WO2005063221A1 - Measuring vasodilating activity of blood samples to track disease course - Google Patents

Measuring vasodilating activity of blood samples to track disease course Download PDF

Info

Publication number
WO2005063221A1
WO2005063221A1 PCT/US2004/042675 US2004042675W WO2005063221A1 WO 2005063221 A1 WO2005063221 A1 WO 2005063221A1 US 2004042675 W US2004042675 W US 2004042675W WO 2005063221 A1 WO2005063221 A1 WO 2005063221A1
Authority
WO
WIPO (PCT)
Prior art keywords
blood
patient
disease
ability
tissue
Prior art date
Application number
PCT/US2004/042675
Other languages
French (fr)
Inventor
Jonathan S. Stamler
Original Assignee
Duke University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duke University filed Critical Duke University
Publication of WO2005063221A1 publication Critical patent/WO2005063221A1/en

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/321—Arterial hypertension

Definitions

  • This invention is directed to measurement related to ability of blood to cause tissue oxygenation and therapies based thereon.
  • PCT US03/13409 discloses invention based on the conception that nitric oxide (NO) level in blood provides a measure of tissue oxygenation and discloses a link between assessment of human condition and a therapeutic response.
  • NO nitric oxide
  • the invention is directed at a method of tracking the course of a disease in a patient where the disease associated with abnormality in tissue of blood oxygenation or impairment in the lungs ability to oxygenate blood and or of determining the severity of said disease, comprising during the course of the disease, measuring the ability of blood sample from the patient to cause blood vessel dilation.
  • the invention is directed to a method of treating a patient having a disease associated with abnormality in tissue or blood oxygenation or impairment in the lungs ability to oxygenate blood, comprising administering to the patient therapeutically effective amount of anaerobic solution of nitric oxide and/or therapeutically effective amount of solution of nitrite, nitrosothiol or alternative red blood cell loading agent (e.g., ethyl nitrite) in response to measurement of ability of blood sample from the patient to cause blood vessel dilation showing lower than normal ability to cause blood vessel dilation.
  • a red blood cell loading agent e.g., ethyl nitrite
  • the invention is directed to a method of treating patient having a disease associated with abnormal red blood cell induced vasodilation, comprising administering to the patient a therapeutically effective amount of agent which causes increase in red blood cell induced vasodilation.
  • disease associated with abnormality in tissue or blood oxygenation is used herein to mean condition associated with impaired tissue oxygenation.
  • disease associated with impairment of the lungs ability to oxygenate blood is used herein to mean lung disease characterized by impaired v/p (i.e., ventilation/perfusion) matching.
  • the diseases associated with abnormality in tissue or blood oxygenation or impairment in lungs ability to oxygenate blood are any diseases in which red blood cells from the patient do not properly dilate blood vessels within 10% of normal as determined, for example, by the test set forth hereinafter.
  • diseases include, for example, angina, heart failure, pulmonary hypertension, sickle cell disease, diabetes and stroke.
  • a test used for determining vasodilating ability involves use of descending rabbit thoracic aorta cut into 3 mm rings and mounted on stirrups at two grams tension attached to force transducers (model FT03, Grass Instruments, Quincy Mass). In an organ chamber the rabbit aortic rings have been pre-constricted with norepinephrine.
  • Red cells sample (250 ⁇ l of 50% hematocrit) is added to organ chamber containing the pre-constricted aortic rings in oxygenated Kreb's buffer solution (1% oxygen) (25 cc). Relaxation of the pre-constricted aortic rings in terms of % of the pre-constricted tension caused by the red cells sample, is determined.
  • the details of the bioassay are described in Stamler, J.. et al., Proc. Natl. Acad. Sci. USA 89, 444-448 (1992) and McMahon, T., et al., Nature Medicine (2002), Vol 8, 711-717.
  • a plurality of measurements are carried out over time, e.g., once a month, and the results from the patient's red blood cells, while the patient is feeling good, serve as a base line.
  • decrease in percent relaxation e.g., from 15% to 10% or from 10% to 5% means the patient is getting worse while increase in percent relaxation means the patient is getting better.
  • a single measurement is useful to determine severity of disease, e.g., extent of percent relaxation less than 15%.
  • the method constitutes a non-invasive measurement of oxygen delivery to tissue and of how well the patient is feeling.
  • the measurement of the ability of blood sample from the patient to cause blood vessel dilation constitutes a measurement of the first embodiment herein.
