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WO2018031286A1 - Préparations et méthodes de traitement utilisant des analogues du glucose - Google Patents

Préparations et méthodes de traitement utilisant des analogues du glucose Download PDF

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Publication number
WO2018031286A1
WO2018031286A1 PCT/US2017/044802 US2017044802W WO2018031286A1 WO 2018031286 A1 WO2018031286 A1 WO 2018031286A1 US 2017044802 W US2017044802 W US 2017044802W WO 2018031286 A1 WO2018031286 A1 WO 2018031286A1
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WIPO (PCT)
Prior art keywords
glucose
deoxy
infection
mice
lps
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PCT/US2017/044802
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English (en)
Inventor
Ruslan Medzhitov
Sarah HUEN
Andrew Wang
Harding LUAN
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Yale University
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Yale University
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Publication of WO2018031286A1 publication Critical patent/WO2018031286A1/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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/08—Deoxysugars; Unsaturated sugars; Osones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Sickness behaviors are a collection of very prominent symptoms of acute illness that include anorexia, lethargy, fever, sleepiness, depression, lack of grooming and social withdrawal. It has been long appreciated that sickness behaviors are motivational states, rather than a result of debilitation of physiological functions (Holmes and Miller, 1963, J Exp Med 118:649-58; Miller, 1964, Bull Br Psychol Soc 17: 1-20). Furthermore, sickness behaviors have been conceptualized as well- organized and adaptive programs that promote survival of acute infections (Hart, 1998, Neurosci Biobhav Rev 12: 123-37; Kluger et al, 1975, Science 188: 166-8). However, the mechanisms whereby different sickness behaviors contribute to survival remain largely unknown.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • physiological changes that are beneficial for the host survival can contribute to elimination of pathogens (resistance) or to mitigation of tissue damage caused by infection (tolerance).
  • pathogens resistance
  • tissue damage caused by infection tolerance
  • the present invention provides a method of treating an infection in a subject.
  • the method comprises administering to the subject an effective amount of at least one sugar analog selected from the group consisting of glucose analogs and heptose analogs.
  • the glucose analog is 2-deoxy-D-glucose (2DG). In one embodiment, 2DG does not suppress ketogenesis.
  • heptose analog is D-manno-heptulose (DMH).
  • the infection is selected from the group consisting of sepsis, a bacterial infection and a parasitic infection. In one embodiment, the infection is selected from the group consisting of a listeria infection and a
  • the method further comprises administering at least one additional therapeutic.
  • the at least one additional therapeutic is selected from an antibiotic and an antiparasitic.
  • the subject is a human.
  • the present invention also provides a method of providing nutritional supplementation to a subject.
  • the method comprising administering to the subject a composition comprising at least one sugar analog selected from the group consisting of glucose analogs and heptose analogs.
  • the glucose analog is 2-deoxy-D-glucose (2DG).
  • heptose analog is D-manno-heptulose (DMH).
  • the subject has an infection selected from the group consisting of sepsis, a bacterial infection and a parasitic infection.
  • bacterial infection is a listeria infection.
  • the parasitic infection is a Plasmodium infection.
  • the composition does not comprise glucose.
  • the method improves survival of the subject. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 depicts results of experiments demonstrating glucose caloric supplementation during Listeria monocytogenes infection worsens survival, while 2-Deoxy-D-glucose (2DG) promotes survival.
  • Figure 1A depicts food consumption after infection with 5 x 10 4 and 5 x 10 5 CFU wild-type L. monocytogenes.
  • Figure IB depicts survival after infection with 5 x 10 4 L. monocytogenes. Mice were per os (po) gavaged with 1 Calorie of Abbott Promote (Food) twice a day, 1 Calorie of Glucose twice a day, or PBS vehicle twice a day, and injected i.p. with 5 mg 2DG or PBS.
  • FIG. 1C depicts survival after L. monocytogenes and indicated treatments. Mice were infected with 5 x 10 4 CFU L. monocytogenes i.v., then treated with PBS, 20 mg glucose, or 5 mg 2DG i.p. twice a day starting 8 hours after L. monocytogenes infection. Figure ID depicts plasma and tissue harvested L. monocytogenes day 4 after 5 x 10 4 L.
  • FIG. IE depicts flow cytometry analysis of CD45+ cells within the liver 4 days after L. monocytogenes infection and treatment with PBS, glucose, or 2DG
  • Figure IF depicts CFU growth of L. monocytogenes after incubation in brain heart infusion broth with or without 15 rriM 2DG for 18 hours.
  • Figure 1G depicts bone marrow-derived macrophages (BMDM) were infected with 5 x 10 5 CFU of L. monocytogenes in the presence or absence of 15 mM 2DG for 24 hours.
  • Figure 2 depicts results of experiments demonstrating glucose caloric supplementation during LPS sepsis worsens survival, while 2DG promotes survival.
  • Figure 2A depicts survival after 15 mg/kg i.p. LPS and po gavage with 1 Calorie of Abbott Promote (Food) twice a day (BID), or PBS vehicle BID. Gavage interventions were initiated one hour after LPS administration.
  • Figure 2B depicts survival after 15 mg/kg i.p. LPS and po gavage with 1 Calorie of Glucose BID, 1 Calorie of olive oil BID, 1 Calorie of casein BID, or PBS vehicle BID. Gavage interventions were initiated one hour after LPS administration.
  • Figure 2C depicts survival after 15 mg/kg i.p. LPS and po gavage with 1 Calorie of Food BID with i.p. injections of PBS or 5 mg 2DG BID starting an hour after LPS administration.
  • Figure 2D depicts survival after 15 mg/kg i.p. LPS and indicated treatments.
  • Mice were given 15 mg/kg i.p. LPS, then treated with PBS, 20 mg glucose, or 5 mg 2DG given i.p. BID. Injection interventions were initiated one hour after LPS administration.
  • Figure 3 depicts flow cytometry analysis of CD45+ cells within the liver 4 days after L. monocytogenes infection and treatment with PBS, glucose, or 2DG. ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • Figure 4 depicts experiments where mice were given 15 mg/kg i.p. LPS, then treated with PBS, 20 mg glucose, or 5 mg 2DG given i.p. twice a day initiated one hour after LPS administration.
