WO2014113048A1 - Compositions et procédés permettant de diagnostiquer et de traiter une sepsie - Google Patents

Compositions et procédés permettant de diagnostiquer et de traiter une sepsie Download PDF

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Publication number
WO2014113048A1
WO2014113048A1 PCT/US2013/035025 US2013035025W WO2014113048A1 WO 2014113048 A1 WO2014113048 A1 WO 2014113048A1 US 2013035025 W US2013035025 W US 2013035025W WO 2014113048 A1 WO2014113048 A1 WO 2014113048A1
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Prior art keywords
sepsis
patient
episode
doses
units
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PCT/US2013/035025
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English (en)
Inventor
Hung Bryant NGUYEN
David J. Baylink
Kin-Hing William Lau
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Loma Linda University
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Priority to PCT/US2013/053186 priority Critical patent/WO2014113068A1/fr
Priority to PCT/US2014/012130 priority patent/WO2014113723A1/fr
Priority to US14/761,939 priority patent/US20150335662A1/en
Publication of WO2014113048A1 publication Critical patent/WO2014113048A1/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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • 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
    • G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • Sepsis is a whole-body inflammatory state produced in response to an infective agent, such as for example bacteria, fungi, parasites or viruses. Sepsis commonly presents with inflammatory signs and symptoms related to an immune response to the infective agent, and typically include one or more than one sign and symptom selected from the group consisting of altered mentation, edema, flushing, hyperthermia, hypothermia, hypotension,
  • ICU intensive care units
  • MODS multiple organ dysfunction syndrome
  • MSOF multisystem organ failure
  • the treatment of an episode of sepsis usually involves antibiotics, antifungal agents, antiparasitic agents or antiviral agents where the underlying infective agent is determined, and cardiovascular support with intravenous fluids and vasopressors to maintain blood pressure.
  • antibiotics antibiotics
  • antifungal agents antiparasitic agents or antiviral agents
  • cardiovascular support with intravenous fluids and vasopressors to maintain blood pressure.
  • mechanical ventilation and dialysis can be used to support the function of the lungs and kidneys, respectively.
  • sepsis continues to result in high mortality.
  • an agent for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of 1 alpha-hydroxyergocalciferol; 1-alpha-hydroxy vitamin D2; 1- alpha-hydroxy vitamin D3; l-alpha(OH)D2; l-alpha(OH)D3; 1 , 24, 25 -trihydroxy vitamin D3; l ,25(OH)2-16-ene-23yne-D3; 19-nor-l , 25 -dihydroxy vitamin D2; 19-nor-l ,25-(OH)2-vitamin D2; 19-nor-l , 25-dihydroxy vitamin D3; 20(17 ⁇ 18)-abeo-la,25-dihydroxy-22-homo-21- norvitamin D(3); 24, 25 -dihydroxy vitamin D3; alfacalc
  • an agent for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the agent consists of a functional analog of one or more than one of the group of 1 alpha-hydroxyergocalciferol; 1- alpha-hy droxy vitamin D2; 1 -alpha-hydroxy vitamin D3; l-alpha(OH)D2; l-alpha(OH)D3; 1 ,24,25-trihydroxyvitamin D3; l ,25(OH)2-16-ene-23yne-D3; 19-nor-l , 25 -dihydroxy vitamin D2; 19-nor-l , 25-(OH)2-vitamin D2; 19-nor-l , 25 -dihydroxy vitamin D3; 20(17 ⁇ 18)-abeo- lcc,25-dihydroxy-22-homo-21-norvitamin D(3);
  • a substance for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the substance comprises an agent according to the present invention, and further comprising one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • At least one of the one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of a binder, a coloring chemical and a flavoring chemical.
  • compositions for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the composition comprises two or more than two agents that are active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome, and where at least one of the two or more than two agents is an agent according to the present invention.
  • compositions for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the composition comprises two or more than two agents that are active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome, and where at least two of the two or more than two agents are agents according to the present invention.
  • compositions for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the composition comprises two or more than two agents that are active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome, and where at least one of the two or more than two agents is an agent selected from the group consisting of 1 alpha-hydroxy ergocalciferol; 1 -alpha-hydroxy vitamin D2; 1 -alpha-hydroxy vitamin D3; 1- alpha(OH)D2; l-alpha(OH)D3; 1 ,24, 25 -trihydroxy vitamin D3; l ,25(OH)2-16-ene-23yne-D3; 19-nor-l ,25-dihydroxyvitamin D2; 19-nor-l ,25-(OH)2-vitamin D2; 19-
  • the composition further comprises one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • the one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of a binder, a coloring chemical and a flavoring chemical.
  • a method for characterizing the severity of an episode of sepsis in a patient comprises: a) identifying a patient with an episode of sepsis; and b) measuring a calcitriol blood level in the patient; where a measured calcitriol blood level below a predetermined amount means that the episode of sepsis is severe.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body temperature greater than 38°C or less than 36°C; b) i) a respiratory rate greater than 20 breaths per minute, or ii) partial pressure of carbon dioxide less than 32 mm Hg; c) a heart rate greater than 90 beats per minute; and d) i) a white blood cell count greater than 12,000 cells per mm3, or ii) a white blood cell count less than 4,000 cells per mm3, or iii) a white blood cell count comprising 10% or more than 10% immature forms.