  • nitric oxide and/or nitrite administration are carried out in the general amounts and with the routes of administration described for the second, third and fourth embodiments of PCT/US03/13409 with a therapeutically effective amount being an amount that increases relaxation percentage in the bioassay described above.
  • Administration of nitrosothiols, e.g., nitrosoglutathione, or alternative red cell loading agent (e.g., ethyl nitrite) can be carried out, e.g., by infusion to establish a blood concentration ranging from 1 nanomolar to 10 millimolar depending on the drug amount.
  • a therapeutically effective amount is an amount that increases relaxation percentage in the bioassay described above or alternative assay with the same function.
  • the determination of disease associated with abnormal red blood cell induced vasodilation is readily determined by measurement of the ability of a blood sample from a patient to cause blood vessel dilation as carried out in the first embodiment herein.
  • the diseases associated with abnormal red blood cell induced vasodilation include those recited above in the description of the first embodiment.
  • any agent which causes increase in red blood cell induced vasodilation can be administered. These include the agent administered for the second embodiment as well as statins and ACE inhibitors, administered, for example, in dosages and with routes of administration as are known for use with a particular statin or ACE inhibitor.
  • Example I A patient has a history of sickle cell disease. In month one, when the patient is feeling good, measurement of ability of a blood sample from the patient shows 20% relaxation in the above-described bioassay. In month six, a blood sample from the patient shows 10% relaxation. The patient has hypoxia and modest pain. Infusion at a rate of 5 nmol/min of NO in 0.9% NaCl is effected. Pain resolves. Blood sample causes 15% relaxation. In month 12, a blood sample from the patient causes constriction. The patient is in asocclusion crisis. Infusion of NO as above together with nitrite at a rate of 10 nmol/min results in decrease in pain and blood sample causes 10% relaxation.
  • Example II A 65-year old male is admitted to a hospital with unstable angina. The patient is given IN. nitroglycerin, heparin and a beta blocker. However, the patient continues to experience chest pain at rest.
  • the patient's normal blood sample caused vasodilation is known from past testing. Measurement of the patient's blood sample caused vasodilation shows the percent relaxation is below normal. Alternatively, the patient's normal percent relaxation is not known from past testing but measurement of the patient's percent relaxation shows it is lower than average. Infusion at a rate of 5 nmol/min of NO in 0.9%NaCl is effected. The chest pain resolves. When nitrite is additionally given at a rate of 100 nmol min, the chest pain resolves more quickly.
  • Example III A 27-year old female with primary pulmonary hypertension class II presents complaining with shortness of breath.
  • the patient's normal blood sample caused percent relaxation is known from prior testing. Measurement of the patient's blood sample caused percent relaxation shows it is below normal. Infusion of NO in 0.9% NaCl at a rate of 5 nmol/min of NO is effected. The shortness of breath symptom resolves. After three days of therapy, pulmonary artery pressure drops 5mm of mercury.
  • Example IN A 40-year old with diabetes presents with poor peripheral perfusion and leg pain. Red blood cells only dilate blood vessels at low PO 2 . Infusion of S- nitrosoglutathione at 1 nmol/kg/min corrects the defect and improves perfusion.
  • Example V A 70-year old with heart failure and pulmonary hypertension has defective red blood cells induced vasodilation in a bioassay. Infusion of NO at 1 nmol/kg/min improves dyspnea.
  • Example VI An 80-year old with a stroke shows increasing cognitive dysfunction. His red blood cells are found to constrict blood vessels in a bioassay. Infusion of NO improves red blood cell vasodilation and cognition.
  • Example VII A 20-year old with sickle cell disease and acute painful crisis has red blood cell vasodilation dysfunction. Lipitor is initiated. Over the following 24 hours, red blood cell vasodilation function normalizes, and the patient is symptomatically improved.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The course of a disease which is associated with abnormality in tissue or blood oxygenation or impairment in the lungs ability to oxygenate blood, e.g., angina, heart failure, pulmonary hypertension, sickle cell disease, diabetes or storke, is tracked or severity of the disease is determined by measurement of ability of blood sample to dilate blood vessels. Treatment with nitric oxide and/or nitrite and/or other agent which causes increase in red blood cell induced vasodilation, can be carried out in response to measurment showing lower than normal ability to cause blood vessel dilation.

