WO2014068320A1 - Inhibiteurs de corps de cétone utilisables dans le traitement d'une lésion de la muqueuse du tractus gastro-intestinal - Google Patents

Inhibiteurs de corps de cétone utilisables dans le traitement d'une lésion de la muqueuse du tractus gastro-intestinal Download PDF

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Publication number
WO2014068320A1
WO2014068320A1 PCT/GB2013/052850 GB2013052850W WO2014068320A1 WO 2014068320 A1 WO2014068320 A1 WO 2014068320A1 GB 2013052850 W GB2013052850 W GB 2013052850W WO 2014068320 A1 WO2014068320 A1 WO 2014068320A1
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Prior art keywords
ketone body
inhibitor
body inhibitor
use according
spp
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PCT/GB2013/052850
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English (en)
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Lars Fändriks
Ville Wallenius
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Benf Ab
Smith, Stephen Edward
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Publication of WO2014068320A1 publication Critical patent/WO2014068320A1/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1783—Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • G01N33/567—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds utilising isolate of tissue or organ as binding agent
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/64—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • proinflammatory cytokines e.g., tumour necrosis factor-a and IL- 1 ⁇
  • the inflamed, and therefore "leaky,” gut may then allow passage of bacteria and/or bacterial components across the intestinal barrier.
  • TLR Toll-like receptor
  • lymph node lymphoid cells mainly omental and mesenteric fat
  • bacterial stimuli may lead to local activation of peroxisome proliferator-activated receptor- ⁇ and therefore induce adipocyte proliferation and differentiation in the mesenteric fat depot, although the underlying mechanisms remain largely unclear.
  • inflammation impairs gut barrier function and results in the leakage of microbial antigens.
  • the present inventors have surprisingly found that the barrier properties of the Gl mucosa are regulated by local (gastrointestinal) ketogenesis and, consequently, that barrier impairment of the Gl tract can be regulated by modifying Gl ketogenesis, Gl ketones and/or effects induced by Gl ketones.
  • Cytosolic HMG-CoA synthase contains sterol regulatory elements that modulate transcriptional activity by sterols, mediated by sterol regulatory element binding proteins (SREBP)-1 and -2 [9, 10], which have not been observed in the promoter of the mitochondrial HMG-CoA synthase.
  • SREBP sterol regulatory element binding proteins
  • PPRE peroxisome proliferator regulatory element
  • the wall of the Gl tract has a general structure. Most of the tube's luminal surface is highly convoluted, a feature that greatly increases the surface area available for absorption. From the stomach on, this surface is covered by a single layer of epithelial cells linked together along the edges of the luminal surfaces by tight junctions.
  • E. cloacae, E. faecalis and E. faecium Escherichia spp. (such as E. coli), Flavobacterium spp., Hafnia spp., Klebsiella spp., Mycobacteria spp., Mycoplasma spp., Peptococcus spp., Plesiomonas shigelloides, Propionibacterium spp (such as P. acnes), Proteus spp., Providencia spp., Pseudomonas spp (such as P. aeruginosa), Ruminococcus spp (such as R.
  • Flavobacterium spp. Hafnia spp., Klebsiella spp., Mycobacteria spp., Mycoplasma spp., Peptococcus spp., Plesiomonas shigello
  • the gastrointestinal mucosa barrier impairment may be associated with increased paracellular or transcellular permeability of the gastrointestinal mucosa.
  • the gastrointestinal mucosa barrier impairment is associated with increased paracellular permeability of the gastrointestinal mucosa.
  • the TJ forms a continuous, circumferential, belt-like structure at the luminal end of the intercellular space, where it serves as a gatekeeper of the paracellular pathway.
  • the TJ plaque is the site of a growing number of TJ-associated protein complexes.
  • the cell membranes of adjacent epithelial cells are brought into intimate focal contact sites in which the intercellular space is obliterated.
  • the TJ In addition to serving as a regulated gate/barrier in the paracellular pathway, the TJ also functions as a fence in the plane of the plasma membrane, where it contributes to the maintenance of asymmetrically distributed integral membrane proteins and lipids.
  • the gastrointestinal tract mucosa barrier impairment is associated with ketogenesis in one or more sites selected from the group consisting of the stomach, duodenum, jejunum, ileum, cecum and colon.
  • the gastrointestinal tract mucosa barrier impairment may not be associated with ketogenesis in one or more sites selected from the group consisting of the stomach, duodenum, jejunum, ileum, cecum and colon; for example, the barrier impairment may not be associated with (i.e., occur independently of) ketogenesis of the colon.
  • the gastrointestinal tract mucosal barrier impairment is present in one or more site selected from the group consisting of the stomach, duodenum, ileum, cecum and colon.
  • the gastrointestinal tract mucosal barrier impairment may be absent from one or more site selected from the group consisting of the stomach, duodenum, ileum, cecum and colon.
  • ketoone body inhibitor we include agents capable of (i) reducing or preventing ketogenesis; (ii) reducing or abolishing ketones themselves; and/or (iii) reducing or preventing ketone-induced effects.
  • the ketone body inhibitor is capable of inhibiting ketone bodies in non-gastrointestinal mucosa tissues by no more than 25%, for example, no more than 24%, 23%, 22%, 21 %, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.1 % or no more than 0%.
  • the ketone body inhibitor may be formulated to reduce or prevent its exposure to non-gastrointestinal mucosa tissue. For example, exposure of the ketone body inhibitor to non-gastrointestinal mucosa tissue may reduced by at least 10%, for example, at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or at least 100%.