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In one embodiment, the plurality of times is two times. In another embodiment, the plurality of times is three times. In another embodiment, the plurality of times is four times. In another embodiment, the plurality of times is more than four times. In one embodiment, the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility.
  • the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis.
  • the predetermined amount is 30 pg/mL. In another embodiment, the predetermined amount is 25 pg/mL. In another embodiment, the predetermined amount is 20 pg/mL. In another embodiment, the
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the characterization of the episode of sepsis as more severe.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for determining a likelihood that a patient with an episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome comprises: a) identifying a patient with an episode of sepsis; and b) measuring a calcitriol blood level in the patient; where a measured calcitriol blood level below a predetermined amount increases the likelihood that the episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body temperature greater than 38°C or less than 36°C; b) i) a respiratory rate greater than 20 breaths per minute, or ii) partial pressure of carbon dioxide less than 32 mm Hg; c) a heart rate greater than 90 beats per minute; and d) i) a white blood cell count greater than 12,000 cells per mm3, or ii) a white blood cell count less than 4,000 cells per mm3, or iii) a white blood cell count comprising 10% or more than 10% immature forms.
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In one embodiment, the plurality of times is two times. In another embodiment, the plurality of times is three times. In another embodiment, the plurality of times is four times. In another embodiment, the plurality of times is more than four times. In one embodiment, the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility.
  • the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis.
  • the predetermined amount is 30 pg/mL. In another embodiment, the predetermined amount is 25 pg/mL. In another embodiment, the predetermined amount is 20 pg/mL. In another embodiment, the predetermined amount is 15.4 pg/mL. In another embodiment, the predetermined amount is 15 pg/mL. In another embodiment, the predetermined amount is 10 pg/mL. In another embodiment, the predetermined amount is 5 pg/mL.
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the likelihood that the episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for determining a likelihood that a patient with an episode of sepsis will die from the episode of sepsis comprises: a) identifying a patient with an episode of sepsis; and b) measuring a calcitriol blood level in the patient; where a measured calcitriol blood level below a predetermined amount increases the likelihood that the patient with the episode of sepsis will die from the episode of sepsis.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In one embodiment, the plurality of times is two times. In another embodiment, the plurality of times is three times.
  • the plurality of times is four times. In another embodiment, the plurality of times is more than four times.
  • the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility. In another embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis. In one embodiment, the predetermined amount is 30 pg/mL.
  • the predetermined amount is 25 pg/mL. In another embodiment, the predetermined amount is 20 pg/mL. In another embodiment, the predetermined amount is 15.4 pg/mL. In another embodiment, the predetermined amount is 15 pg/mL. In another embodiment, the
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the likelihood that the patient with the episode of sepsis will die from the episode of sepsis.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for treating a patient with an episode of sepsis comprises: a) determining that the patient has an episode of sepsis; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby treating the patient with the episode of sepsis.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg.
  • the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In one embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to
  • the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses.
  • the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for treating a patient with an episode of sepsis comprises: a) determining that the patient has an episode of sepsis; and b) administering to the patient one or more than one dose of calcitriol, thereby treating the patient with the episode of sepsis.
  • the one or more than one dose administered is between 0.01 meg and 10,000 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.01 meg and 10,000 meg of calcitriol. In another embodiment, the one or more than one dose administered is between
  • the one or more than one dose administered is between 0.1 meg and 100 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.1 meg and 1 meg of calcitriol. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In another embodiment, the plurality of doses is two doses.
  • the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the severity of an episode of sepsis in a patient comprises: a) determining that the patient has a severe episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the severity of the episode of sepsis in the patient.
  • the one or more than one dose administered is between 0.01 ng and 1 gram. In another embodiment, the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In one embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units.
  • the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the likelihood that a patient with sepsis will progress to sepsis with multiple organ dysfunction syndrome comprises: a) determining that the patient has an increased likelihood to progress to sepsis with multiple organ dysfunction syndrome according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will progress to sepsis with multiple organ dysfunction syndrome.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg.
  • the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In one embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units.
  • the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral.
  • the one or more than one dose is a plurality of doses.
  • the plurality of doses is two doses.
  • the plurality of doses is three doses.
  • the plurality of doses is four doses.
  • the plurality of doses is more than four doses.
  • the plurality of doses are administered between one hour and seventy-two hours apart.
  • the plurality of doses are administered between one hour and thirty-six hours apart.
  • the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the likelihood that a patient with an episode of sepsis will die from the episode of sepsis comprises: a) determining that the patient has an increased likelihood to die from the episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent of according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will die from the episode of sepsis.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In one embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units.