  • Figure 4A depicts O2 saturation, respiratory rate, heart rate and body temperature 24 hours after LPS.
  • Figure 4B depicts blood glucose measured at 2, 6, 18 hours after LPS. Plasma troponin-I, ALT, and creatinine levels measured at 24 hours after LPS.
  • Figure 5 depicts results of experiments demonstrating caloric supplementation and glucose utilization is required for surviving influenza infection.
  • Figure 5A depicts food consumption after infection with 450 plaque forming units (pfu) of Influenza strain A/WSN/33.
  • Figure 5F depicts mRNA expression of whole lung tissue at day 6.
  • Figure 5G depicts plasma IFNa measured by ELISA.
  • Figure 51 depicts histologic scoring of lung tissue 6 days after Influenza infection.
  • Figure 5 J depicts C saturation, respiratory rate, heart rate and body temperature after Influenza infection.
  • Figure 6 comprising Figure 6A through Figure 6E depicts results of experiments.
  • Figure 6A depicts survival after infection with 800 pfu Influenza. Mice were gavaged with 1 Calorie of Abbott Promote (Food), 1 Calorie of Casein, 1 Calorie of Olive Oil twice a day, or PBS vehicle twice a day.
  • Figure 6B depicts mRNA expression of whole lung tissue at day 6 after 375 pfu Influenza.
  • Figure 6C depicts flow cytometric analysis of Lung and BAL on day 6 after 700 pfu Influenza.
  • Figure 7 depicts results of experiments demonstrating inhibition of glucose utilization is lethal in Poly(LC) inflammation.
  • Figure 7A depicts survival of mice after i.v. injection of 30 mg/kg Poly(LC) and treatment with either i.p. PBS, 20 mg Glucose, or 5 mg 2DG BID initiated one hour after Poly(LC) administration.
  • Figure 7B depicts survival of B6 wild-type mice and Ifhar-/- mice after i.v. injection of 30 mg/kg
  • Figure 8 depicts experiments where mice were given 30 mg/kg Poly(I:C) i.v., then treated with either i.p. PBS, Glucose, or 2DG initiated one hour after Poly(I:C) administration. Blood glucose measured at 2, 6, and 18 hours after Poly (I: C). Plasma troponin-I, ALT and creatinine measured at 24 hours after
  • Figure 9 depicts results of experiments demonstrating inhibition of glucose utilization in Poly(I:C)-induced inflammation enhances ER stress.
  • Figure 9B depicts survival of B6 wild-type mice and Ddit3-/- mice after i.v. injection of 30 mg/kg Poly(I:C) and treatment with i.p.
  • FIGE depicts MEFs treated with vehicle, IFNa, Poly (I: C), and Thapsigargin, in the presence of vehicle, glucose or 2DG for 24 hours.
  • Figure 10 depicts results of experiments demonstrating glucose utilization in LPS sepsis promotes oxidative stress.
  • Figure 10B depicts survival after 8 mg/kg LPS and treatment with glucose. Mice were treated with vehicle, valproic acid (VA) or levetiracetam (Keppra) starting 6 hours after LPS.
  • VA valproic acid
  • Keppra levetiracetam
  • FIG. 1 depicts HEt staining of brain from nice mice given i.p. LPS then initiated with PBS, glucose, and 2DG treatment 1 hour after LPS and staining 24 hours after LPS.
  • Figure 10D depicts TU EL staining of brain sections 24 hours after LPS and treatment with PBS, glucose, or 2DG. Quantification of TUNEL positive cells per high power field (400x magnification). *p ⁇ 0.05, ***p ⁇ 0.001.
  • Figure 11 depicts results of experiment.
  • Figure 11 A depicts whole blood glucose at 0, 2, 6, and 24 hours after LPS with treatments as indicated.
  • Figure 11B depicts representative images of heart, lung, liver, and kidney tissue stained for TUNEL 24 hours after LPS, shown at 400x magnification.
  • Figure 11C depicts brain tissue stained for TUNEL 24 hours after LPS. Representative images of brain tissue stained for TUNEL. Area enclosed by the dotted-line box shown at 400x magnification below tiled image.
  • Figure 12 depicts results of experiments demonstrating the role of ketogenic program in surviving bacterial, but not viral inflammation.
  • FIG. 12E depicts survival after 8 mg/kg i.p. LPS in WT and Ppara-/- mice. 2DG treatment was initiated one hour after LPS.
  • Figure 12H depicts a proposed model of glucose utilization during viral and bacterial-mediated inflammation supporting unique tissue tolerance mechanisms.
  • Figure 13 depicts survival after 375 pfu Influenza in WT and Fgf21-/- mice.
  • Figure 14 depicts survival of mice challegened with LPS or Poly I:C and treated with 2DG or D Mannoheptulose.
  • the present invention relates to the discovery that the glucose analog 2- Deoxy-D-glucose (2DG) and D-manno-heptulose (DMH) improve survival of subjects with sepsis, a bacterial infection or a parasitic infection, while glucose worsens the subject's mortality.
  • the present invention is directed to methods and compositions for treating infections and inflammation.
  • the composition does not inhibit ketogenesis.
  • the composition comprises a glucose analog.
  • the composition comprises 2DG or DMH.
  • the invention is a method of treating inflammation or infection in a subject.
  • the subject is administered a composition comprising a glucose analog.
  • the subject is administered 2DG or DMH.
  • the infection is sepsis, a bacterial infection or a parasitic infection.
  • the invention is a method of providing nutritional supplementation to a subject by administering a composition comprising glucose analog.
  • the subject is administered 2DG or DMH.
  • the subject has an infection such as a bacterial infection, a parasitic infection, or sepsis.
  • an element means one element or more than one element.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a disorder in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result. Such results may include, but are not limited to, the inhibition of virus infection as determined by any means suitable in the art.