Description

MEASURING VASODILATING ACTIVITY OF BLOOD SAMPLES TO TRACK DISEASE COURSE
Technical Field This invention is directed to measurement related to ability of blood to cause tissue oxygenation and therapies based thereon.
Background of the Invention PCT US03/13409 discloses invention based on the conception that nitric oxide (NO) level in blood provides a measure of tissue oxygenation and discloses a link between assessment of human condition and a therapeutic response.
Summary of the Invention It is now conceived that a.more accurate way of assessing human condition related to abnormality in tissue or blood oxygenation is based on the inability of red cells to properly cause vasodilation under hypoxic conditions and is by determining the extent to which blood sample causes dilation of blood vessels. This method directly measures parameters that govern blood flow (and therefore tissue oxygenation) and is independent of NO in a cell that is not measurable. In one embodiment, denoted the first embodiment, the invention is directed at a method of tracking the course of a disease in a patient where the disease associated with abnormality in tissue of blood oxygenation or impairment in the lungs ability to oxygenate blood and or of determining the severity of said disease, comprising during the course of the disease, measuring the ability of blood sample from the patient to cause blood vessel dilation. In another embodiment, denoted the second embodiment, the invention is directed to a method of treating a patient having a disease associated with abnormality in tissue or blood oxygenation or impairment in the lungs ability to oxygenate blood, comprising administering to the patient therapeutically effective amount of anaerobic solution of nitric oxide and/or therapeutically effective amount of solution of nitrite, nitrosothiol or alternative red blood cell loading agent (e.g., ethyl nitrite) in response to measurement of ability of blood sample from the patient to cause blood vessel dilation showing lower than normal ability to cause blood vessel dilation. In another embodiment, denoted the third embodiment, the invention is directed to a method of treating patient having a disease associated with abnormal red blood cell induced vasodilation, comprising administering to the patient a therapeutically effective amount of agent which causes increase in red blood cell induced vasodilation. The term "disease associated with abnormality in tissue or blood oxygenation" is used herein to mean condition associated with impaired tissue oxygenation. The term "disease associated with impairment of the lungs ability to oxygenate blood" is used herein to mean lung disease characterized by impaired v/p (i.e., ventilation/perfusion) matching.
Detailed Description The diseases associated with abnormality in tissue or blood oxygenation or impairment in lungs ability to oxygenate blood are any diseases in which red blood cells from the patient do not properly dilate blood vessels within 10% of normal as determined, for example, by the test set forth hereinafter. These diseases include, for example, angina, heart failure, pulmonary hypertension, sickle cell disease, diabetes and stroke. A test used for determining vasodilating ability involves use of descending rabbit thoracic aorta cut into 3 mm rings and mounted on stirrups at two grams tension attached to force transducers (model FT03, Grass Instruments, Quincy Mass). In an organ chamber the rabbit aortic rings have been pre-constricted with norepinephrine. Red cells sample (250 μl of 50% hematocrit) is added to organ chamber containing the pre-constricted aortic rings in oxygenated Kreb's buffer solution (1% oxygen) (25 cc). Relaxation of the pre-constricted aortic rings in terms of % of the pre-constricted tension caused by the red cells sample, is determined. The details of the bioassay are described in Stamler, J.. et al., Proc. Natl. Acad. Sci. USA 89, 444-448 (1992) and McMahon, T., et al., Nature Medicine (2002), Vol 8, 711-717. When healthy red cells are added in the assay, 15 ± 1.5% to 30 ± 3.0% relaxation is obtained in the assay. Below 15 ± 1.5% means defective tissue oxygenation. A common type of response depending on the disease and severity thereof has been noted. For sickle cell disease: When there is a vasocclusive crisis, the red cells from the patient cause further constriction rather than relaxation. When the patient has modest pain, the percent relaxation might be about 10%. When a sickle cell patient feels generally good, the patient's red cells cannot be distinguished from normal red blood cells in the bioassay. In determination of the course of a disease, a plurality of measurements are carried out over time, e.g., once a month, and the results from the patient's red blood cells, while the patient is feeling good, serve as a base line. Over time, decrease in percent relaxation, e.g., from 15% to 10% or from 10% to 5% means the patient is getting worse while increase in percent relaxation means the patient is getting better. ^ A single measurement is useful to determine severity of disease, e.g., extent of percent relaxation less than 15%. The method constitutes a non-invasive measurement of oxygen delivery to tissue and of how well the patient is feeling. We turn now to the second embodiment herein. The measurement of the ability of blood sample from the patient to cause blood vessel dilation constitutes a measurement of the first embodiment herein. The treatments herein of nitric oxide and/or nitrite