  • the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In another embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In another embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • Figure 1 is a table of baseline patient characteristics identified in patients studied according to the present invention relating the baseline patient characteristics to patient survival or patient nonsurvival (mortality);
  • Figure 2 is a table of vitamin D status characteristics, and of other potentially relevant characteristics (creatinine, total calcium, albumin, and total bilirubin blood levels) measured at 0, 24, 48, and 72 hours from admission, and analyzed to determine their predictive value for patient survival and patient nonsurvival at thirty days from admission for sepsis;
  • Figure 3 is a table of the predictive value of variables found to have potential relevance to patient survival and patient nonsurvival at thirty days from admission with sepsis;
  • Figure 4 is a graph of receiver operating characteristics (ROC) curves that were generated to determine the predictive value of age, total calcium and calcitriol blood levels at 48 hours after admission with respect to patient survival and patient nonsurvival at thirty days from admission with sepsis;
  • ROC receiver operating characteristics
  • Figure 5 is a graph of Kaplan-Meir analysis performed to obtain patient survival curves over thirty days from admission for calcitriol blood levels, the variable with the highest area under the receiver operating characteristics curve;
  • Figure 6 is a graph of the natural log of calcitriol blood levels as a function of the natural log of calcidiol blood levels for all patients;
  • Figure 7 is a table of calcidiol blood levels and calcitriol blood levels in patient survivors and patient non-survivors from repeated measures regression analysis of the values in Figure 6, showing that calcitriol production was lower in non-survivors for the same substrate calcidiol blood levels in survivors;
  • Figure 8 is a graph of the natural log of calcitriol blood levels as a function of the natural log of parathyroid hormone (PTH) levels for all patients.
  • one or more than one agent for treating a patient with an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome there is provided one or more than one substance for treating a patient with an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome.
  • the substance comprises one or more than one agent according to the present invention.
  • one or more than one composition for treating a patient with an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome where the composition comprises a plurality of agents according to the present invention.
  • a method for characterizing the severity of an episode of sepsis in a patient comprising first, identifying a patient with sepsis, and then, measuring a calcitriol blood level in the patient, where a measured calcitriol blood level below a predetermined amount means that the episode of sepsis is severe.
  • a method for determining a likelihood that a patient with sepsis will progress to sepsis with multiple organ dysfunction syndrome multiple organ failure (MOF) (multisystem organ failure (MSOF)).
  • MOF multiple organ failure
  • MSOF multisystem organ failure
  • a method for determining a likelihood that a patient with an episode of sepsis will die from the episode of sepsis According to another embodiment of the present invention, there is provided a method for treating a patient with an episode of sepsis.
  • the method comprises categorizing the severity of the episode of sepsis in the patient according to the present invention. In another embodiment, the method comprises determining a likelihood that the patient with sepsis will progress to sepsis with multiple organ dysfunction syndrome according to the present invention. In another embodiment, the method comprises determining a likelihood that a patient with an episode of sepsis will die from the episode of sepsis according to the present invention. In one embodiment, the method comprises administering to the patient an agent or a substance or a composition for treating a patient with an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome according to the present invention.
  • a method for decreasing the severity of an episode of sepsis in a patient comprises a) determining that the patient has a severe episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the severity of the episode of sepsis in the patient.
  • a method for decreasing the likelihood that a patient with sepsis will progress to multiple organ dysfunction syndrome is provided.
  • the method comprises a) determining that the patient has an increased likelihood to progress to multiple organ dysfunction syndrome according to present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will progress to multiple organ dysfunction syndrome.
  • an agent according to the present invention or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding
  • the method comprises a) determining that the patient has an increased likelihood to die from the episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will die from the episode of sepsis.
  • an agent according to the present invention or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding
  • systemic inflammatory response syndrome produced in response to an infective agent, such as for example bacteria, fungi, parasites or viruses, where the whole-body inflammatory state presents with inflammatory signs and symptoms comprising one or more than one sign and symptom selected from the group consisting of altered mentation, bandemia, edema, flushing, hyperthermia, hypothermia, hypotension, hyperventilation, leukocytosis, leukopenia, lightheadedness, tachycardia, and a combination of the preceding, as will be understood by those with skill in the art with respect to this disclosure.
  • septic shock means "sepsis with refractory
  • hypotension "where the refractory hypotension is characterized by the presence of a persistent systolic blood pressure of less than 90 mm Hg or a reduction of more than 40 mm Hg from baseline in the absence of causes of hypotension other than sepsis despite adequate fluid resuscitation, as will be understood by those with skill in the art with respect to this disclosure.
  • multiple organ dysfunction syndrome is equivalent to “multiple organ failure” (MOF), and “multisystem organ failure” (MSOF) and means “septic shock,” where the function of two or more than two organs are altered due to hypoperfusion, hypermetabolism, or both hypoperfusion and hypermetabolism, such that homeostasis cannot be maintained without intervention, and where the two or more than two organs are selected from the group consisting of adrenal glands, brain, gastrointestinal tract, heart, kidneys, liver, lungs, pancreas and spleen, as will be understood by those with skill in the art with respect to this disclosure.
  • agent means a chemical that is active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome (MODS).
  • MODS multiple organ dysfunction syndrome
  • “functional analog” means a chemical having at least 10% as much biological activity on calcium metabolism or immunomodulation in vivo.
  • “substance” means an agent that is active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome (MODS), combined with one or more than one chemical that is not active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome (MODS), where examples of the one or more than one chemical that is not active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome include a binder, a coloring chemical and a flavoring chemical, as will be understood by those with skill in the art with respect to this disclosure.
  • composition means a combination of two or more than two agents, where each of the two or more than two agents are a chemical that is active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome (MODS).
  • MODS multiple organ dysfunction syndrome
  • the composition can further comprise one or more than one chemical that is not active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome (MODS), where examples of the one or more than one chemical that is not active for the diagnosis, treatment, or diagnosis and treatment of an episode of sepsis, sepsis with septic shock or sepsis with multiple organ dysfunction syndrome include a binder, a coloring chemical and a flavoring chemical, as will be understood by those with skill in the art with respect to this disclosure.