  • the ketone body inhibitor may be an inhibitor of a ketogenic enzyme.
  • HMG-CoA synthase also known as 3-hydroxy-3-methylglutaryl- Coenzyme A synthase 2 (mitochondrial), H GCS2, );
  • BC044217.1 (version BC044217.1) .
  • HMGCS2 (transcript variant 2) ; GenBank Accession No. :
  • An antibody of desired specificity may alternatively be generated using well-known molecular biology methods, including selection from a molecular library of recombinant antibodies, or grafting or shuffling of complementarity-determining regions (CDRs) onto appropriate framework regions.
  • Human antibodies may be selected from recombinant libraries and/or generated by grafting CDRs from non-human antibodies onto human framework regions using well-known molecular biology techniques.
  • an expression vector containing a nucleotide sequence as described in the second aspect of the invention In a third aspect of the invention there is provided an expression vector containing a nucleotide sequence as described in the second aspect of the invention.
  • a typical mammalian cell vector plasmid is pSVL available from Pharmacia (Piscataway, NJ, USA). This vector uses the SV40 late promoter to drive expression of cloned genes, the highest level of expression being found in T antigen-producing cells, such as COS-1 cells.
  • An example of an inducible mammalian expression vector is pMSG, also available from Pharmacia (Piscataway, NJ, USA). This vector uses the glucocorticoid-inducible promoter of the mouse mammary tumour virus long terminal repeat to drive expression of the cloned gene.
  • a further method uses synthetic molecules called linkers and adaptors.
  • DNA fragments with blunt ends are generated by bacteriophage T4 DNA polymerase or E.coli DNA polymerase I which remove protruding 3' termini and fill in recessed 3' ends.
  • Synthetic linkers, pieces of blunt-ended double-stranded DNA which contain recognition sequences for defined restriction enzymes, can be ligated to blunt-ended DNA fragments by T4 DNA ligase. They are subsequently digested with appropriate restriction enzymes to create cohesive ends and ligated to an expression vector with compatible termini.
  • Adaptors are also chemically synthesised DNA fragments which contain one blunt end used for ligation but which also possess one preformed cohesive end.
  • Synthetic linkers containing a variety of restriction endonuclease sites are commercially available from a number of sources including International Biotechnologies Inc, New Haven, CN, USA.
  • a desirable way to modify the DNA encoding the polypeptide of the invention is to use the polymerase chain reaction as disclosed by Saiki et al (1988) Science 239, 487-491.
  • the DNA to be enzymatically amplified is flanked by two specific oligonucleotide primers which themselves become incorporated into the amplified DNA.
  • the said specific primers may contain restriction endonuclease recognition sites which can be used for cloning into expression vectors using methods known in the art.
  • a host cell comprising a nucleotide sequence or expression vector as described in the second and third aspects of the invention.
  • DNA encoding the polypeptide constituting the compound of the invention may be joined to a wide variety of other DNA sequences for introduction into an appropriate host.
  • the companion DNA will depend upon the nature of the host, the manner of the introduction of the DNA into the host, and whether episomal maintenance or integration is desired.
  • Eukaryotic promoters include the CMV immediate early promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters and the promoters of retroviral LTRs. Other suitable promoters will be known to the skilled artisan.
  • the expression constructs will desirably also contain sites for transcription initiation and termination, and in the transcribed region, a ribosome binding site for translation. (WO 98/16643)
  • the vector is then introduced into the host through standard techniques. Generally, not all of the hosts will be transformed by the vector and it will therefore be necessary to select for transformed host cells.
  • One selection technique involves incorporating into the expression vector a DNA sequence marker, with any necessary control elements, that codes for a selectable trait in the transformed cell.
  • markers include dihydrofolate reductase, G418 or neomycin resistance for eukaryotic cell culture, and tetracyclin, kanamycin or ampicillin resistance genes for culturing in E.coli and other bacteria.
  • the gene for such selectable trait can be on another vector, which is used to co-transform the desired host cell. Host cells that have been transformed by the recombinant DNA of the invention are then cultured for a sufficient time and under appropriate conditions known to those skilled in the art in view of the teachings disclosed herein to permit the expression of the polypeptide, which can then be recovered.
  • bacteria eg. E.coli and Bacillus subtilis
  • yeasts eg. Saccaromyces cerevisiae
  • insect cell systems transformed with, for example, viral expression vectors (eg. baculovirus)
  • plant cell systems transfected with, for example viral or bacterial expression vectors
  • animal cell systems transfected with, for example, adenovirus expression vectors.
  • a pharmaceutical composition comprising a ketone body inhibitor as described in the first aspect of the invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • pharmaceutically acceptable is included that the formulation is sterile and pyrogen free.
  • Suitable pharmaceutical carriers are well known in the art of pharmacy. The carriers) must be “acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Typically, the carriers will be water or saline which will be sterile and pyrogen free; however, other acceptable carriers may be used.
  • pharmaceutically acceptable carrier and pharmaceutically acceptable excipient includes any compound(s) used in forming a part of the formulation that is intended to act merely as a carrier, i.e., not intended to have biological activity itself.