  • an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compositions and methods of the invention.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the nucleic acid, peptide, and/or composition of the invention or be shipped together with a container which contains the nucleic acid, peptide, and/or composition.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c), intravenous (i.v.), intramuscular (i.m), or intrasternal injection, or infusion techniques.
  • s.c subcutaneous
  • i.v. intravenous
  • i.m intramuscular
  • intrasternal injection or infusion techniques.
  • subject refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder
  • contemplated herein or the potential to develop a disease or disorder contemplated herein with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a diseaser or disorder contemplated herein, at least one sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • the present invention is based on the unexpected discovery that 2- Deoxy-D-glucose (2DG) and D-manno-heptulose (DMH) improve survival and tissue protection through the modulation of metabolic programs in certain inflammatory diseases and disorders.
  • 2DG 2- Deoxy-D-glucose
  • DMH D-manno-heptulose
  • the present invention provides methods and compositions for treating a bacterial disease or disorder.
  • the method comprises administering to the subject an effective amount of 2DG, DMH, an analog thereof, or a combination thereof.
  • Another aspect of the invention provides a method of providing caloric supplementation to a subject by administering a composition of the invention.
  • the method comprises administering a composition for caloric supplementation, wherein the composition does not comprise glucose, heptose or any analog thereof.
  • the method comprises administering a composition for caloric supplementation comprising at least one of 2DG and DMH.
  • the subject has an infectious disease or disorder such as a bacterial infection, a parasitic infection or sepsis.
  • the composition for caloric supplementation is a food or a medical food.
  • the invention provides a method of improving survival of a patient having a disease or disorder by administering 2DG or DMH.
  • the patient has a bacterial infection, a parasitic infection or sepsis.
  • the patient is receiving a nutritional supplement wherein the nutritional supplement does not comprise glucose.
  • the composition for caloric supplementation is a food or a medical food.
  • the invention provides compositions for treating an infection in a subject.
  • the present invention includes compositions for improving survival of a subject having disease or disorder, such as an infection or inflammation.
  • the compositions of the invention do not inhibit ketogenesis.
  • the composition of the invention comprises a glucose analog.
  • the composition comprises a sugar that can be metabolized into 2-DG, such as 2-deoxy-D-galactose, as well as disaccharide embodiments such as lactose and sucrose analogues containing 2-DG, and halogenated and other conjugated derivatives of deoxy sugars (as set forth above), such as fluoro-2-deoxy- D-glucose, conjugated deoxy sugars (as set forth above) that are metabolized to 2-DG, and compositions having effects similar to 2-DG.
  • the composition comprises 2-deoxy -D-glucose (2-DG) or 3-bromopyruvate.
  • the composition of the invention comprises a heptose analog.
  • the composition comprises D-manno- heptulose (DMH).
  • DMH D-manno- heptulose
  • the composition comprises a derivative of DMH such as perseitol, or sedoheptulose.
  • the composition comprises a sugar that can be metabolized into DMH, as well as disaccharide embodiments of DMH, and halogenated or other conjugated derivatives of DMH and compositions having similar effects to DMH.
  • the composition comprises 2DG, DMH or a combination thereof.
  • compositions comprising 2-DG and methods using said compositions will be understood to encompass preparations of 2-deoxy glucose as the D-stereoisomer, as well as racemic mixtures thereof comprising any combination of D- and L-2-deoxy glucose, provided that the percentage of the D-stereoisomer is greater than zero.
  • mannoheptulose and methods of using said compositions will be understood to encompass preparations of mannoheptulose as the D-stereoisomer, as well as racemic mixtures thereof comprising any combination of D- and L- mannoheptulose provided that the percentage of the D-stereoisomer is greater than zero.
  • 2-DG and DMH are available commercially, and preferably are produced according to the standards and guidelines of the pharmaceutical industry and in compliance with all relevant regulatory requirements.
  • 2-DG and DMH can also be synthesized using methods well-established in the art (see, for example, THE MERCK INDEX, 12.sup.th Ed., Monograph 2951, New Jersey: Merck & Co., 1997; Bergmann et al, 1922, Ber. 55: 158; Snowden et al, 1947, JACS 69: 1048; Bolliger et al, 1954, Helv. Chim.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • ether e.g., tetrahydrofuran, methyl tert-butyl ether
  • alcohol e.g., ethanol
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol.
  • the compounds described herein exist in unsolvated form.
  • prodrugs In one embodiment, compounds described herein are prepared as prodrugs.
  • a "prodrug” refers to an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • this invention provides a nutritional package for providing nutrition to subject comprising a nutritional composition for enteral administration and being in at least two forms selected from solid, semi-solid, and liquid forms.
  • the present invention provides compositions for nutritional supplementation.
  • the composition of the invention comprises a glucose analog.
  • the composition of the invention comprises D-manno-heptulose (DMH) or derivatives thereof that are converted into DMH, 2- deoxy glucose or derivatives thereof that are converted to 2-DG in a subject, or a related deoxy-substitution of glucose, such as 3-deoxy-D-glucose, 4-deoxy-D- glucose, 5-deoxy-D-glucose, 6-deoxy-D-glucose, or any combination thereof.
  • the composition does not comprise glucose.
  • the composition further comprises a protein source and a carbohydrate source.
  • the composition further comprises a fat source.
  • Sources of protein include, but are not limited to, casein, soy, whey, and pea protein.
  • Carbohydrate sources include, but are not limited to, dietary fiber.
  • Dietary fiber passes through the small intestine undigested by enzymes and represents a kind of natural and necessary laxative.
  • Suitable sources of dietary fiber include soy, oat, and gum arabic.
  • Fat sources may include long chain triglycerides (LCT), including olive oil, corn oil, canola oil, palm kernel oil, sunflower oil, peanut oil, soy lecithin and residual milk fat or medium chain triglycerides.
  • the composition further comprises vitamins, minerals and trace elements
  • compositions of the invention may be incorporated into any formulation known in the art.
  • the composition of the invention is formulated for oral administration.
  • the nutritional supplement is a nutritional formulation, medical food, a medical beverage, a dietary supplement, or a food additive as a powder for dissolution.
  • the nutritional supplement is in the form of a complete meal, or part of a meal.
