股份有限公司 一种检测注射用微球制剂中乳酸和乙醇酸含量的方法
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CN114807289A (zh) * 2022-03-11 2022-07-29 武汉大学 用于制备治疗肝癌药物的新型代谢标志物及其应用
EP4203932A4 (fr) * 2020-08-26 2024-07-31 Axcess Global Sciences, LLC Compositions contenant hmb et des corps cétoniques et procédés pour augmenter le rapport masse maigre/masse grasse
US12090129B2 (en) 2017-11-22 2024-09-17 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US12128020B2 (en) 2016-04-19 2024-10-29 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
US12167993B2 (en) 2019-06-21 2024-12-17 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US12329734B2 (en) 2017-12-19 2025-06-17 Axcess Global Sciences, Llc Use of S-beta-hydroxybutyrate compounds for induction and maintenance of flow
US12433912B2 (en) 2019-05-15 2025-10-07 Axcess Global Sciences, Llc Autobiotic compositions and method for promoting healthy gut microbiome
US12496283B2 (en) 2016-04-19 2025-12-16 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
US12521378B2 (en) 2016-04-19 2026-01-13 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate salt blend and related compounds in humans
US12533346B2 (en) 2016-04-19 2026-01-27 Axcess Global Sciences, Llc Administration of berberine metabolites
US12533331B2 (en) 2018-04-18 2026-01-27 Axcess Global Sciences, Llc S-beta-hydroxybutyric acid compositions and methods for delivery of ketone bodies
US12551455B2 (en) 2018-04-18 2026-02-17 Axcess Global Sciences, Llc Compositions and methods for keto stacking with beta-hydroxybutyrate and acetoacetate
US12599579B2 (en) 2016-04-19 2026-04-14 Axcess Global Sciences, Llc Compositions and compounds containing ketone bodies and/or ketone body precursors and one or more amino acids

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