  • the pharmaceutically acceptable carrier or excipient is generally safe, non-toxic, and neither biologically nor otherwise undesirable.
  • a pharmaceutically acceptable carrier or excipient as used herein includes both one and more than one such carrier or excipient.
  • the medicaments and agents will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice (for example, see Remington: The Science and Practice of Pharmacy, 19 th edition, 1995, Ed. Alfonso Gennaro, Mack Publishing Company, Pennsylvania, USA, which is incorporated herein by reference).
  • the medicaments and agents can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • the medicaments and agents may also be administered via intracavernosal injection.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the medicaments and agents of the invention can also be administered parenterally, for example, intravenously, intra-articularly, intra-arterially, intraperitoneally, intra- thecally, intraventricularly, intrasternally, intracranially, intra-muscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the daily dosage level of the medicaments and agents will usually be from 1 to 1000 mg per adult (i.e. from about 0.015 to 15 mg/kg), administered in single or divided doses.
  • the medicaments and agents can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134A3 or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EA3), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1 ,1 ,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • the medicaments and agents can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the compounds of the invention may also be transdermal ⁇ administered, for example, by the use of a skin patch. They may also be administered by the ocular route.
  • the medicaments and agents can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • a sustained-release drug delivery system such as a microsphere. These are designed specifically to reduce the frequency of injections.
  • a sustained-release drug delivery system such as a microsphere.
  • Nutropin Depot which encapsulates recombinant human growth hormone (rhGH) in biodegradable microspheres that, once injected, release rhGH slowly over a sustained period.
  • Sustained-release immunoglobulin compositions also include liposomally entrapped immunoglobulin.
  • Liposomes containing the immunoglobulin are prepared by methods known per se. See, for example Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688- 92 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030-4 (1980); U.S. Patent Nos. 4,485,045; 4,544, 545; 6,139,869; and 6,027,726.
  • the liposomes are of the small (about 200 to about 800 Angstroms), unilamellar type in which the lipid content is greater than about 30 mole percent (mol. %) cholesterol; the selected proportion being adjusted for the optimal immunoglobulin therapy.
  • polypeptide medicaments and agents can be administered by a surgically implanted device that releases the drug directly to the required site.
  • Electroporation therapy (EPT) systems can also be employed for the administration of proteins and polypeptides.
  • EPT Electroporation therapy
  • a device which delivers a pulsed electric field to cells increases the permeability of the cell membranes to the drug, resulting in a significant enhancement of intracellular drug delivery.
  • Proteins and polypeptides can also be delivered by electroincorporation (El).
  • El occurs when small particles of up to 30 microns in diameter on the surface of the skin experience electrical pulses identical or similar to those used in electroporation. In El, these particles are driven through the stratum corneum and into deeper layers of the skin.
  • the particles can be loaded or coated with drugs or genes or can simply act as "bullets" that generate pores in the skin through which the drugs can enter.
  • Protein and polypeptide pharmaceuticals can also be delivered orally.
  • One such system employs a natural process for oral uptake of vitamin B12 in the body to co- deliver proteins and polypeptides. By riding the vitamin B12 uptake system, the protein or polypeptide can move through the intestinal wall.
  • Complexes are produced between vitamin B12 analogues and the drug that retain both significant affinity for intrinsic factor (IF) in the vitamin B12 portion of the complex and significant bioactivity of the drug portion of the complex.
  • IF intrinsic factor
  • the skilled person will appreciate that the most appropriate formulation will depend on a number of factors including route of administration, patient type (e.g. patient age, weight/size).
  • Roux-en-Y Gastric Bypass results in reduced incidence and long-term remission of obesity associated metabolic comorbidities: insulin resistance/type-2 diabetes, hypertension and dyslipidemia. Its effect on type-2 diabetes does not seem to depend only on weight loss and is not to a large extent considered to be caused by food restriction or malabsorption. The mechanisms of action of GBP on type-2 diabetes are considered by the scientific community to be largely unresolved. It is also known that GBP reduces endotoxinemia and the signs on a systemic inflammatory reaction (Monte et a/., Surgery. 2012 Apr;151(4):587-93). Also the mechanisms to this are principally unknown.
  • the high-fat-fed jejunal mucosa produces ketone bodies upon exposure to fat and fatty acids
  • the level of ketone-bodies in the blood leaving the small intestine increased upon luminal exposure to a mixture of emulsified lipids (Intralipid, 0.1 ml) in mice on HFD with confirmed jejunal H GCS2 expression.
  • standardized mucosal scrapings dissolved in saline from the HFD mice contained more ketone bodies than when obtained from LFD-mice (2.06 ⁇ 0.7 versus 1.2 ⁇ 0.4 mM).
  • obesity is associated with expression of the ketogenic enzyme HMGCS2 the small intestinal mucosa; fat and/or fatty acids in the intestinal lumen result in intestinal mucosal ketogenesis and that this response is mediated by H GCS2; and