  • the nutritional supplement is in the form of a pharmaceutical formulation such as in the form of a tablet, pill, sachet or capsule or by tube feeding such as by means of nasogastric, nasoduodenal, esophagostomy, gastrostomy, or jejunostomy tubes, or peripheral or total parenteral nutrition.
  • the compositions of the invention may be administered orally as a dietary supplement or medical food.
  • composition of the present invention comprises a combination of deoxy glucose derivatives described herein.
  • the composition comprises a combination comprising at least two of 2-deoxy-D-glucose, 3-deoxy-D-glucose, 4- deoxy-D-glucose, and 5-deoxy-D-glucose, 6-deoxy-D-glucose, 2-deoxy-D-galactose, 2-deoxy-D-lactose, 2-deoxy-D-sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5-deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D-glucose, 3, 5-deoxy-D- glucose, 3, 6-deoxy-D-glucose, 4,5-deoxy-D-glucose, 4,6-deoxy-D-glucose and 5,6- deoxy-D-glucose.
  • the present invention provides a composition, wherein the composition comprises a combination comprising at least three of 2- deoxy-D-glucose, 3-deoxy-D-glucose, 4-deoxy-D-glucose, and 5-deoxy-D-glucose, 6- deoxy-D-glucose, 2-deoxy-D-galactose, 2-deoxy-D-lactose, 2-deoxy-D-sacrose, 2,3- deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5-deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D-glucose, 3, 5-deoxy-D-glucose, 3, 6-deoxy-D-glucose, 4,5-deoxy-D- glucose, 4,6-deoxy-D-glucose and 5, 6-deoxy-D-glucose.
  • the present invention provides a composition, wherein the composition comprises a combination comprising at least four of a 2-deoxy-D-glucose, 3-deoxy-D-glucose, 4- deoxy-D-glucose, and 5-deoxy-D-glucose, 6-deoxy-D-glucose, 2-deoxy-D-galactose, 2-deoxy-D-lactose, 2-deoxy-D-sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5-deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D-glucose, 3, 5-deoxy-D- glucose, 3, 6-deoxy-D-glucose, 4,5-deoxy-D-glucose, 4,6-deoxy-D-glucose and 5,6- deoxy-D-glucose.
  • a 2-deoxy-D-glucose 3-
  • the present invention provides a composition, wherein the composition comprises a combination comprising 2-deoxy-D-glucose, 3- deoxy-D-glucose, 4-deoxy-D-glucose, and 5-deoxy-D-glucose, 6-deoxy-D-glucose, 2- deoxy-D-galactose, 2-deoxy-D-lactose, 2-deoxy-D-sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5-deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D- glucose, 3, 5-deoxy-D-glucose, 3, 6-deoxy-D-glucose, 4,5-deoxy-D-glucose, 4,6- deoxy-D-glucose and 5,6-deoxy-D-glucose, and any combination thereof.
  • composition of the present invention comprises a combination of deoxy glucose derivative and at least one additional therapeutic useful for treating inflammation or infections.
  • additional compounds may comprise compounds of the present invention or other compounds, such as commercially available compounds, known to treat, prevent, or reduce the signs or symptoms of a disease or disorder, such as inflammation and infection.
  • a glucose derivative of the invention may be used in combination with a therapeutic agent such as an antibiotic, including but not limited tolipopeptide, fluoroquinolone, ketolide, cephalosporin, amikacin, gentamicin, kanamycin, neomycin, netilmicin,
  • a therapeutic agent such as an antibiotic, including but not limited tolipopeptide, fluoroquinolone, ketolide, cephalosporin, amikacin, gentamicin, kanamycin, neomycin, netilmicin,
  • pivmecillinam pivmecillinam, ticarcillin, sulfamethizole, sulfamethoxazole, sulfisoxazole, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxy tetracycline, tetracycline, linezolid, clindamycin, metronidazole, vancomycin, vancocin, mycobutin, rifampin, nitrofurantoin, and chloramphenicol.
  • a glucose derivative of the invention may be used in combination with a therapeutic agent such as an antiparasitic, including but not limited to bephenium, diethylcarbamazine, ivermectin, niclosamide, praziquantel, pyrantel, pyrvinium, albendazole,
  • a therapeutic agent such as an antiparasitic, including but not limited to bephenium, diethylcarbamazine, ivermectin, niclosamide, praziquantel, pyrantel, pyrvinium, albendazole,
  • mebendazole thiabendazole, benzyl benzoate, benzyl benzoate disulfiram, crotamiton, lindane, malathion , quinine, permethrin, doxycycline, tetracycline, clindamycin, chloroquine, amodiaquine, pyrimethamine, chloroguanide, atovaquone, mefloquine, primaquine, artemisinin, artemether, halofantrine and clindamycin.
  • a composition comprising a combination of therapeutics described herein has an additive effect, wherein the overall effect of the combination is approximately equal to the sum of the effects of each individual therapeutic. In other embodiments, a composition comprising a combination of therapeutics described herein has a synergistic effect, wherein the overall effect of the combination is greater than the sum of the effects of each individual therapeutic.
  • a composition comprising a combination of molecules comprises individual therapeutics in any suitable ratio.
  • the composition comprises a 1 : 1 ratio of two individual therapeutics.
  • the composition comprises a 1 : 1 : 1 ratio of three individual therapeutics.
  • the combination is not limited to any particular ratio. Rather any ratio that is shown to be effective is encompassed.
  • the invention provides methods of treating an infection in a subject in need thereof.
  • the method comprises administering to the subject an effective amount of at least one sugar analog selected from at least one glucose analog.
  • the method comprises administering to the subject an effective amount of at least one sugar analog selected from at least one heptose analog.
  • the method comprises administering to the subject an effective amount of at least one sugar analog selected from at least one glucose analog and at least one heptose analog
  • the method treats a bacterial or parasitic infection or inflammation associated with a bacterial or parasitic infection.
  • the glucose analog or heptose analog does not suppress ketogenesis.