  • MODS organ dysfunction syndrome
  • "calcidiol” a prehormone primarily produced in the liver, means (E,3S,6S)-6-[(lR,3aR,4E,7aS)-4-[(2Z)-2-[(5S)-5-hydroxy-2-methylidene- cyclohexylidene]ethylidene] -7a-methyl-2 , 3 , 3a, 5 , 6 , 7-hexahydro- 1 H-inden- 1 -yl] -2 , 3-dimethyl- hept-4-en-2-ol (also known as (6R)-6-[(lR,3aR,4E,7aR)-4-[(2Z)-2-[(5S)-5-Hydroxy-2- methylidene-cyclohexylidene] ethylidene] -7a-methyl-2 , 3 , 3a, 5 , 6 , 7-hexahydro- 1
  • 24,25-dihydroxycholecalciferol, an inactive form of vitamin D means
  • parathyroid hormone means the 84 amino acids polypeptide that is secreted by the chief cells of the parathyroid glands and that acts to increase the concentration of calcium (Ca2 +) in the blood (also known as parathormone; parathyrin; and PTH)
  • vitamin D status means blood levels of the following four chemicals: 1) calcidiol; 2) calcitriol; 3) 24,25-dihydroxycholecalciferol; and 4) parathyroid hormone.
  • an agent for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of 1 alpha-hydroxyergocalciferol; 1-alpha-hydroxy vitamin D2; 1- alpha-hydroxy vitamin D3; l-alpha(OH)D2; l-alpha(OH)D3; 1 , 24, 25 -trihydroxy vitamin D3; l ,25(OH)2-16-ene-23yne-D3; 19-nor- 1 ,25 -dihydroxy vitamin D2);
  • 19-nor-l ,25-(OH)2-vitamin D2 (19-nor- 1 ,25 -dihydroxy vitamin D2; paricalcitol; Zemplar ® Abbott Laboratories Corp. , Abbott Park, IL US); 19-nor- 1 ,25 -dihydroxy vitamin D3;
  • doxercalciferol ergocalciferol
  • EB1089 24a,26a27a-tri-homo-22,24-diene- lalpha,25(OH)2D3)
  • HM l ,25(OH)2-16-ene-D3
  • KH1060 (20-epi-22-oxa-24a,26a,27a-tri- homo-lalpha,25(OH)2D3)
  • MC1288 (l ,25(OH)2-20-epi-D3) and parathyroid hormone.
  • the agent is a functional analog of 1 alpha-hydroxyergocalciferol; 1- alpha-hy droxy vitamin D2; 1 -alpha-hydroxy vitamin D3; l-alpha(OH)D2; l-alpha(OH)D3; l ,24,25-trihydroxyvitamin D3; l ,25(OH)2-16-ene-23yne-D3; 19-nor- 1 ,25 -dihydroxy vitamin D2); 19-nor-l ,25-(OH)2-vitamin D2 (19-nor- 1 ,25 -dihydroxy vitamin D2; paricalcitol;
  • the substance for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • the substance comprises one or more than one agent that is active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome, and one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • the one or more than one agent is an agent according to the present invention.
  • one of the one or more than one agent is calcidiol.
  • one of the one or more than one agent is calcitriol.
  • the one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of a binder, a coloring chemical and a flavoring chemical.
  • compositions for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome where the composition comprises two or more than two agents that are active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • At least one of the two or more than two agents is an agent according to the present invention.
  • one of the two or more than two agents is calcitriol.
  • two of the two or more than two agents is an agent according to the present invention.
  • the composition further comprises one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome.
  • the one or more than one chemical that is not active for the treatment of a patient with an episode of sepsis, sepsis with septic shock, or sepsis with multiple organ dysfunction syndrome is selected from the group consisting of a binder, a coloring chemical and a flavoring chemical.
  • a method for characterizing the severity of an episode of sepsis in a patient comprises, first, identifying a patient with an episode of sepsis, and then, measuring a calcitriol blood level in the patient, where a measured calcitriol blood level below a predetermined amount means that the episode of sepsis is severe.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body temperature greater than 38°C or less than 36°C; b) i) a respiratory rate greater than 20 breaths per minute, or ii) partial pressure of carbon dioxide less than 32 mm Hg; c) a heart rate greater than 90 beats per minute; and d) i) a white blood cell count greater than 12,000 cells per mm3, or ii) a white blood cell count less than 4,000 cells per mm3, or iii) a white blood cell count comprising 10% or more than 10% immature forms.
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In a preferred embodiment, the plurality of times is two times. In another preferred embodiment, the plurality of times is three times. In another preferred embodiment, the plurality of times is four times. In another preferred embodiment, the plurality of times is more than four times.
  • the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility.
  • the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis.
  • the predetermined amount is 30 pg/mL. In another preferred embodiment, the predetermined amount is 25 pg/mL. In another preferred embodiment, the predetermined amount is 20 pg/mL. In another preferred embodiment, the predetermined amount is 15.4 pg/mL. In another preferred embodiment, the predetermined amount is 15 pg/mL. In another preferred embodiment, the predetermined amount is 10 pg/mL. In another preferred embodiment, the predetermined amount is 5 pg/mL.
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the characterization of the episode of sepsis as more severe.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for determining a likelihood that a patient with an episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome (MODS) ("multiple organ failure” (MOF), and “multisystem organ failure” (MSOF)).