administration are carried out in the general amounts and with the routes of administration described for the second, third and fourth embodiments of PCT/US03/13409 with a therapeutically effective amount being an amount that increases relaxation percentage in the bioassay described above. Administration of nitrosothiols, e.g., nitrosoglutathione, or alternative red cell loading agent (e.g., ethyl nitrite) can be carried out, e.g., by infusion to establish a blood concentration ranging from 1 nanomolar to 10 millimolar depending on the drug amount. A therapeutically effective amount is an amount that increases relaxation percentage in the bioassay described above or alternative assay with the same function. We turn now to the third embodiment herein. The determination of disease associated with abnormal red blood cell induced vasodilation is readily determined by measurement of the ability of a blood sample from a patient to cause blood vessel dilation as carried out in the first embodiment herein. The diseases associated with abnormal red blood cell induced vasodilation include those recited above in the description of the first embodiment. For the third embodiment, any agent which causes increase in red blood cell induced vasodilation can be administered. These include the agent administered for the second embodiment as well as statins and ACE inhibitors, administered, for example, in dosages and with routes of administration as are known for use with a particular statin or ACE inhibitor. It is apparent that average relaxation in a bioassay for ability to cause blood vessel dilation will depend on degree of tone, buffer and related conditions and that the means of relaxation can be different under these different condit ons, i.e., the average characteristic can be individualized to the bioassay so that what is 15% in the described bioassay may be 10% in another bioassay or 30% in a third bioassay but the principle of different degrees in the bioassays as a function of disease holds. In addition, one can alternatively assay ability of blood sample from a patient to cause blood vessel relaxation as a graded response across a range of PO2s ranging from 60 to 0 mm Hg as described in MacMahon et al cited above. The average PO2 at which red cells switch from constriction effect to dilation effect is about 10 mm Hg in the normal red cell. More vigorous (healthy) vasodilation implies that the switch occurs at higher PO2 whereas dysfunctional red cells switch at lower PO2. The invention is illustrated by the following working examples. Example I A patient has a history of sickle cell disease. In month one, when the patient is feeling good, measurement of ability of a blood sample from the patient shows 20% relaxation in the above-described bioassay. In month six, a blood sample from the patient shows 10% relaxation. The patient has hypoxia and modest pain. Infusion at a rate of 5 nmol/min of NO in 0.9% NaCl is effected. Pain resolves. Blood sample causes 15% relaxation. In month 12, a blood sample from the patient causes constriction. The patient is in asocclusion crisis. Infusion of NO as above together with nitrite at a rate of 10 nmol/min results in decrease in pain and blood sample causes 10% relaxation.
Example II A 65-year old male is admitted to a hospital with unstable angina. The patient is given IN. nitroglycerin, heparin and a beta blocker. However, the patient continues to experience chest pain at rest. The patient's normal blood sample caused vasodilation is known from past testing. Measurement of the patient's blood sample caused vasodilation shows the percent relaxation is below normal. Alternatively, the patient's normal percent relaxation is not known from past testing but measurement of the patient's percent relaxation shows it is lower than average. Infusion at a rate of 5 nmol/min of NO in 0.9%NaCl is effected. The chest pain resolves. When nitrite is additionally given at a rate of 100 nmol min, the chest pain resolves more quickly.
Example III A 27-year old female with primary pulmonary hypertension class II presents complaining with shortness of breath. The patient's normal blood sample caused percent relaxation is known from prior testing. Measurement of the patient's blood sample caused percent relaxation shows it is below normal. Infusion of NO in 0.9% NaCl at a rate of 5 nmol/min of NO is effected. The shortness of breath symptom resolves. After three days of therapy, pulmonary artery pressure drops 5mm of mercury.
Example IN A 40-year old with diabetes presents with poor peripheral perfusion and leg pain. Red blood cells only dilate blood vessels at low PO2. Infusion of S- nitrosoglutathione at 1 nmol/kg/min corrects the defect and improves perfusion.
Example V A 70-year old with heart failure and pulmonary hypertension has defective red blood cells induced vasodilation in a bioassay. Infusion of NO at 1 nmol/kg/min improves dyspnea.
Example VI An 80-year old with a stroke shows increasing cognitive dysfunction. His red blood cells are found to constrict blood vessels in a bioassay. Infusion of NO improves red blood cell vasodilation and cognition.
Example VII A 20-year old with sickle cell disease and acute painful crisis has red blood cell vasodilation dysfunction. Lipitor is initiated. Over the following 24 hours, red blood cell vasodilation function normalizes, and the patient is symptomatically improved.
Variations Many variations of the above will be obvious to those skilled in the art. Thus, the invention is defined by the claims.