  • the at least one glucose analog is 2-deoxy-D-glucose, 3-deoxy-D-glucose, 4-deoxy-D-glucose, and 5-deoxy- D-glucose, 6-deoxy-D-glucose, 2-deoxy-D-galactose, 2-deoxy-D-lactose, 2-deoxy-D- sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5-deoxy-D-glucose, 2,6- deoxy-D-glucose, 3,4-deoxy-D-glucose, 3,5-deoxy-D-glucose, 3,6-deoxy-D-glucose, 4,5-deoxy-D-glucose, 4,6-deoxy-D-glucose, 5, 6-deoxy-D-glucose, or any
  • the at least one heptose analog is D- manno-heptulose, perseitol, or sedoheptulos.
  • the method comprises administering to the subject a composition deficient of glucose or carbohydrates.
  • the present invention also provides a method of providing nutritional supplementation to a patient.
  • the method comprises administering to the subject a composition comprising at least one sugar analog selected from at least one glucose analog and/or at least one heptose analog.
  • the at least one glucose analog is 2-deoxy-D-glucose, 3-deoxy-D-glucose, 4-deoxy-D- glucose, and 5-deoxy-D-glucose, 6-deoxy-D-glucose, 2-deoxy-D-galactose, 2-deoxy- D-lactose, 2-deoxy-D-sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy-D-glucose, 2,5- deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D-glucose, 3,5-deoxy-D-glucose, 3,6-deoxy-D-glucose, 4,5-deoxy-
  • the composition does not comprise glucose.
  • the at least one heptose analog is D- manno-heptulose, perseitol, or sedoheptulos.
  • method comprises administering to the subject a composition deficient of glucose or carbohydrates.
  • the subject has sepsis, a bacterial infection or a parasitic infection.
  • the sepsis is bacterial sepsis.
  • the sepsis is not viral sepsis.
  • the subject is human.
  • the method further comprises first diagnosing the subject as having bacterial sepsis. In another embodiment, the method further comprises first diagnosing the subject as not having viral sepsis.
  • the subject does not have sepsis, but rather is at risk for sepsis.
  • the method of preventing sepsis comprises administering to the subject a composition comprising at least one sugar analog selected from at least one glucose analog and/or at least one heptose analog.
  • the at least one glucose analog is 2-deoxy-D-glucose, 3-deoxy-D- glucose, 4-deoxy-D-glucose, and 5-deoxy-D-glucose, 6-deoxy-D-glucose, 2-deoxy-D- galactose, 2-deoxy-D-lactose, 2-deoxy-D-sacrose, 2,3-deoxy-D-glucose, 2,4-deoxy- D-glucose, 2,5-deoxy-D-glucose, 2,6-deoxy-D-glucose, 3,4-deoxy-D-glucose, 3,5- deoxy-D-glucose, 3,6-deoxy-D-glucose, 4,5-deoxy-D-glucose, 4,6-deoxy-D-glucose, 5, 6-deoxy-D-glucose, or any combination thereof.
  • the composition does not comprise glucose.
  • the method of preventing sepsis comprises administering to the subject a composition deficient of glucose or carbohydrates.
  • the subject is at risk for sepsis.
  • Subjects at risk for sepsis include, but are not limited to those infected with gram- positive and gram-negative organisms such as E. coli, K. pneumoniae, P. aeruginosa, S. pyogenes, S. aureus, or S. epidermidis; surgical pateints, elderly patients, low birth weight infants, burn patients and trauma patients.
  • the subject displays a symptom indicative of sepsis.
  • Symptoms indicative of sepsis include, but are not limited to weakness, metabolic disturbance, dehydration, tachycardia, tachypnea or hyperpnea, hypotension, hypoperfusion, oliguria, leukocytosis or leukopenia, pyrexia or hypothermia.
  • the at least one heptose analog is D-manno-heptulose, perseitol, or sedoheptulos.
  • Exemplary bacterial infections that may be treated by way of the present invention includes, but is not limited to, infections caused by bacteria from the taxonomic genus of Bacillus, Bartonella, Bordetella, Borrelia, Brucella,
  • Enterococcus Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Ureaplasma, Vibrio, and Yersinia.
  • the bacterial infection is an infection of Bacillus anthracis, Bacillus cereus, Bartonella henselae, Bartonella quintana, Bordetella pertussis, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, Borrelia recurrentis, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus
  • Exemplary diseases caused by bacterial infections include but are not limited to, bacterially mediated meningitis, sinus tract infections, pneumonia, endocarditis, pancreatitis, appendicitis, gastroenteritis, biliary tract infections, soft tissue infections, urinary tract infections, cystitis, pyelonephritis, osteomyelitis, bacteremia,
  • Actinomycosis Whooping cough, Secondary bacterial pneumonia, Lyme disease (B. burgdorferi), Relapsing fever, Brucellosis, Enteritis, bloody diarrhea, Guillain-Barre syndrome, Atypical pneumonia, Trachoma, Neonatal conjunctivitis, Neonatal pneumonia, Nongonococcal urethritis(NGU), Urethritis, Pelvic inflammatory disease, Epididymitis, Prostatitis, Lymphogranuloma venereum (LGV), Psittacosis, Botulism: Mainly muscle weakness and paralysis, Pseudomembranous colitis, Anaerobic cellulitis, Gas gangrene Acutefood poisoning, Tetanus, and Diphtheria.
  • Exemplary parasitic infections that may be treated by way of the present invention includes, but is not limited to, infections caused by Protozoan organisms, tapeworms, Flukes, Roundworms, or Ectoparasites.
  • the parasitic infection includes, but is not limited to Acanthamoeba spp., Balamuthia mandrillaris, Babesia B. divergens, B. bigemina, B. equi, B. microfti, B.
  • duncani Balantidium coli, Blastocystis spp., Cryptosporidium spp., Cyclospora cayetanensis, Dientamoeba fragilis, Entamoeba histolytica, Giardia lamblia, Isospora belli,
  • Schistosoma sp. Schistosoma mansoni andSchistosoma intercalatum, Schistosoma haematobium, Schistosoma japoni cum, Schistosoma mekongi -, Echinostoma echinatum,
  • Trichobilharzia regenti Schott al.
  • Schistosomatidae Trichobilharzia regenti,Schistosomatidae, Ancylostoma duodenale,Necator americanus, Angiostrongylus costaricensis, Anisakis, Ascaris sp.Ascaris
  • the parasitic infection is a Plasmodium infection.
  • Exemplary diseases caused by parasitic infections include but are not limited to, Acanthocephaliasis, Amoebiasis, Angiostrongyliasis, Anisakiasis, Asian intestinal schistosomiasis, Babesiosis, Balantidiasis, Baylisascariasis, Bedbug, Bertielliasis, Blastocystosis, Calabar swellings, Chagas disease, Chigoe flea, Chinese Liver Fluke, Clonorchiasis, Cryptosporidiosis, Cyclosporiasis, Dientamoebiasis, Dioctophyme renalis infection, Giardiasis, Gnathostomiasis, Granulomatous amoebic encephalitis, Guinea worm , Halicephalobiasis, Halzoun Syndrome, Hookworm, Human Botfly, Lung Fluke, intestinal fluke, Isosporiasis, Lancet liver
  • the parasitic infection causes malaria.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset of an infection. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions of the present invention may be carried out using known procedures, at dosages and for periods of time effective to treat inflammation or infections in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the inflammation or infection in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of infections in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • compositions of the invention are administered to the patient continuously.
  • compositions of the invention are administered to the patient in dosages that range from one to five times per day or more.
  • the compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.
  • Compounds of the invention for administration may be in the range of from about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 3050 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1 ,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms in a patient.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • compositions of the invention include intravenous, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g.
  • vaginal e.g., trans- and perivaginally
  • intranasal and (trans)rectal intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose;
  • granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone,
  • hydroxypropylcellulose or hydroxypropylmethylcellulose hydroxypropylmethylcellulose
  • fillers e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc, or silica
  • disintegrates e.g., sodium starch gly collate
  • wetting agents e.g., sodium lauryl sulphate
  • the tablets may be coated using suitable methods and coating materials such as OPADRYTM film coating systems available from Colorcon, West Point, Pa.
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation.”
  • solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents.
  • the low melting solids when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.
  • the liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together.
  • the resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.
  • melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.
  • U.S. Patent No. 5,169,645 discloses directly compressible wax- containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.
  • the present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders.
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389;
  • Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952;
  • Additional dosage forms of this invention also include dosage forms as described in
  • the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of infections in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the viral load, to a level at which the improved disease is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.
  • the compounds for use in the method of the invention may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • Example 1 Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation
  • CHOP knockout mice are strain B6.129S(Cg)- Ddit3tm2.1Dron/J purchased from Jackson Laboratory (Stock No. 005530).
  • PPARa knockout mice are strain B6; 129S4-Pparatml Gonz/J purchased from Jackson Laboratory (Stock No. 008154).
  • FGF21 knockout mice were a generous gift from Dr. David J. Mangelsdorf.
  • mice were gavaged PBS control or the equivalent of one calorie of the indicated substance (glucose, casein, olive oil, or Abbott Promote) twice a day starting 8 hours post-infection in infection models and 1 hour post-injection in sterile inflammatory models.
  • the indicated substance glucose, casein, olive oil, or Abbott Promote
  • mice were injected intraperitoneally with glucose (20 mg in 100 ⁇ water) or 2DG (5 mg in 100 ⁇ water) twice a day starting 8 hours post-infection in infection models and 1 hour post-injection in sterile inflammatory models.
  • Valproic acid and levetiracetam were administered intraperitoneally starting 6 hours post-injection at 125 mg/kg and 18 mg/kg in 100 PBS, respectively.
  • FGF21 supplementation was done by retro- orbital injection of recombinant FGF21 (R&D Systems 8409-FG/CF) twice daily at 5 ng in 100 ⁇ PBS per injection.
  • Blood oxygen saturation, breath rate, and heart rate were measured by pulse oximetry using the MouseOx Plus (Starr Life Sciences Corp.). Core body temperature was measured by rectal probe thermometry
  • mice were injected retro-orbitally with 5xl0 4 CFU of L. monocytogenes.
  • Influenza virus strain A/WSN/33 was originally obtained from the laboratory of Dr. Akiko Iwasaki and was propagated using MDCK cells as described (Okuda et al, 2001, Vaccine 19:3681-91).
  • mice were anesthetized with a ketamine/xylazine mixture and indicated PFU of influenza in 30 ⁇ PBS was administered dropwise.
  • mice were injected intraperitoneally with the indicated dose of LPS derived from Escherichia coli 055 :B5 (Sigma- Aldrich L2880) diluted in 100 ⁇ PBS.
  • LPS LPS derived from Escherichia coli 055 :B5
  • Poly(LC) viral inflammation model mice were injected retro-orbitally with 30 mg/kg of high molecular weight Poly(LC) (InvivoGen tlrl-pic-5) diluted in 100 ⁇ of normal saline provided by the manufacturer.
  • BMDMs Bone marrow derived macrophages
  • Mouse embryonic fibroblasts were cultured in DMEM (Sigma- Aldrich D5796) supplemented with 10% FBS (Gibco 10438-026), 1% penicillin-streptomycin (Gibco 15140-163), 2 mM L-glutamine (Gibco 25030-164), 1 mM sodium pyruvate (Gibco 11360-070), and 0.01 M HEPES (AmericanBio AB06021-00100).
  • MEFs were plated at a density of lxl 0 5 cells per well in a 24 well plate. After overnight rest, cells were treated with the indicated chemicals or cytokines in the presence of additional glucose (final concentration 9 g/L), 15 mM 2DG, or vehicle control.
  • Thapsigargin (Cayman Chemical 10522) was administered at 1 ⁇ .
  • Poly(LC) was given at 20 ⁇ g/mL.
  • Recombinant mouse IFNa (R&D Systems 12100-1) was used at 1000 U/ml.
  • L. monocytogenes titers were determined by plating titrated amounts of liver and spleen homogenate on BHI plates as previously described (Auerbuch et al, 2004, J Exp Med 200:527-33). For in vitro assays testing the effect of 2DG on . monocytogenes growth in macrophages, titrated amounts of culture supernatant and cell lysate were plated on BHI plates and grown overnight at 37 °C. To test the effect of 2DG on growth of L. monocytogenes in BHI broth, 5 xlO 3 L. monocytogenes was inoculated into 25 ml of BHI with or without 10 mg/ml of 2DG. Flasks were incubated overnight. Titrated volumes of L. monocytogenes containing BHI broth were plated the following day on BHI plates and incubated overnight for
  • Influenza titers in the lung and bronchoalveolar lavage fluid were determined as previously described (Okuda et al, 2001, Vaccine 19:3681-91). Plasma cytokine, metabolite, and tissue injury marker analysis
  • Plasma TNFa and IL-6 concentration were assayed by sandwich ELISA using capture antibodies (eBioscience 14-7423-85 and 14-7061-85), biotin-conjugated detection antibodies (eBioscience 13-7341-85 and BD 554402), HRP-conjugated streptavidin (BD 554066), and TMB substrate reagent (BD 555214). Plasma IFNa and IL- ⁇ concentrations were assayed using kits according to the manufacturer's protocols (eBioscience BMS6027 and eBioscience 88-7013-22).
  • Plasma Tropinin-I concentration and Alanine Aminotransferase (ALT) activity were assayed using kits according to manufacturers' protocols (Life Diagnostics CTNI-1-HSP and Cayman Chemical 700260). Plasma creatinine was assayed using HPLC by The George M. O'Brien Kidney Center at Yale. Plasma non-esterified fatty acid concentration was measured using a kit according the manufacturer's protocols (Wako Diagnostics 999- 34691, 995-34791, 991-34891, and 993-35191). Plasma ⁇ -hydroxybutyrate concentrations were measured using a kit according the manufacturer's protocols (Cayman Chemical 700190).
  • qRT-PCR reactions were performed on either a CFX96 Real-Time System or CFX384 Real-Time System (Bio-Rad) using PerfeCTa SYBR Green SuperMix (Quanta Biosciences) and transcript levels were normalized to Rpll3a. Primers used for qRT-PCR are listed in Table 1.
  • Antibodies to the following mouse antigens were used for flow cytometry: CD4-FITC (GK1.5), CDl lc-FITC (N418), B220-PE (RA3-6B2), Grl- PECy7 (RB6-8C5), CD45-APC/eFluor780 (30-Fl l), CD4-B.V.421 (GK1.5), NK1.1- PeCy7 (PK136), CDl lb-B.V.421 (Ml/70) (eBioscience), and TCR-beta-FITC (H57- 597), Ly6C-PE (AL-21), CD8-APC (53-6.7) (BD Biosciences), and EMA (Biotium, Hayward, CA), F4/80-PECy5 (BM8) (Biolegend).
  • Samples were Fc-blocked with functional grade mouse anti-CD 16/32 antibody (93) (eBioscience). Annexin V-FITC and PI were used for apoptosis assays and the manufacturer's protocol was followed (eBioscience). For tissue analyses, at least 1 x 10 5 cells were acquired on CD45+ cells within the singlet live gate, as defined by size, granularity and pulse-width. Samples were acquired on an LSRII flow cytometer (BD Biosciences), and analyzed using FlowJo (Tree Star Technologies).
  • mice 24 hours after administration of indicated treatments, mice were injected with 0.2 mg of hydroethidine (HEt) in 100 ⁇ PBS. After 30 minutes, mice were anesthetized with a ketamine/xylazine mixture and perfused with 4%
  • DAPI ThermoFisher Scientific D1306
  • mice were imaged on the Inveon small animal PET/CT scanner (Siemens Medical Solutions, Malvern, PA) using 5.3 ⁇ 3.9 MBq of 18F-FDG. Mice were scanned for 1 hour under isoflurane anesthesia. Regions-of-interest were delineated in the heart, lung and liver (manually drawn) and brain substructures (using a template (Ma et al, 2005, Neuroscience 134: 1203-15)). Standard uptake values (SUVs) at 40-60 min post-injection were used to assess glucose metabolism.
  • SUVs Standard uptake values
  • mice All mice were euthanized by carbon dioxide asphyxiation and perfused with PBS or fixative. Tissues were immersion-fixed in either 10% neutral buffered formalin or Bouin's fixative (Ricca Chemical Corporation). Tissues were trimmed, processed, embedded, and sectioned and stained for hematoxylin and eosin by routine methods. Tissues were evaluated by a veterinarian trained in veterinary pathology with extensive expertise in mouse pathology blinded to both experimental and genetic manipulations.
  • Digital light microscopic images were acquired using a Zeiss Axio Imager Al microscope, an AxioCam MRc5 Camera, and AxioVision 4.8.3.0 imaging software (Carl Zeiss Microimaging, Inc.). The resulting images were optimized using Adobe Photoshop 13.0. lx 64.
  • TU EL staining was performed as previously described (Babar et al, 2012, PNAS 109:E1695-704). TUNEL images were not captured by CJB. These images were captured on a Leica DMI6000B. All other images were captured by CJB.
  • Results were statistically analyzed using Student's t test or an analysis of variance (ANOVA) test with multiple comparisons where appropriate using Prism 6.0 (GraphPad Software, Inc). Kaplan Meier survival curves were compared using log-rank Mantel-Cox test. A p value of ⁇ 0.05 was considered to be statistically significant.
  • IP injection of glucose was sufficient to recapitulate the lethal effects of enteral glucose (Figure 1C).
  • Figure 1C To assess if glucose was necessary for lethality, L.
  • the advantage of the LPS sepsis model is that it isolates the immune response, as opposed to direct pathogen toxicity, as the source of tissue damage.
  • this model whether the effects of nutrient intake are linked to altered magnitude of the immune response can be assessed. If they are not, then any differential pathological outcomes must be due to tissue tolerance to immunopathology.