  • the method comprises, first, identifying a patient with an episode of sepsis, and then, measuring a calcitriol blood level in the patient, where a measured calcitriol blood level below a predetermined amount increases the likelihood that the episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body temperature greater than 38°C or less than 36°C; b) i) a respiratory rate greater than 20 breaths per minute, or ii) partial pressure of carbon dioxide less than 32 mm Hg; c) a heart rate greater than 90 beats per minute; and d) i) a white blood cell count greater than 12,000 cells per mm3, or ii) a white blood cell count less than 4,000 cells per mm3, or iii) a white blood cell count comprising 10% or more than 10% immature forms.
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In a preferred embodiment, the plurality of times is two times. In another preferred embodiment, the plurality of times is three times. In another preferred embodiment, the plurality of times is four times. In another preferred embodiment, the plurality of times is more than four times.
  • the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility.
  • the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis.
  • the predetermined amount is 30 pg/mL. In another preferred embodiment, the predetermined amount is 25 pg/mL. In another preferred embodiment, the predetermined amount is 20 pg/mL. In another preferred embodiment, the predetermined amount is 15.4 pg/mL. In another preferred embodiment, the predetermined amount is 15 pg/mL. In another preferred embodiment, the predetermined amount is 10 pg/mL. In another preferred embodiment, the predetermined amount is 5 pg/mL.
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the likelihood that the episode of sepsis will progress to sepsis with multiple organ dysfunction syndrome.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for determining a likelihood that a patient with an episode of sepsis will die from the episode of sepsis comprises, first, identifying a patient with an episode of sepsis, and then, measuring a calcitriol blood level in the patient, where a measured calcitriol blood level below a predetermined amount increases the likelihood that the patient with the episode of sepsis will die from the episode of sepsis.
  • identifying the patient comprises reference to medical records relevant to the patient.
  • identifying the patient comprises diagnosing the episode of sepsis in the patient.
  • diagnosing the episode of sepsis in the patient comprises determining that the patient has the following criteria: 1) either i) a suspected or confirmed source of infection determined by the treating clinician, or ii) a serum lactate level greater than 2.5 mmol/L or both; and 2) two or more criteria selected from the group consisting of: a) a body temperature greater than 38°C or less than 36°C; b) i) a respiratory rate greater than 20 breaths per minute, or ii) partial pressure of carbon dioxide less than 32 mm Hg; c) a heart rate greater than 90 beats per minute; and d) i) a white blood cell count greater than 12,000 cells per mm3, or ii) a white blood cell count less than 4,000 cells per mm3, or iii) a white blood cell count comprising 10% or more than 10% immature forms.
  • measuring the calcitriol blood level in the patient comprises measuring the calcitriol blood level in the patient a plurality of times. In a preferred embodiment, the plurality of times is two times. In another preferred embodiment, the plurality of times is three times. In another preferred embodiment, the plurality of times is four times. In another preferred embodiment, the plurality of times is more than four times.
  • the calcitriol blood level is measured upon admission to a health care facility. In another embodiment, the calcitriol blood level is measured upon diagnosing the patient with the episode of sepsis. In one embodiment, the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after admission to a health care facility.
  • the calcitriol blood level is measured at one or more than one time selected from the group consisting of 0, 24, 48, 72 and 96 hours after diagnosing the patient with the episode of sepsis.
  • the predetermined amount is 30 pg/mL. In another preferred embodiment, the predetermined amount is 25 pg/mL. In another preferred embodiment, the predetermined amount is 20 pg/mL. In another preferred embodiment, the predetermined amount is 15.4 pg/mL. In another preferred embodiment, the predetermined amount is 15 pg/mL. In another preferred embodiment, the predetermined amount is 10 pg/mL. In another preferred embodiment, the predetermined amount is 5 pg/mL.
  • the method further comprises determining a presence of one or more than one patient criterion in the patient selected from the group consisting of age, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and a presence of stroke comorbidity, and where the presence of one or more than one criterion of an age greater than 70 years, an Acute Physiology and Chronic Health Evaluation II score greater than 25, and stroke comorbidity further increases the likelihood that the patient with the episode of sepsis will die from the episode of sepsis.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • a method for treating a patient with an episode of sepsis comprises a) determining that the patient has an episode of sepsis; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby treating the patient with the episode of sepsis.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg.
  • the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In another embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to
  • the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses.
  • the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for treating a patient with an episode of sepsis comprises a) determining that the patient has an episode of sepsis; and b) administering to the patient one or more than one dose of calcitriol, thereby treating the patient with the episode of sepsis.
  • the one or more than one dose administered is between 0.01 meg and 10,000 meg of calcitriol.
  • the one or more than one dose administered is between 0.1 meg and 1 ,000 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.1 meg and 100 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10 meg of calcitriol. In another embodiment, the one or more than one dose administered is between 0.1 meg and 1 meg of calcitriol. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In another embodiment, the plurality of doses is two doses.
  • the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • the method comprises a) determining that the patient has an episode of sepsis; and b) administering to the patient one or more than one dose of calcidiol, thereby treating the patient with the episode of sepsis.
  • the one or more than one dose administered is between 1 meg and 1 ,000 meg.
  • the one or more than one dose administered is between 100 units to 10,000,000 units.
  • the one or more than one dose administered is between 400 units to 10,000,000 units.
  • the one or more than one dose administered is between 1000 units to 10,000,000 units.
  • the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses.
  • the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the severity of an episode of sepsis in a patient comprises a) determining that the patient has a severe episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the severity of the episode of sepsis in the patient.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In another embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units.
  • the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the likelihood that a patient with sepsis will progress to sepsis with multiple organ dysfunction syndrome comprises a) determining that the patient has an increased likelihood to progress to sepsis with multiple organ dysfunction syndrome according to present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will progress to sepsis with multiple organ dysfunction syndrome.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg.
  • the one or more than one dose administered is between 1 ng and 10,000 meg.
  • the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In another embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units. In another embodiment, the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units.
  • the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral.
  • the one or more than one dose is a plurality of doses.
  • the plurality of doses is two doses.
  • the plurality of doses is three doses.
  • the plurality of doses is four doses.
  • the plurality of doses is more than four doses.
  • the plurality of doses are administered between one hour and seventy-two hours apart.
  • the plurality of doses are administered between one hour and thirty-six hours apart.
  • the plurality of doses are administered between one hour and twenty-four hours apart.
  • a method for decreasing the likelihood that a patient with an episode of sepsis will die from the episode of sepsis comprises a) determining that the patient has an increased likelihood to die from the episode of sepsis according to the present invention; and b) administering to the patient one or more than one dose of an agent according to the present invention, or a substance according to the present invention, or a composition according to the present invention, or a combination of the preceding, thereby decreasing the likelihood that the patient will die from the episode of sepsis.
  • the one or more than one dose administered is between 0.01 ng and 1 gram.
  • the one or more than one dose administered is between 0.01 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 ng and 10,000 meg. In another embodiment, the one or more than one dose administered is between 0.1 meg and 10,000 meg. In another embodiment, the one or more than one dose administered is between 1 meg and 1 ,000 meg. In another embodiment, the one or more than one dose administered is between 100 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 400 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 1 ,000,000 units.
  • the one or more than one dose administered is 1000 units to 100,000 units. In another embodiment, the one or more than one dose administered is between 1000 units to 10,000 units. In one embodiment, the one or more than one dose is administered by a route selected from the group consisting of intrarectal, intramuscular, intraperitoneal, intrathecal, intravenous and oral. In one embodiment, the one or more than one dose is a plurality of doses. In one embodiment, the plurality of doses is two doses. In another embodiment, the plurality of doses is three doses. In another embodiment, the plurality of doses is four doses. In another embodiment, the plurality of doses is more than four doses. In one embodiment, the plurality of doses are administered between one hour and seventy-two hours apart. In another embodiment, the plurality of doses are administered between one hour and thirty-six hours apart. In another embodiment, the plurality of doses are administered between one hour and twenty-four hours apart.
  • vitamin D status was determined in patients with sepsis as follows, where vitamin D status was defined as blood levels of calcidiol, calcitriol, 24,25-dihydroxycholecalciferol and parathyroid hormone.
  • An analysis of stored plasma samples was conducted, where the stored plasma samples were taken from ninety-one patients diagnosed with sepsis that were admitted to the Medical Intensive Care Unit at Loma Linda University Medical Center (Loma Linda, CA, US).
  • Baseline patient characteristics were obtained at admission, including Acute Physiology and Chronic Health Evaluation (APACHE) II scores, comorbidities, demographics, routine laboratories including cultures, and notation of any suspected source of infection. Additionally, serial measurements of vitamin D status were made at hours 0, 24, 48, 72 after admission. The primary outcome measurement was recorded as patient nonsurvival (mortality) at thirty days after admission, which was considered synonymous with multiple organ dysfunction syndrome.
  • APACHE Acute Physiology and Chronic Health Evaluation
  • Calcidiol blood levels were measured according to standard techniques using a Food and Drug Administration (FDA, US) approved direct, competitive chemiluminescence immunoassay (CLIA) using a DiaSorin LIAISON ® 25-OH Vitamin D Total Assay (Diasorin S.p.A. , 13040 Saluggia (Vercelli) IT).
  • FDA Food and Drug Administration
  • DiaSorin LIAISON 25-OH Vitamin D Total Assay
  • This assay is co-specific for calcidiol and calcitriol, and utilizes a specific antibody to calcidiol coating magnetic particles (solid phase) and a vitamin D analogue, 22-carboxy-23,24,25,26,27-pentanorvitamin D 3 , linked to an isoluminol derivative.
  • calcidiol is dissociated from its binding protein, and competes with the isoluminol labeled analogue for binding sites on the antibody.
  • the unbound material is removed with a wash cycle.
  • the starter reagents are added and a flash chemiluminescent reaction is initiated.
  • the light signal is measured by a photomultiplier as relative light units (RLU) and is inversely proportional to the concentration of calcidiol present in a calibrator, a control or a sample of interest.
  • the assay has a normal range of between 30 ng/niL and 80 ng/niL, with inter- and intra-assay coefficients of variability of 11.2% and 8.1 % , respectively.
  • Calcitriol blood levels were measured according to standard techniques using an assay that extracts and purifies vitamin D metabolites from serum or plasma using C180H cartridges. Following extraction, the sample of interest is assayed using a competitive radioimmunoassay (RIA) procedure based on a polyclonal antibody that is specific for both ercalcitriol and calcidiol. The sample of interest, antibody and tracer are incubated for two hours at between 20-25 °C. Phase separation is accomplished after twenty minutes of incubation at 20-25 °C with a second antibody precipitating complex. After centrifugation and decantation, the bound fraction remaining in the pellet is counted in a gamma counter. Values are calculated directly from a calibrator curve of known concentrations. The assay has a normal range of between 20 pg/mL and 50 pg/mL, with inter- and intra-assay coefficients of variability of 12.6 % and 9.8% , respectively.
  • RIA radioimmunoassay
  • 24,25(OH)2D3 was assayed by radioimmunoassay (RIA). [3H]-24,25(OH)2D3 was used to estimate losses.
  • the RIA method was based on an antibody which was co-specific for 24,25-dihydroxycholecalciferol and 24,25(OH)2D2.
  • the sample of interest, antibody and tracer are incubated for 120 minutes at 20-25 °C. Phase separation is accomplished after twenty minutes incubation at 20-25 °C with a second antibody precipitating complex.
  • NSB/Addition buffer is added after this incubation prior to centrifugation to aid in reducing non-specific binding. Radioactivity was quantitated by the ⁇ -radiation counting system with use of a smooth-spline method.
  • the assay has a normal range of between 1 ng/niL and 3 ng/niL, with inter- and intra-assay coefficients of variability of 10.0% and 8.0% ,
  • Parathyroid hormone blood levels were measured according to standard techniques using a Food and Drug Administration (FDA, US) approved DiaSorin's N-tact ® PTH SP immunoradiometric assay (IRMA).
  • FDA Food and Drug Administration
  • IRMA DiaSorin's N-tact ® PTH SP immunoradiometric assay
  • This assay utilizes two different polyclonal antibodies that have been purified using affinity chromatography. These purified antibodies are specific for two different regions of the parathyroid hormone molecule. The first antibody, is specific for parathyroid hormone amino acids 39-84 and is bound to a solid phase (polystyrene bead). The second antibody is specific for parathyroid hormone amino acids 1-34 and is labeled with iodine- 125. The sample of interest is incubated simultaneously with both antibodies.
  • Intact parathyroid hormone 1-84 contains both the 1-34 and 39-84 amino acid sequences and is the only form of parathyroid hormone that will be bound to both the antibody on the bead and the antibody labeled with iodine- 125. Since the antibody coupled to the solid phase is specific for C-terminal and mid-region fragments as well as intact parathyroid hormone, the capacity of the solid phase is designed to accommodate very high levels of parathyroid hormone. This prevents interference by extremely elevated C-terminal and mid-region parathyroid hormone fragments in samples. Following the incubation period, each bead is washed to remove any unbound labeled antibody. The radioactivity present in the remaining bound labeled antibody is then measured using a gamma counter.
  • the concentration of intact parathyroid hormone in the sample of interest is directly proportional to the radioactivity measured.
  • the assay has a normal range of between 15 pg/mL and 65 pg/mL, with inter- and intra-assay coefficients of variability of 4.3 % and 2.7% , respectively.
  • the baseline patient characteristics were analyzed to determine their relationship with patient survival and patient nonsurvival at thirty days from admission with sepsis by comparing the baseline patient characteristics between patient survivors and patient non- survivors using the student's T-test for normally distributed continuous variables, and the Mann- Whitney U test for skewed variables. The chi-squared test was used for categorical variables. Referring now to Figure 1 , there is shown a table of baseline patient
  • Example I relating the baseline patient characteristics to patient survival or patient nonsurvival.
  • the data are presented as mean + standard error, or count (a percentage of the column).
  • the vitamin D status and other potentially relevant characteristics were analyzed to determine their relationship with patient survival and patient nonsurvival at thirty days from admission with sepsis.
  • a Time variable was created to represent repeated measurements over hours 0, 24, 48, and 72.
  • the Time variable was utilized in repeated measures analysis of variance (ANOVA), which was performed on the vitamin D status characteristics to test for the significance of changes in values over time and to obtain least square estimated group means. Natural log transformations were required for variables that violate the assumptions of linear regression.
  • FIG. 2 there is shown a table of vitamin D status characteristics, and of other potentially relevant characteristics (creatinine, total calcium, albumin, and total bilirubin blood levels) measured at 0, 24, 48, and 72 hours from admission, and analyzed to determine their predictive value for patient survival and patient nonsurvival at thirty days from admission for sepsis.
  • the Time trend p-value is the change in the variable over the four measurement periods derived from a repeated measure ANOVA.
  • the overall estimated mean is the least-square mean derived from a repeated measure ANOVA.
  • the results indicated by the ⁇ reflect analysis of the natural log transformed variables. The data are presented as mean + standard error.
  • FIG. 4 there is shown a graph of receiver operating characteristics (ROC) curves that were generated to determine the predictive value of age, total calcium and calcitriol blood levels at 48 hours after admission with respect to patient survival and patient nonsurvival at thirty days from admission with sepsis, where the area under the receiver operating characteristics curve is AUC.
  • ROC receiver operating characteristics
  • FIG. 5 there is shown a graph of Kaplan-Meir analysis performed to obtain patient survival curves over thirty days from admission for calcitriol blood levels, the variable with the highest area under the receiver operating characteristics curve, showing that patients with calcitriol blood levels ⁇ 15.4 pg/mL at hour 48 had a mean survival time of 14.7 days, while patients with calcitriol blood levels > 15.4 pg/mL had a mean survival time of 25.0 days.