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Abstract

L'invention concerne un inhibiteur de corps de cétone pour l'utilisation dans le traitement ou la prévention de : une lésion de la barrière du tractus gastro-intestinal (tractus GI) et/ou une maladie ou un état associé(e) à une lésion de la barrière du tractus gastro-intestinal. Des aspects associés de l'invention concernent des compositions pharmaceutiques de l'invention, conjointement avec leurs procédés d'identification et d'utilisation.
PCT/GB2013/052850 2012-11-01 2013-10-31 Inhibiteurs de corps de cétone utilisables dans le traitement d'une lésion de la muqueuse du tractus gastro-intestinal WO2014068320A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1219678.8A GB201219678D0 (en) 2012-11-01 2012-11-01 Ketone body inhibitors and uses thereof
GB1219678.8 2012-11-01

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WO2014068320A1 true WO2014068320A1 (fr) 2014-05-08

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WO2015079254A1 (fr) * 2013-11-29 2015-06-04 University Of East London Antagonistes des recepteurs des leucotrienes et leurs derives pour utilisation en tant qu'agents antibacteriens
CN105510261A (zh) * 2015-11-30 2016-04-20 山东博科生物产业有限公司 一种灵敏度高的d3-羟丁酸（d3h）检测试剂及其检测方法
CN110179782A (zh) * 2019-06-19 2019-08-30 曾辉 一种治疗aml的药物及应用
CN110420228A (zh) * 2019-09-16 2019-11-08 山东大学齐鲁医院 脆弱拟杆菌ych46在制备治疗或辅助治疗高血压的药物中的应用
CN116059406A (zh) * 2022-10-21 2023-05-05 西南医科大学附属医院 一种用于治疗糖尿病肾脏疾病的Bdh1基因药物

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