  • Plasma from endotoxemic mice treated with PBS, glucose, or 2DG at two, six, and eighteen hours post-LPS injection was collected, circulating levels of TNFa and IL-6 were identical at all time points (Figure 2E). Livers of mice four hours post-LPS treatment were also harvested to look at acute phase response genes by gene expression and there was no difference found between groups (Figure 2F).
  • ChREBP carbohydrate- responsive element-binding protein
  • mice had acute lymphoid necrosis/apoptosis consistent with the LPS mouse model and no differences in histopathologic changes were seen except for decreased dark, shrunken neurons in the brains of LPS mice given 2DG compared mice given LPS and PBS or glucose. Together, these data implicate neuronal dysfunction as a possible proximal cause of death in LPS endotoxemia. Inhibition of Glucose Utilization is Lethal in Influenza Infection
  • the lethal effects of inhibiting glucose utilization in the influenza infection may be due to effects on tissue tolerance and likely acting on the brain.
  • the Poly (I: C) model was utilized as a general model of viral inflammation (Smorodintsev et al., 1978, Vopr Virusol 201-6).
  • 30 mg/kg Poly (I: C) was injected intravenously, and, as in the LPS model, the mice were treated with glucose or 2DG.
  • Administration of 2DG was uniformly lethal within 24 hours of Poly(LC) challenge (Figure 7A).
  • mice were subjected to 2-deoxy-2- [18F] fluorodeoxy-D-glucose-positron emission tomography-computed tomography (18FDG-PET-CT) analyses.
  • FDG-PET-CT 2-deoxy-2- [18F] fluorodeoxy-D-glucose-positron emission tomography-computed tomography
  • HDAC-I HD AC -inhibition
  • GABA transduction GABA transduction
  • PI3K and calcium handling Hsiech et al, 2012, Toxicol 291 :32-42; Kondo et al., 2014, PLoS One 9:el04010; Li et al, 2014, Sci Rep 4:7207.
  • Ketone bodies have also been implicated as HDAC-I of the same class as VA, and have recently been shown to coordinate gene expression programs that confer resistance to ROS-mediated damage (Shimazu et al, 2013, Science 339:211- 4).
  • mice deficient in PPARa and FGF21 were subjected to both LPS and influenza. Both PPARa and FGF21 deficient mice displayed enhanced mortality (Figure 12A). It was verified that PPARa-deficient mice have severely impaired ketogenesis following LPS challenge, and no significant changes in the level of BHOB was observed in FGF21 -deficient animals, consistent with findings observed in the fasting state (Potthoff et al, 2009, PNAS 106: 10853-8) ( Figure 12B). Consistent with other data, an increase in systemic cytokines was not detected, and if anything, IL-6 level was decreased in PPARa deficient mice ( Figure 12C).
  • FGF21 is a known downstream target of PPARa (Feingold et al, 2012, Endocrinol 153:2689- 700; Inagaki et al, Cell Metab 5:415-25), it was tested if defective FGF21 production was the causative lesion in PPARa-deficiency. PPARa-deficient and FGF21 -deficient mice were reconstituted with recombinant FGF21 given intravenously.
  • ketotic pre-conditioning has been shown to improve other neurologic conditions such as epilepsy (Levy et al, 2012, Cochrane Database Sys Rev, CD001903), it was tested if ketotic pre-conditioning would improve survival to LPS. Mice which were pre-fasted, on ketogenic diets for 3 days, or pre-treated with valproic acid displayed no difference or enhanced mortality to LPS. The possibility that ketoacidosis was driving death was excluded. These data indicate that the activation of the ketogenic program and subsequent HDAC-I must be temporally coupled to evolution of the inflammatory challenge.
  • Host responses to infectious challenge involve both host resistance and host tolerance mechanisms. Whereas host resistance promotes pathogen clearance, host tolerance relies on adaptation to a given level of pathogen, and by extension, a given level of inflammatory response (Raberg et al, 2009, Phios trans R Sco Lond B Biol Sci 318:812-4; Raberg et al, 2007, Science 318:812-4; Schneider and Ayres, 2008, Nat Rev immunol 8: 889-95). Disease morbidity and mortality can be a result of either inadequate or impaired host resistance, characterized by high pathogen burden, or as a result of impaired host tolerance.
  • Immunopathology falls into the latter category, and insufficient tissue protection is likely to be an important determinant in conditions characterized by excessive inflammation, such as sepsis (Figueiredo et al, 2013, Immunity 39:874-84; Larsen et al, 2010 Sci Transl Med 2:51ra71). Tissue protection is likely a function of cellular stress adaptation pathways, which allow cells to adapt and survive noxious states such as increased free radicals and accumulation of unfolded proteins (Figueiredo et al., 2013, Immunity 39:874-84; Larsen et al., 2010 Sci Transl Med 2:51ra71).
  • ROS-mediated cytotoxicity is a well-appreciated phenomenon in bacterial sepsis (Hoetzenecker et al., 2012, Nat Med 18: 128-34; Kolls, 2006, J Clin Invest 116:860-3), and ROS-detoxification pathways have been implicated in mitigating tissue damage and mortality. Shimazu et al recently reported that BHOB functioned as an HDAC-1 inhibitor, and that this lead to transcription of ROS-detoxification pathways (Shimazu et al, 2013, Science 339:211-4). The data described herein provides evidence that the fasting state is required to maintain resistance to oxidative stress in LPS sepsis.
  • Viral infections are known to stimulate the unfolded protein response as a cytoprotective mechanism but also as a resistance mechanism to limit the amount of viral protein translation, and this has been shown to be in part mediated via the PERK-eIF2a-ATF4-CHOP unfolded protein response pathway (Janssens et al, 2014, Nat Immunol 15:910-9). When this pathway is engaged, the cell can either adapt to the ER stress, or induce apoptosis through CHOP if the ER stress cannot be managed (Tabas and Ron, 2011, Nat Cell Biol 13: 184-90). The data presented herein suggests that glucose utilization is required for the cytoprotective response in the setting of viral inflammation, as inhibition of glucose utilization lead to cell death, which was dependent on CHOP.

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Abstract

La présente invention concerne la découverte selon laquelle les analogues de sucres améliorent la survie de sujets atteints d'une maladie.
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