  • Figure 6 and Figure 7 there are shown, respectively, a graph of the natural log of calcitriol blood levels as a function of the natural log of calcidiol blood levels for all patients (Figure 6); and a table of calcidiol blood levels and calcitriol blood levels in patient survivors and patient non-survivors from repeated measures regression analysis of the values in Figure 6, showing that calcitriol production was lower in non-survivors for the same substrate calcidiol blood levels in survivors ( Figure 7).
  • AUC area under the curve (AUC) of the receiver operating characteristics (ROC) curve for calcitriol blood levels measured at hours 0, 24, 48, and 72 for
  • the area under the curve of the receiver operating characteristics curve for total calcium measured at hours 0, 24, 48, and 72 were 0.65, 0.76, 0.83, and 0.81 , respectively.
  • the area under the curve of the receiver operating characteristics curve for age were 0.72. Since the area under the curve for both calcitriol and total calcium showed the highest area under the curve at hour 48, this time point was chosen for determining the receiver operating characteristics curve of the combined model.
  • the area under the curve of the receiver operating characteristics of the combined model including age, total calcium, and calcitriol at hour 48 was 0.98 as shown in Figure 4.
  • calcitriol blood levels have a strong predictive value for patient survival and patient nonsurvival at thirty days from admission with sepsis, while calcidiol blood levels were not strongly predictive value for patient survival and patient nonsurvival at thirty days from admission with sepsis. Additionally, calcitriol blood levels ⁇ 15.4 pg/mL at hour 48 after admission had the strongest predictive value for patient nonsurvival at thirty days from admission with sepsis from progression to multiple organ dysfunction syndrome, while calcitriol blood levels > 15.4 pg/mL at hour 48 after admission had the strongest predictive value for patient survival at thirty days from admission with an episode of sepsis.
  • the slope of ln(calcitriol) as a function of ln(calcidiol) ( Figure 6) was equivalent in both patient survivors and patient non-survivors.
  • the lower calcidiol blood levels in patient non-survivors were insufficient to account for the large decrease in calcitriol blood levels such that for the same calcidiol blood level, there would be a significantly lower calcitriol blood level in the patient non-survivors compared to patient survivors.
  • one of the main regulators of the 1 cc-hydroxylase activity is serum parathyroid hormone.
  • Parathyroid hormone blood levels were increased in both patient survivors and patient non- survivors, but more in patient non-survivors. Generally, an increase in parathyroid hormone would be accompanied by increased calcitriol, as seen in hyperparathyroidism. Contrary to the expected positive correlation between parathyroid hormone blood levels and calcitriol blood levels, however, there was a negative correlation, that is, calcitriol blood levels decreased at high levels of parathyroid hormone blood levels in both patient survivors and patient non- survivors.
  • both renal lcc-hydroxylase and the endocrine production of calcitriol is pivotally disturbed in sepsis, leading to a dysfunction of calcitriol action throughout the body, including in white blood cells and epithelial cells which plays a critical role in immunity, containing "leaky” vasculature and an increase in cytokine production associated with sepsis, and regulating cathelicidin which act to kill invading microbes.
  • the analyses also indicate that total calcium blood levels were significantly decreased in the patient non-survivors compared with the patient survivors.

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Abstract

La présente invention concerne un ou plusieurs agents, substances et compositions permettant de traiter un patient présentant un épisode de sepsie, une sepsie avec choc septique ou une sepsie avec syndrome de dysfonctionnement de plusieurs organes. L'invention concerne un procédé permettant de classer par catégories la gravité d'un épisode de sepsie chez un patient. L'invention concerne un procédé permettant de déterminer une probabilité pour qu'un patient présentant un épisode de sepsie évolue vers une sepsie avec une défaillance de plusieurs organes. L'invention concerne un procédé permettant de déterminer une probabilité pour qu'un patient présentant un épisode de sepsie meure de l'épisode de sepsie. L'invention concerne une méthode permettant de traiter un patient présentant un épisode de sepsie.
PCT/US2013/035025 2013-01-18 2013-04-02 Compositions et procédés permettant de diagnostiquer et de traiter une sepsie WO2014113048A1 (fr)

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US20070299041A1 (en) * 2004-05-26 2007-12-27 Cedars-Sinai Medical Center Induction of innate immunity by vitamin d3 and its analogs
US20100093677A1 (en) * 2008-10-10 2010-04-15 Erica Brook Goodhew Method of inducing negative chemotaxis
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US20100227835A1 (en) * 1995-06-05 2010-09-09 Eisai R&D Management Co., Ltd Substituted liposaccharides useful in the treatment and prevention of endotoxemia
US20070099832A1 (en) * 2002-08-13 2007-05-03 Stefan Simianer Combination Therapy with p38 MAP Kinase Inhibitors and their Pharmaceutical Compositions
US20070299041A1 (en) * 2004-05-26 2007-12-27 Cedars-Sinai Medical Center Induction of innate immunity by vitamin d3 and its analogs
US20100093677A1 (en) * 2008-10-10 2010-04-15 Erica Brook Goodhew Method of inducing negative chemotaxis
US20100196308A1 (en) * 2009-01-27 2010-08-05 Jimenez Joaquin J Vitamin d3 and analogs thereof for alleviating side effects associated with chemotherapy

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