Claims

WHAT IS CLAIMED IS:
1. A method of tracking the course of a disease in a patient where the disease is associated with abnormality in tissue or blood oxygenation or impairment in the lungs ability to oxygenate blood or of determining the severity of said disease, comprising, during the course of the disease, measuring the ability of blood sample from the patient to cause blood vessel dilation.
2. A method of treating a patient having a disease associated with abnormality in tissue or blood oxygenation or impairment in the lungs ability to oxygenate blood, comprising administering to the patient therapeutically effective amount of anaerobic solution of nitric oxide and/or therapeutically effective amount of solution of nitrite, nitrosothiol or alternative red blood cell loading agent, in response to measurement of ability of blood sample from the patient to cause blood vessel dilation, showing lower than normal ability to cause blood vessel dilation.
3. A method of treating a patient having a disease associated with abnormal red blood cells induced vasodilation comprising administering to the patient therapeutically effective amount of agent which causes increase in red blood cell induced vasodilation.
PCT/US2004/042675 2003-12-19 2004-12-16 Measuring vasodilating activity of blood samples to track disease course WO2005063221A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US53061303P 2003-12-19 2003-12-19
US60/530,613 2003-12-19

Publications (1)

Publication Number Publication Date
WO2005063221A1 true WO2005063221A1 (en) 2005-07-14

Family

ID=34738602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/042675 WO2005063221A1 (en) 2003-12-19 2004-12-16 Measuring vasodilating activity of blood samples to track disease course

Country Status (1)

Country Link
WO (1) WO2005063221A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5187183A (en) * 1988-06-15 1993-02-16 Brigham & Women's Hospital S-nitroso derivatives of ACE inhibitors and the use thereof
US5278192A (en) * 1992-07-02 1994-01-11 The Research Foundation Of State University Of New York Method of vasodilator therapy for treating a patient with a condition
US6465516B1 (en) * 1997-04-10 2002-10-15 Nitrosystems, Inc. Method of stimulating nitric oxide synthase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5187183A (en) * 1988-06-15 1993-02-16 Brigham & Women's Hospital S-nitroso derivatives of ACE inhibitors and the use thereof
US5278192A (en) * 1992-07-02 1994-01-11 The Research Foundation Of State University Of New York Method of vasodilator therapy for treating a patient with a condition
US6465516B1 (en) * 1997-04-10 2002-10-15 Nitrosystems, Inc. Method of stimulating nitric oxide synthase

Similar Documents

Publication Publication Date Title
Vehkavaara et al. In vivo endothelial dysfunction characterizes patients with impaired fasting glucose.
Jörneskog et al. Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications
Fatouros et al. Oxidative stress responses in older men during endurance training and detraining
Máttar et al. Cardiac arrest in the critically III: II. Hyperosmolal states following cardiac arrest
Kestenbaum et al. Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease
US8137994B2 (en) Methods of identifying responders to dopamine agonist therapy and treating metabolic conditions thereof
US4762820A (en) Therapeutic treatment for congestive heart failure
Delclaux et al. Factors associated with dyspnea in adult patients with sickle cell disease
Karetzky et al. Effect of thoracentesis on arterial oxygen tension
Kelm et al. Thrombospondin‐1 mediates Drp‐1 signaling following ischemia reperfusion in the aging heart
Oettinger et al. Profiles of endogenous prostaglandin F2α, thromboxane A2 and prostacyclin with regard to cardiovascular and organ functions in early septic shock in man
Gorenflo et al. Metabolites of the L-arginine-NO pathway in patients with left-to-right shunt
Ewald et al. Reduced vascular reactivity in diabetic children and its relation to diabetic control
Barach THE ENERGY INDEX: CARDIOVASCULAR ENERGY AS INDICATED BY THE ARTERIAL PRESSURE PER MINUTE
WO2005063221A1 (en) Measuring vasodilating activity of blood samples to track disease course
RU2466396C1 (en) Method for prediction of probability of fatal outcome of ischemic stroke in patients without depression of consciousness
Miller et al. Abnormalities in the renal and vascular responses to LBNP in humans with early diabetes
Lagos et al. Role of spinal nitric oxide synthase-dependent processes in the initiation of the micturition hyperreflexia associated with cyclophosphamide-induced cystitis
Kisters et al. NURSES’NIGHTSHIFT WORKLOAD: PSYCHOLOGIC, METABOLIC AND CARDIOVASCULAR DATA
CN108289936A (en) The composition and method of postoperative complications for treating Cardio-pulmonary Operation
Wang et al. Alcohol abuse in patients with dilated cardiomyopathy: laboratory vs clinical detection
Mellstedt et al. (D)-Penicillamine Treatment in Systemic Sclerosis (Scleroderma): Effect on Nutritional Capillary Circulation
Semianiv Hormonal and metabolic risk factors of essential arterial hypertension depending on polymorphic variants of the AGTR1 (rs5186) and VDR (rs2228570) genes
Nonaka et al. Characteristics of older patients with heart failure readmitted due to acute exacerbations within the past year
Kulchanarat et al. Revalence and factors associated with sarcopenia among patients with open heart surgery

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase